PAINWeek Journal Vol 7, Q3 by PAINWeek

vol. 7 q 3 2019

the emperor’s new clothes: multimodal engagement & improving access to care p.20 i’m not a doctor, but i play one in dc: federal action and its impacts on care p.34 everybody’s greasing up, but should you rub it in? a review of topical analgesics and available evidence in clinical trials p.42 la femme migraineur p.58

www.painweek.org

KEEP ADVANCING

Shouldn’t opioid treatments continue to change with the times?

MORPHABOND ER With SentryBond™ Technology Is a Single-Agent, Abuse-Deterrent Morphine1,2

IN JE CT IO N

Retains its extended-release properties even if manipulated

IN TR AN AS AL

Bioequivalent to MS Contin®

Expected to deter abuse by both of the following routes:

Abuse of MORPHABOND ER is still possible by intranasal, intravenous, and oral routes INDICATION --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------MORPHABOND™ ER (morphine sulfate) extended-release tablets, for oral use, CII is an opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve MORPHABOND ER for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. MORPHABOND ER is not indicated as an as-needed (prn) analgesic.

References: 1. MORPHABOND ER [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2018. 2. Data on file. Daiichi Sankyo, Inc.

Opioid Analgesic REMS To ensure that the beneﬁts of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to • complete a REMS-compliant education program, • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and • consider other tools to improve patient, household, and community safety

For more information, visit MORPHABONDhcp.com

Please see additional Important Safety Information on the following pages. Please see Brief Summary of full Prescribing Information, including BOXED WARNINGS, on adjacent pages.

IMPORTANT SAFETY INFORMATION BOXED WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS (continued) Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of MORPHABOND ER. Monitor for respiratory depression, especially during initiation of MORPHABOND ER or following a dose increase. Instruct patients to swallow MORPHABOND ER tablets whole; crushing, chewing, or dissolving MORPHABOND ER tablets can cause rapid release and absorption of a potentially fatal dose of morphine. Accidental Ingestion Accidental ingestion of even one dose of MORPHABOND ER, especially by children, can result in a fatal overdose of morphine. Neonatal Opioid Withdrawal Syndrome Prolonged use of MORPHABOND ER during pregnancy can result in neonatal

opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. • Reserve concomitant prescribing of MORPHABOND ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate • Limit dosages and durations to the minimum required • Follow patients for signs and symptoms of respiratory depression and sedation

CONTRAINDICATIONS --------------------------------------------------------------------------------------------------

• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patientprescriber responsibilities

MORPHABOND ER is contraindicated in patients with: significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days; known or suspected gastrointestinal obstruction, including paralytic ileus; and hypersensitvity (eg, anaphylaxis) to morphine.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse --------------------------------------------------------------------------------------------MORPHABOND ER contains morphine, a Schedule II controlled substance, and thus exposes its users to the risks of addiction, abuse, and misuse. Because extended-release products such as MORPHABOND ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed MORPHABOND ER. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing MORPHABOND ER, and monitor all patients receiving MORPHABOND ER for development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness. The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as MORPHABOND ER, but use in such patients necessitates intensive counseling about the risks of proper use of MORPHABOND ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of MORPHABOND ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing MORPHABOND ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper storage and disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Opioid Analgesic REMS --------------------------------------------------------------------------------------------------------------To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain

Life-Threatening Respiratory Depression ------------------------------------------------------------

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of MORPHABOND ER, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases with MORPHABOND ER. To reduce the risk of respiratory depression, proper dosing and titration of MORPHABOND ER are essential. Overestimating the MORPHABOND ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Neonatal Opioid Withdrawal Syndrome ---------------------------------------------------------------Prolonged use of MORPHABOND ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ----------------------------------------------------------------------------------------------------------------------------------Profound sedation, respiratory depression, coma, and death may result from the concomitant use of MORPHABOND ER with benzodiazepines or other CNS system depressants (eg, non-benzodiazepine sedatives/ hypnotics, tranquilizers, muscle relaxants, general anesthetics, anxiolytics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risks of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with concomitant use of other CNS depressant drugs with opioid analgesics.

Please see additional Important Safety Information on the following pages. Please see Brief Summary of full Prescribing Information, including BOXED WARNINGS, on adjacent pages.

WARNINGS AND PRECAUTIONS Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (continued) -----------------------------------------------------------------------------------------------

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness --------------------

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when MORPHABOND ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

In patients who may be susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), MORPHABOND ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with MORPHABOND ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of MORPHABOND ER in patients with impaired consciousness or coma.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients ---------------------------------------------------------------------------------------------------------------------------

The morphine in MORPHABOND ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during MORPHABOND ER therapy.

The use of MORPHABOND ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: MORPHABOND ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of MORPHABOND ER. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating MORPHABOND ER and when MORPHABOND ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of nonopioid analgesics in these patients.

Interaction with Monoamine Oxidase Inhibitors ----------------------------------------

Risks of Use in Patients with Gastrointestinal Conditions ------------

MORPHABOND ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The morphine in MORPHABOND ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders -----------------------------------------------------------------------------------------------------------------------------------

Withdrawal ---------------------------------------------------------------------------------------------------------------------------------------------------Avoid the use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including MORPHABOND ER. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing MORPHABOND ER, gradually taper the dosage. Do not abruptly discontinue MORPHABOND ER.

Risks of Driving and Operating Machinery --------------------------------------------------------MORPHABOND ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of MORPHABOND ER and know how they will react to the medication.

Adverse Reactions -------------------------------------------------------------------------------------------------------------------------------

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. MORPHABOND ER should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

In clinical trials, the most common adverse reactions with morphine sulfate extended-release were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood.

Adrenal Insufficiency -----------------------------------------------------------------------------------------------------------------------

• Concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of respiratory depression, profound sedation, coma and death • The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome • Mixed agonist/antagonist and partial agonist opioid analgesics may reduce the analgesic effect of MORPHABOND ER and/or may precipitate withdrawal symptoms • Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression • MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (eg, respiratory depression, coma) • The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death • Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone • The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus • The concomitant use of P-gp-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension --------------------------------------------------------------------------------------------------------------------------MORPHABOND ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of MORPHABOND ER. In patients with circulatory shock, MORPHABOND ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of MORPHABOND ER in patients with circulatory shock.

Drug Interactions -----------------------------------------------------------------------------------------------------------------------------------

MORPHABOND™ ER (morphine sulfate) extended-release tablets, for oral use CII Initial U.S. Approval: 1941 BRIEF SUMMARY: See package insert for full prescribing information. WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse MORPHABOND™ ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing MORPHABOND ER, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to • complete a REMS-compliant education program, • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and • consider other tools to improve patient, household, and community safety. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of MORPHABOND ER. Monitor for respiratory depression, especially during initiation of MORPHABOND ER or following a dose increase. Instruct patients to swallow MORPHABOND ER tablets whole; crushing, chewing, or dissolving MORPHABOND ER tablets can cause rapid release and absorption of a potentially fatal dose of morphine [see Warnings and Precautions (5.3)]. Accidental Ingestion Accidental ingestion of even one dose of MORPHABOND ER, especially by children, can result in a fatal overdose of morphine [see Warnings and Precautions (5.3)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of MORPHABOND ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5), Drug Interactions (7)]. • Reserve concomitant prescribing of MORPHABOND ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation. 1 INDICATIONS AND USAGE MORPHABOND ER is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see Warnings and Precautions (5.1)], reserve MORPHABOND ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • MORPHABOND ER is not indicated as an as-needed (prn) analgesic.

4 CONTRAINDICATIONS MORPHABOND ER is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.3)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.7)/Drug Interactions (7)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)] • Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)] 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse MORPHABOND ER contains morphine, a Schedule II controlled substance. As an opioid, MORPHABOND ER exposes its users to the risks of addiction, abuse, and misuse. Because extended-release products such as MORPHABOND ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed MORPHABOND ER. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing MORPHABOND ER, and monitor all patients receiving MORPHABOND ER for development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as MORPHABOND ER, but use in such patients necessitates intensive counseling about the risks of proper use of MORPHABOND ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of MORPHABOND ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death [see Overdosage (10)]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing MORPHABOND ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper storage and disposal of unused drug [see Patient Counseling Information (17) in the full prescribing information]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patientprescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. 5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close

observation, supportive measures, and use of opioid antagonists, depending on the patientâ&#x20AC;&#x2122;s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of MORPHABOND ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of MORPHABOND ER. To reduce the risk of respiratory depression, proper dosing and titration of MORPHABOND ER are essential [see Dosage and Administration (2) in the full prescribing information]. Overestimating the MORPHABOND ER dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of MORPHABOND ER, especially by children, can result in respiratory depression and death due to an overdose of morphine. 5.4 Neonatal Opioid Withdrawal Syndrome Prolonged use of MORPHABOND ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17) in the full prescribing information]. 5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of MORPHABOND ER with benzodiazepines or other CNS system depressants (e.g., non-benzodiazepine sedatives/ hypnotics, tranquilizers, muscle relaxants, general anesthetics, anxiolytics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when MORPHABOND ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17) in the full prescribing information]. 5.6 Life -Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of MORPHABOND ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: MORPHABOND ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of MORPHABOND ER [see Warnings and Precautions (5.3)]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients

as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)]. Monitor such patients closely, particularly when initiating and titrating MORPHABOND ER and when MORPHABOND ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3, 5.5)]. Alternatively, consider the use of non-opioid analgesics in these patients. 5.7 Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. MORPHABOND ER should not be used in patients taking MAOIs or within 14 days of stopping such treatment. 5.8 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.9 Severe Hypotension MORPHABOND ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of MORPHABOND ER. In patients with circulatory shock, MORPHABOND ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of MORPHABOND ER in patients with circulatory shock. 5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), MORPHABOND ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with MORPHABOND ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of MORPHABOND ER in patients with impaired consciousness or coma. 5.11 Risks of Use in Patients with Gastrointestinal Conditions MORPHABOND ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The morphine in MORPHABOND ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.12 Increased Risk of Seizures in Patients with Seizure Disorders The morphine in MORPHABOND ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during MORPHABOND ER therapy. 5.13 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including MORPHABOND ER. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)]. When discontinuing MORPHABOND ER, gradually taper the dosage [see Dosage and Administration (2.5) in the full prescribing information]. Do not abruptly discontinue MORPHABOND ER [see Drug Abuse and Dependence (9.3)]. 5.14 Risks of Driving and Operating Machinery MORPHABOND ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of MORPHABOND ER and know how

they will react to the medication [see Patient Counseling Information (17) in the full prescribing information]. 6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] • Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.5)] • Adrenal Insufficiency [see Warnings and Precautions (5.8)] • Severe Hypotension [see Warnings and Precautions (5.9)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)] • Seizures [see Warnings and Precautions (5.12)] • Withdrawal [see Warnings and Precautions (5.13)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. MORPHABOND ER may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)]. Most Frequently Observed Reactions In clinical trials, the most common adverse reactions with morphine sulfate extended-release were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood. Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Less Frequently Observed Reactions Cardiovascular disorders: tachycardia, bradycardia, palpitations Eye disorders: visual impairment, vision blurred, diplopia, miosis Gastrointestinal disorders: dry mouth, diarrhea, abdominal pain, constipation, dyspepsia General disorders and administration site conditions: chills, feeling abnormal, edema, edema peripheral, weakness Hepatobiliary disorders: biliary colic Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: muscle rigidity, muscle twitching Nervous system disorders: presyncope, syncope, headache, tremor, uncoordinated muscle movements, convulsion, intracranial pressure increased, taste alteration, paresthesia, nystagmus Psychiatric disorders: agitation, mood altered, anxiety, depression, abnormal dreams, hallucination, disorientation, insomnia Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effect Reproductive system and breast disorders: reduced libido and/or potency Respiratory, thoracic and mediastinal disorders: laryngospasm Skin and subcutaneous tissue disorders: pruritus, urticaria, rash Vascular disorders: flushing, hypotension, hypertension 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of morphine sulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Amenorrhea, asthenia, bronchospasm, confusional state, drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo. Serotonin syndrome: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in MORPHABOND ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) in the full prescribing information].

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with MORPHABOND ER. Table 1: Clinically Significant Drug Interactions with MORPHABOND ER Benzodiazepines and other Central Nervous System (CNS) Depressants

Clinical Impact:

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increase the risk of respiratory depression, profound sedation, coma, and death.

Intervention:

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].

Examples:

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs

Clinical Impact: Intervention:

Example:

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue MORPHABOND ER if serotonin syndrome is suspected. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.7)].

Intervention:

Do not use MORPHABOND ER in patients taking MAOIs or within 14 days of stopping such treatment.

Examples:

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact:

May reduce the analgesic effect of MORPHABOND ER and/or precipitate withdrawal symptoms.

Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MORPHABOND ER and/or the muscle relaxant as necessary. Cimetidine Clinical Impact: The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MORPHABOND ER and/or cimetidine as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. (continued)

Table 1: Clinically Significant Drug Interactions with MORPHABOND ER

Data

Anticholinergic Drugs

Human Data The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design. Animal Data Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on a human daily dose of 60 mg morphine using a body surface area comparison (HDD). Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear. Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity. An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated. In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, socialinteraction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater. Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD). Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second

Clinical Impact: Intervention:

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when MORPHABOND ER is used concomitantly with anticholinergic drugs.

P-Glycoprotein (P-gp) Inhibitors

Clinical Impact:

The concomitant use of P-gp-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MORPHABOND ER and/or the P-gp-inhibitor as necessary.

Example:

quinidine

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no available data with MORPHABOND ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [see Human Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [see Animal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. MORPHABOND ER is not recommended for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including MORPHABOND ER, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD). 8.2 Lactation Risk Summary Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with extendedrelease morphine, including MORPHABOND ER. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with MORPHABOND ER. Clinical Considerations Monitor infants exposed to MORPHABOND ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2) in the full prescribing information]. In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology (13) in the full prescribing information]. 8.4 Pediatric Use The safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use The pharmacokinetics of MORPHABOND ER have not been studied in elderly patients. Clinical studies of morphine sulfate extended-release did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of MORPHABOND ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)]. Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Hepatic Impairment Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of MORPHABOND ER and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.7 Renal Impairment Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of MORPHABOND ER and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) in the full prescribing information]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance MORPHABOND ER contains morphine, a Schedule II controlled substance.

9.2 Abuse MORPHABOND ER contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. MORPHABOND ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)]. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. MORPHABOND ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help limit abuse of opioid drugs. Risks Specific to Abuse of MORPHABOND ER MORPHABOND ER is for oral use only. Abuse of MORPHABOND ER poses a risk of overdose and death. This risk is increased with concurrent abuse of MORPHABOND ER with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved MORPHABOND ER enhances drug release and increases the risk of overdose and death. Parenteral abuse of MORPHABOND ER can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Abuse Deterrence Studies MORPHABOND ER is formulated with inactive ingredients that make the tablet more difficult to adulterate for misuse and abuse while maintaining extended-release characteristics even if the tablet is subjected to physical manipulation, and/or chemical extraction. To evaluate the ability of the abuse-deterrent technology to reduce the potential for abuse of MORPHABOND ER, a series of in vitro laboratory manipulation, extraction, and syringeability, studies was conducted. An in vivo clinical abuse potential study was also conducted. The results of these studies are summarized below. Overall, the results indicate that MORPHABOND ER has properties that are expected to reduce abuse or misuse via injection or insufflation; however, abuse by these routes is still possible.

In Vitro Testing MORPHABOND ER has been tested in vitro using methods of manipulation that drug abusers commonly use for preparation of extended-release opioids for administration by various routes, including oral consumption, intranasal insufflation, injection, and smoking. Abusers may manipulate extended-release opioids in order to prepare the tablets for oral, intranasal, or intravenous administration. The laboratory test data demonstrated that, relative to morphine sulfate extended-release tablet, MORPHABOND ER has increased resistance to cutting, crushing, or breaking using a variety of tools. When subjected to a liquid environment the manipulated MORPHABOND ER formulation forms a viscous material that resists passage through a needle.

Clinical Studies A randomized, double-blind, double-dummy, placebo-controlled, singledose four-way crossover study in 25 non-dependent recreational opioid users with a history of intranasal drug abuse was performed to determine the relative bioavailability and abuse potential of crushed intranasal MORPHABOND ER 60 mg tablets compared with crushed intranasal morphine sulfate extended-release tablet 60 mg tablets, and intact orally administered MORPHABOND ER 60 mg tablets. The intact oral tablets were included as a reference for evaluating abuse potential after manipulation and administration via an unintended route. Drug liking was measured on a 100 mm bipolar visual analog scale (VAS) where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar scale of 0 to 100 where 50 represents a neutral response, 0 represents the strongest negative response (‘definitely would not take drug again’) and 100 represents the strongest positive response (‘definitely would take drug again’). Intranasal administration of crushed MORPHABOND ER was associated with statistically significantly lower drug liking (Emax) scores (P < 0.0001), and significantly lower willingness to take the drug again (Emax) scores (P = 0.034), compared to crushed extended-release morphine (Table 2). Drug liking and take drug again scores for crushed intranasal MORPHABOND ER were not significantly different from those of MORPHABOND ER taken orally intact. These data are consistent with the similar relative bioavailability after crushed intranasal and intact oral administration of MORPHABOND ER that support retention of its extended release properties when manipulated compared to morphine sulfate extended-release tablets [see Clinical Pharmacology (12.3) in the full prescribing information]. Table 2. Summary of Maximum Drug Liking (Emax) and Take Drug Again (Emax) Following Administration of MORPHABOND ER, morphine sulfate extended-release tablet, and Placebo in Recreational Opioid Users (n=25) Crushed Intranasal morphine sulfate Crushed extended-release Intranasal tablet vs. Crushed morphine Intranasal sulfate MORPHABOND ER Crushed Intranasal extendedDifference of MORPHABOND ER release LS Means 60 mg tablet 60 mg Placebo (95% CI) Drug Liking Mean (Emax) (SEM) Median (Range) Take Drug Mean Again (Emax) (SEM) Median (Range)

71.7 (2.87)

85.3 (2.42)

54.3 (1.63)

72 (50-100)

85 (56-100)

51 (50-80)

66.4 (3.76)

76.4 (4.17)

49.1 (2.21)

64.0 (38-100)

75.0 (17-100)

50.0 (0-64)

13.65 (7.80, 19.51)

9.96 (0.77, 19.14)

Figure 1 demonstrates a comparison of peak drug liking scores for crushed MORPHABOND ER compared to crushed extended-release morphine in subjects who received both treatments intranasally. Seventy-six percent of subjects (n = 19) experienced some reduction in Emax of Drug Liking VAS with crushed MORPHABOND ER compared with crushed extended-release morphine, 48%; (n = 12) experienced at least a 30% reduction in Emax and 32% (n = 8) experienced at least a 50% reduction in Emax of drug liking.

Percent of Subjects (%)

Figure 1. Percent Reduction Profiles for Emax of Drug Liking for MORPHABOND ER vs. Morphine Sulfate ER Tablets (n=25), Following Intranasal Administration 100 90 80 70 60 50 40 30 20 10 0 Percent Reduc�on in Emax (%)

Summary The in vitro data demonstrate that MORPHABOND ER has physiochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from in vitro data, also indicate that

MORPHABOND ER has physicochemical properties that are expected to reduce abuse by the intranasal route of administration. However, abuse by intranasal, intravenous, and oral routes is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of MORPHABOND ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. MORPHABOND ER should not be abruptly discontinued [see Dosage and Administration (2.5) in the full prescribing information]. If MORPHABOND ER is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with MORPHABOND ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) in the full prescribing information]. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to morphine overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Because the duration of reversal would be expected to be less than the duration of action of morphine in MORPHABOND ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. MORPHABOND ER will continue to release morphine and add to the morphine load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist. Healthcare professionals can telephone Daiichi Sankyo, Inc. (1-877-437-7763) for information on this product. Manufactured for: Daiichi Sankyo, Inc. Basking Ridge, NJ 07920 ©2017, Daiichi Sankyo, Inc. USPI-MOR-0918-r103-B

eXeCUTiVe eDiTOR KEViN L. ZACHAROFF md, facpe, facip, faap

eeK

PUBLiSHeR PAINW

ART DiReCTOR DARRYL FOSSA

eDiTORiAL DiReCTOR DeBRA WeiNeR eDiTOR HOLLY CASTeR

eDiTORiAL BOARD

Charles E. Argoff md, cpe Professor of Neurology Albany Medical College Department of Neurology Director Comprehensive Pain Center Albany Medical Center Department of Neurology Albany, ny Jennifer Bolen jd Founder Legal Side of Pain Knoxville, tn Martin D. Cheatle PhD Associate Professor Director, Pain and Chemical Dependency Program Perelman School of Medicine University of Pennsylvania Center for Study of Addiction Philadelphia, pa Paul J. Christo md, mba Associate Professor Johns Hopkins University School of Medicine Department of Anesthesiology and Critical Care Medicine Baltimore, md Michael R. Clark MD, MPH, MBA Associate Professor of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore, md Chair of Psychiatry Inova Health System Falls Church, VA

David Cosio PhD, ABPP Psychologist Jesse Brown VA Medical Center University of Illinois at Chicago College of Medicine, Pain Medicine Northwestern Feinberg School of Medicine, Psychiatry and Behavioral Sciences Chicago, il

Srinivas Nalamachu md Clinical Assistant Professor Kansas University Medical Center Department of Rehabilitation Medicine Kansas City, ks President and Medical Director International Clinical Research Institute Overland Park, ks

David M. Glick DC, DAAPM, CPE, FASPE CEO & Medical Director HealthQ2 Richmond, va

Steven D. Passik phd Vice President Scientific Affairs, Education, and Policy Collegium Pharmaceuticals, Inc. Canton, ma

Douglas L. Gourlay MD, MSc, FRCPC, DFASAM Educational Consultant Former Director, Wasser Pain Centre Pain and Chemical Dependency Division Toronto, Ontario Gary W. Jay md, faapm Clinical Professor University of North Carolina Department of Neurology Chapel Hill, nc Jay Joshi MD, DABA, DABA-FM, FABA-FM CEO and Medical Director National Pain Centers Vernon Hills, il Theresa Mallick-Searle MS, NP-BC, ANP-BC Nurse Practitioner Stanford Health Care Division of Pain Medicine Stanford, ca

Joseph V. Pergolizzi md Chief Operating Officer nema Research Inc. Naples, fl Michael E. Schatman phd, cpe, daspe Editor-in-Chief Journal of Pain Research Adjunct Clinical Assistant Professor Tufts University School of Medicine Department of Health & Community Medicine Boston, ma Kathryn A. Schopmeyer PT, DPT, CPE Physical Therapy Program Coordinator Pain Management San Francisco va Healthcare System San Francisco, ca

Mary Lynn McPherson pharmd, ma, mde, bcps Professor and Vice Chair University of Maryland School of Pharmacy Department of Pharmacy Practice and Science Hospice Consultant Pharmacist Baltimore, md

Copyright © 2019, PAINWeek, a division of Tarsus Medical Group. The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff. PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises. All rights are reserved by PAINWeek to accept, reject, or modify any advertisement submitted for publication. It is the policy of PAINWeek to not endorse products. Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

The national conference on pain for frontline practitioners.

