PAINWeek Journal Vol 5, Q4 by PAINWeek

vol. 5 q 4 2017

disability claimants and the implementation of a web-based pain assessment/ pain management program p.20 what’s all the “gaba” ‘bout?: pregabalin and gabapentin abuse p.30 kissing the wrong frog: exploring common factors in pain management p.38 the perfect “solution”: topical opioids for reducing systemic opioid exposure p.50

THe PeNDULUM SWiNGS iN BOTH DiReCTiONS.

eDUCaTiON GOeS FORWaRD.

Provide pain relief for the intended, while helping protect against intravenous and intranasal abuse by the unintended Abuse of MORPHABOND ER is still possible by intranasal, intravenous, and oral routes

AVAILABLE TO PRESCRIBE

The only single-agent, abuse-deterrent, ER morphine with SentryBond™ Technology1,2

IN JE CT IO N

Retains its extended-release properties even if manipulated and/or chemically extracted

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.

ER=extended release. References: 1. MORPHABOND ER [package insert]. Basking Ridge, NJ: Inspirion Delivery Sciences LLC; 2017. 2. Data on file. Daiichi Sankyo, Inc.

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.

For more information, visit MORPHABONDhcp.com

Please see additional Important Safety Information, including BOXED WARNINGS on following pages.

IMPORTANT SAFETY INFORMATION BOXED WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS (continued) Accidental Ingestion Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Accidental ingestion of even one dose of MORPHABOND ER, especially by children, can result in a fatal overdose of morphine. Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in Neonatal Opioid Withdrawal Syndrome profound sedation, respiratory depression, coma, and death. Prolonged use of MORPHABOND ER during pregnancy can result in • Reserve concomitant prescribing of MORPHABOND ER and neonatal opioid withdrawal syndrome, which may be life-threatening benzodiazepines or other CNS depressants for use in patients for if not recognized and treated, and requires management according to whom alternative treatment options are inadequate protocols developed by neonatology experts. If opioid use is required for • Limit dosages and durations to the minimum required a prolonged period in a pregnant woman, advise the patient of the risk • Follow patients for signs and symptoms of respiratory depression of neonatal opioid withdrawal syndrome and ensure that appropriate and sedation treatment will be available.

CONTRAINDICATIONS 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 hypersensitivity (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. As 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 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 MORPHABOND ER, and monitor all patients receiving MORPHABOND ER for development of these behaviors or conditions. Patients at increased risk may be prescribed extended-release opioid formulations 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. Opioid agonists such as MORPHABOND ER 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.

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.

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. 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. 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.

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

WARNINGS AND PRECAUTIONS 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. 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 non-opioid analgesics in these patients.

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.

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.

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.

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), 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.

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 -----------------------------------------------------------------------------------------------------------------------------------------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.

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

Drug Interactions ---------------------------------------------------------------------------------------------------------------------------------------------• Concomitant use of benzodiazepines or other CNS depressants 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 • 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 PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death

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; 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)]. 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 (5.2)]. 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 (5.2)]. 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 (5.3)]. 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 (5.4), 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 (5.2)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.5)] • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.6)/Drug Interactions (7)]

• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)] • 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) in the full prescribing information]. 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 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 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. 5.3 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].

5.4 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]. 5.5 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 (5.2)]. 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 (5.2)]. 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 (5.2, 5.4)]. Alternatively, consider the use of non-opioid analgesics in these patients. 5.6 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. 5.7 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. 5.8 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. 5.9 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. 5.10 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. 5.11 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. 5.12 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 (2.4) in the full prescribing information]. Do not abruptly discontinue MORPHABOND ER [see Drug Abuse and Dependence (9.3) in the full prescribing information]. 5.13 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 (5.2)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.4)] • Adrenal Insufficiency [see Warnings and Precautions (5.7)] • Severe Hypotension [see Warnings and Precautions (5.8)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] • Withdrawal [see Warnings and Precautions (5.12)]

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 postapproval 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 (5.4)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. 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 MORPHABOND ER if serotonin syndrome is suspected. Example: 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 (5.6)]. 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 Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase 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 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 (5.3)]. 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 (5.3)]. 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. Data 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 nonrandomized 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, social-interaction) 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 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 extended-release 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 (5.5)]. 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 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. 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 productâ&#x20AC;&#x2122;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 ÂŠ2017, Daiichi Sankyo, Inc. P1800821-B