2020

SePTeMBeR 8â&#x20AC;&#x201D;12

Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 39.0 AMA PRA Category 1 Credit(s)â&#x201E;˘. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing, and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.

vol. 7 q3 2019

20 34 42 58 66 71 72 63 74 76 79 14

multimodal

the emperor’s new clothes multimodal engagement & improving access to care

by david cosio

medical/legal

i’m not a doctor, but i play one in dc federal action and its impacts on pain care

by michael barnes

pharmacotherapy

everybody’s greasing up, but should you rub it in? a review of topical analgesics and available evidence in clinical trials

by timothy j. atkinson meredith w. crumb

chronic pain syndromes

la femme migraineur

by meredith barad

op-ed

the pit and the pendulum experts address the cdc guideline

pw next generation

with tanya j. uritsky

clinical pearls

by doug gourlay

by michael r. clark, mark garofoli, gary w. jay, theresa mallick-searle, michael e. schatman

pain by numbers one-minute clinician

with ravi prasad, brett stacey, martin cheatle, robert barkin, gary w. jay, elaine s. date

pundit profile

with stephen j. ziegler

PWJ | www.painweek.org

puzzled?

by wendy caster

Q 3 | 2019

CHANGES WHAT HAPPENS HERE

EXCESS NGF IS ONE OF THE KEY DRIVERS OF CHRONIC PAIN In response to injury or inflammation, cells at the site of pain release a number of biochemical mediators, including prostaglandins, cytokines, and a neurotrophin called nerve growth factor (NGF). NGF plays a key role in driving chronic pain. Excess NGF can change the way nerves signal pain. In the periphery, excess NGF can lead to peripheral and central sensitization, amplifying pain signaling and heightening the perception of pain.1-5

WHAT EXCESS NGF DOES HERE

Discover more at

KeyPainDrivers.com References: 1. Chang D, Hsu E, Hottinger D, Cohen SP. Anti-nerve growth factor in pain management: current evidence. J Pain Res. 2016;9:373383. 2. Pinho-Ribeiro F, Verri Jr W, Chiu I. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 2017;38: 5-19. 3. Latremoliere A, Woolf C. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895-926. 4. McGreevy K, Bottros MM, Raja SN. Preventing chronic pain following acute pain: risk factors, preventive strategies, and their efficacy. Eur J Pain. 2011;5(suppl):365-372. 5. Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology. 2011;115:189-204.

MY MiNDSeT

topical analgesics as a possible adjunct to this time of year is quite regimented; this help tailor treatment to patients who could Kevin L. Zacharoff will be my 13th year as a faculty member at benefit the most from agents delivered by PAINWeek and that’s usually my main focus this route of administration. by mid-summer. In fact, as I write this letter, I am busy working on my slide presentations and also thinking about the broad variety of topics that will When we think about people with chronic headache pain, we may autobe covered. There is so much that can and should be addressed. I wonder matically consider migraine as the common headache type and women how the curriculum will intersect with what I’ve witnessed in the field of afflicted more often than men. What we may not think about is the pain management over the course of this year and what will likely be the relationship between estrogen, menstruation, and migraine headaches. most pressing issues for meeting attendees. I always challenge myself to Dr. Meredith Barad provides us with a comprehensive review of menstrual see how and whether this issue of the Journal can potentially complement migraine, including classification of subtypes, the science behind the relathe subject matter covered at the annual conference, along with what is tionship of menstruation and migraine, and targeted treatment options happening out there on “Main Street.” My feeling is that everything in this when the diagnosis is made. After reading this article, you’ll have a much issue of PWJ is on target for that goal and will likely mean that you’ll want better understanding of the role of estrogen in women who suffer from menstrual migraine and potentially how to help them the most. to keep it on hand to refer to long after the conference has taken place.

Terms like multidisciplinary treatment, multimodal treatments, and interprofessional approaches have been used liberally in the context of chronic pain management for well over 20 years. Despite this, virtually any clinician involved in treating people with chronic pain knows that there are many obstacles which stand in the way of these and other oftenrecommended potentially complementary strategies. Dr. David Cosio gives us insight into barriers that exist in our healthcare system that may prevent us from employing many of these diverse interventions. Referring to the Emperor’s New Clothes fairy tale, this article explores how difficult it may be to challenge the financial burdens and restrictions to minimize pain and suffering, ultimately shifting the “cost” to the patient’s quality of life. This timely article highlights very important aspects of chronic pain management: access to care, realistic goals of treatment, appropriately managing expectations. You might not expect to see an article in PWJ by an attorney, but realistically there are many matters today that require us to think about the ethical principle of justice when managing patients with chronic pain. It is also important to understand the legal perspective of regulatory decisions that potentially impact clinicians and people with chronic pain, addiction, and substance use disorders. Michael Barnes gives us an in-depth legal perspective of state and federal approaches that have been implemented over the past decade to help stem opioid-related overdose deaths. Particular attention is given to the 2016 Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain and the recent report from the Pain Management Best Practices Inter-Agency Task Force. It’s imperative for us to consider how all this factors into our decision-making process so we can navigate their policies but still help patients to the best degree possible. Drs. Timothy Atkinson and Meredith Crumb present us with a detailed review of the clinical evidence supporting the role of topical analgesics in the management of chronic pain. At a time when clinicians treating people with chronic pain are being encouraged to consider nonopioid pharmacologic alternatives, it is incumbent on us to be aware of all the options, to be familiar with the science behind topical analgesics, and to offer the most evidence-based choices to patients we possibly can to achieve safe and effective pain treatment outcomes. It’s important for us to consider

PWJ | www.painweek.org

This issue’s Pundit Profile spotlights a very important contributor to education and dialogue in the pain community, Stephen J. Ziegler. In fact, when I think of a true champion of public policy in pain management, Dr. Ziegler is the first to come to mind. His own words say it all and accurately—he is all about research, public service, and helping to reduce human suffering. It took me five minutes after meeting Stephen to figure out that his long-term goals closely align with mine: to help change things enough to make a positive and sustainable difference. It’s a pleasure for me to have you “meet” someone I respect so much. Tanya J. Uritsky is the focus of this issue’s Next Generation. She was a co-founder of the Palliative Care Service at the Hospital of the University of Pennsylvania with a social worker and a chaplain. Together, they formed a robust interdisciplinary team with inpatient/outpatient services at multiple healthcare sites. Need I say more? A modern clinician, she balances family and professional life, and you’ll learn what inspires her. I hope there a many more passionate young clinicians behind her. Also worthy of mention is an editorial piece from a number of respected experts in the field (all PAINWeek faculty) regarding the CDC’s Guideline for Prescribing Opioids for Chronic Pain. This issue dovetails nicely with the annual conference and I hope you enjoy it. If you attend the meeting, please don’t hesitate to find me and say hello and offer suggestions for future articles! Kevin L. Zacharoff MD, FACIP, FACPE, FAAP

Kevin L. Zacharoff is Faculty and Clinical Instructor at suny Stony Brook School of Medicine in New York, and is Ethics Committee Chair at St Catherine of Siena Medical Center in Smithtown, New York.

Q 3 | 2019

PaiNWeeKeNDâ&#x201E;¢ ReGiONaL CONFeReNCe SeRieS

2019 visit www.painweekend.org for more information. aNaHeiM CA aTLaNTa GA aUSTiN TX BaLTiMORe MD BiRMiNGHaM AL BUFFaLO NY CHaRLeSTON SC CHaRLOTTe NC CHiCaGO IL

CLeVeLaND OH

MORRiSTOWN NJ

SaN DieGO CA

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SCOTTSDaLe AZ

DaLLaS TX

NaSHViLLe TN

HOUSTON TX

PHiLaDeLPHia PA

DeNVeR CO

iNDiaNaPOLiS IN JaCKSONViLLe FL LOS aNGeLeS CA

MiNNeaPOLiS MN

MORGaNTOWN WVA

PROViDeNCe RI

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SaCRaMeNTO CA SaN aNTONiO TX

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SOUTHFieLD MI

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Timothy J. Atkinson PharmD, BCPS, CPE

p.42

Timothy J. Atkinson is a Clinical Pharmacy Specialist in Pain Management, and Director, PGY-2 Pain & Palliative Care Pharmacy Residency Program, at the VA Tennessee Valley Healthcare System in Murfreesboro. He coauthored his article with Meredith W. Crumb, pharmd, BCPS, a Clinical Pharmacy Specialist in Pain Management at the VA Tennessee Valley Healthcare System in Nashville.

Meredith Barad MD

p.58

Meredith Barad is an Associate Professor of Anesthesia (Pain Management) and Neurology & Neurological Sciences, as well as the Associate Division Chief of Education and Associate Program Director for the Pain Fellowship. She is the chair of the headache and facial pain special interest group for the American Academy of Pain Medicine. She also sits on the board of the American Interventional Headache Society.

Michael Barnes JD, MIEP

p.34

Michael Barnes is Managing Partner and Founder of DCBA Law & Policy, a law firm recognized nationally for its work in healthcare and drug policy. He is also Chairman of the Center for U.S. Policy, a not-for-profit organization advancing solutions to the nation’s intertwined crises of substance abuse, improperly treated pain, and suicide. Mr. Barnes often provides legal, political, and issue analysis for national news networks, including FOX News, FOX Business, CNBC, CNN, and HLN. He was a political appointee under President George W. Bush, having served as confidential counsel in the White House Office of National Drug Control Policy.

David Cosio PhD, ABPP

p.20

David Cosio is a Board Certified, Licensed Clinical Health Psychologist at the Jesse Brown VA Medical Center, at the University of Illinois at Chicago College of Medicine, Pain Medicine, and at the Northwestern Feinberg School of Medicine, Psychiatry and Behavioral Sciences. In 2008, he received his PhD from Ohio University with a specialization in Health Psychology and completed a behavioral medicine internship at the University of Massachusetts-Amherst Mental Health Services. He then completed a Post-doctoral Fellowship at the Edward Hines Jr. VA Hospital. He achieved specialist certification in Clinical Health Psychology by the American Board of Professional Psychology in 2017.

PWJ | www.painweek.org

Q 3 | 2019

home with youâ&#x20AC;&#x201D;

By David Cosio PhD, ABPP

Multimodal Engagement & Improving Access to Care

The causes of chronic pain are many, and the remedies are complicated and often not available. â&#x20AC;Śthe best evidence of all the treatment modalities for pain reduction averages around 30% in about half of treated patients.

multimodal

In Hans Christian Andersen’s fairy tale, The Emperor’s New Clothes, weavers promise an emperor a new suit of clothes that they say is invisible to those who are incompetent or unfit for their positions. When the Emperor parades before his subjects nude, no one dares to say anything for fear that they’ll be seen as such.

he sentiments of the Emperor’s subjects are mirrored in how many pro-

viders feel towards our current healthcare system. The causes of chronic pain are many, and the remedies are complicated and often not available. In addition, the best evidence of all the treatment modalities for pain reduction averages around 30% in about half of treated patients.1 Furthermore, clinical trials indicate the comparable efficacy of numerous diverse treatment interventions for chronic pain, such as acupuncture, behavioral therapy, exercise therapy, nonsteroidal anti-inflammatory drugs.2 Overall, the current evidence provides little support for choosing one approach over another. The following is a review of the effectiveness of treatments for chronic, noncancer pain and the potential costs to patients.

The Current State of Research Medication Management Medication management has continued to be the mainstay of chronic pain treatment over the past two decades. The classes of drugs most commonly used are opioids, nonsteroidal antiinflammatory drugs (NSAIDs), antidepressants, anticonvulsants, muscle relaxants, and topical agents. The effectiveness of opioids has been evaluated using a meta-analysis which concluded that opioids result in small improvements in pain severity and function compared with placebo.3 Opiates, like hydrocodone (Norco and Vicodin), can cost about $18 for 30 tablets (325 mg).4 The efficacy of NSAIDs has been established for some patients with pain (such as arthritis and back), but has not been investigated in others (such as neuropathic pain and fibromyalgia).5,6 For mild, shorter-term pain, a provider may recommend over-the-counter (OTC) drugs (such as acetaminophen and ibuprofen), which can cost about $5 to $25, depending on the quantity and whether the patient buys a name brand or its generic equivalent.4 Meta-analyses have also suggested that antidepressants result in moderate symptom reduction and are superior to placebo for the treatment of chronic, noncancer

24 PWJ | www.painweek.org

pain.7 Antidepressants (such as amitriptyline) can cost about $12 for 30 tablets (10 mg).4 The best evidence supports the efficacy of anticonvulsant drugs.8-10 Anticonvulsants, such as carbamazepine (Tegretol), can cost about $53 for 30 capsules (100 mg).4 Muscle relaxants are typically recommended as adjuvant therapy and seem to have a restricted role.11,12 Topical agents have also been shown to effectively reduce chronic pain in comparison to placebo.13 [For programs that provide free or discounted drugs, based on patient incomes, go to the www.needymeds.org clearinghouse.]

Pain Interventions Interventional pain medicine involves the application of various techniques that can be used for diagnostics or pain relief. Epidural steroid and facet injections are the most commonly used in the US.14 However, the evidence for epidural steroid injection use as long-term monotherapy is not clear.15,16 Facet injections have some evidence for use with facet joint pain, but are not clearly effective for other syndromes.17,18 Surgery is the most common treatment for persistent pain only after medication management. Evidence has rated lumber fusion as fair and both discectomy and laminectomy as good,19 with the provision that significant pain can persist even after spinal surgery.20,21 Approximately Q 3 | 2019

31,000 lumbar surgeries are performed each year at an estimated cost of about $27,577 per patient. Insured patients still have to pay the specialist copay, a hospital copay of $100 or more, and coinsurance of 10% to 50%.4 Several meta-analyses have evaluated the efficacy of spinal cord stimulation and concluded that there was moderate evidence for improvement in pain.22-25 Another systematic review evaluated the efficacy of epidural and intrathecal drug delivery systems, and determined that there were moderate reductions in pain but the long-term effectiveness remains unclear.26 Surgically implanted devices can typically cost anywhere between $27,577 to $55,134.4

Psychological Treatments Psychological treatment as a whole results in modest improvements in pain and emotional functioning. However, there is insufficient evidence to recommend one therapeutic approach over another—whether behavioral therapy, cognitive behavioral therapy (CBT), psychodynamic therapy, stress management, emotional disclosure, biofeedback, or hypnosis.27-32 A 1-hour session of psychotherapy, for example CBT, typically starts at $125 and can cost more than $250 for those uninsured. There is a copay of $10 to $75 per session or coinsurance of 10% to 50% or more if insured.4 Interestingly, the modest reductions in pain severity witnessed with psychological interventions were similar to those noted with pharmacological, interventional, and physical and rehabilitative approaches.33

Complementary & Integrative Health (CIH) CIH refers to a group of medical and healthcare systems, practices, and products that can be categorized into 4 general categories (and examples):

○○ Mind-body medicine: biofeedback, hypnosis, yoga ○○ Natural-biological based: aromatherapy and herbs ○○ Manipulation-body based: chiropractor, massage, spinal manipulation ○○ Energy medicine: acupuncture and healing touch Each type of CIH modality can be accessed in the community but may be related to some out-of-pocket costs. The total out-ofpocket costs for CIH among adults in the US was approximately $33.9 billion in 2007.34 Acupuncture typically costs $75 to $95 for an initial visit, but some acupuncture colleges will offer reduced costs to the community.4 If the insurance company doesn’t cover acupuncture, it is important to ask if they have an “affinity program,” which will allow the patient to select providers at a 20% to 40% discount. Some United Healthcare plans offer $20 toward a gym membership every month at certain fitness centers if the patient goes 12 or more times a year. Some BlueCross/BlueShield and Aetna plans offer subscribers a discount on their massage therapy sessions as long as they use a network provider. For a reiki session to be covered or discounted, it has to be woven Q 3 | 2019

into the treatment plan and delivered by a nurse or licensed professional during a hospital stay.35 There is some evidence to support the use of yoga, tai chi, music therapy, mindfulness-based interventions, and hypnosis for general, chronic pain conditions. There is also some scientific evidence to support the use of CIH for specific, noncancer pain conditions:

○○ Low back pain: acupuncture, massage, progressive relaxation, spinal manipulation, yoga, herbal products, topicals ○○ Osteoarthritis: acupuncture, massage, tai chi/qi gong ○○ Rheumatoid arthritis: dietary supplements containing omega-3 fatty acids ○○ Headaches: acupuncture, biofeedback, massage, relaxation techniques, spinal manipulation, tai chi, herbs ○○ Irritable bowel syndrome: hypnotherapy, probiotics, peppermint oil Other conditions for which CIH has shown evidence include facial, nerve, chronic pelvic, elbow, endometriosis, carpal tunnel syndrome, gout, and cancer pain. There is limited scientific evidence to support the use of CIH for neck pain (eg, acupuncture, massage, and spinal manipulation) and fibromyalgia (eg, acupuncture, tai chi, yoga, mindfulness, biofeedback, and vitamin D supplements).36

Physical Medicine and Rehabilitation (PM&R) Evidence suggests that exercise can effectively decrease pain and improve function, but no conclusions can be made about exercise type.37 Physical therapy typically costs between $50 to $350 per session for uninsured patients. There is also a copay of $10 to $75 per session or coinsurance of 10% to 50% if insured.4 PM&R providers are also responsible for teaching patients proper body mechanics and how to use self-care aids, like transcutaneous electrical nerve stimulator (TENS) units, during the rehabilitation process. A TENS unit can cost about $100 or more.4 Physical medicine approaches are commonly included as components of interdisciplinary pain rehabilitation programs—the embodiment of the biopsychosocial model of care for patients with chronic pain.38 The reduction of pain after treatment at an interdisciplinary pain rehabilitation program has been reported to be significant.32,39 In fact, the American Academy of Pain Medicine released a position statement which recommends, at a minimum, that a proposed program of treatment should include medical management, pain interventions, psychological treatments, CIH modalities, and interdisciplinary care.40 In the US, there is currently only one interdisciplinary program for every 670,000 patients with chronic pain.41 The average cost of a pain program is about $4,873.4 www.painweek.org | PWJ

A small child, who didn’t understand the apparent necessity for pretense, piped up, “ But he has nothing on!” The bubble of pretense burst and soon all the onlookers were repeating what the child had said, whilst the Emperor continued the procession, attempting to maintain his dignity by pretending that nothing had happened.

Table 1. Insurance Company Coverage Websites Insurance Company

Website

Aetna

Medical Clinical Policy Bulletins www.aetna.com/health-careprofessionals/clinical-policy-bulletins/ medical-clinical-policy-bulletins.html

Anthem (BlueCross/BlueShield)

Policies and Guidelines www.anthem.com/provider/policies/

Cigna

Resources Documents cignaforhcp.cigna.com/web/public/ resourcesGuest/

Humana

Medical and Pharmacy Coverage Policies apps.humana.com/tad/Tad_New/Home. aspx

United Health Group (Medicare/Medicaid)

Policies and Protocols www.uhcprovider.com/en/policiesprotocols.html

Access as a Barrier to Care Frontline providers report failure to explore some of the other pain management modalities because access is a barrier to care. This topic of access to care focuses on 3 components: insurance coverage, health services, and timeliness of care. When it comes to insurance coverage, there are a number of medical costs that are not covered and come with major costs for consumers. These include services like long-term care, cosmetic surgery, infertility treatment, weight loss programs/surgery, private nursing, acupuncture, children/adult dental services, and children’s eye care.42 Interestingly, mental healthcare is not among those conditions listed. That is because the Mental Health Parity and Addiction Equity Act requires insurance groups that offer coverage for mental health or substance use disorders to provide the same level of benefits as for medical treatment.43 In order to determine whether access is truly a barrier to care, it is important to note what America’s 5 biggest health insurance providers—United Health Group-Medicare/Medicaid, Anthem-BlueCross/BlueShield, Aetna, Cigna, and Humana— cover in terms of health services.44 (See Table 1.) Disclaimer, Frontline practitioners must still further inquire about coverage based on the state and type of policy their patient has in their possession. Many health plans will at least partly cover treatment, but usually after conventional methods have failed,

Q 3 | 2019

among other restrictions. For example, if the policy says therapies are covered only if they are medically necessary, the provider may be able to challenge the denial in an appeal. There are other particular ways in which patients can add services to their insurance plans. For example, the Group Health Cooperative based in Seattle offers a Complementary Choices program that can add coverage to the patient’s health insurance and that will provide discounts for sessions with personal fitness and exercise trainers, yoga, tai chi, and Pilates classes. Stanford University also has developed a “chronic disease self-management program” that is available in nearly every state through local area agencies on aging. If the patient doesn’t have insurance coverage, then they may be able to use the money in their Flexible Spending Account (FSA) to pay for CIH approaches as long as their provider can prove they are medically necessary.35

What Else Can Providers Do? Often, providers feel they lack the information or the time to engage their patients in multimodal treatment plans and to improve access to care. As a result, frontline practitioners continue to use the standard of care, which has been shown to be typically insufficient to treat chronic, noncancer pain. The

www.painweek.org | PWJ

Frontline providers report failure to explore some… pain management modalities because access is a barrier to care…insurance coverage, health services, and timeliness of care.

purpose of this article is to create some insight and lay the foundation to motivate frontline providers to make a change in their standard practice. They can begin to make a change by providing more education to their patients, utilizing a stepped-care approach, and finding another way to do things.

Education Is the Best Analgesic Frontline providers can spend time educating patients about some common misconceptions.45 Before they come in for a consultation, ask the patient to try taking OTC medications like Tylenol or Advil for a few days. Approximately 90% of low-back pain subsides within 12 weeks without medical intervention. Tell patients to get out of bed! For every day the patients are lying there, they lose 1% to 3% of muscle strength, and then start to feel stiff simply because they are not moving. Also speak to patients about ways to assist their movement, such as using Epsom salt baths, heating pads or ice packs, relaxation practices, distracting word games, and lumbar support/traction/ TENS units. Make the most of the visit by teaching patients what they can do on their own. Speak to them about healthy living, including diet/water intake, physical activity/recreation, social

28 PWJ | www.painweek.org

support/spirituality, sleep hygiene, and weight management. Let patients know that their back and neck pain may have little or nothing to do with their abnormal MRI. Discourage elective surgery: a Consumer Reports survey found that only 60% of those who had back surgery were completely or very satisfied with the results. Set realistic goals and expectations.45 Chances are, chronic pain patients are never going to be 100% painfree. The treatment goal is to get rid of 30% to 60% of their pain and to help them to be more functional. Real pain control takes time. It takes 50% of patients with moderate pain at least 6 months to reach a point of real control. The more severe the pain, the longer it takes to get it under control.

Use a Stepped-Care Approach There are several models available to help guide providers in pain management. In 2009, the Department of Veterans Affairs advocated for the Stepped Model of Pain Care as a best practice model.46 (Available at: www.va.gov/PAINMANAGEMENT/Providers/IntegratedTeambasedPainCare.asp.) The stepped-care model gives providers the ability to escalate treatment options to include specialized care and multidisciplinary approaches. Q 3 | 2019

Figure. A Stepwise Pain Management Ladder

Neuroablation Implantable Devices Long-Term Oral Narcotics Corrective Surgery Behavioral Programs Nerve Blocks PT/Manipulation/TENS/Relaxation NSAIDS/Over-The-Counter Drugs

← LEAST INVASIVE

Low intensity interventions requiring self-care are considered the first step, followed by a sequential process of more aggressive, expensive, and often risky interventions when appropriate. Step #2 recommends primary care assessment and management of pain conditions and can include pain health education programs. Step #3 requires a secondary consultation, including behavioral medicine. Step #4 is a tertiary level of care, which recommends a referral to an interdisciplinary pain center. The frontline practitioner who works in a private practice may not be able to follow the structure outlined above. In their case, they can use a stepwise approach.47 In Step #1, the practitioner provides self-management education, including general health promoting activities—mindfulness, healthy relationships, sleep hygiene, healthy eating, physical fitness/ movement, tobacco cessation, and engagement in activities that reflect personal values; and pain management strategies—posture, weight management, anti-inflammatory diet, physiologic relaxation strategies, self-trigger-point massage, action-oriented support groups, and education about fear and catastrophizing. In Step #2, the practitioner explores nonpharmacologic therapies—psychological treatments, CIH therapies, physical medicine and rehabilitation approaches, and exercise. In Step #3, the practitioner can begin to explore pharmacological treatments as delineated previously. Finally, in Step 4, the practitioner may refer to the patient to an interdisciplinary rehabilitation program. In this scenario, a team approach is used to set expectations for pain management, address comorbidities, and manage opioid trials—using assessment, risk mitigation strategies, opioid use disorder treatment and naloxone distribution, and starting taper plans. Q 3 | 2019

MOST INVASIVE →

An example of a stepwise approach can be illustrated with a pain ladder.48 There are many examples of modified pain ladders available in the literature. Providers can use the Figure to educate patients about the range of treatments available based on how invasive they are.49 The lowest part of the ladder shows the treatments that are the least invasive, while the upper rungs show the more invasive. Oftentimes patients and frontline providers ask how to determine the best treatment modality to use. Remember, the current evidence provides little support for choosing one approach over another. However, there are other things to consider in treatment planning, including pain-related (eg, type and intensity of pain, physical and cognitive abilities, and coexisting symptoms); individual-related (eg, previous experiences and expectations for outcome, cultural and spiritual influences, and patient preferences and coping styles); and environmental factors (eg, involvement of friends and family).

Find Another Way Timeliness is one of the 3 components to access to care. This component is going to require outside-the-box solutions by medical systems, including using shared medical appointments, telehealth, investing in and expanding the workforce, and reducing administrative burden. At the provider level, it is important to have resources available to assist patients in accessing some of the treatments. One such resource is the cell phone, which is like a little pocket supercomputer that people constantly carry around with them supplying useful information. Table 2 shows a listing of mobile apps by genre that providers may find helpful to assist patients in their pain management.48 Another resource is the internet, which can give providers access to a wide range of information about www.painweek.org | PWJ

Table 2. Mobile Apps Pain Specific

Lifestyle

○○ My Pain Diary: Chronic Pain & Symptom Tracker ○○ Pain Killer + 2.0 ○○ Chronic Pain Tracker ○○ PainScale—Pain Diary ○○ CatchMyPain ○○ FibroMapp Pain Manager+

○○ FitStar Yoga ○○ Map My Run ○○ MOVE! (Weight Loss) Coach ○○ Stay Quit (Tobacco) Coach ○○ YOGAmazing ○○ Acupressure: Heal Yourself ○○ Fooducate

Medications

Sleep

○○ MedCoach ○○ Medisafe ○○ DoseCast ○○ MedHelper ○○ Pillbox

○○ CBT-i coach ○○ SimplyNoise ○○ Sleep Cycle Meditation/Biofeedback

Mental Health ○○ Pacifica for Stress ○○ Mood Coach: US Department of Veterans Affairs ○○ Talkspace ○○ AIMS (Anger & Irritability Management Skills)

○○ Headspace ○○ BrainWave ○○ Mindfulness Coach ○○ Simply Being ○○ Breath2Relax ○○ Pain Relief Hypnosis ○○ Insight Timer—Free Meditation

Table 3. A Reference Guide to Healthcare Associations American Academy of Physical Medicine & Rehabilitation ○○ Members.aapmr.org/AAPMR/AAPMR_FINDER.aspx ○○ Healthprofs.com/us/physical-therapists American Association of Acupuncture & Oriental Medicine ○○ Aaaomonline.org/directory ○○ Healthprofs.com/us/acupuncturists American Board of Professional Psychology ○○ Abpp.org/directory?activateFull=false ○○ Psychologytoday.com/us/therapists American Chiropractic Association ○○ https://www.acatoday.org/Find-a-Doctor ○○ Healthprofs.com/us/chiropractors American Massage Therapy Association ○○ https://www.amtamassage.org/ findamassage/index.html ○○ Healthprofs.com/us/massage-therapists

American Nutrition Association ○○ americannutritionassociation.org/ professionaldirectory ○○ Healthprofs.com/us/nutritionists-dietitians American Society of Clinical Hypnosis ○○ Asch.net/public/memberreferralSearch.aspx Association for Applied Psychophysiology and Biofeedback ○○ www.aapb.org/i4a/pages/index.cfm?pageid=3281 Commission on Accreditation of Rehabilitation Facilities ○○ www.carf.org/providerSearch.aspx Substance Abuse & Mental Health Services Administration, National Directory of Drug and Alcohol Abuse Treatment Facilities - 2019 ○○ www.samhsa.gov/data/report/national-directorydrug-and-alcohol-abuse-treatment-facilities-2019

associations of different disciplines and can help with locating local agencies.49 Table 3 shows a reference guide to some healthcare associations by discipline.

Conclusions So, the connection between The Emperor’s New Clothes and healthcare is clear: the willingness of people to engage in an unspoken contract to willfully disbelieve what they know to be true. The truth is, the issue we face in healthcare is not one of access, but rather one of coverage and tempering the general publics’ expectations of pain management. We must also look beyond treatment recommendations and consider how nonspecific factors—such as the patient, the therapeutic alliance, and placebo—play a role in outcomes. It is then that we will truly be able to make more of an impact in pain management in our current healthcare system, and stop ignoring the naked truth. References 1. Turk D, Wilson H, Cahana A. Treatment of chronic non-cancer pain. Lancet. 2011;377:2226–2235. 2. Keller A, Hayden J, Bombardier C, et al. Effect sizes of non-surgical treatments of non-specific low-back pain. Eur Spine J. 2007;16:1776–1788. 3. Furlan A, Sandoval J, Mailis-Gagnon A, et al. Opioids for chronic non-cancer pain: a meta-analysis of effectiveness and side effects. Can Med Assoc J. 2006;174:1589–1594. 4. Cost Helper-Health. How much does pain management cost? Available at: health.costhelper.com/pain-doctor.html. 5. Roelofs P, Deyo R, Koes B, et al. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev. 2008;23(1):CD000396.

15. Armon C, Argoff C, Samuels J, et al. Assessment: use of epidural steroid injections to treat radicular lumbosacral pain: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2007;68:723–729. 16. Friedly J, Nishio I, Bishop M, et al. The relationship between repeated epidural steroid injections and subsequent opioid use and lumbar surgery. Arch Phys Med Rehabil. 2008;89:1011–1015. 17. Chou R, Atlas S, Stanos S, et al. Nonsurgical interventional therapies for low back pain. Spine. 2009;34:1078–1093. 18. Luijsterburg P, Verhagen A, Ostelo R, et al. Effectiveness of conservative treatments for the lumbosacral radicular syndrome: a systematic review. Eur Spine J. 2007;16:881–899. 19. Chou R, Baisden J, Carragee E, et al. Surgery for low back pain: a review of the evidence for an American Pain Society Clinical Practice Guideline. Spine. 2009;34:1094–1109. 20. DeBerard M, Masters K, Colledge A, et al. Outcomes of posterolateral lumbar fusion in Utah patients receiving workers’ compensation: a retrospective cohort study. Spine. 2001;26:738–746. 21. Hornberger J, Kumar K, Verhulst E, et al. Rechargeable spinal cord stimulation versus nonrechargeable system for patients with failed back surgery syndrome: a cost-consequences analysis. Clin J Pain. 2008;24:244–252. 22. Chou R, Loeser J, Owens D, et al. Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain. Spine. 2009;34:1066–1077. 23. Frey M, Manchikanti L, Benyamin R, et al. Spinal cord stimulation for patients with failed back surgery syndrome: a systematic review. Pain Phys. 2009;12:379–397. 24. Taylor R, Van Buyten J, Buchser E. Spinal cord stimulation for chronic back and leg pain and failed back surgery syndrome: a systematic review and analysis of prognostic factors. Spine. 2005;30:152–160. 25. Turner J, Loeser J, Deyo R, et al. Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain. 2004;108:137–147.

6. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 1999;56:18–24.

26. Turner J, Sears J, Loeser J. Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications. Clin J Pain. 2007;23:180–195.

7. Kroenke K, Krebs E, Bair M. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry. 2009;31:206–219.

27. Dixon K, Keefe F, Scipio C, et al. Psychological interventions for arthritis pain management in adults: a meta-analysis. Health Psychol. 2007;26:241–250.

8. Attal N, Cruccu G, Baron R. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17:1113-e88.

28. Henschke N, Ostelo R, van Tulder M, et al. Behavioural treatment for chronic low-back pain. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD002014.

9. Dworkin R, O’Connor A, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clinic Proceedings. 2010;85:S3-S14.

29. Hoffman B, Papas R, Chatkoff D, et al. Meta-analysis of psychological interventions for chronic low back pain. Health Psychol. 2007;26:1–9.

10. Finnerup N, Sindrup S, Jensen T. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150:573–581. 11. Arnold L, Keck P, Welge J. Antidepressant treatment of fibromyalgia: a meta-analysis and review. Psychosomatics. 2000;41:104–113. 12. See S, Ginzburg R. Choosing a skeletal muscle relaxant. Am Fam Phys. 2008;78:365–370. 13. Mason L, Moore R, Edwards J, et al. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. Br Med J. 2004;328:995.

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14. Manchikanti L. The growth of interventional pain management in the new millennium: a critical analysis of utilization in the Medicare population. Pain Phys. 2004;7:465–482.

30. Jensen M, Patterson D. Hypnotic treatment of chronic pain. J Behav Med. 2006;29:95–124. 31. Montgomery G, DuHamel K, Redd W. A meta-analysis of hypnotically induced analgesia: how effective is hypnosis? Int J Clin Exp Hypnosis. 2000;48:138–153. 32. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy and behavior therapy for chronic pain in adults, excluding headache. Pain. 1999;80:1–13. 33. Verhaak P, Kerssens J, Dekker J, et al. Prevalence of chronic benign pain disorder among adults: a review of the literature. Pain. 1998;77:231–239.

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34. Nahin R, Barnes P, Stussman B, et al. Costs of complementary and alternative medicine (CAM) and frequency of visits of CAM practitioners: United States 2007. US Department of Health & Human Services. National Health Statistics Reports. Number 18; 2009. 35. Orenstein B. 5 surprising things your health plan may cover. 2016. Available at: www.insure.com/health-insurance/what-does-your-health-plan-may-cover.html. 36. National Center for Complementary & Integrative Health. Chronic pain: in depth. 2018. Available at: nccih.nih.gov/health/pain/chronic.htm#hed3. 37. van Tulder M, Malmivaara A, Hayden J, et al. Statistical significance versus clinical importance: trials on exercise therapy for chronic low back pain as example. Spine. 2007;32:1785–1790. 38. Townsend C, Rome J, Bruce B, et al. Interdisciplinary pain rehabilitation programs. In: Ebert MH, Kerns RD, eds. Behavioral and Pharmacological Pain Management. Cambridge University Press: New York, New York; Cambridge University Press: 2011:114–128. 39. Guzman J, Esmail R, Karjalainen K, et al. Multidisciplinary rehabilitation for chronic low back pain: systematic review. Br Med J. 2001;322:1511–1516. 40. American Academy of Pain Medicine. minimum insurance benefits for patients with chronic pain. 2014. Available at: www.painmed.org/files/minimum-insurance-benefits-for-patients-with-chronic-pain.pdf. 41. Schatman M. Interdisciplinary chronic pain management: international perspectives. 2012. Available at: s3.amazonaws.com/rdcms-iasp/files/production/public/Content /ContentFolders/Publications2/PainClinicalUpdates/Archives/PCU_20–7_web. pdf. 42. Mayer K. Top 10 medical services not covered by health insurance. 2013. Available at: www.benefitspro.com/2013/08/01/top-10-medical-services-not-covered-byhealth-insu/?t=core-group&page=10&slreturn=20180410143746. 43. Wellstone P, Domenici P. Mental Health Parity and Addiction Equity Act. 2008. Available at: www.cms.gov/cciio/programs-and-initiatives/other-insurance-protections/mhpaea_factsheet.html. 44. Forbes. Americas Biggest Health Insurance Providers. 2018. Available at : www.forbes.com/pictures/fefi45ejdih/the-biggest-health-insur/#4a80d57c76ee. 45. Crouch M. 24 secrets pain doctors won’t tell you. 2018. Available at: www.rd.com/health/conditions/13-things-your-pain-doctor-wont-tell-you/. 46. Kerns R, Otis J, Rosenberg R, et al. Veterans’ reports of pain and associations with ratings of health, health-risk behaviors, affective distress, and use of the healthcare system. J Rehabil Res Dev. 2003;40:371–379. 47. U.S. Department of Veterans Affairs. Transforming the treatment of chronic pain: moving beyond opioids. PBM Academic Detailing Service. 2017. 48. Doleys D, Olson K. Psychological Assessment and Intervention in Implantable Pain Therapies. Minneapolis, Minn: Medtronic Inc; 2007. 49. Cosio D. Pain Relief: Managing Chronic Pain Through Traditional, Holistic, & Eastern Practices. Springfield, Utah: Cedar Fort Publishing; 2018.

Opioid and other drug abuse, addiction, and overdose are

By Michael Barnes JD, MIEP

perhaps some of the most complicated issues facing our nation today. In recent years, however, the nation’s response has been oversimplified, focusing largely on reducing the supply of, and access to, prescription opioids. This approach has led to unintended consequences that, for some, have been devastating. The individuals driving sweeping change in pain and addiction policy are not doctors—they are legislators, regulators, and judges in capitals and courthouses across the nation. Like them, I am not a doctor. I am an attorney. But I know, as they should, that knee-jerk reactions make bad policy. Federal and state responses to our nation’s overdose crisis have been rooted more in emotion than science and economics. In fact, recent evidence indicates that there is no causal relationship between opioid prescribing rates and opioid-related overdose deaths. Fortunately, a growing number of federal and state decision makers representing all three branches of government are beginning to acknowledge the difficulty of these issues, the unintended consequences stemming from reactionary policy, and that future efforts must account for the complexity of the crisis and the individuals whose lives it affects.

By Michael Barnes JD, MIEP

Federal action and its impacts on pain care

medical/legal

ver the past decade, legislators and regulators responding to

the drug overdose crisis in the United States have focused unwaveringly on limiting the prescribing and dispensing of Food and Drug Administration (FDA)-approved opioid pain medications. This knee-jerk response, drawn largely from disdain for opioid medications and the companies that make and distribute them, is failing Americans.

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Q 3 | 2019

Roughly two-thirds of opioid-related deaths involve illicit substances, not FDA-approved medications.

A minor decline in all opioid-related overdose deaths, down to 69,100 in 2018 from 72,300 in 2017, according to preliminary data from the Centers for Disease Control and Prevention (CDC), is largely attributable to increased access to naloxone, an opioid overdose-reversal medication.1-4 Roughly two-thirds of opioid-related deaths involve illicit substances, not FDAapproved medications. Meanwhile, drug abuse trends are shifting predictably with rates of deaths involving stimulants, such as methamphetamine and cocaine, having increased recently by about one-third.5 The broadly anti-opioid approach implemented by states and the federal government, rooted in emotion rather than science and economics, has resulted in an indiscriminate reduction in the number of opioids prescribed for pain management. Opioid analgesic prescribing peaked in 2012 but decreased 25% by 2017.6 Yet, a June 2019 report analyzing CDC’s own data spanning a 20-year period provides convincing evidence that there is no relationship between opioid prescribing rates and opioid-related mortality.7 In other words, “almost the entirety of the public narrative that shapes federal and state opioid policy is wrong.”8 Still, to many policy makers and law enforcement agencies, a lower number of prescriptions in and of itself means success. On top of existing reductions in opioid analgesic prescribing, the federal government is seeking to cut nationwide prescription opioid dispensing by an additional one-third by 2021.9 Q 3 | 2019

Healthcare professionals report intense pressure not to prescribe opioids and to reduce dosages or fully taper patients off of opioids—even those who are stable on an opioid treatment plan.10 The resultant barriers to access often have unintended consequences, like driving patients with uncontrolled pain or opioid use disorder to the black market, where illicit substances can yield fatal overdoses, or even suicide.11 When government interferes with qualified professionals’ ability to individualize healthcare, patients suffer.

ederal Executive Branch

Part of the problem began with guidance from the CDC. The federal agency issued a guideline for primary care providers on prescribing opioid pain relievers for certain patients with chronic pain that included suggested limits on dose and duration.12 Unfortunately, these suggested dose and duration guidelines for a subset of patients new to treatment were transformed into a standard rule that insurance companies have since applied to all beneficiaries, even those stable on opioid pain relievers.13 Patients were either receiving opioids “appropriately” and could continue receiving coverage, or they were getting prescriptions against the guidance—and payment for the legitimate medical www.painweek.org | PWJ

medical/legal

When government interferes with qualified professionals’ ability to individualize healthcare, patients suffer.

use of an FDA-approved medication was terminated.14-16 This result was particularly harmful to people with chronic pain who had tolerated their opioid therapy well for years. Now that their opioid dose and duration—set by their prescriber long before the CDC guidance—were deemed over the limit, insurance coverage and access to the therapy were lost. The fact that the guidance was indicated for only a narrow category of patients didn’t matter. What did was that insurance companies now had a reason not to pay for these medications. Naturally, providers are concerned. A group of more than 300 physicians wrote to the CDC in March 2019 expressing concern about the harm patients were experiencing from misapplication of the guideline.17-19 Around the same time, the FDA issued a safety announcement identifying the serious harm that can occur with rapid discontinuation of opioid pain medicine, stating that “[n]o standard opioid tapering schedule exists that is suitable for all patients. Create a patient-specific plan to gradually taper the dose of the opioid and ensure ongoing monitoring and support.”20 In response to public pressure, the CDC finally issued a follow-up to its pain guideline in April 2019, entitled “No Shortcuts to Safer Opioid Prescribing.”21 It emphasized that “some policies and practices purportedly derived from the guideline have in fact been inconsistent with, and often go beyond, its recommendations.”21 Specifically, the CDC stated that “inflexible application of recommended dosage and duration thresholds

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and policies that encourage hard limits and abrupt tapering of drug dosages, resulting in sudden opioid discontinuation or dismissal of patients from a physician’s practice” are “likely to result in harm to patients.”21 The CDC further clarified “the Guideline includes recommendations for clinicians to work with patients to taper or reduce dosages only when patient harm outweighs patient benefit of opioid therapy. The recommendation on high-dose prescribing focuses on initiation.”18,19 As the CDC recognized, there must be greater forethought in the regulation of opioids. We must reduce the risk of abuse of, addiction to, and overdose from opioid medications. We must also not take treatments away from patients for whom they are safe and effective. This point is underscored by the analysis showing no causal relationship between opioid prescribing rates and opioid-related mortality. Last year, the Department of Health and Human Services established the Pain Management Best Practices Inter-Agency Task Force (PMTF), which recently released a report emphasizing the importance of individualized, patient focused pain management.22 The PMTF found that, among a wide array of gaps in the current standard of care, “the national crisis of illicit drug use, with overdose deaths, is confused with appropriate therapy for patients who are being treated for pain. This confusion has created a stigma that contributes to barriers to proper access to care.”22 Q 3 | 2019

We are beginning to see federal executive action in support of much needed thoughtfulness in health policy making. Some of the people who play doctors in courthouses and capitals are also starting to understand that the body of law which impacts Americans’ health and safety is much like the human body: it must be treated with care, and potential adverse outcomes must be considered and minimized.

insurers to provide coverage for opioids for as long as they are prescribed.27 States are also beginning to support access to individually appropriate treatments for people with pain. In Ohio, the opioid task force convened by former Governor John Kasich released a recommendation for managing pain, including access to treatments such as massage, acupuncture, chiropractic adjustment, and other integrative therapies.28 This recommendation yielded a state policy expanding Medicaid coverage to include these alternative pain management therapies.28

n the Courts

With momentum building in the executive branch, the chorus of voices recognizing the harms of demonizing all things opioid includes some deliberative officials within the judicial branch. In Connecticut, Judge Thomas Moukawsher of the Hartford District Superior Court dismissed lawsuits brought by multiple municipalities that sued 25 manufacturers and distributors of prescription pain relievers.23 Noting that finding harm without attributing it to specific action is insufficient, Judge Moukawsher wrote “[c]an all of us line up in court and ask for our personal share of the extra taxes, declining property values, rising crime rates and personal anguish we suffer from the addictions surrounding us? Not if we want a rational legal system.”23 In North Dakota, Judge James S. Hill dismissed a claim brought by the state attorney general against a pharmaceutical manufacturer of FDA-approved opioids, finding that “the state’s effort to hold one company to account for this entire, complex public health issue oversimplifies the problem.”24

onclusion

In Washington, DC and a growing number of states, leaders representing all 3 branches of government are beginning to recognize the harms of indiscriminate policies rooted in disdain. Those playing doctor in Washington, state capitals, and courthouses are starting to acknowledge the complexity of our nation’s problems of drug abuse, addiction, and overdose. For patients with unmanaged pain or opioid use disorder who need treatments individualized to their needs, solutions espousing compassion and common sense, rather than contempt, can’t come soon enough. References 1. CDC Centers for Disease Control and Prevention. National Center for Health Statistics. NVSS vital statistics rapid releases. Provisional drug overdose death counts. Available at: www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm?mod=article_inline. 2. Abouk R, Pacula RL, Powell D. Association between state laws facilitating pharmacy distribution of naloxone and risk of fatal overdose. JAMA Intern Med. 2019; May 6. [ePub ahead of print] Available at: www.ncbi.nlm.nih.gov/pubmed/31058922. 3. Mueller SR, Walley AY, Calcaterra SL, et al. A review of opioid overdose prevention and naloxone prescribing: implications for translating community programming into clinical practice. Subst Abus. 2015;36(2):240–253.

egislative Action

Echoing concerns from the executive and judicial branches, members of Congress and state legislators are also recognizing the need for more level-headed responses to drug abuse, addiction, and overdoses. Sen. Lamar Alexander (R-TN), Chairman of the Senate Health, Education, Labor, and Pensions (HELP) Committee, said that the committee will take up the PMTF’s recommendations on how to balance the needs of pain patients against policies tightening opioid prescription practices.25 In an email summarizing the hearing, Sen. Alexander concluded “as we address the opioid crisis, we must keep in mind the millions of Americans who are in chronic pain.”26 States lawmakers have also begun to acknowledge and mitigate the impacts of opioid therapy coverage denials. In New York, state legislators have introduced a bill that would require Q 3 | 2019

4. Kamp J. Overdose deaths likely to fall for first time since 1990. Wall Street J. June 26, 2019. Available at: www.wsj.com/articles/ overdose-deaths-likely-to-fall-for-first-time-since-1990–11561541406. 5. Newman K. The evolving nature of the U.S. drug epidemic: a new CDC study underscores the fact that opioids aren’t the only drug to blame for overdose deaths in America. U.S.News. May 2, 2019. Available at: www.usnews.com/news/healthiest-communities/articles/2019–05–02/ overdose-deaths-involving-cocaine-drugs-like-meth-rise-in-us. 6. CDC Centers for Disease Control and Prevention. U.S. opioid prescribing rate maps. Available at: www.cdc.gov/drugoverdose/maps/rxrate-maps.html. 7. Lawhern RA, Nadeau SE, Trescot A. Recommendations of the HHS Pain Management Task Force: a response by medical professionals and patient advocates. June 2019. Available at: www.practicalpainmanagement.com/sites/default/files/ Lawhern.ResponseHHSPainManagementTaskForce_June2019.pdf. 8. Lawhern RA. Stop persecuting doctors for legitimately prescribing opioids for chronic pain. STAT. June 28, 2019. Available at: www.statnews.com/2019/06/28/ stop-persecuting-doctors-legitimately-prescribing-opioids-chronic-pain/?utm_ source=STAT+Newsletters&utm_campaign=9a2416631d-First_Opinion&utm_medium= email&utm_term=0_8cab1d7961–9a2416631d-149730937.

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9. White House Fact Sheets. President Donald J. Trump’s initiative to stop opioid abuse and reduce drug supply and demand. October 24, 2018. Available at: www. whitehouse.gov/briefings-statements/president-donald-j-trumps-initiative-stopopioid-abuse-reduce-drug-supply-demand-2/. 10. Rubin R. Limits on opioid prescribing leave patients with chronic pain vulnerable. JAMA. 2019;321(21):2059–2062. 11. Nicholson KM, Hoffman DE, Kollas CD. Overzealous use of the CDC’s opioid prescribing guideline is harming pain patients. STAT. December 6, 2018. Available at: www.statnews.com/2018/12/06/overzealous-use-cdc-opioid-prescribing-guideline/. 12. Dowell D, Haegerick TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49. 13. Norton A. Insurers’ denials of opioid coverage spurs CDC to clarify guidelines. HealthDay. April 9, 2019. Available at: consumer.healthday.com/bone-and-jointinformation-4/opioids-990/insurers-denials-of-opioid-coverage-spurs-cdc-toclarify-guidelines-744875.html. 14. Prior authorizations for opioid prescriptions. Health Partners Plans. October 19, 2017. Available at: www.healthpartnersplans.com/providers/provider-news/2017/ prior-authorizations-for-opioid-prescriptions. 15. Ingold J. Colorado’s Medicaid program is reducing opioid doses to combat addiction and overdoses: new policy includes exemption for cancer, hospice patients. Denver Post. July 24, 2017. Available at: www.denverpost.com/2017/07/24/ opioid-addiction-colorado-medicaid-program/. 16. Rothstein MA. The opioid crisis and the need for compassion in pain management. Am J Public Health. 2017;107(8):1253–1254. 17. Health professionals call on the CDC to address misapplication of its Guideline on opioids for chronic pain through public clarifications and impact evaluation [letter]. HP3 Health Professionals for Patients in Pain. March 6, 2019. Available at: healthprofessionalsforpatientsinpain.org/the-letter-1. 18. Two federal agencies speak against mandated or precipitous opioid reductions in chronic pain patients. HP3 Health Professionals for Patients in Pain. April 10, 2019. Available at: healthprofessionalsforpatientsinpain.org/press-release.