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

eeK

PUBLiSHeR PAINW

ART DiReCTOR DARRYL FOSSA

eDiTORiAL DiReCTOR DeBRA WeiNeR eDiTOR HOLLY CASTeR

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 Paul Arnstein rn, phd, acns-bc, fnp-c, faan Clinical Nurse Specialist for Pain Relief Massachusetts General Hospital Boston, ma Said R. Beydoun md, faan Professor of Neurology Director of the Neuromuscular Program Keck Medical Center of University of Southern California Los Angeles, ca Jennifer Bolen jd Founder Legal Side of Pain Knoxville, tn 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 Vice Chair, Clinical Affairs Johns Hopkins University School of Medicine Department of Psychiatry and Behavioral Sciences Director, Pain Treatment Programs Johns Hopkins Medical Institutions Department of Psychiatry and Behavioral Sciences Baltimore, md Geralyn Datz phd Affiliate University of Southern Mississippi Department of Psychology Clinical Director Southern Behavioral Medicine Associates Hattiesburg, ms

eDiTORiAL BOARD

Peter A. Foreman dds, daapm Consultant Rotorua Hospital and Private Practice Rotorua, New Zealand Gary W. Jay md, faapm, facfei Clinical Professor Department of Neurology Division: Headache University of North Carolina Chapel Hill, nc Mary Lynn McPherson pharmd, bcps, cpe, faspe Professor and Vice Chair University of Maryland School of Pharmacy Department of Pharmacy Practice and Science Hospice Consultant Pharmacist Baltimore, md 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 Bruce D. Nicholson md Clinical Associate Professor Department of Anesthesia Penn State College of Medicine Hershey Medical Center Hershey, pa Director of Pain Specialists Lehigh Valley Health Network Department of Anesthesiology Allentown, pa

Marco Pappagallo md Director of Medical Intelligence Grünenthal usa Bedminster, nj Director Pain Management & Medical Mentoring New Medical Home for Chronic Pain New York, ny Steven D. Passik phd VP, Scientific Affairs, Education, and Policy Collegium Pharmaceuticals, Inc. Canton, ma Joseph V. Pergolizzi md Chief Operating Officer nema Research Inc. Naples, fl Robert W. Rothrock pa-c, mpa University of Pennsylvania Department of Anesthesiology and Critical Care Pain Medicine Division Philadelphia, pa 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 Sanford M. Silverman md, pa CEO and Medical Director Comprehensive Pain Medicine Pompano Beach, fl Thomas B. Strouse md Medical Director Stewart and Lynda Resnick Neuropsychiatric Hospital at ucla Los Angeles, ca

Copyright © 2017, 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.

vol. 5 q 4 2017

20 30 38 50 57 58 59 60 62

technology

disability claimants and the implementation of a web-based pain assessment/pain management program

by stephen f. butler j. michael lacroix simon h. budman

pharmacotherapy

what’s all the “gaba” ‘bout? pregabalin and gabapentin abuse

by courtney kominek abigail brooks

behavioral

kissing the wrong frog: exploring common factors in pain management

by david cosio

palliative care

the perfect “solution”: topical opioids for reducing systemic opioid exposure

by annas aljassem levi m. hall

pw next generation

with kate schopmeyer

clinical pearls

by douglas gourlay

pain by numbers one-minute clinician

with jeffrey fudin, heather tick, steven george, georgine lamvu, michael barnes

pundit profile

with forest tennant

PWJ | www.painweek.org

Q4 | 2017

2018

SePTeMBeR 4â&#x20AC;&#x201D;8

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 36.0 AMA PRA Category 1 Credit(s)TM. 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.

Next is an interesting article by Drs. Annas Aljassem and Levi M. Hall about a novel use approach the end of 2017, we have no choice of opioid analgesics that may help minimize Kevin L. Zacharoff but to consider the controversy swirling systemic “exposure” and opioid related around the needs of patients with chronic adverse effects. The authors present a case pain, and the unfortunate societal circumstances which intersect the role study of a “typical patient” who is an appropriate postsurgical candidate of opioid analgesics in its management. In all my years of involvement in for opioid analgesia and discuss the potential role of the topical route the pain management community, never have I seen more need for edu- for managing pain. Mechanism of action, benefits, and considerations cation, dialogue, and rationally compassionate broad thinking. While some for topical opioids are presented, in addition to cautions about safe and clinicians feel it may be appropriate to take 2 steps back, we must take effective use. The authors point out that the current state of the “opioid steps forward, even if one at a time. Patients, as I have written many times epidemic” in our country may dictate the need for thinking about different before, are the mission and the reason we are here. As we look at PWJ, strategies to battle the physiologic states of dependence and tolerance. we’ll see how we must continue to explore, to challenge, and to think about Whether this approach can help mitigate opioid abuse and misuse while both good and potentially bad options for pain care and treatment to help maintaining safety and efficacy remains to be seen. Meanwhile, this article us to live up to our mission. is worth the read. There is no question that when we think about common types of chronic pain that back pain is the “behemoth in the room” along with other musculoskeletal disorders. Additionally, there is a high likelihood that when we think about working patients with chronic back pain, we think about the possibility of the need for short-term disability progressing to long-term disability. Drs. Stephen Butler and Simon Budman, along with J. Michael Lacroix, provide the reader with some interesting findings measuring the impact of innovative tools on progression from short- to long-term disability in patients with musculoskeletal diagnoses. Using PainCAS, an electronic standardized pain assessment, and painACTION, a web-based interactive self-management program, these researchers were able to show some promising results in mitigating this disability transition. Tools like these are likely to play a role in pain management moving forward and in some cases, as this article shows us, the future is now. The article by Drs. Courtney Kominek and Abigail Brooks focuses on gabapentinoids. The role of drugs in this class in managing chronic pain is discussed along with something that may be surprising to many—the prevalence of misuse and abuse of these medications. Often considered to be first-line treatments for certain types of neuropathic pain, gabapentin and pregabalin have both similarities and differences, as described in this article. Patterns of abuse are characterized and it is noted that, not unlike opioids, sources of the medications can be traced back to healthcare provider prescriptions and/or family or friends. This is a highly clinically relevant subject for prescribers who may not think about monitoring patients for signs of this type of abuse and misuse. Dr. David Cosio provides us with a slightly different take on managing patients with chronic pain. He points out that current treatment modalities may only provide 30% improvement in pain rating in as many as one half of patients, then analyzes these treatment approaches and their application in common types of representative cases, posing interesting questions to the reader along the way. Referencing the concept of a “common factors” approach used in psychotherapy as early as 1936, Dr. Cosio describes how this concept may be imported into the “art” of pain management along with good science, using easy to understand analogies and underscoring the ever-important need to approach pain in a multifaceted way. This article provokes creative and innovative thought. I’m sure you’ll enjoy this piece as much as I did.