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19. Redfield RR. Letter to Daniel P. Alford. April 10, 2019. U.S. Department of Health and Human Services. Available at: img1.wsimg.com/blobby/go/3d70257f-a143–4a5bb9df-f7d265df0d3d/downloads/Alford%20Final%20.pdf?ver=1556148791199. 20. FDA Drug Safety Communications. FDA identifies harm reported from sudden discontinuation of opioid pain medicines and requires label changes to guide prescribers on gradual, individualized tapering. 4–9-2019. Available at: img1.wsimg.com/ blobby/go/3d70257f-a143–4a5b-b9df-f7d265df0d3d/downloads/FDA%20Drug%20 Safety%20Communication%20Opioid%20Tapering.pdf?ver=1556148791347. 21. Dowell D, Haegerich T, Chou R. Perspective: no shortcuts to safer opioid prescribing. N Engl J Med. 2019;380:2285–2287. 22. Pain Management Best Practices Inter-Agency Task Force report: updates, gaps, inconsistencies, and recommendations. May 9, 2019. Available at: www.hhs.gov/sites/ default/files/pmtf-final-report-2019–05–23.pdf. 23. Bronstad A. Judge dismisses opioid suits that sought ‘junk justice’ for Connecticut cities. Connecticut Law Tribune. January 9, 2019. Available at: www.law. com/ctlawtribune/2019/01/09/judge-dismisses-opioid-suits-that-sought-junkjustice-for-connecticut-cities/. 24. State ex rel. DeWine v. Purdue Pharma, L.P. Justia US Law. Available at: law. justia.com/cases/ohio/fourth-district-court-of-appeals/2018/18ca3668.html. 25. Rennie J. Opioid crackdown said to leave out chronic pain patients. McClatchy DC Bureau. February 12, 2019. Available at: www.mcclatchydc.com/news/policy/healthcare/article226149735.html. 26. Llorente E. Senate committee focuses on pain suffers denied painkillers amid opioid crisis. Fox News. Available at: www.foxnews.com/health/ chronic-pain-patients-opioids-senate-committee-hearing. 27. New York State Assembly. Relates to insurance coverage for opioid medications. January 9, 2019. Available at: nyassembly.gov/ leg/?default_fld=&leg_video=&bn=AB+102&term=0&Summary=Y&Actions=Y&Text=Y. 28. Ross C. As the opioid crisis grows, states are opening Medicaid to alternative medicine. STAT. January 17, 2018. Available at: www.statnews.com/2018/01/17/ medicaid-opioids-alternative-medicine/.

Q 3 | 2019

Introducing Pain Points of View™ Supporting the Pain Community With a Community of Support PainPointsofView.com offers resources and pain management

Resources to Help You Help Your Patients View an informative video about risk reduction strategies and download tools to assist with provider-patient communications

Personal Views on Pain Featuring a selection of personal accounts from individuals who deal with pain every day

Viewpoints From Government Agencies

Organizations for Pain Professionals

Links to pain management guidelines and recommendations, including the CDC Guideline for Prescribing Opioids for Chronic Pain

Learn about the societies that focus on the medical practice of pain management and connect with professional organizations that advocate for patients and professionals

This program is brought to you by Collegium Pharmaceutical, Inc. Collegium is committed to being the leader in responsible pain management.

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PP-CORP-US-0170 05-19

information for you and your patients, including:

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lief market, according to Allied Market Research, in 2017 and is n o li il b . .4 7 $ t by 2025 was valued a n o i l l i b 3.2 reach $1 iven by an aging d o t d e t r n projec e been d effectiveness, a v a h s e s Increa s.1 The ess of n n o e i r t a a c w i a d me ion, populat es to avoid oral sics continues c ge preferen for topical anal ver-the-counter demand ncluding both o ucts. With so di od to expan prescription pr cult to navigate d fi (OTC) an ns, it can be dif which products tio te many op ce and apprecia ost benefit for m en vide the n buying these the evid o r p o t are likely atients are ofte of pain relief it .P patients cations in pursu ovidersâ&#x20AC;&#x201D;and i r OTC med nsulting their p without a y co vailabilit eness without a without t a h t g assumin dicates effectiv iders may . Prov tion in prescrip adverse effects prescribing risk of rtable o f m esics. o g l c a l n e a e f l a t no ce opic ailable t mine the eviden v a y n a m a s le, we ex pical analgesic c i t r a s i In th use of to o effective g n i t r o p sup ight int s n i r e f f to o providers use and assist cation u d e ve . ffecti e h nts t i e i w t a ir p e h t for

Table 1. Advantages and Disadvantages of Topical Analgesics Advantages

Disadvantages

Limited systemic absorption

Erratic local absorption

Effective for localized pain

Variable depth of penetration

Tissue concentration > oral

Inaccuracy of dosing

Limited side effect profile

Require frequent applications Oleaginous “greasy” feeling Expensive

a recent study surveying provider perspectives across multiple specialties, 78% of providers reported prescribing lidocaine, 41% reported prescribing topical NSAIDs, but there was no other significant prescribing of topical analgesics, and these decisions were made largely on anecdotal evidence.2 Both topical and transdermal medications are available and can be effective, but they are designed for different purposes. A topical medication exerts a local effect directly under the application site but is not intended to be absorbed into systemic circulation. A transdermal medication is designed to penetrate and achieve therapeutic concentrations in plasma similar to oral or IV dosage forms but represents an alternative delivery method avoiding gastrointestinal or infusion related adverse effects.3 Topical analgesics are often recommended in clinical practice guidelines but differences between formulations and routes of administration often lead to confusion. Notable topical analgesics include rubefacients, capsaicin, lidocaine, NSAIDs, and customizable compounded analgesic preparations, all of which will be discussed here. The advantages and disadvantages of topical analgesics are listed in Table 1. Q 3 | 2019

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pharmacotherapy

Rubefacients

Rubefacients are a class of counterirritants widely used for relief of localized pain complaints. They exert their effect by causing irritation of the skin, and are believed to relieve pain in muscles, joints, tendons, and other musculoskeletal pains. Irritation of the sensory nerve endings alters or offsets pain in the underlying muscle or joints that are served by the same nerves.4 Rubefacients are generally available OTC, with common ingredients being camphor, menthol, trolamine salicylate, methyl salicylate, histamine dihydrochloride, and turpentine. Menthol, for example, activates a transient receptor potential melastatin 8 (or TRPM8) on sensory nerves and on the vasculature, inducing a cooling sensation on the skin, the result of which is increased cutaneous blood flow and potentially increased absorption.5 Menthol is often combined with another agent such as methyl salicylate to increase absorption and provide a soothing effect. Methyl salicylate is an ester oil (wintergreen oil) that induces skin redness and irritation leading to an analgesic effect and conversion to salicylate in the skin.6,7A meta-analysis reviewing effectiveness of salicylate-containing rubefacients determined that the evidence was limited and the results complicated by questions of quality, validity, and study size. The number needed to treat (NNT) was 3.2 for acute pain conditions while relative risk (RR) of adverse effects was 1.9. It was less effective for chronic conditions with the NNT of 6.2 and RR of adverse effects being 1.6.6 The conclusion of the meta-analysis: the evidence does not support the use of topical salicylate-containing rubefacients for either acute or chronic pain.6

Capsaicin

Capsaicin is a widely available and highly utilized topical analgesic found in numerous OTC formulations but only 1 prescription product in the United States and internationally. It is available in a variety of strengths: the most common are 0.25%, 0.75%, and 0.1% which can be used without supervision, while the prescription-only high-potency capsaicin 8% patch must be used in a provider’s office under her/his care. Capsaicin is often referred to as a counterirritant, but this is a tremendous oversimplification. Capsaicin is a transient receptor potential vanilloid 1 (TRPV1) agonist derived from the “pungent component” of the hot chili pepper. TRPV1 receptors are expressed in sensory neurons that detect noxious painful stimuli, and the agonist effect of capsaicin results in analgesia by causing the death of distal nerve twigs. This direct desensitization leads to a reversible loss of C fibers.8 Capsaicin has also shown that it reversibly inhibits signal conduction of alpha delta fibers.9 Capsaicin also appears to inhibit the activity of injected bradykinin, a neuropeptide involved in the inflammatory process.10 After discontinuation, it takes time for the reinnervation process, which involves thvve return in density and functional activity of autonomic and sensory nerve fibers to normal levels. In a small study using a topical capsaicin 0.1% cream application 3 times a day for 2 days, the nerve fiber recovery process was

46 PWJ | www.painweek.org

measured. Autonomic nerves recovered in 40 to 50 days while sensory nerve fibers took longer with an average delay of 140 to 150 days.11 The effectiveness of capsaicin topical creams has been established for years and there is little current interest in additional studies for creams.12-14 Most recent studies for capsaicin revolve around the high-potency capsaicin 8% patch. The prescription capsaicin patch is FDA-approved for postherpetic neuralgia (PHN) alone, while the European Medicines Agency approved it for peripheral neuropathic pain. The patch should be applied for 60 minutes for PHN or 30 minutes for HIV-associated neuropathy directly on the site of peripheral neuropathic pain. The application site should be unbroken dry skin, while the face, hairline, and mucous membranes should be avoided. It is recommended to apply a local anesthetic and oral pain medications prior to the capsaicin patch application to avoid discomfort. Despite the high potency of the product, the maximum measured systemic serum concentration after a 60 minute application is only 5 times the average dietary intake of capsaicin, and levels decline rapidly after removal with an elimination half-life of 130 minutes.15 There is also evidence that the effects of both the capsaicin high-potency patch and topical cream treatment persist and efficacy improves with repeated applications at appropriate intervals.16 The most common adverse effects are application site pain and erythema.15 Neuropathic pain guidelines agree that capsaicin can be effective for peripheral neuropathic pain but differ significantly in specific recommendations for use (see Table 2). The European Federation of Neurological Societies (EFNS) recommends capsaicin for 2nd or 3rd line use in PHN with evidence favoring the capsaicin 8% patch.17 The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) similarly recommended capsaicin 8% patches as a 2nd line option stating evidence for capsaicin cream was inconclusive.18 The most recent guideline, however, from the National Institute for Health and Care Excellence (NICE) for neuropathic pain recommends oral medications as 1st line therapies but state that capsaicin cream is reasonable for patients with peripheral neuropathy who are unable or prefer not to take oral medications to use 1st line, as the majority of results showed capsaicin cream consistently reduces pain compared with placebo. NICE further recommended the use of cream over the capsaicin 8% patch both for probability of pain relief, economics, and practicality of accessing treatment.16,19 The most recent studies indicate the capsaicin high-potency patch has demonstrated effectiveness compared to pregabalin at targeting dynamic mechanical allodynia, with reductions in area affected and percentage of patients with complete resolution both superior to pregabalin.20

Lidocaine

Lidocaine is an amide-type local anesthetic or numbing agent that works by inhibiting sodium channels required for the initiation and conduction of impulses, reducing the frequency rather Q 3 | 2019

Table 2. Recommendations for Use of Capsaicin from Neuropathic Pain Guidelines Formulation

Capsaicin cream

Capsaicin 8% patch

American Academy of Neurology19

European Federation of Neurological Societies17

Neuropathic Pain Special Interest Group/International Association for the Study of Pain18

National Institute for Health and Care Excellence16

1st line peripheral diabetic neuropathy

2nd line postherpetic neuralgia

N/A

3rd line peripheral neuropathy standard treatment; 1st line if localized or avoiding oral meds

N/A

1st line postherpetic neuralgia

than the duration of neuronal firing in the affected area.6 Several formulations of lidocaine are available including ointments, creams, and patches of various strengths, the most common of which are 4% and 5%. While the majority of the formulations are available OTC, the lidocaine 5% patch is a prescription-only medication. The lidocaine 5% patch is FDA-approved for relief of pain associated with PHN. Up to 3 patches may be used at one time on the most painful areas for any 12 hours in a 24 hour period, and the patches may be cut into smaller pieces to fit a specific size or application site. Removal after 12 hours is necessary to avoid consistent inhibition of the nerve impulses in the same area potentially leading to adverse effects, but at least 95% of the medication remains in the patch after removal, allowing continued utilization at other sites for a few days with benefit.21 Topically administered lidocaine does not result in significant systemic serum concentrations primarily due to poor penetration and high protein binding (70%).22 The mean peak serum concentration of topically administered lidocaine is roughly 0.13 ug/mL, which is about 10 times less than the therapeutic concentration required to treat cardiac arrhythmias and 50 times less than concentrations associated with toxicity. Neuropathic pain guidelines recommend topical lidocaine both for known efficacy and a predictable safety profile. Topical lidocaine recommended in guidelines generally refers to the prescription lidocaine 5% patch that was studied most in PHN in 2 enriched enrollment studies. The smaller study (32 patients) results were positive but in the larger study (263 patients) results were negative in the intent to treat (ITT) population but positive in the per protocol population. Several studies of shorter duration (<3 weeks) found efficacy with the patch, and it is notable that safety and tolerability were excellent in all studies.18 The American Academy of Neurology (AAN) and EFNS both recommend topical lidocaine as 1st line therapy for PHN, and AAN recommends as 2nd line for PDN. IASP recommends topical lidocaine as 2nd line therapy for mixed neuropathies. NICE indicated there was insufficient evidence to recommend topical lidocaine in either form and also recommended additional research to evaluate effectiveness. Q 3 | 2019

2nd line Last line peripheral neuropathy peripheral neuropathy

Topical NSAIDs

Arthritis is the leading cause of work disability among US adults. According to the CDC, from 2013 to 2015 an estimated 54.4 million US adults (22.7%) had been diagnosed with some form of arthritis (includes rheumatoid arthritis, osteoarthritis, gout, lupus) and 23.7 million reported arthritis-attributable activity limitations. In 2015, 15 million adults in the US reported severe joint pain due to arthritis. By 2040, the number of US adults diagnosed with arthritis is projected to increase to 78 million driven mainly by an aging population.23 Currently, there are multiple salicylate formulations available OTC but only 3 topical diclofenac products available with a prescription. NSAIDs have been the standard of care for the treatment of arthritis for over 100 years and continue to be effective as evidenced by utilization with roughly 50% of NSAID prescriptions being written for osteoarthritis (OA).24 The routine use of NSAIDs has become controversial due to concern for potential gastrointestinal, cardiovascular, and renal adverse effects. For example, the incidence of serious GI adverse events with oral NSAIDs is 15% and >2 times as likely in people >60 years old.24 Growing concern over the consequences of oral NSAID use has led to increasing recommendations for topical NSAIDs. There is also significant evidence for efficacy in a localized area and topical NSAIDs may provide a reasonable alternative or preferred solution for many patients. Tissue concentrations (subcutis, muscles, tendons) of topical NSAIDs are several times higher than after an oral administration.25 There appears to be substantial confusion surrounding the place of NSAIDs in therapy with concern for oral NSAID toxicity and NSAID class effect warnings for cardiovascular and gastrointestinal risk. Confusion is understandable given the same warnings are applied to all NSAID products in the package labeling. A safety review of the NSAID diclofenac was performed by Australia’s Therapeutic Goods Administration in 2014 where they queried the Adverse Drug Reaction Reporting System, the European equivalent of the FDA’s Adverse Events Reporting System. 84 reports of adverse events with topical diclofenac www.painweek.org | PWJ

pharmacotherapy

Table 3. Pharmacokinetics of Available Prescription Topical Diclofenac Formulations Brand Name

Form

Strength

Dose

Tablets

50 mg

Voltaren

Gel

Solaraze® Flector®

Diclofenac (Voltaren®, Cataflam®, generic)

Pennsaid®

Cmªx

Tmªx (hr)

(ng/hr/mL)

TID

2270 ± 778

6.5

3890 ± 1710

48 g/day*

53.8 ± 32

807 ± 478

Gel

2g TID x 6 days

5±5

4.5 ± 8

9 ± 19

Patch

1.3%

BID x 5 days

1.3 - 8.8

120

Topical Solution

1.5% weight/ weight

QID x 7 days

19.4 ± 9.3

4 ± 6.5

745.2 ± 374.7

(ng/mL)

AUC

*Above the maximum daily dose recommended

were reported to the database, but when oral diclofenac was excluded, only 2 reports of liver function test abnormalities and 1 of a GI bleed were left. The conclusion: “Based on the available information the risk/benefit for topical diclofenac remains favorable. There is a paucity of evidence of serious systemic side effects with topical diclofenac.”26 An examination of the pharmacokinetics of these products can assist with explaining the lack of systemic adverse effects. The systemic concentration of diclofenac necessary to reduce platelet aggregation by 41% is 400 ng/mL, but most topical NSAIDs rarely achieve a fraction of that level.25 The maximal plasma concentrations of prescription diclofenac preparations available in the US are included in Table 3, and all maximum plasma concentrations are well below drug response indicators for effectiveness (IC50) values, for COX-1 and COX-2.27 One common question is whether a topical NSAID can be added to an oral NSAID safely. Only 1 quality study has evaluated the addition of a topical NSAID to oral NSAID therapy but the combination did not demonstrate a statistically significant benefit.28 It is notable that the incidence of adverse effects was similar to the oral NSAID group alone, leading the investigators to conclude that in some patients where oral NSAIDs provide insufficient relief, the combination therapy may provide increased relief in a localized area with minimal risk of adverse events compared to increasing oral NSAIDs.28 Guideline recommendations are beginning to favor topical NSAID use in a variety of arthritic conditions particularly for localized or peripheral pain in the smaller joints. The American College of Rheumatology recommends topical NSAIDs for 1st line treatment of hand OA and alternative treatment for knee OA.29 The Veterans Affairs/Department of Defense recommend topical NSAID use as an alternative to 1st line oral NSAIDs for knee OA.30 NICE recommends topical NSAIDs as 1st line therapy

48 PWJ | www.painweek.org

for both knee and hand OA.31 Osteoarthritis Research Society International recommends topical NSAIDs as 1st line therapy for knee OA as a preferred treatment over oral NSAIDs.32

Compounded Topical Analgesics

In addition to traditional topical analgesics, compounded topical analgesics are highly promoted and widely utilized from compounding pharmacies with unique recipes of combined medications, at substantial cost. These topical preparations often contain multiple medications with some measure of evidence for pain management via alternative dosage forms (IV, oral) and dosed by percent weight compared to the total compounded topical preparation. Examples of commonly used active ingredients include ketamine, clonidine, gabapentin, ketoprofen, baclofen, and cyclobenzaprine, none of which have sufficient evidence to support efficacy and safety when delivered peripherally in a compounded cream. Small observational studies have provided mixed evidence but lack of dose standardization and effective follow-up for efficacy and adverse effects have complicated interpretation. Historically, well controlled, randomized, double-blind studies have not been performed to evaluate these products due to a lack of available funding. A recent report, however, indicates that the cost to health systems finally became prohibitive enough to justify funding a study. Compounded topical analgesics with multiple ingredients can cost anywhere from hundreds of dollars to thousands of dollars per prescription. Tricare, the health plan that insures US military personnel and their families, reported spending $259 million on compounded topical analgesics in 2013 and an additional $746 million in 2014.33 Medicare Part D similarly reported spending nearly half a billion dollars for compounded Q 3 | 2019

The American College of Rheumatology recommends topical NSAIDs for 1st line treatment of hand OA and alternative treatment for knee OA. pain creams in 2015, prompting Congress to require evidence for their efficacy. The Department of Defense funded a study to evaluate their efficacy and a double-blind randomized and placebo-controlled study at Walter Reed was organized and conducted from August 2015 to February 2018. 399 participants (>50% women) were enrolled in the study, composed of 43% active military and the remaining either retired military or spouses/dependents. The participants were further divided into 2 groups: compounded topical analgesics vs placebo cream.33 All participants had localized pain complaints and were divided into 3 groups: neuropathic pain, nociceptive pain, or mixed pain. The compounded topical analgesics per pain type:

○○ Neuropathic pain: ketamine, gabapentin, clonidine, lidocaine ○○ Nociceptive pain: ketoprofen, baclofen, cyclobenzaprine, lidocaine ○○ Mixed pain: ketamine, gabapentin, diclofenac, cyclobenzaprine, lidocaine Participants were instructed to apply the cream 3 times per day and record pain scores in their pain diary twice per day. All patients had a long-term history of chronic pain, reporting an average baseline pain of 4/10 or greater. The results, published in February 2019, indicate there was no statistically significant result compared to placebo for any of Q 3 | 2019

the 3 groups.33 The study confirms concerns for efficacy and makes recommending these expensive compounded topical analgesics inappropriate.

Conclusion

There are a wide variety of topical analgesics available with significant evidence supporting an expanding role in the management of localized pain. While often considered an alternative or adjunct treatment option, more recently several topical formulations have begun to receive endorsements for 1st line therapy. Topical analgesics can be a critical part of any treatment plan when providers truly understand the benefits and limitations inherent in this class of medications. An understanding and appreciation for these principles will empower providers to deliver effective solutions for localized pain that targets pathology appropriately while minimizing systemic exposure or risk of adverse events. References: 1. Allied Market Research. Topical pain relief market by therapeutic class: global opportunity analysis and industry forecast, 2018–2025. June 2018. Available at: www.alliedmarketresearch.com/topical-pain-relief-market. 2. Smith M, Cho K, Rodgers P. Provider perspectives on topical analgesics. J Pain Palliat Care Pharmacother. 2018;32(1):44–48.

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3. Leppert W, Malec-Milewska M, Zajaczkowska R, et al. Transdermal and topical drug administration in the treatment of pain. Molecules. 2018;23(3):E681.

23. CDC. Arthritis-related statistics. Updated July 18, 2018. Available at: www.cdc.gov/arthritis/data_statistics/arthritis-related-stats.htm.

4. Moore RA, Derry S, Mcquay HJ. Topical analgesics for acute and chronic pain in adults. Cochrane Database Syst Rev. 2010;(7).

24. Heyneman C, Lawless-Liday C, Wall G. Oral versus topical NSAIDs in rheumatic diseases a comparison. Drugs. 2000;60(3):555–574.

5. Craighead D, Alexander L. Topical menthol increases cutaneous blood flow. Microvasc Res. 2016;107:39–45.

25. Petersen B, Rovati S. Diclofenac epolamine (Flector®) patch evidence for topical activity. Clin Drug Invest. 2009;29(1):1–9.

6. Derry S, Matthews PR, Wiffen PJ, et al. Salicylate-containing rubefacients for acute and chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2014;(11):CD007403.

26. Australian Government Department of Health. Therapeutic Goods Administration. Safety review of diclofenac. October 7, 2014. Available at: www.tga.gov.au/safety-review-diclofenac.

7. U.S. Department of Health & Human Services. U.S. Food & Drug Administration. Application 022029. Salonpas (10% Methyl Salicylate & 3% 1-Menthol) Pain Relief Patch. February 20, 2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/ nda/2008/022029TOC.cfm.

27. Drago S, Imboden R, Schlatter P, et al. Pharmacokinetics of transdermal etofenamate and diclofenac in healthy volunteers. Basic Clin Pharmacol Toxicol. 2017;121:423–429.

8. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107(4):490–502. 9. Beydoun A, Dyke DB, Morrow TJ, et al. Topical capsaicin selectively attenuates heat pain and Aδ fiber-mediated laser-evoked potential. Pain. 1996;65(2–3):189–196. 10. Crimi N, Polosa R, Maccarrone C, et al. Effect of topical application with capsaicin on skin responses to bradykinin and histamine in man. Clin Exp Allergy. 1992;22(10):933–939. 11. Gibbons CH, Wang N, Freeman R. Capsaicin induces degeneration of cutaneous autonomic nerve fibers. Ann Neurol. 2010;68(6):888–898. 12. Biesbroeck R, Bril V, Hollander P, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther. 1995;12:111–120. 13. Donofrio P, Capsaicin study group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care. 1992;15:159–165. 14. Low PA, Opfer-Gehrking TL, Dyck PJ, et al. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain. 1995;62:163–168.

28. Simon L, Grierson L, Naseer Z, et al. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143(3):238–245. 29. Hochberg M, Altman R, April K, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465–474. 30. Non-Surgical Management of Hip and Knee Osteoarthritis Working Group. VA/DoD clinical practice guideline on the non-surgical management of hip and knee osteoarthritis (OA). Washington (DC): Department of Veterans Affairs, Department of Defense; 2014. 31. National Institute for Health and Clinical Excellence (NICE). National Collaborating Centre for Chronic Conditions. Osteoarthritis: care and management. London, UK; 2014. 32. Physician Summary. Non-surgical treatment of osteoarthritis of the knee. OARSI. March 4, 2014. Available at: www.oarsi.org/education/oarsi-guidelines. 33. Brutcher RE, Kurihara C, Bicket MC, et al. Compounded topical pain creams to treat localized chronic pain. A randomized controlled trial. Ann Intern Med. 2019;170:309–318.

15. European Medicines Agency. Qutenza capsaicin 8% patch. December 11, 2009. Available at: www.ema.europa.eu/en/medicines/human/EPAR/qutenza. 16. Neuropathic pain – pharmacologic management: NICE clinical guideline 173. November 2013. Updated February 2017. Available at: www.nice.org.uk/guidance/ cg173/evidence/full-guideline-pdf-4840898221. 17. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17:1113–1123. 18. Finnerup N, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. Lancet Neurol. 2015;14(2):162–173. 19. Bril V, England J, Granklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758–1765. 20. Cruccu G, Nurmikko T, Ernault E, et al. Superiority of capsaicin 8% patch versus oral pregabalin on dynamic mechanical allodynia in patients with peripheral neuropathic pain. Eur J Pain. 2018;22:700–706. 21. U.S. Department of Health & Human Services. U.S. Food & Drug Administration. Lidoderm [Label]. Drugs@FDA: FDA approved drug products. 3/19/19. Available at: www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview. process&ApplNo=020612. 22. U.S. Department of Health & Human Services. U.S. Food & Drug Administration. Application 20–612. Lidoderm topical patch. March 19, 1999. Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/99/20612.cfm.

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Q 3 | 2019

Should youâ&#x20AC;¦

Abuse Concern Respiratory depression

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Scrutiny Responsibility hological dependence

Efficacy

Responsibility Abuse Psychological dependence

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Tolerability

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INDICATION *BELBUCA® (buprenorphine buccal film) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioid formulations, reserve BELBUCA® for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • BELBUCA® is not indicated as an asneeded (prn) analgesic.

IMPORTANT SAFETY INFORMATION about BELBUCA® WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse BELBUCA® exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk prior to prescribing BELBUCA®, and monitor patients regularly for the development of these behaviors and conditions. Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of

addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to • complete a REMS-compliant education program, • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and • consider other tools to improve patient, household, and community safety.

When managing chronic pain*...

RETHINK RELIEF

(buprenorphine buccal film)

A Responsible Choice

BELBUCA® is the first and only Schedule III long-acting opioid that uses novel buccal film technology to deliver buprenorphine for appropriate patients living with chronic pain1-3*

•

Proven efficacy and sustained chronic pain* relief1

•

Established tolerability with side effects comparable to placebo1

•

Flexible dosing with a broad range of 7 dosage strengths, 75 mcg to 900 mcg1

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of BELBUCA®. Monitor for respiratory depression, especially during initiation of BELBUCA® or following a dose increase. Misuse or abuse of BELBUCA® by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death. Accidental Exposure Accidental exposure to even one dose of BELBUCA®, especially by children, can result in a fatal overdose of buprenorphine. Neonatal Opioid Withdrawal Syndrome Prolonged use of BELBUCA® during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management

according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Risks from Concomitant Use with Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. Please see full Important Safety Information at BELBUCA.com, as well as the brief summary of full Prescribing

Information for BELBUCA on the following pages. To report SUSPECTED ADVERSE REACTIONS, contact BioDelivery Sciences International, Inc. at 1-800-469-0261 or the FDA at 1-800-FDA-1088 or www.fda.gov/safety/ medwatch. Intended for healthcare professionals of the United States of America only. References: 1. BELBUCA® (Prescribing Information). Raleigh, NC: BioDelivery Sciences International, Inc; December 2018. 2. Data on file. DOF-BL-04. BioDelivery Sciences International, Inc.; 2015. 3. Center for Drug Evaluation and Research (U.S.). Orange book: approved drug products with therapeutic equivalence evaluations. Rockville, MD: U.S. Dept. of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Office of Generic Drugs, 1985. http://purl.access.gpo. gov/GPO/LPS1445. Accessed July 30, 2019.

Rx Only BELBUCA® is a registered trademark of BioDelivery Sciences International, Inc. © 2019 BioDelivery Sciences International, Inc. All rights reserved. Printed in USA. BEL-0060.3 August 2019 BELBUCA.com 1-800-469-0261

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION (buprenorphine buccal film)

For complete details, please see the full Prescribing Information and Medication Guide.

BELBUCA® (buprenorphine buccal film), CIII Initial U.S. Approval: 1981 WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning (prescribing information section numbers listed here). • BELBUCA exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk prior to prescribing BELBUCA, and monitor patients regularly for these behaviors and conditions (5.1,10). • To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers (5.2). • Serious, life-threatening, or fatal respiratory depression may occur with use of BELBUCA. Monitor for respiratory depression, especially during initiation of BELBUCA or following a dose increase. Misuse or abuse of BELBUCA by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death (5.3). • Accidental exposure to even one dose of BELBUCA, especially in children, can result in a fatal overdose of buprenorphine (5.3). • Prolonged use of BELBUCA during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.4). • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation (5.5,7). INDICATIONS AND USAGE BELBUCA (buprenorphine buccal film) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioid formulations [see Warnings and Precautions], reserve BELBUCA for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • BELBUCA is not indicated as an as-needed (prn) analgesic.

CONTRAINDICATIONS BELBUCA is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions]. • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions]. • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions]. • Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions and Adverse Reactions]. WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse BELBUCA contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing BELBUCA, and monitor all patients receiving BELBUCA for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as BELBUCA but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, along with intensive monitoring for signs of addiction, abuse, or misuse. Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death [see Overdosage]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing BELBUCA. Strategies to reduce the risk include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the REMS requirements, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to complete a REMS-compliant education program; to discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients or caregivers; to emphasize to patients and caregivers the importance of reading the Medication Guide; and to consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patientprescriber responsibilities. To obtain further information on the REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression when initiating therapy

with BELBUCA and following dosage increases. To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential. Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose. Accidental exposure to BELBUCA, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine. Neonatal Opioid Withdrawal Syndrome Prolonged use of BELBUCA during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations]. Risks due to Interactions with Benzodiazepines or Other Central Nervous System Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BELBUCA with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when BELBUCA is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of benzodiazepines or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions]. Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of BELBUCA in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: BELBUCA-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of BELBUCA [see Warnings and Precautions]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared with younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating BELBUCA and when BELBUCA is given concomitantly with other drugs that depress respiration [see Warnings and Precautions]. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. QTc Prolongation BELBUCA has been observed to prolong the QTc interval in some subjects participating in clinical trials. Consider these observations in clinical decisions when prescribing BELBUCA to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Periodic electrocardiographic (ECG) monitoring is recommended in these patients. Avoid the use of BELBUCA in patients with a history of Long QT Syndrome (or an immediate family member with this condition) or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval [see Adverse Reactions]. Severe Hypotension BELBUCA may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of BELBUCA. In patients with circulatory shock, BELBUCA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BELBUCA in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BELBUCA may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with BELBUCA. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BELBUCA in patients with impaired consciousness or coma. Hepatotoxicity Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual formulations of buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse events reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzymes abnormalities, infection with hepatis B and C virus, concomitant usage of other potential hepatotoxic drugs, and ongoing injection drug abuse which may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically during treatment with BELBUCA. Risk of Overdose in Patients with Moderate or Severe Hepatic Impairment In a pharmacokinetic study of subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment but not in subjects

with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Use in Specific Populations]. Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. BELBUCA is contraindicated in patients with a history of hypersensitivity to buprenorphine. Risk of Use in Patients with Gastrointestinal Conditions BELBUCA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. BELBUCA may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The buprenorphine in BELBUCA may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during BELBUCA therapy. Risks of Use in Cancer Patients with Oral Mucositis Cancer patients with oral mucositis may absorb buprenorphine more rapidly than intended and are likely to experience transiently higher plasma levels of the opioid. A dose reduction is recommended in these patients. Monitor carefully for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. Risks of Driving and Operating Machinery BELBUCA may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to side effects of BELBUCA and know how they will react to the medication. ADVERSE REACTIONS The following serious adverse reactions described in the labeling include: • Addiction, Abuse, and Misuse [see Warnings and Precautions] • Life-Threatening Respiratory Depression [see Warnings and Precautions] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions] • Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions] • Adrenal Insufficiency [see Warnings and Precautions] • QTc Prolongation [see Warnings and Precautions] • Severe Hypotension [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Anaphylactic/Allergic Reactions [see Warnings and Precautions] • Gastrointestinal Adverse Reactions [see Warnings and Precautions] • Seizures [see Warnings and Precautions] The most common adverse reactions (≥5%) reported by patients treated with BELBUCA in clinical trials were nausea, constipation, headache, vomiting, fatigue, dizziness, somnolence, diarrhea, dry mouth, and upper respiratory tract infection. Postmarketing Experience The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal

insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in BELBUCA. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids. DRUG INTERACTIONS Benzodiazepines Clinical Impact: There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Intervention: Closely monitor patients with concurrent use of BELBUCA and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BELBUCA, and warn patients to use benzodiazepines concurrently with BELBUCA only as directed by their physician. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BELBUCA is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. Intervention: If concomitant use is necessary, consider dosage reduction of BELBUCA until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azoleantifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase, which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BELBUCA dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin

Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BELBUCA if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions]. Intervention: The use of BELBUCA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of BELBUCA and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients receiving muscle relaxants and BELBUCA for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BELBUCA and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when BELBUCA is used concomitantly with anticholinergic drugs. Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs) Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. Intervention: None Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. Intervention: Patients who are on chronic BELBUCA treatment should have their dose monitored if NNRTIs are added to their treatment regimen. Examples: efavirenz, nevirapine, etravirine, delavirdine

Antiretrovirals: Protease inhibitors (PIs) Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Intervention: Monitor patients taking BELBUCA and atazanavir with and without ritonavir, and reduce the dose of BELBUCA if warranted. Examples: atazanavir, ritonavir USE IN SPECIFIC POPULATIONS Pregnancy Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions]. There are no adequate and well-controlled studies of BELBUCA or buprenorphine in pregnant women. Limited published data on use of buprenorphine, the active ingredient in BELBUCA, in pregnancy, have not shown an increased risk of major malformations. Reproductive and developmental studies in rats and rabbits identified adverse events at approximately 2 times the maximum recommended human dose (MRHD) of 1.8 mg/day of BELBUCA. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 54 and 2.2 times, respectively, the MRHD of 1.8 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 2.7 times and above and dystocia at approximately 27 times the MRHD of 1.8 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 5 times or greater than the MRHD of 1.8 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 5.4 and 10.8 times the MRHD of 1.8 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. BELBUCA is not recommended for use in women immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including BELBUCA, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Data Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m2) to MRHD of 1.8 mg buprenorphine via BELBUCA. Following oral administration to rats no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 1351 times the MRHD of 1.8 mg). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 432 times the MRHD of 1.8 mg). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 161 times and 324 times, respectively, the MRHD of 1.8 mg). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, doserelated post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 54 times the MRHD of 1.8 mg). In the rabbit, increased postimplantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 54 times, respectively, the MRHD of 1.8 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4.3 and 8.7 times, respectively, the MRHD of 1.8 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 865 times the MRHD of 1.8 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 270 times the MRHD of 1.8 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 5.4 times the MRHD of 1.8 mg), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 54 times the MRHD of 1.8 mg) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately 10.8 times the MRHD of 1.8 mg) were not statistically significant. In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/ day or greater (estimated exposure approximately 2.2 times the MRHD of 1.8 mg). Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine during gestation and lactation at 5 mg/kg/day (approximately 27 times the MRHD of 1.8 mg). Fertility, pre-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 4.3 times the MRHD of 1.8 mg), after IM doses of 0.5 mg/kg/day and up (approximately 2.7 times the MRHD of 1.8 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD of 1.8 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 432 times the MRHD of 1.8 mg). Lactation Risk Summary Based on two studies in 13 lactating women being treated for opioid dependence and their breastfed infants, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants [see Data]. There are no data on the effects of BELBUCA on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with BELBUCA. Clinical Considerations Monitor infants exposed to BELBUCA through breast milk

for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breastfeeding is stopped. Data Based on limited data from a study of six lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose. The median concentrations of buprenorphine and norbuprenorphine in infant urine were 1.0 nmol/L and 2.3 nmol/L, respectively. Based on limited data from a study of seven lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L, respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose. No adverse reactions were observed in the infants in these two studies. Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use The safety and efficacy of BELBUCA have not been established in pediatric patients. Geriatric Use Of the total number of patients that were treated with BELBUCA in controlled and open-label chronic pain trials (2,127), 340 patients were 65 years and older. Of those, 49 patients were aged 75 years and older. The incidences of selected BELBUCA-related adverse effects were higher in older subjects. No notable differences in pharmacokinetics were observed from population pharmacokinetic analysis in subjects aged 65 compared to younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between the elderly and younger patients. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use. Titrate the dosage of BELBUCA slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions]. Buprenorphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Hepatic Impairment BELBUCA has not been evaluated in patients with severe hepatic impairment. The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. Given that increased buprenorphine plasma levels are associated with a greater risk of toxicity and overdose, a dosage reduction in patients with severe hepatic impairment (i.e., Child-Pugh C) is recommended. Monitor patients with severe hepatic impairment for signs and symptoms of overdose. A dosage reduction in patients with moderate hepatic impairment (Child-Pugh B) is not needed; however, monitor these patients for signs and symptoms of toxicity or overdose. A dosage reduction in patients with mild hepatic impairment (Child-Pugh A) is not needed [see Warnings and Precautions].

DRUG ABUSE AND DEPENDENCE Controlled Substance BELBUCA contains buprenorphine hydrochloride, a Schedule III controlled substance. Abuse BELBUCA contains buprenorphine, a substance with a potential for abuse similar to other Schedule III opioids. BELBUCA can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions]. All patients treated with opioids, including BELBUCA, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carry the risk of addiction, even under appropriate medical use. Prescription drug abuse is the intentional, non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating healthcare providers(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all persons with substance use disorders. In addition, abuse of opioids can occur in the absence of true addiction. BELBUCA, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of BELBUCA BELBUCA is intended for buccal use only. Abuse of BELBUCA poses a risk of overdose and death. This risk is increased with concurrent abuse of BELBUCA with alcohol and other substances, including other opioids and benzodiazepines [see Warnings and Precautions, Drug Interactions]. Intentional compromise of the buccal film might result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions]. Abuse may occur by applying the buccal film in the absence of legitimate purpose, or by swallowing, snorting, or injecting buprenorphine extracted from the buccal film. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine). Physical dependence may not

occur to a clinically significant degree until after several days to weeks of continued opioid usage. BELBUCA should not be abruptly discontinued [see Dosage and Administration]. If BELBUCA is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop including:irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, or diarrhea or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations]. OVERDOSAGE Clinical Presentation Acute overdosage with BELBUCA is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology]. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema, as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BELBUCA, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required for at least 24 hours because of the possibility of extended effects of buprenorphine. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Healthcare professionals can telephone BioDelivery Sciences International, Inc. (1-800-469-0261) for information on this product. Manufactured for: BioDelivery Sciences International, Inc. Raleigh, NC 27612 USA BELBUCA is a trademark of BioDelivery Sciences International, Inc. © 2019 BioDelivery Sciences International, Inc. All rights reserved. BEL-0062.2 December 2018

By Meredith Barad MD

chronic pain syndromes

bstract. Clinically, the impact of estrogen on the female migraineur is commonly seen. The pathophysiology, however, is challenging to understand as estrogen has such a diverse array of actions throughout the body. This article explores the most common types of estrogen influences on migraines and recommends treatment options. is known to occur 2 to 3 times more frequently in women than men. Migraine peaks at age 35 to 45 for women, with 25% to 30% of females affected vs 8% of males.1 This divergence prevalence emerges after puberty. Whereas before puberty the prevalence of migraine is 3% to 10% with no difference between boys and girls, after puberty migraine prevalence becomes higher in girls than boys, with 50% of attacks shown to be menstrually related.2 It is thus a logical conclusion that estrogen is a trigger for migraine, as demonstrated in numerous studies. Peroutka et al rated it number 5 out of top 10 migraine triggers.3 While it is beyond the scope of this article to review the vast influences of estrogen on the brain and the body, our goal is to help practitioners develop an understanding of the different types of estrogen-related migraines a woman can have over her lifetime. 60 PWJ | www.painweek.org

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Table. The International Classification of Headache Disorders 3: Criteria for Migraine Related to Menstruation Pure menstrual migraine without aura A. Attacks, in a menstruating woman, fulfilling criteria for migraine without aura and criterion B below B. Occurring exclusively on day 1 ± 2 days of menstruation in ≥2 out of 3 menstrual cycles and at no other times of the cycle Menstrually related migraine without aura A. Attacks, in a menstruating woman, fulfilling criteria for migraine without aura and criterion B below B. Occurring on day 1 ± 2 of menstruation in ≥2 out of 3 menstrual cycles, and additionally at other times of the cycle These same criteria exist for migraine with aura

ICHD 3: CRITERIA FOR MIGRAINE RELATED TO EXOGENOUS HORMONES Headache attributed to long-term use of nonheadache medication A. Headache present on ≥15 days/month and fulfilling criterion C B. Long-term use of a medication has occurred for purposes other than the treatment of headache C. Evidence of causation demonstrated by >2 of the following: 1. Headache has developed in temporal relation to the commencement of medication intake 2. ≥1 of the following: a. Headache has significantly worsened after an increase in dosage of the medication b. Headache has significantly improved or resolved after a reduction in dosage of the medication c. Headache has resolved after cessation of the medication 3. The medication is recognized to cause headache, in at least some people, during long-term use D. Not better accounted for by another ICHD-3 diagnosis Estrogen-withdrawal headache A. Headache or migraine fulfilling criterion C B. Daily use of exogenous estrogen for ≥3 weeks, which has been interrupted C. Evidence of causation demonstrated by both of the following: 1. Headache or migraine has developed within 5 days after the last use of estrogen 2. Headache or migraine has resolved within 3 days of its onset D. Not better accounted for by another ICHD-3 diagnosis Olesen J. International Classification of Headache Disorders. Lancet Neurol. 2018;17(5):396–397.

Menstrual migraine (MM) is the term for a migraine specifically associated with menstruation. MM is divided into 2 categories: pure menstrual migraine (PMM) and menstrually related migraine (MRM) (see Table).4 MM most frequently occurs in the second decade of life around the onset of menarche and is typically without aura. MRM is common, occurring in 60% of women who have migraine attacks perimenstrually as well as at other times of the month. A much smaller percentage, 7% to 35%, of women experience PMM, which is defined as migraine attacks that may occur before, during, or after menstruation, seen in at least 2 out of every 3 cycles with no migraine at any other time of the month. The prevalence for MM peaks around age 40 and as menopause approaches, prevalence declines.5 The attacks may differ from the patient’s typical migraine in that they are often more severe, of longer duration, and less responsive to treatment. The diagnosis of MM is dependent on Q 3 | 2019

recording, through a headache diary, where the migraine falls in relation to the cycle. For an MM diagnosis, the migraine must fall 2 days prior to or in the first 3 days of the cycle.4 Headaches in general can be associated with premenstrual dysphoric disorder but as part of a constellation of symptoms other than purely somatic, including mood and behavioral symptoms.6 A sharp decline in estrogen during the late luteal phase and late follicular phase is believed to be responsible for triggering MM.7,8 Pavlovic et al compared 114 female migraineurs to 223 female controls and showed that women with a history of migraine have faster decline of estradiol in the late luteal phase just prior to menses than controls. This decline occurs regardless of the headache. There was no significant difference noted between www.painweek.org | PWJ

While hormonal treatments are an option, there are other nonpharmacological steps that should be performed.

absolute peak of estradiol, progesterone, luteinizing hormone, or follicle stimulating hormone. The authors suggested that this faster rate of estrogen decline is unique to migraineurs and may increase their risk for perimenstrual attack.9 There is some research into the impact of estrogen decline on blood vessels in that it makes them more permeable to proinflammatory mediators such as prostaglandins. It has been shown that prostaglandin levels are elevated 3-fold in the luteal phase with a further increase during menstruation, and therefore thought to play a role in MRM. This phenomenon may also explain why MM seems to be less responsive to typical abortive therapies but NSAIDs, which are prostaglandin inhibitors, are usually effective.5,10 Curiously the role of anemia and iron deficiency in menstrual migraine has not been well studied. A Turkish study noted an increased prevalence of iron deficiency anemia in all migraine patients as compared to healthy controls and significant association between migraine and iron deficiency anemia in the menstrual migraine subgroup.11 At the brain level, there are also many changes that occur in response to estrogen. Neuroimaging studies have demonstrated that pain-related brain activation changes during the menstrual cycle. We know that estrogen is synthesized as estradiol in many neurons throughout the brain, hypothalamus, basal forebrain, cerebral cortex, hippocampus, thalamus, cerebellum, and brainstem. Importantly, many of the brain areas associated with estradiol biosynthesis are involved in migraine.12-15 The amygdala is one region that shows changes across the menstrual cycle, specifically an increase in gray matter volume in

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the dorsal part of the left amygdala during the premenstrual phase compared with the late follicular phase.16 This suggests that fluctuations in estrogen are perceived at a central level although the effect is not yet known. Estrogen is thought to be predominantly excitable in the central nervous system; thus, estrogen may alter neuronal excitability in brain regions implicated in migraine. For example, since estrogen is present in brainstem modulatory pathways like the periaqueductal gray, it may be that low estrogen levels reduce activity in these pathways that inhibit pain processing.15,17

Treatment options include preventive medications Treatment options for menstrual migraine differ from migraine alone in that the headache itself may occur less frequently or in short succession but may also be more recalcitrant. While hormonal treatments are an option, there are other nonpharmacological steps that should be performed. First, it is extremely important to identify the relationship between migraines and menstrual cycle. A diary is the best means to do so. Second, review nonpharmacologic strategies with the patient, such as regular sleep, hydration, meals, and avoidance of known triggers. A trigger in a non-MM attack may be different from the trigger for a MM attack, and treatments that are beneficial in non MM may not work for MM.5,18 Women with menstrual migraine are frequently interested in menstrual cessation as a way to manage their headaches Overall the literature to support this approach is not robust. In a recently published consensus Q 3 | 2019

statement from the European Headache Federation and the European Society of Contraception and Reproductive Health (EHF/ESCRH) on the hormonal management of migraine, the primary recommendations were all considered weak due to the low quality of evidence.19 Thus including nonhormonal options in your management plan should also be considered. For acute medications, triptans with the possible addition of NSAIDs and/ or an antiemetic is a good first choice. Preventive medication should be considered if MM is occurring 3 to 4 days per month or MM is not responsive to acute therapy. One common option is a short-term preventive treatment used around the time of menstruation, known as mini-prophylaxis. Nonhormonal mini-prophylaxis options include the perimenstrual use of NSAIDs. For example, naproxen sodium (550 mg BID) or mefenamic acid (500 mg TID) may be used effectively 2 to 4 days prior to the MM and continued through day 3 of menstrual flow. Modified triptans regimens including sumatriptan (25 mg TID), naratriptan (1 mg BID), or frovatriptan (2.5 mg BID) are effective for mini-prophylaxis. This regimen should be started 2 days prior to the onset of MM and continued for a total of 3 to 5 days. Standard preventive medications used for migraine may be used for 5 to 7 days prior to the onset of menses and continued through the end of the vulnerable time period for migraine, which can be assessed by a diary. If a patient is currently taking a preventive agent, the dose can be transiently increased during the same window.18,20 If a woman decides to try combined hormonal contraception (CHC), headaches can improve or worsen. There remains poor evidence that CHC prevents migraine. For MRM specifically, it is thought that exogenous estrogen during the placebo week can blunt the impact of the naturally falling estrogen, limiting the menstrual migraine. The EHF/ESCRH consensus statement recommended CHC for women with MRM who require CHC for medical reasons, who would prefer CHC to other preventive options, or who have failed other preventive options. Evidence suggests an extended regimen of oral pills without placebo or the vaginal ring are options. For a mini-prophylaxis approach with hormones supplementation, transdermal supplementation with estradiol gel is recommended over an estradiol patch during the week of menses.19 Migraine with aura (MwA) carries an increased risk of stroke compared to migraine without aura. This risk was demonstrated primarily in older studies with women receiving significantly higher doses of estrogen in an oral contraceptive. Emerging evidence from clinical practice, however, suggests that there is lower risk in prescribing the current low‐estrogen formulations to patients with MwA, assuming they have a low vascular risk profile (nonsmokers, no cardiovascular risk factors).21,22 In women for whom estrogen-containing contraceptives are contraindicated, a progesterone-only pill can be considered, and the EHF/ESCRH consensus statement suggests desogestrel (the only progestin studied) for MRM patients who require contraception or treatment for medical reasons, or who have failed other preventive options.19 Q 3 | 2019

Pregnancy, hormonal balance, and medication risks When a woman becomes pregnant, the hormonal balance again changes. As estrogen levels rise during the first trimester, transient migraine worsening may occur, but overall migraine frequently improves during pregnancy. Half to 75% of women experience improvement in their migraines during pregnancy and this is thought to be due to the lack of estrogen fluctuation during this period.23 Migraine can persist beyond the first trimester. Studies suggest that severe maternal migraines may increase the occurrence of adverse delivery outcomes. In one retrospective study, over half of the pregnant women seeking treatment for acute migraine experienced an adverse outcome including preeclampsia, preterm birth, and low birthweight.24 A Taiwanese retrospective study concluded that women with migraines were at increased risk of having the same 3 adverse outcomes.25 Thus it is important to manage migraines effectively during pregnancy and to pay attention to warning signs of alternate pathology. While it is possible for migraine to present for the first time during pregnancy, it is uncommon, and often presents as migraine with aura. It is imperative to rule out secondary headache due to an alternative pathology or secondary cause, such as tumor or infection, if migraines present de novo or dramatically worsen or change in character during the pregnancy.23 Treatment options for migraine during pregnancy start with simple strategies such as reassurance, rest, ice, acupuncture, biofeedback, and short-term disability leave from work. For women who have severe or prolonged migraine accompanied by nausea, vomiting, and dehydration, medical therapy is indicated, and for severe cases, IV treatments with fluids, magnesium, and anti-emetics may be recommended. The first line acute therapy for migraine during pregnancy is acetaminophen. Several NSAIDs are generally considered safe but only in the second trimester. In the first trimester there are concerns of miscarriage. In the third trimester, where there is a noted increased fetal risk of premature closure of the ductus arteriosus, impaired renal function, oligohydramnios, an intraventricular hemorrhage, it is probably best to avoid NSAIDs. It is also best to avoid opiates; while they are considered safe, they can exacerbate nausea and reduce gastric motility, and the chronic use of opiates can increase the risk of medication overuse headache. Antiemetics such as prochlorperazine, promethazine, ondansetron, and metoclopramide are safe to use in pregnancy, but long-term use of metoclopramide should be avoided due to the risk of extrapyramidal side effects. A greater occipital nerve block can alleviate pain and reduce the number of headache days and medication consumption. In general, triptans are relatively contraindicated during pregnancy; however, under careful consideration and monitoring, there may be a role for these medications in specific situations.23 Marchenko et al preformed a meta-analysis of 6 studies including 4,208 infants of women who used sumatriptan or other triptan medications. They noted no significant increases in rates for major congenital www.painweek.org | PWJ

Estrogen plays an important role in the lifecycle of a female migraineur.

malformations (MCMs), prematurity, or spontaneous abortions when comparing the triptan exposed group to the migraine/ no-triptan control group. No increase in the rate of MCMs or prematurity was seen in the triptan exposed group as compared with the healthy controls; however, a significant increase in the spontaneous abortion rate was seen. The migraine/no triptan group also showed a significant increase in the rates of MCMs as compared with healthy controls. This leaves many questions to be answered but overall the data appear to not entirely contraindicate triptans.26

Prevention during pregnancy For prevention of migraine during pregnancy, topiramate and sodium valproate are contraindicated as they are teratogenic.23 In a recent randomized controlled trial, aspirin <100 mg once a day is often helpful and appears to be safe until 36 weeks’ gestation.27 Beta blockers such as low dose propranolol (10 to 40 mg 3 times a day) can be used, and once daily dosing may improve adherence. Historically, there have been concerns about effects on fetal growth from beta blockers. Older studies typically used higher doses and studied mothers with hypertension or cardiac diseases, making it difficult to differentiate the drug effects from the underlying condition. A recent study has shown that the first trimester of pregnancy is not associated with a higher risk of specific congenital anomalies.28 Low dose tricyclic antidepressants (such as amitriptyline) or serotonin reuptake inhibitors (such as fluoxetine) can also be considered, but the risk of fetal malformation has been reported and this should be discussed with patients.20,23

this transition can take many years. On average, women enter perimenopause in their mid-40s, or earlier, and tend to reach menopause by age 55.29 The perimenopausal transition is a period of significant fluctuations in hormone levels and can lead to a temporary worsening of headaches. The erratic menses characteristic of perimenopause makes MM challenging to predict and may also lead to an increase in rescue medication. A population based study looking at the rate of high frequency migraine in 3,664 patients showed the perimenopausal group had the highest frequency of migraines as compared to pre- and postmenopause.30 This makes perimenopausal women especially vulnerable to medication overuse headache during this transition. Perimenopause can be associated with a constellation of symptoms including hot flashes, forgetfulness, concentration challenges, irritability, fatigue, night sweats, insomnia, drop in libido, and weight gain, all of which may contribute to migraine. Hormone replacement therapy (HRT) is often provided to women during perimenopause. Depending on the type, dose, and route of administration of estrogen, migraine can be affected. In general, HRT is not prescribed for migraine alone but is used primarily to control the symptoms of peri- or postmenopause. It should not be used in a migraineur who has aura or other vascular risk factors. If HRT worsens migraine, consideration can be given to HRT modifications including changing the type of estrogen, reducing the dose, or switching to noncycling estrogen supplement, with the goal being to provide stable hormonal physiologic levels. If adjustments are unhelpful, other nonhormonal options include gabapentin, venlafaxine, and natural supplements.20

Conclusion Migraine in older women lessens… eventually Migraine tends to improve with age, especially in women who have menstrual migraine as menopause leads to less estrogen cycling and therefore reduction in headache. Unfortunately,

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Estrogen plays an important role in the lifecycle of a female migraineur. While we have focused primarily on menstrual related migraine, estrogen is a likely factor in migraine in general, and it is important that the headache practitioner address the impact of both endogenous and exogenous estrogen on the migraine patient. Q 3 | 2019

References 1. Stewart WF, Lipton RB, Celentano DD, et al. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA. 1992;267(1):64–69. 2. Karli N, Baykan B, Ertas M, et al. Impact of sex hormonal changes on tension-type headache and migraine: a cross-sectional population-based survey in 2,600 women. J Headache Pain. 2012;13(7):557–565. 3. Peroutka SJ. What turns on a migraine? A systematic review of migraine precipitating factors. Curr Pain Headache Rep. 2014;18(10):454. 4. Olesen J. International Classification of Headache Disorders. Lancet Neurol. 2018;17(5):396–397. 5.

Calhoun AH. Understanding menstrual migraine. Headache. 2018;58(4):626–630.

23. Negro A, Delaruelle Z, Ivanova TA, et al. Headache and pregnancy: a systematic review. J Headache Pain. 2017;18(1):106. 24. Grossman TB, Robbins MS, Govindappagari S, et al. Delivery outcomes of patients with acute migraine in pregnancy: a retrospective study. Headache. 2017;57(4):605–611. 25. Chen HM, Chen SF, Chen YH, et al. Increased risk of adverse pregnancy outcomes for women with migraines: a nationwide population-based study. Cephalalgia. 2010;30(4):433–438. 26. Marchenko A, Etwel F, Olutunfese O, et al. Pregnancy outcome following prenatal exposure to triptan medications: a meta-analysis. Headache. 2015;55(4):490–501. 27. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613–622.

6. Mishra S, Marwaha R. Premenstrual Dysphoric Disorder. In: StatPearls. Treasure Island, Florida; 2019.

28. Bergman JEH, Lutke LR, Gans ROB, et al. Beta-blocker use in pregnancy and risk of specific congenital anomalies: a European case-malformed control study. Drug Saf. 2018;41(4):415–427.

7. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63(2):351–353.

29. Ibrahimi K, Couturier EG, MaassenVanDenBrink A. Migraine and perimenopause. Maturitas. 2014;78(4):277–280.

8. Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology. 1972;22(4):355–365.

30. Martin VT, Pavlovic J, Fanning KM, et al. Perimenopause and menopause are associated with high frequency headache in women with migraine: results of the American Migraine Prevalence and Prevention Study. Headache. 2016;56(2):292–305.

9. Pavlovic JM, Allshouse AA, Santoro NF, et al. Sex hormones in women with and without migraine: evidence of migraine-specific hormone profiles. Neurology. 2016;87(1):49–56. 10. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis--part I. Headache. 2006;46(1):3–23. 11. Gur-Ozmen S, Karahan-Ozcan R. Iron deficiency anemia is associated with menstrual migraine: a case-control study. Pain Med. 2016;17(3):596–605. 12. Burstein R, Jakubowski M, Garcia-Nicas E, et al. Thalamic sensitization transforms localized pain into widespread allodynia. Ann Neurol. 2010;68(1):81–91. 13. Maleki N, Becerra L, Borsook D. Migraine: maladaptive brain responses to stress. Headache. 2012;52(suppl 2):102–106. 14. Choi JC, Park SK, Kim YH, et al. Different brain activation patterns to pain and pain-related unpleasantness during the menstrual cycle. Anesthesiology. 2006;105(1):120–127. 15. Borsook D, Erpelding N, Lebel A, et al. Sex and the migraine brain. Neurobiol Dis. 2014;68:200–214. 16. Ossewaarde L, van Wingen GA, Rijpkema M, et al. Menstrual cycle-related changes in amygdala morphology are associated with changes in stress sensitivity. Hum Brain Mapp. 2013;34(5):1187–1193. 17. Loyd DR, Murphy AZ. Androgen and estrogen (alpha) receptor localization on periaqueductal gray neurons projecting to the rostral ventromedial medulla in the male and female rat. J Chem Neuroanat. 2008;36(3–4):216–226. 18. Sullivan E, Bushnell C. Management of menstrual migraine: a review of current abortive and prophylactic therapies. Curr Pain Headache Rep. 2010;14(5):376–384. 19. Sacco S, Merki-Feld GS, Ægidius KL, et al. Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH). J Headache Pain. 2018;19(1):76. 20. Todd C, Lagman-Bartolome AM, Lay C. Women and migraine: the role of hormones. Curr Neurol Neurosci Rep. 2018;18(7):42. 21. Sacco S, Ricci S, Degan D, et al. Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain. 2012;13(3):177–189. 22. de Falco FA, de Falco A. Migraine with aura: which patients are most at risk of stroke? Neurol Sci. 2015;36(suppl 1):57–60.

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www.painweek.org | PWJ

N D

GAROFOLI

P I T

CLARK

T H E

SCHATMAN

MALLICK-SEARLE

JAY

EXPERTS ADDRESS THE CDC GUIDELINE

In March of 2016, the Centers for Disease Control and Prevention issued the CDC Guideline for Prescribing Opioids for Chronic Pain using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. They offered recommendations based on a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. Earlier this year, the CDC issued a clarification in the form of a letter from Deborah Dowell, MD, MPH, Chief Medical Officer for the CDC’s National Center for Injury Prevention and Control, to three medical associations— American Society of Clinical Oncology, American Society of Hematology, and National Comprehensive Cancer Network—expressing concern over misapplication of the guideline by payers to patients with cancer and sickle cell disease. In the clarification, released to the public April 9, Dr. Dowell wrote, “The Guideline is not intended to deny any patients who suffer with chronic pain from opioid therapy as an option for pain management. Rather, the Guideline is intended to ensure that clinicians and patients consider all safe and effective treatment options for payments. CDC encourages physicians to continue to use their clinical judgement and base treatment on what they know about their patients, including the use of opioids if determined to be the best course of treatment.” Other problems with the Guideline, including a paucity of underlying evidence, and misinterpretation by primary care as a directive rather than advice, have been noted at PAINWeek and PAINWeekEnd forums since the 2016 issuance. The Journal asked PW faculty to comment on the clarification letter.

Michael R. Clark MD, MPH, MBA

Gary W. Jay MD, FAAPM

● Guidelines in general are no substitute for true education that drives practice and the development of expertise.

● The CDC “Guideline” was produced by a so-called expert panel of addictionologists and nonpain experts—some affiliated with PROP (Physicians for Responsible Opioid Prescribing), some with significant conflicts of interest, and some antiopioid zealots.

● The problem with standardized questionnaires, diagnostic criteria, treatment algorithms, and guidelines is that they are blunt tools that cannot be wielded by just anyone. ● Whenever we release a new policy or practice there will unintended consequences, many of which could be predicted if we give the issues some careful thought.

Mark Garofoli PharmD, MBA, BCGP, CPE ● I find it very concerning that our society needed this clarification, as the intended audience was clearly stated in the original Guideline. Will ears actually listen this time? ● One extreme to the opposite: If I am ever diagnosed with a painful cancer, and prescribed/dispensed highrisk opioid dosages as deemed appropriate by this clarification (and the original Guideline), I hope my clinicians take action with risk reduction strategies, such as ❶ Utilizing a PDMP—what better time for my identity to be stolen? ❷ Checking my adherence with a urine drug screening/test—I may try to be tough and not rely on my medications ❸ Reminding me to store my medications under lock and key—for the sake of my child and nieces Doesn’t every patient deserve the best care with risk-reduction strategies regardless of any situation? Aren’t we to Do No Harm? Distinguishing between the morphine milligram equivalent (MME) listing and the risk-reduction strategies within the CDC Opioid Guideline of 2016 is needed. Let’s perhaps clarify that! ● Last I heard buprenorphine is effective for pain management, yet still omitted from the infamous MME listing, with good intentions of not swaying clinicians away from medication assisted therapy, but still needed for completeness and justification to the entire MME listing. Buprenorphine was originally included as an MME of 10, then revised to 30, and then eliminated from the listing. If anything needs clarification, let’s start there!

Q 3 | 2019

● Forced detoxification from opioids in chronic pain patients without a “stain” on their records occurred against their will. They were functional, holding a job, taking care of their family, but once they had significant decrements in their pain medication— if it wasn’t taken down to zero, which in many patients it was—it caused many to become nonfunctional and increased the percentage of patients who tried to regain function by using illegal medications as they couldn’t find legal pain medications or a physician to give them the medications they needed. To try to regain function, some of these folk experienced “one trial conditioning”—they took heroin that was, unknown to them, laced with fentanyl, and died. And were called drug addicts. ● The FDA further stated in their letter, “Rapid discontinuation can result in uncontrolled pain or withdrawal symptoms [and] lead patients to seek other sources of opioid pain medicines, which may be confused with drug-seeking for abuse. Patients may attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.” They then added, “Health care professionals should not abruptly discontinue opioids in a patient who is physically dependent. When you and your patient have agreed to taper the dose of opioid analgesic, consider a variety of factors, including the dose of the drug, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient.” Unfortunately, that is not how the CDC Guideline has either been perceived or utilized. While it appears that there may be some tantalizing beginnings of a bit of intelligence applied to opioid use, “Bad Things” are still being planned. For example, Oregon proposed tapering the majority of Medicaid patients off opioids, if they were on an opioid for more than 90 days and switched to an “alternative pain treatment.” That would be over a million people. This move was recently placed “on hold.”

Theresa Mallick-Searle MS, NP-BC, ANP-BC ● Overall, as an attempt for achieving improved communication, reduced risk, and improved safety, I am in full appreciation of the 2016 Guideline.

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Unfortunately, on a national, local, and even international level we have seen the use and often misuse of this Guideline to justify personal agendas. ● From the day that the 2016 Guideline went out, there has been much emphasis and reemphasis on the statement, “The Guideline is not intended for patients who are in active cancer treatment, palliative care, or end-of-life care.” The need for the CDC to clarify what was clearly stated in 2016 speaks to the way the initial Guideline was misinterpreted and possibly misused. The letter additionally calling out and placing emphasis on patients with sickle cell disease is difficult for me to understand. I do not differentiate the treatment in pain with a sickle cell crisis much differently than, say, pain associated with other advanced chronic pain conditions, such as poststroke pain, complex regional pain syndrome, or spinal cord injury pain. Additionally, in my personal experience, the population that struggles with sickle cell disease is, in part probably related to the lifelong struggle with recurrent acute and chronic pain, at a higher risk of opioid dependence and addiction. I am not saying that patients with sickle cell disease are addicts. The point that I am making is that those with an ongoing exposure to opioids are potentially at risk for a learned behavior of chronic opioid use and dependence.

Michael E. Schatman PhD ● The letter of clarification from Dr. Dowell is certainly good news for patients suffering from pain due to cancer and sickle cell disease. These patients’ pain has been progressively more undertreated since the onset of opioid hysteria. ● The clarification does little, if anything, however, for the tens of millions of Americans who suffer from high-impact intractable pain due to other causes. It is curious that the pain mechanisms for all of these chronic pain conditions are identical. ● The CDC Guideline is not the problem, per se. Rather, it is the weaponization of the Guideline by state legislatures, medical boards, insurers, hospital systems, and pharmacy systems that transformed the Guideline from de facto law to de jure law. Dr. Dowell’s letter of clarification is unlikely to have any impact on the Guideline’s weaponization, and, consequently, chronic pain patients will continue to be stigmatized and marginalized.

● Much more effort needs to be focused on identifying those who use the CDC Guideline as an opportunity to achieve personal gain, such as the practice of payers refusing to pay for opioids over an arbitrary daily MME, applying to all patients in all clinical scenarios.

Michael R. Clark MD, MPH, MBA Vice Chair, Clinical Affairs ● Johns Hopkins University School of Medicine ● Department of Psychiatry and Behavioral Sciences ● Baltimore, MD ● Chairman Inova Health System ● Falls Church, VA Mark Garofoli PharmD, MBA, BCGP, CPE Clinical Assistant Professor ● West Virginia University (WVU) School of Pharmacy ● Clinical Pain Management Pharmacist ● WVU Medicine Center for Integrative Pain Management ● Morgantown, WV Gary W. Jay MD, FAAPM Clinical Professor ● University of North Carolina ● Department of Neurology ● Chapel Hill, NC Theresa Mallick-Searle MS, NP-BC, ANP-BC Nurse Practitioner ● Stanford Health Care ● Division of Pain Medicine ● Stanford, CA Michael E. Schatman PhD Director of Research and Network Development ● Boston Pain Care ● Adjunct Clinical Assistant Professor ● Department of Public Health & Community Medicine ● Tufts University School of Medicine ● Editor-in-Chief ● Journal of Pain Research

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Tanya J. Uritsky pharmd, bcps Clinical Pharmacy Specialist Pain Medication Stewardship Hospital of the University of Pennsylvania (hud)

I…strive to provide tireless patient advocacy in pain management, especially at the end of life…

tanya URiTSKY GPS Bryn Mawr, PA. Typical Day Up at 4:45A for an hour workout, then a protein shake, a shower, off to the train. Start off work with a cup of tea, follow up on projects, organize and attend meetings, see complex pain management patients, then back to the train, get the kids, then dinner, a dance party with the kids, and bedtime and next-day prep. Rinse and repeat! Persona I have learned a lot, some things the hard way, others through mentors and those around me. I have amazing colleagues who have supported me and thrown me into the national and international arena, giving me opportunities to learn and to shine. My beautiful children, Alexander and Evelyn, inspire me every day with their creativity and love for the simple things, and together with my supportive husband, Dmitry Uritsky, give me the room and encouragement to grow and work hard. Social Media Habits I really only check Facebook: I love seeing what other people are up to, but I also really love my professional website groups. They help me stay connected and up to date, and also see others’ achievements. I have been told I should get on Twitter, but I cannot imagine having another thing to do at this time. Contribution I was a Co-Founder of the Palliative Care Service at HUP with a Nurse Practitioner, a part-time social worker, and a chaplain. We are now a robust interdisciplinary team with outpatient/inpatient services at multiple sites. I promised my father, when he was dying, that I would help others and do something in his honor. I now strive to provide tireless patient advocacy in pain management, especially at the end of life, as well as expert pain and symptom management as an ongoing legacy. I have written many articles and spoken at many conferences to impart this knowledge to help improve patient care on a broader scale. I got the Pain and Palliative Care Practitioner of the Year aware at PAINWeek a few years ago, and that was really unexpected and cool . People I tend to admire those around me more than the infinitely famous. The strengths and special traits of individuals in my life inspire me. If I had to pick a public person to admire, it would be Oprah Winfrey. Seems a little random, but I grew up watching her talk show; she always was honest about her real-life struggles despite wealth and power, and her generosity for the greater good of the world has been a pillar she has long stood for on every public platform she has served. Words I do not read many “adult” books nowadays. All things ninja and nursery rhymes fill my personal life, but I do enjoy reading short blogs. The bulk of my longer reading endeavors tends to be in preparation for writing and presentations. Popcorn My husband always jokes that I just watch the same comedies and romance movies over and over again, but really I just love mindless, funny, entertaining movies! I have seen such movies as Dirty Dancing, Clueless, Wedding Crashers, and Forgetting Sarah Marshall more times than I can count! PAINWeek PAINWeek gives me the chance to be with my colleagues; share thoughts, wisdom, knowledge, and clinical expertise with an engaged and diverse audience. I love the number of disciplines represented by the presenters, bringing many different perspectives to the forefront. The diversity of the programming really caters to all different backgrounds and practice areas, but also there is an edginess to the programming and “finger on the pulse” content that is the core of the meeting. Q 3 | 2019

www.painweek.org | PWJ

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By Doug Gourlay md, msc, frcpc, Dfasam

“When dealing with a higher risk patient, your prescriptions and frequency of follow-up should reflect this risk assessment.” That generally means the patient should be picking up their medication at tighter intervals than a low risk patient would expect. Similarly, the frequency of healthcare provider contact should also increase. This may result in some level of inconvenience to the patient, including unexpected pharmacy co-pays, but is necessary to ensure that the level of risk and treatment plans are consistent with each other.

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Q3 | 2019

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Myofascial temporomandibular disorder (mTMD) is experienced by >10% of women, and ≤18% of sufferers also have widespread pain conditions. A research team interviewed

with mTMD, including 26 patients with fibromyalgia, to determine what treatment approaches they were using and their effectiveness. Oral appliances were used by 59% of respondents, physical therapy by 54%, and in-home jaw exercises by 34%. 84% of respondents reported that ≥1 of the self-administered treatment approaches provided some degree of pain relief, while just 64% of oral appliance users reported any benefit, and 11% felt their pain was made worse.1

In 2015, Medicare Part D spent

in coverage for prescription topical pain preparations. A study, conducted from 2015 to 2018, engaged 399 participants aged 18 to 90, and 51% female. Study subjects had localized pain in the face, back, buttocks, neck, abdomen, chest, groin, and/or extremities with an average duration of 6.7 years. Participants were randomized to receive a compounded topical preparation or placebo for application 3x daily. Pain score reports showed no statistically significant difference.2

Meta-analysis of data from 21 studies of mindfulness based stress reduction (MBSR) spanning

—predominantly women, aged 35 to 65, and presenting with pain conditions including musculoskeletal pain, fibromyalgia, low back pain, rheumatoid arthritis, osteoarthritis, and temporomandibular disorder— were selected for review. 13 studies compared cognitive behavioral therapy (CBT) to control cohorts, 7 compared MBSR to controls, and 1 compared MBSR and CBT to controls. The study could not determine the effectiveness of CBT or MBSR.3

A study focused on prescribing patterns for transmucosal immediate release fentanyls (TIRFs) from 2012 to 2017. A Risk Evaluation and Mitigation Strategy (REMS) program was initiated by FDA in 2011, and included a “closed distribution system” requiring TIRF makers to demonstrate compliance via annually submitted reports. In their 2016 annual submission to FDA under the REMS program, TIRF makers were reporting that between

of TIRF prescriptions were to patients who lacked opioid tolerance.4

A study reported that an intervention using virtual reality (VR) may encourage patients with chronic low back pain (CLBP) to overcome their fear of being physically active. Narcotic prescriptions for CLBP increased 300% since the 1990s, and provide little to no benefit in terms of pain relief or reduction in disability.

with CLBP and maladaptive pain beliefs were enrolled and, following administration of a 3 day VR protocol, the intervention was shown to be particularly effective in reducing average daily pain and pain related interference among patients with high levels of both.5

The incidence of nonsuicidal self-injury (NSSI) among adolescents is 10% of boys and 25% of girls conducting such behavior each year. A study sought to examine the “enigmatic” level of understanding of how subjects experience pain during such episodes.

aged 15 to 21 with a history of NSSI, and 70% female, were given a smartphone app enabling researchers to question them 5x daily for 2 weeks on their latest incident of NSSI. Subjects were also queried on levels of physical pain and on the presence of ≥1 of 21 emotional states including feelings of anxiety, sadness, loneliness, anger.6

1. https://bit.ly/2NMgfiz 2. https://bit.ly/2UqaOZk 3. https://bit.ly/2EFS69w 4. https://bit.ly/2TFiU2W 5. https://bit.ly/2H92k5Q 6. https://bit.ly/2NOS57d

Q 3 | 2019

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Patient Barriers to Pain Management and Acceptance Ravi Prasad MD

The barriers that we face when we tell patients they “can learn to live with pain” are quite vast. There are some patients who say “I don’t want to live with pain. The pain has taken a lot out of my life and I don’t want to learn to live with it. I just want it gone.” That’s a significant barrier, but it’s understandable, and the way that we approach dealing with that is by helping a patient work toward a model of acceptance. “Acceptance” doesn’t mean that they give up the fight. It means accepting the reality of the chronicity of their pain and learning how they can still have very good quality of life despite the presence of pain. For a lot of patients it’s hard to conceptualize that, because their experience of pain is just what it is at that time. When you tell a patient “You have to learn to live with pain” they think it’s learning to live with pain at that level of intensity and with that degree of interference. But managed pain is completely different. The discomfort of course will still be there, but if a person is able to be engaged in more productive activities, things that are more meaningful, then the pain becomes more of a nuisance variable. When we conceptualize that to patients, or help them start to see what that can look like, that goes a long way, and we’re able to help shift their conceptualization of learning to live with pain and they become more open to it.

Neuropathic Pain — We Can and Should Do Better! Brett Stacey MD

In terms of diagnosis and treatment of neuropathic pain, we have a long way to go. Many patients have a component of neuropathic pain to their overall pain experience that is not recognized by those taking care of them. And then often when it is recognized, it’s not treated adequately. An example would be the person who comes to see you for something else, and they mention that their feet burn at night and you discover they have diabetes. So, now you treat their diabetes and that can be very good for their overall health. But in terms of where we are with treating neuropathic pain, we don’t have great agents, and we don’t use them very well. I think that the treatment guidelines for neuropathic pain are helpful because they tell you the evidence behind the treatments we have. What they

PWJ | www.painweek.org

don’t do is help select which patient to give which drug to and in which order. And they also don’t consider other things that we know are important to the patient’s quality of life: sleep, regular exercise, diet and general health; their depression, anxiety, and mental health situation. Guidelines don’t really look at treatments that aren’t pharmacologic. But if you’re going to select a medication for treating neuropathic pain, it makes sense to stick with things that are in the guidelines. The French have done a better job of disseminating their neuropathic pain guidelines such that they get read, so primary care providers in France do a fantastic job of identifying neuropathic pain almost 90% of the time. Then once they identify neuropathic pain, they select a firstline agent 90% of the time. In the US, the evidence suggests that’s not the case. A study from Bob Dworkin looked at treatment of postherpetic neuralgia in the community and showed that only 25% of patients got a firstline drug. Other surveys of patients with neuropathic pain found that many are on medications that don’t have any evidence of working for neuropathic pain. So, we have a way to go to be more like the French. Our guidelines are not well utilized, and I don’t think they’re placed where primary care physicians see them. If I was a primary care physician I would never have seen the neuropathic pain special interest group treatment guidelines for neuropathic pain. I would not have stumbled across that because I don’t read Lancet and Neurology. We need to make sure that this kind of data get presented in venues where primary care are actually going to see it.

Pain, Addiction, and Suicide: Recognition and Response Martin Cheatle phd

I think we’ve been so focused on this opioid crisis that we have forgotten that these are very brittle people who have significant psychiatric comorbidities, including depression, anxiety, sleep disorders, substance use disorders. I think that suicide is really a silent epidemic that has not been focused on because of our concern about opioid misuse and abuse. If you look at the data, anywhere from 15% to 50% of patients with chronic noncancer pain have daily suicidal thoughts. 40% of people with substance use disorders endorse having suicidal thoughts. If someone has an alcohol use disorder, they’re 10 times more likely to take their life than the general population. If they have an injection use disorder, they’re 14 times more likely to commit suicide than the general population. So people who have pain and a substance use disorder are particularly vulnerable to committing suicide. And there are pain specific risk factors such as pain intensity and pain duration. People who tend to catastrophize, as patients with pain do, are at increased risk of suicide and sleep disorders. We have to be more aware of these risk factors. I think that every person who takes care of patients with chronic pain should have an action plan. Physicians don’t want to ask two questions of patients: “What’s your pain level” and “Are you suicidal?” These are patients who need to be assessed and monitored for their risk of suicide. They should have a very good hotline to local mental health facilities and crisis units because, again, the statistics speak for themselves. Some of these risk factors you can’t change. You can’t change the genetic predisposition. You can’t change gender or age. But other risk factors are treatable. Cognitive behavioral therapy for pain catastrophizing can lower the risk for suicide. In my practice, I tell patients I am not

Q 3 | 2019

going to take on their case unless they do something to break the cycle of isolation and burdensomeness that they are feeling. They can volunteer; talk to their priest, their minister, their rabbi; get involved in the community; attend AA, NA, OA, whatever A, but they need to break that cycle because I think that’s one risk factor that’s going to lead them into this rabbit hole of no return.

Postoperative Pain: Start Early, Focus on What You Can Do

experience, their social history, psychiatric history, past medical history, their comorbidities, their renal function, the outcomes of the surgery. We tell the postoperative patient “You will experience pain but our goal is to decrease that on two fronts—how much and how often.” It’s important to talk with our patients—not talk to them. Consider patient and family needs and expectations. What other pain states do they have concurrently with the surgical pain? Listen and follow up to see how they are doing and never promise what you can’t deliver. Remind your patients if you can with open dialogue about the outcome that you’re trying to achieve to satisfy both their needs and the family needs.

Robert Barkin MBA, pharmd, FCP, DAPM Gary Jay MD, FAAPM, FACFEI

Dr. Jay: Chronic postsurgical pain is a significant problem because it results in decreased activities of daily living, reduced quality of life, and overutilization of medication and healthcare resources, so it’s very costly. The main cause is peripheral stimulation, because of course once a surgeon breaks the skin he’s cutting sensory nerves and you have the neuron developing a neuroma, which has ectopic or spontaneous conduction. You have dorsal root ganglion and dorsal horn of the spinal cord changes that, because of constant peripheral input, can induce central sensitization. You then have the pain go up through the brainstem into the limbic system including the hypothalamus, then to the cortex, and then it goes back down. So this is all neurologically-based but it’s also significantly psychologically-based. Pre-emptive analgesia may be helpful if engaged correctly. What you want to do, I believe, is use the antihyperalgesic drugs such as a combination of gabapentin and Celebrex (or celecoxib) for two to three weeks so that you develop a new homeostasis and the patient goes into surgery with significant changes in how the synapses work and how certain drugs are functioning. Dr. Barkin: Individual patient characteristics should guide the treatment plan. One creates a postsurgical treatment plan that is personalized. So it’s patient-specific, patient-centered, patient-focused personalized care plan. We have a world of generic drugs. We have no generic patients. Each patient is assessed and reassessed on a personal individualized level. Their fears or anxieties, the length of surgery, how many surgeries they’ve gone through, their past

Q 3 | 2019

Lessons From a County Hospital: Pain Management How-To Elaine S. Date MD

I think the unique concepts or unique problems that we have at our San Mateo County Medical Center is limitation of resources, first of all. There’s a limitation sometimes in the number of hours that we can have at our clinic, the total number of clinicians we can use, the number of hours in general. But more than that, I think, is really the patient population and that sometimes they’re very limited in their resources. For example, some of them are homeless. Many don’t have the ability to get to a bus or on a bus to get to our hospital on a frequent basis. We work very hard to try to get them the proper resources so they can attend our clinics on a regular basis. Pain management is very difficult to manage if the resources are limited. There are ways to get around it. There are modalities that we use at our pain clinic that are not expensive, that are nonpharmacologic mostly. For example, we use mindfulness, we use meditation methods, we use acupuncture, we use some noninvasive procedures. Therapy is huge—physical therapy and mental health therapy—to try to manage pain. We try to work around our limited resources by getting patients in group settings, where they themselves can come in for a small time period but participate in a lot of different conferences, a lot of different classes without having to go back and forth.

www.painweek.org | PWJ

short cuts

with

stephen j.

ziegler

phd, jd

76 PWJ | www.painweek.org

Q3 | 2019

“…life, like fiction, is never too late to revise.”

What inspired you to do what you do?

Research, public service, and the reduction of human suffering have been three consistent themes throughout my career. I started college with the intention of becoming an anesthesiologist (I came from a medical family), but I was also interested in drug policy reform, research, social science, and the behavior of institutions and individuals in the political process. I attended school part-time to pay for my education, and over the early course of my career I worked as a police officer, detective, agent for the federal Drug Enforcement Administration, and did some comedy writing and performing (a long story best left for another day). I then entered law school with the hope that the legal profession was actually interested in effectively solving problems, worked as a defense attorney and prosecutor (not at the same time), and eventually enrolled in graduate school out of a desire to continue to improve people’s lives and become a college professor.

Why did you focus on pain management?

My interest in anesthesiology and issues at the intersection of law, medicine, and ethics began in college and continue to this day. While I was attending law school in the mid-1990s, Dr. Jack Kevorkian was assisting in the suicide of terminally ill patients in Michigan. Although not everyone agrees on whether assisted suicide should be legal, I thought it would be quite the human tragedy if people were seeking to accelerate their death because their pain and symptoms were not being effectively managed. Consequently, my interests in this area expanded in graduate school and my doctoral dissertation (and my subsequent career)

Q 3 | 2019

focused on the identification and reduction of the medico-legal barriers to accessing palliative care and essential medicines.

Who were your mentors?

Although I have been fortunate to have many mentors throughout my career, the most significant was Dr. Nicholas Lovrich. He was a member of my doctoral committee at Washington State University and had a significant impact on my training and career. He has unselfishly dedicated his life to education, research, public service, and his students. Like any good mentor, he was a constant source of encouragement and had a love for new ideas.

Q If you weren’t a healthcare provider or professor, what would you be?

a Actor, writer, and comedian, but not a stand-up comedian. Although I have enjoyed writing, acting, and pitching comedy ideas, stand-up comedy is a different beast, so that particular form of art is something that I would probably not pursue. But life, like fiction, is never too late to revise. Q

What is your most marked characteristic?

Thinking outside the box.

Q What do you consider your greatest achievement?

a That is hard to say because it is like someone asking you which kid is your favorite (a decision you may have to make when the oxygen masks drop out of the ceiling). I am fortunate to have received www.painweek.org | PWJ

short cuts

“…it would be quite the human tragedy if people were seeking to accelerate their death because their pain and symptoms were not being effectively managed.”

recognition for several professional achievements: an award and publication from the American Judges Foundation while in law school for my scholarly work involving domestic violence prosecutions and the novel use of a rule of evidence; a research fellowship in Zurich; becoming a pain scholar and fellow via the Mayday Pain Foundation; and all of the publications, presentations, and consults that have resulted. I have been fortunate enough to have contributed “a verse” (Walt Whitman), and will continue to do so!

Q If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be?

Book: David Trottier’s The Screenwriter’s Bible (I have over 100 pages of notes for a comedy I want to write)

Film: Creator (1985), a great comedy on a variety of levels that features a screenplay written by a former academic and the beauty of California and its coastline Music: That one piece of music would have to be delivered through some satellite service to enable access to both classical and music from the 80s, otherwise, I really would never be able to get that one song out of my head.

78 PWJ | www.painweek.org

What would you like your legacy to be?

I helped change the world by reducing unnecessary human suffering.

Any plans for the future?

a I am working on finding ways to increase access to liquid morphine in developing countries for the millions who are suffering at the end of life, and I want to become involved in the effective regulation of cannabis. These areas can overlap, and both recognize the need to reform drug policy domestically and internationally in an effort to ensure access while at the same time prevent abuse. To carry out this work, I will need to create a 501(c)(3) or contract with a nonprofit fiscal sponsor so that the funds raised will go towards research, education, publications, outreach, and reform. Q

What is your motto?

a A few caring people can change the world. “For indeed, that’s all who ever have.” Margaret Mead Stephen J. Ziegler, phd, jd, is a Professor emeritus of Public Policy at Purdue University in Fort Wayne (formerly, ipfw), and ceo of Drug & Health Policy Consulting, llc.

Q 3 | 2019

short cuts

By Wendy Caster

Across

1. Tacky newspaper 4. Piccolo’s big sister 9. Stroke of a violin or cello 14. Yoko ____ 15. Monday in Madrid 16. Come in second, as in a horse race 17. Rowdy crowd 18. Belonging to Ms. Thompson 19. Oxidizes 2 0. The clinical conference of mirth and medicine* 22. Broken ribs are an example of this type of injury* 23. ____ It Romantic 24. “Eureka!” 25. Refugee from Eden 26. Books such as “Chronic Pain Remedies for Dummies”* 29. Mideast ruler 3 0. Daisy Ridley’s “Star Wars” character 31. Photographer Adams 32. God of Canaan and Phoenicia 33. Unpleasant shooting or burning sensation caused by nerve damage or nervous system malfunction* 4 0. Eons 41. Hirsute 42. Glum 45. Pain may be a ____ of fibromyalgia* 46. Mammal endemic to Madagascar (anagram of “center”) 47. Malicious mutt 4 8. Attempt 49. Reddish-brown gem 5 0. South American corn pancakes 52. Neurological condition that is the third most prevalent illness in the world* 56. ____ NeuroMusculoskeletal Institute in Stratford, nj* 57. Actress Marisa 58. Door opener 59. Not working (with “on the”) 6 0. Be apologetic 61. “Are you a man ____ mouse?” 62. Queen of the North on “Game of Thrones” 63. Pain is seen in this condition, which is the result of coming up from deep water too quickly* 64. Vetoes

Down

1. Cavort or gambol 2. Midget buffalo

3. Mongolian desert 4. Aviated on one’s own 5. Units of light 6. Not fulfilled (as in needs) 7. Hardwood used in furniture 8. Letter that begins more words in English than any other 9. Hubbub 10. In addition 11. Turkey ____ 12. Eight notes 13. Dylan album “John ___ Harding” 21. Fertilizer ingredient 22. Some like it hot 24. Female servants in Asia 26. Sci-fi hero ____ Solo 27. 327,053 divided by 327,053 2 8. Univ. located in Pullman and Spokane 29. Consumed 32. Loose

34. Two of them get beaten by three of a kind 35. Bing ____ 36. Chinese bear 37. It’s inspired 38. Rage 39. Home of the Hospital for Special Surgery’s Pain Management Division, in brief* 42. ____ up or down, as in food 43. Display of natural light 44. Enticed 45. Poem part 46. What’s left 49. Simple or Carly 51. Strokes 52. Bit of dust 53. Russian idol 54. Detective Wolfe 55. Young hawk 57. Pain medication may be prescribed in this form (in brief)*

*Themes clues/answers. Puzzle solution: painweek.org/crossword. Q 3 | 2019

www.painweek.org | PWJ

Xtampza® ER (oxycodone): The power of ER oxycodone in a novel abuse-deterrent formulation

Engineered to deliver pain relief and resist manipulation. However, abuse by injection and via the oral and nasal routes is still possible. Misuse and Abuse Deterrence Efficacy

Proven pain relief of ER oxycodone

12-hour duration of action Acetaminophen was the only rescue medication allowed during the clinical study1

Maintains its PK profile even when manipulated1 The only single-agent ER oxycodone with oral, intranasal, and intravenous abuse-deterrent labeling1,2 The only oral opioid with novel DETERx abuse-deterrent technology engineered to resist3: • Crushing • Grinding

• Cutting • Dissolving in solutions • Chewing • Injecting after crushing, melting, or extracting

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS: • Xtampza ER is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected gastrointestinal obstruction, including paralytic ileus, and hypersensitivity (eg, anaphylaxis) to oxycodone

WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse • Xtampza ER contains oxycodone, a Schedule II controlled substance. As an opioid, Xtampza ER exposes users to the risks of addiction, abuse, and misuse. As extended-release products such as Xtampza ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed Warning, on accompanying pages.

References: 1. Xtampza ER [package insert]. Stoughton, MA: Collegium Pharmaceutical, Inc.; 2017. 2. OxyContin [package insert]. Stamford, CT: Purdue Pharma LP; 2016. 3. US Food and Drug Administration. FDA advisory committee briefing document: Xtampza ER (extended-release oxycodone). https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pink%20Sheet%20DAILY/2015/September/Collegium_ oxycodone_AC_company_brfg.pdf. Published September 11, 2015. Accessed January 31, 2018. 4. Gudin J, Levy-Cooperman N, Kopecky EA, et al. Comparing the effect of tampering on the oral pharmacokinetic profiles of two extended-release oxycodone formulations with abusedeterrent properties. Pain Med. 2015;16(11):2142-2151. doi:10.1111/pme.12834. 5. Brennan MJ, Kopecky EA, Marseilles A, et al. The comparative pharmacokinetics of physical manipulation by crushing of Xtampza® ER compared with OxyContin®. Pain Manag. 2017;7(6):461-472.

Only Xtampza® ER maintained its Xtended-release ® PK profile—OxyContin did not

Comparative pharmacokinetic data validated in two separate studies.1 ,4,5

Mean Plasma Oxycodone Concentration (ng/mL)

Xtampza ER extended-release profile maintained whether crushed or intact.4

70 60 50 40 30 20

Reformulated OxyContin showed a rapid release of oxycodone when crushed; bioequivalent to oxycodone IR crushed.4

10 0 0

Hours Crushed Xtampza ER

Intact Xtampza ER

Crushed oxycodone IR

Crushed OxyContin

Intact OxyContin

In a 2015 randomized, open-label, active-controlled, five-treatment crossover study, Gudin et al compared the PK of crushed oxycodone IR to Xtampza ER (crushed and intact) and reformulated OxyContin (crushed and intact) taken orally in 42 subjects. 1,4

The findings above do not indicate that Xtampza ER can entirely prevent abuse via oral and nasal administration; abuse of Xtampza ER by the oral and nasal routes is still possible. The impact of the oral PK studies on misuse, abuse, and diversion of Xtampza ER has yet to be determined. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of Xtampza ER on the abuse liability of the drug.

Xtampza ER is clinically demonstrated to reduce oral abuse potential vs. oxycodone IR (n=52)1 : • Statistically lower drug liking (mean) score • Statistically lower take drug again (mean VAS*) score *VAS: Visual Analog Scale.

Abuse of Xtampza ER by injection and by the oral and nasal routes of administration is still possible.

Learn more at XtampzaERADF.com

Xtampza ER and DETERx are registered trademarks of Collegium Pharmaceutical, Inc. OxyContin is a registered trademark of Purdue Pharma LP. © 2019 Collegium Pharmaceutical, Inc. All rights reserved. PP-XT-US-1183 02/19

IMPORTANT SAFETY INFORMATION for Xtampza® ER (oxycodone) continued WARNINGS AND PRECAUTIONS continued Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMScompliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss with patients and/or their caregivers, with every prescription, the safe use, serious risks, and proper storage and disposal of these products. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist. • Consider other tools to improve patient, household, and community safety such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. • For further information on the REMS and a list of accredited REMS CME/CE, call 1-800503-0784, or visit www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/ OpioidAnalgesicREMSBlueprint.

Life-threatening Respiratory Depression • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids

Neonatal Opioid Withdrawal Syndrome • Prolonged use of Xtampza ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers • Concomitant use of Xtampza ER with a CYP3A4 inhibitor, such as macrolide antibiotics (eg, erythromycin), azole-antifungal agents (eg, ketoconazole), and protease inhibitors (eg, ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Xtampza ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Xtampza ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using Xtampza ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Xtampza ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Xtampza ER until stable drug effects are achieved • Concomitant use of Xtampza ER with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using Xtampza ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur

Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Xtampza ER with benzodiazepines or other CNS depressants (eg, non-benzodiazepine sedatives/ hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate • Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics

Risk of Life-threatening Respiratory Depression in Patients With Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Xtampza ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients With Chronic Pulmonary Disease: Xtampza ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Xtampza ER.

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating Xtampza ER and when Xtampza ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients. Use an alternative analgesic for patients who require a dose of Xtampza ER less than 9 mg.

Adrenal Insufficiency • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include nonspecific symptoms and signs, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency

Severe Hypotension • Xtampza ER may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Xtampza ER. In patients with circulatory shock, Xtampza ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Xtampza ER in patients with circulatory shock

• Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Xtampza ER in patients with impaired consciousness or coma

Risks of Use in Patients With Gastrointestinal Conditions • Xtampza ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus • The oxycodone in Xtampza ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

Risk of Use in Patients With Seizure Disorders • The oxycodone in Xtampza ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Xtampza ER therapy

Withdrawal • Avoid the use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including Xtampza ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms • When discontinuing Xtampza ER, gradually taper the dosage. Do not abruptly discontinue Xtampza ER

Risks of Driving and Operating Machinery • Xtampza ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Xtampza ER and know how they will react to the medication

Laboratory Monitoring • Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative.” Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results

ADMINISTRATION WITH FOOD: • Instruct patients to always take Xtampza ER capsules with food and with approximately the same amount of food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, Xtampza ER can also be taken as a sprinkle on soft foods or sprinkled into a cup and administered directly into the mouth, or through a nasogastric or gastric feeding tube

ADVERSE REACTIONS: • The most common adverse reactions (>5%) reported by patients in the Phase III clinical trial comparing Xtampza ER with placebo were nausea, headache, constipation, somnolence, pruritus, vomiting, and dizziness

Please see Brief Summary of full Prescribing Information for Xtampza ER on accompanying pages.

Risks of Use in Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness • In patients who may be susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), Xtampza ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Xtampza ER

Xtampza ER and DETERx are registered trademarks of Collegium Pharmaceutical, Inc. OxyContin is a registered trademark of Purdue Pharma, LP. © 2019 Collegium Pharmaceutical, Inc. All rights reserved. PP-XT-US-1183 02/19

XTAMPZA® ER (OXYCODONE) EXTENDED-RELEASE CAPSULES, FOR ORAL USE, CII BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see Full Prescribing Information and Medication Guide at XtampzaER.com.) WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse XTAMPZA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing XTAMPZA ER and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to • complete a REMS-compliant education program, • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and • consider other tools to improve patient, household, and community safety. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of XTAMPZA ER. Monitor for respiratory depression, especially during initiation of XTAMPZA ER or following a dose increase [see Warnings and Precautions (5.3)]. Accidental Ingestion Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.3)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of XTAMPZA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4)]. Cytochrome P450 3A4 Interaction The concomitant use of XTAMPZA ER with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving XTAMPZA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.6), Drug Interactions (7)]. • Reserve concomitant prescribing of XTAMPZA ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation.

4 CONTRAINDICATIONS XTAMPZA ER is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.3)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)] • Hypersensitivity (e.g., anaphylaxis) to oxycodone. 5

WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As extended-release products such as XTAMPZA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed XTAMPZA ER. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing XTAMPZA ER, and monitor all patients receiving XTAMPZA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as XTAMPZA ER, but use in such patients necessitates intensive counseling about the risks and proper use of XTAMPZA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death [see Overdosage (10)]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing XTAMPZA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/ or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • Consider using other tools to improve patient, household, and community safety, such as patientprescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. 5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and

death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of XTAMPZA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of XTAMPZA ER. To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential [see Dosage and Administration (2)]. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. 5.4 Neonatal Opioid Withdrawal Syndrome Prolonged use of XTAMPZA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)]. 5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of XTAMPZA ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.3)], particularly when an inhibitor is added after a stable dose of XTAMPZA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in XTAMPZA ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using XTAMPZA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in XTAMPZA ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of XTAMPZA ER until stable drug effects are achieved [see Drug Interactions (7)]. Concomitant use of XTAMPZA ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using XTAMPZA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)]. 5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of XTAMPZA ER with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when XTAMPZA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)]. 5.7 Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of XTAMPZA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: XTAMPZA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of XTAMPZA ER [see Warnings and Precautions (5.3)]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating XTAMPZA ER and when XTAMPZA ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3)]. Alternatively, consider the use of non-opioid analgesics in these patients. Use an alternative analgesic for patients who require a dose of XTAMPZA ER less than 9 mg. 5.8 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.9 Severe Hypotension XTAMPZA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of XTAMPZA ER. In patients with circulatory shock, XTAMPZA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of XTAMPZA ER in patients with circulatory shock. 5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), XTAMPZA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with XTAMPZA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of XTAMPZA ER in patients with impaired consciousness or coma. 5.11 Risks of Use in Patients with Gastrointestinal Conditions XTAMPZA ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The oxycodone in XTAMPZA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.12 Risk of Use in Patients with Seizure Disorders The oxycodone in XTAMPZA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during XTAMPZA ER therapy. 5.13 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including XTAMPZA ER. In these patients, mixed agonist/ antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing XTAMPZA ER, gradually taper the dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue XTAMPZA ER. 5.14 Risks of Driving and Operating Machinery XTAMPZA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of XTAMPZA ER and know how they will react to the medication. 5.15 Laboratory Monitoring Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative”. Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.6)] • Adrenal Insufficiency [see Warnings and Precautions (5.8)] • Severe Hypotension [see Warnings and Precautions (5.9)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)] • Seizures [see Warnings and Precautions (5.12)] • Withdrawal [see Warnings and Precautions (5.13)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of XTAMPZA ER was evaluated in a Phase 3, randomized-withdrawal, double-blind clinical trial involving 740 patients with moderate-to-severe chronic lower back pain. In the double-blind maintenance phase, 389 patients were randomized and 193 patients were assigned to the XTAMPZA ER treatment group. The most common AEs (>5%) reported by patients in the Phase 3 clinical trial during the titration phase were: nausea (16.6%), headache (13.9%), constipation (13.0%), somnolence (8.8%), pruritus (7.4%), vomiting (6.4%), and dizziness (5.7%). The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing XTAMPZA ER with placebo are shown in Table 1 below: Table 1:

Common Adverse Reactions (>5%) Titration

Adverse Reaction

Nausea Headache Constipation Somnolence Pruritus Vomiting Dizziness

Maintenance

XTAMPZA ER (n = 740) (%)

XTAMPZA ER (n = 193) (%)

Placebo (n = 196) (%)

16.6 13.9 13.0 8.8 7.4 6.4 5.7

10.9 6.2 5.2 <1 2.6 4.1 1.6

4.6 11.7 0.5 <1 1.5 1.5 0

In the Phase 3 clinical trial, the following adverse reactions were reported in patients treated with XTAMPZA ER with incidences of 1% to 5%: Eye disorders: vision blurred Gastrointestinal disorders: abdominal pain, upper abdominal pain, diarrhea, gastroesophageal reflux disease General disorders and administration site conditions: chills, drug withdrawal syndrome, fatigue, irritability, edema, pyrexia Injury, poisoning and procedural complications: excoriation Metabolism and nutrition disorders: decreased appetite, hyperglycemia Musculoskeletal and connective tissue disorders: arthralgia, back pain, musculoskeletal pain, myalgia Nervous system disorders: migraine, tremor Psychiatric disorders: anxiety, insomnia, withdrawal syndrome Respiratory, thoracic and mediastinal disorders: cough, oropharyngeal pain Skin and subcutaneous tissue disorders: hyperhidrosis, rash Vascular disorders: hot flush, hypertension In the Phase 3 clinical trial, the following treatment-related adverse reactions were reported in patients treated with XTAMPZA ER with incidences of less than 1% of patients. Investigations: increased gamma-glutamyl transferase, increased heart rate Nervous system disorders: lethargy, memory impairment, poor-quality sleep Psychiatric disorders: abnormal dreams, euphoric mood, restlessness Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: night sweats 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in XTAMPZA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)]. 7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with XTAMPZA ER. Table 2:

Clinically Significant Drug Interactions with XTAMPZA ER

Inhibitors of CYP3A4 and CYP2D6 Clinical Impact:

The concomitant use of XTAMPZA ER and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of XTAMPZA ER and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of XTAMPZA ER is achieved [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.

Intervention:

Examples:

If concomitant use is necessary, consider dosage reduction of XTAMPZA ER until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

Examples:

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)

Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact:

CYP3A4 Inducers Clinical Impact:

Intervention:

Examples:

The concomitant use of XTAMPZA ER and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Intervention:

Examples:

Intervention:

Examples:

Clinical Impact:

Intervention: Examples:

If concomitant use is necessary, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved [see Dosage and Administration (2.4)]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider XTAMPZA ER dosage reduction and monitor for signs of respiratory depression.

Clinical Impact:

Intervention:

Rifampin, carbamazepine, phenytoin

Due to additive pharmacological effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

Intervention:

May reduce the analgesic effect of XTAMPZA ER and/or precipitate withdrawal symptoms. Avoid concomitant use. Butorphanol, nalbuphine, pentazocine, buprenorphine

Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of XTAMPZA ER and/or the muscle relaxant as necessary.

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical Impact:

Benzodiazepines and other sedatives/ hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue XTAMPZA ER if serotonin syndrome is suspected.

phenelzine, tranylcypromine, linezolid

Diuretics

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

The use of XTAMPZA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Muscle Relaxants

Intervention:

Serotonergic Drugs Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)].

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact:

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when XTAMPZA ER is used concomitantly with anticholinergic drugs.

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. There are no available data with XTAMPZA ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there was no embryo-fetal toxicity when oxycodone hydrochloride was orally administered to rats and rabbits, during the period of organogenesis, at doses 1.3 to 40 times the adult human dose of 60 mg/day, respectively. In a pre- and postnatal toxicity study, when oxycodone was orally

administered to rats, there was transiently decreased pup body weight during lactation and the early post-weaning period at the dose equivalent to an adult dose of 160 mg/day. In several published studies, treatment of pregnant rats with oxycodone hydrochloride at clinically relevant doses and below resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration of use, and severity of neonatal opioid withdrawal syndrome may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)]. Labor or delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. XTAMPZA ER is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including XTAMPZA ER, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 1.3 and 40 times an adult human dose of 160 mg/day, respectively on a mg/m2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by dams given the highest dose used (6 mg/ kg/day, equivalent to an adult human dose of 160 mg/day, on a mg/m2 basis). However, body weight of these pups recovered. In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human oral dose of 60 mg/day on a mg/m2 basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/m2 basis). 8.2 Lactation Risk Summary Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. The lactation studies did not assess breastfed infants for potential adverse reactions. Lactation studies have not been conducted with extendedrelease oxycodone, including XTAMPZA ER, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with XTAMPZA ER. Clinical Considerations Infants exposed to XTAMPZA ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2)]. 8.4 Pediatric Use Safety and effectiveness of XTAMPZA ER in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3)]. Of the total number of subjects entered into the titration phase of the Phase 3 study for XTAMPZA ER (740), 88 (12%) were age 65 and older. In this clinical trial with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received XTAMPZA ER. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. Use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease, and use of other drug therapy. Respiratory depression is the chief risk in elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of XTAMPZA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6, 5.7)]. 8.6 Hepatic Impairment A study in patients with hepatic impairment demonstrated greater plasma oxycodone concentrations than those seen at equivalent doses in persons with normal hepatic function. A similar effect on plasma oxycodone concentrations can be expected for patients with hepatic impairment taking XTAMPZA ER. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg. [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. 8.7 Renal Impairment In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Follow a conservative approach to dose initiation and adjust according to the clinical situation. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg. [see Clinical Pharmacology (12.3)]. 8.8 Sex Differences In pharmacokinetic studies with XTAMPZA ER, healthy female subjects demonstrate up to 20% higher oxycodone plasma exposures than males, even after considering differences in body weight or BMI. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages. In the Phase 3 clinical trial there was a greater frequency of typical opioid adverse events for females than males; there was no male/female difference detected for efficacy. 9

DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance XTAMPZA ER contains oxycodone, a Schedule II controlled substance. 9.2 Abuse XTAMPZA ER contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)]. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other

activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. XTAMPZA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of XTAMPZA ER XTAMPZA ER is for oral use only. Abuse of XTAMPZA ER poses a risk of overdose and death. The risk is increased with concurrent use of XTAMPZA ER with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Abuse Deterrence Studies XTAMPZA ER capsules contain microspheres formulated with inactive ingredients intended to make the formulation more difficult to manipulate for misuse and abuse. In Vitro Testing In vitro physical and chemical manipulation studies were performed to evaluate the success of different methods of defeating the extended-release formulation. Results support that, relative to immediate-release oxycodone tablets, XTAMPZA ER is less susceptible to the effects of grinding, crushing, and extraction using a variety of tools and solvents. XTAMPZA ER resisted attempts to pass the melted capsule contents or the microspheres suspended in water through a hypodermic needle. Pharmacokinetic Studies The pharmacokinetic profile of manipulated XTAMPZA ER capsule contents (36 mg; [equivalent to 40 mg oxycodone HCl]) was characterized following oral (three studies) and intranasal (two studies) administration. The studies were conducted in a randomized, cross-over design. In studies assessing manipulation by crushing, the most effective crushing method identified in previous in vitro studies was applied to the product(s). Oral Pharmacokinetic Studies, Manipulated and Intact XTAMPZA ER The effect of two types of product manipulation (crushing and chewing) on XTAMPZA ER pharmacokinetics was measured in three studies. In one oral pharmacokinetic study, XTAMPZA ER capsule contents were crushed or chewed prior to oral administration in healthy, naltrexone-blocked volunteers. The two comparators in this study were intact XTAMPZA ER capsules and an immediaterelease solution of oxycodone at an equivalent dose. In two oral pharmacokinetic studies, XTAMPZA ER capsule contents were crushed prior to oral administration in healthy, naltrexone-blocked volunteers. The comparators in these studies included intact XTAMPZA ER capsules, intact and crushed reformulated OXYCONTIN® (oxycodone hydrochloride) extendedrelease tablets at an equivalent dose, and crushed immediaterelease oxycodone tablets at an equivalent dose. The data displayed in Table 3 illustrate the findings from the oral pharmacokinetic studies (data were similar for the two oral pharmacokinetic studies comparing XTAMPZA ER to OXYCONTIN). Collectively, the data demonstrated that crushing or chewing XTAMPZA ER prior to administration did not increase the maximum observed plasma concentration (Cmax) or total exposure (AUC0-INF) relative to dosing the intact product under fed conditions. Relative to immediate-release oxycodone and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets, the Cmax for all XTAMPZA ER treatments was lower and the Tmax longer, consistent with an extendedrelease profile.

Table 3:

Oxycodone Pharmacokinetic Parameters, Administration of Manipulated and Intact Dosage Forms (36mg of XTAMPZA ER or equivalent) Cmax (ng/mL)

Tmax (hr)

AUC0-INF (hr•ng/ mL)

Treatment

Oral Pharmacokinetic Study 1

Intact XTAMPZA ER Capsules (fed)

62.3 (13.0)

4.0 (1.5-6)

561 (124)

Crushed XTAMPZA ER Capsule Contents (fed)

57.6 (12.6)

4.5 (2.5-6)

553 (134)

Chewed XTAMPZA ER Capsule Contents (fed)

55.6 (10.9)

4.5 (2.5-8)

559 (113)

Immediate-Release Oxycodone Solution (fasted)

115 (27.3)

0.75 (0.5-2)

489 (80.2)

Oral Pharmacokinetic Study 2 Intact XTAMPZA ER Capsules (fed)

67.5 (17.6)

3.5 (1.25 – 6.0)

581 (138)

Crushed XTAMPZA ER Capsule Contents (fed)

62.9 (12.6)

4.0 (2.0 – 7.0)

597 (149)

Intact reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed)

64.9 (13.8)

5.0 (2.010.0)

611 (145)

Crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed)

78.4 (12.9)

1.75 (0.55.0)

587 (132)

Crushed ImmediateRelease Oxycodone Tablets (fed)

79.4 (17.1)

1.75 (0.54.0)

561 (146)

Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum). Nasal Pharmacokinetic Studies The pharmacokinetic profile following intranasal administration of crushed XTAMPZA ER capsule contents was characterized in two clinical studies. In Nasal Pharmacokinetic Study 1, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent, naltrexone-blocked subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and oxycodone HCl powder (intranasal) at an equivalent dose. In Nasal Pharmacokinetic Study 2, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and crushed oxycodone immediate-release tablets (intranasal) at an equivalent dose. The results of Nasal Pharmacokinetic Studies 1 and 2 are comparable and both studies demonstrated that intranasal administration of crushed XTAMPZA ER capsule contents did not result in higher peak plasma concentration (Cmax) or shorter time to peak concentration (Tmax) than taking XTAMPZA ER orally. The data from Nasal Pharmacokinetic Study 2 are displayed in Table 4 to represent these findings.

Table 4: Oxycodone Pharmacokinetic Parameters, Nasal Pharmacokinetic Study 2: Cmax (ng/ mL)

Tmax (hr)

AUC0-INF (hr•ng/ mL)

Intact XTAMPZA ER Capsules (oral)

41.0 (10.0)

5.1 (1.6-8.1)

477 (89.6)

Crushed XTAMPZA ER Capsule Contents (nasal)

29.8 (6.6)

5.1 (1.6-12.1)

459 (106)

Crushed ImmediateRelease Tablets (nasal)

60.9 (11.9)

2.6 (0.3-6.1)

577 (124)

Treatment

Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum). Clinical Studies Oral Abuse Potential Studies: The oral abuse potential of chewed XTAMPZA ER was evaluated in two studies. In a randomized, double-blind, active- and placebo-controlled, single-dose, six-way crossover pharmacodynamic study, 52 non-dependent recreational opioid users received orallyadministered active and placebo treatment. The six treatment arms were intact XTAMPZA ER (36 mg, fed and fasted); chewed XTAMPZA ER (36 mg, fed and fasted); crushed immediate-release (IR) oxycodone HCl in solution (40 mg, fasted, equivalent to 36 mg of XTAMPZA ER), and placebo. Data for chewed and intact XTAMPZA ER and crushed IR oxycodone in the fasted state are described below. Drug Liking was measured on a bipolar 100-point Visual Analog Scale (VAS) where 50 represents a neutral response, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar 100-point VAS where 50 represents a neutral response, 0 represents the strongest negative response (e.g., ‘definitely would not take drug again’), and 100 represents the strongest positive response (e.g., ‘definitely would take drug again’). Fifty-two subjects completed the study, and the results are summarized in Table 5. The oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking and Take Drug Again VAS scores compared with crushed immediate-release oxycodone. In addition, the Drug Liking and Take Drug Again scores were similar for XTAMPZA ER taken in the intact and chewed states. Table 5:

Drug Liking* (Emax)

Take Drug Again (Emax)*

Thirty-six subjects completed the study. Intranasal administration of crushed XTAMPZA ER was associated with statistically lower mean Drug Liking and Take Drug Again scores compared with crushed immediate-release oxycodone (summarized in Table 6). Table 6:

Summary of Maximum Drug Liking and Take Drug Again (Emax) Following Intranasal Administration

Drug Liking* (Emax)

Take Drug Again* (Emax)

XTAMPZA ER Intranasal

Crushed IR Oxycodone Intranasal

Placebo

Mean (SD)

61.81 (15.64)

82.72 (10.95)

54.5 (11.77)

Median (Range)

59.5 (16-94)

84 (60-100)

51 (28-93)

Mean (SD)

47.67 (27.84)

71.36 (23.49)

45.92 (17.50)

50 (0-100)

78.5 (18-100)

50 (0-97)

Median (Range)

* Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response). Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. Figure 1 demonstrates a comparison of Drug Liking for intranasal administration of crushed XTAMPZA ER compared to crushed immediate-release oxycodone in subjects who received both treatments (N=36). The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for XTAMPZA ER vs. immediate-release oxycodone greater than or equal to the value on the X-axis. Approximately 92% (n = 33) of subjects had some reduction in drug liking with XTAMPZA ER relative to crushed immediate-release oxycodone HCl. Approximately 78% (n = 28) of subjects had a reduction of at least 30% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl, and approximately 58% (n = 21) of subjects had a reduction of at least 50% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl. Figure 1: Percent Reduction Profiles for Emax of Drug Liking VAS for Crushed XTAMPZA ER vs. Crushed Immediate-release Oxycodone, N=36 Following Intranasal Administration

Summary of Maximum Drug Liking and Take Drug Again (Emax) Following Oral Administration Crushed

Placebo

XTAMPZA ER Intact (Fasted)

XTAMPZA ER Chewed (Fasted)

Mean (SD)

73.9 (15.10)

73.3 (14.93)

86.40 (12.01)

55.8 (9.94)

Median (Range)

73.5 (50-100)

88.5 (52-100)

50.0 (50-86)

Mean (SD)

77.98 (21.07)

77.85 (18.30)

87.69 (12.90)

50.79 (21.41)

Median (Range)

80.5 (1-100)

81.5 (50-100)

90.5 (50-100)

50.0 (0-100)

IR Oxycodone (Fasted)

* Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. A prior, similarly-designed study was also conducted to evaluate the oral abuse potential of chewed XTAMPZA ER. Although the oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking scores compared with crushed immediate-release oxycodone, the results for Take Drug Again showed small differences that were not statistically significant. Nasal Abuse Potential Study: In a randomized, double-blind, active- and placebo-controlled, single-dose, four-way crossover pharmacodynamic study, 39 recreational opioid users with a history of intranasal drug abuse received nasally administered active and placebo drug treatment. The four treatment arms were crushed XTAMPZA ER 36 mg dosed intranasally; intact XTAMPZA ER 36 mg dosed orally; crushed immediate-release oxycodone HCl 40 mg (equivalent to 36 mg of XTAMPZA ER) dosed intranasally; and placebo. Data for intranasal XTAMPZA ER and crushed immediate-release oxycodone are described below.

Summary The in vitro data demonstrate that XTAMPZA ER has physicochemical properties expected to make abuse by injection difficult. The data from pharmacokinetic and human abuse potential studies, along with support from the in vitro data, also indicate that XTAMPZA ER has physicochemical properties that are expected to reduce abuse via the oral and intranasal routes. The data from the oral pharmacokinetic studies of crushed or chewed XTAMPZA ER demonstrated a lack of dose dumping with no increase in oxycodone levels compared to intact XTAMPZA ER. However, abuse of XTAMPZA ER by injection and by the oral and nasal routes of administration is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of XTAMPZA ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. XTAMPZA ER contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1)]. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the

administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. XTAMPZA ER should not be abruptly discontinued [see Dosage and Administration (2.5)]. If XTAMPZA ER is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with XTAMPZA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. Because the duration of reversal would be expected to be less than the duration of action of oxycodone in XTAMPZA ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. XTAMPZA ER will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or only brief in nature, administer additional antagonist as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of the usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. Healthcare professionals can telephone Collegium Pharmaceutical’s Medical Affairs Department (1-855-331-5615) for information on this product. Manufactured by: Patheon Pharmaceuticals, Cincinnati, OH 45237 U.S. Patent Nos. 7,399,488; 7,771,707; 8,449,909; 8,557,291; 8,758,813; 8,840,928; 9,044,398; 9,248,195; 9,592,200; 9,682,075; 9,737,530; 9,763,883; 9,968,598 and 10,004,729. Xtampza ER is a registered trademark of Collegium Pharmaceutical, Inc. OxyContin is a registered trademark of Purdue Pharma, LP. This brief summary is based on the Xtampza ER prescribing information. Revised 09/2018. COL 006

When prescribing an ER oxycodone, choose Xtampza ER. INDICATIONS AND USAGE

Xtampza® ER (oxycodone) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Xtampza ER for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain • Xtampza ER is not indicated as an as-needed (prn) analgesic

IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse Guide every time it is provided by their with all cytochrome P450 3A4 inhibitors Xtampza ER exposes patients and other pharmacist, and may result in an increase in oxycodone users to the risks of opioid addiction, abuse, • Consider other tools to improve patient, plasma concentrations, which could and misuse, which can lead to overdose increase or prolong adverse drug effects household, and community safety. and death. Assess each patient’s risk prior and may cause potentially fatal respiratory Life-Threatening Respiratory Depression to prescribing Xtampza ER and monitor all depression. In addition, discontinuation Serious, life-threatening, or fatal respiratory of a concomitantly used cytochrome P450 patients regularly for the development of depression may occur with use of Xtampza these behaviors or conditions. 3A4 inducer may result in an increase in ER. Monitor for respiratory depression, oxycodone plasma concentration. Monitor Opioid Analgesic Risk Evaluation and especially during initiation of Xtampza ER patients receiving Xtampza ER and any Mitigation Strategy (REMS) or following a dose increase. CYP3A4 inhibitor or inducer. To ensure that the benefits of opioid Risks From Concomitant Use With Accidental Ingestion analgesics outweigh the risks of addiction, Benzodiazepines or Other Accidental ingestion of even one dose of abuse, and misuse, the Food and Drug CNS Depressants Xtampza ER, especially by children, can Administration (FDA) has required a Concomitant use of opioids with result in a fatal overdose of oxycodone. REMS for these products. Under the benzodiazepines or other central nervous requirements of the REMS, drug companies Neonatal Opioid Withdrawal Syndrome system (CNS) depressants, including with approved opioid analgesic products Prolonged use of Xtampza ER during alcohol, may result in profound sedation, must make REMS-compliant education pregnancy can result in neonatal opioid respiratory depression, coma, and death. programs available to healthcare providers. withdrawal syndrome, which may be life• Reserve concomitant prescribing of Healthcare providers are strongly threatening if not recognized and treated, Xtampza ER and benzodiazepines or encouraged to and requires management according other CNS depressants for use in patients to protocols developed by neonatology • Complete a REMS-compliant education for whom alternative treatment options experts. If opioid use is required for program, are inadequate a prolonged period in a pregnant • Counsel patients and/or their caregivers, • Limit dosages and durations to the woman, advise the patient of the risk with every prescription, on safe use, minimum required of neonatal opioid withdrawal syndrome serious risks, storage, and disposal of • Follow patients for signs and symptoms and ensure that appropriate treatment these products, of respiratory depression and sedation will be available. • Emphasize to patients and their caregivers Cytochrome P450 3A4 Interaction The concomitant use of Xtampza ER the importance of reading the Medication

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed Warning, on accompanying pages.