PWJ | www.painweek.org

This issue’s Pundit Profile spotlights Dr. Forest Tennant. The word pundit is defined as “an expert in a particular subject or field who is frequently called on to give opinions about it to the public.” There is no more seasoned, respected, experienced, progressive person that I know in the pain management community who aligns with this definition. With over 50 years of experience—from clinical practice to military practice to sports practice, from addiction to primary care—Dr. Tennant has seen and done it all. Enjoy this glimpse into a legend and what made him the person he is. Our Next Generation focuses on Kate Schopmeyer, a Physical Therapy Program Coordinator—an often-important practitioner piece of multidisciplinary pain management. The information she shares about her role in the San Francisco va Healthcare System shows palpable enthusiasm for her work, and her life, her goals, and her persona. This profile is yet another opportunity to positively enlighten us about practitioners who will lead us into the future of pain management. This issue carries us to the end of 2017, acknowledges the controversy, and feeds the desire for different approaches, different ways of thinking, and even different areas of concern relevant to everyday clinical practice. As the controversies continue to swell, we need to think about what we can and will do to help patients with chronic pain instead of just saying “No.” Have a happy and healthy new year!

—Kevin L. Zacharoff md, facip, facpe, faap

Kevin L. Zacharoff is Pain Educator and Consultant and Faculty, Clinical Instructor at suny Stony Brook School of Medicine, Department of Preventive Medicine, in Stony Brook, New York.

Q4 | 2017

6.0–12.0 Ce/CMe credits

Live Medical Conference

PaiN MaNaGeMeNT FOR THe MaiN STReeT PRaCTiTiONeR

PaiNWeeKeND™ ReGiONaL CONFeReNCe SeRieS

2018 painweekend.org

This activity is provided by Global Education Group. 6.0–12.o AMA Category 1 Credits™ This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard.

Annas Aljassem md

P.50

Annas Aljassem is an Assistant Professor at the Oakland University William Beaumont School of Medicine, Department of Physical Medicine and Rehabilitation, in Rochester, Michigan. Dr. Aljassem coauthored his article with Levi M. Hall, pharmd, bcps, Assistant Professor at the Oakland University William Beaumont School of Medicine, Adjunct Faculty at the Wayne State University College of Pharmacy and Health Sciences, and Clinical Pharmacy Specialist of Pain and Palliative Medicine, Department of Pharmaceutical Services, Beaumont Hospital, in Royal Oak, Michigan.

Stephen J. Butler phd

P.20

Stephen Butler is a clinical and research psychologist specializing in pain and addiction, and is Chief Science Officer at Inflexxion, Inc. He has been Principal Investigator on over 35 NIH grants, and appears in more than 100 publications. Dr. Butler coauthored his article with J. Michael Lacroix, phd, Associate Medical Director with Aetna Disability. Dr. Lacroix is a licensed psychologist who has worked in the overlapping areas of Disability and Workers’ Compensation for the last 30 years. Coauthor Simon Budman, phd, passed away in January 2017. He was a thought leader, researcher, and innovator who lectured around the world and was an expert in data driven health quality improvement, publishing more than 100 articles and books.

David Cosio phd

P.38

David Cosio is the psychologist in the pain clinic and the carf-accredited, interdisciplinary pain program at the Jesse Brown va Medical Center, in Chicago. He received his PhD from Ohio University, with a specialization in Health Psychology; completed a behavioral medicine internship at the University of Massachusetts-Amherst Mental Health Services; and a Primary Care/Specialty Clinic Post-doctoral Fellowship at the Edward Hines Jr. va Hospital. Dr. Cosio has published several articles on health psychology, specifically in the area of patient pain education. He achieved specialist certification in Clinical Health Psychology by the American Board of Professional Psychology in 2017.

Courtney Kominek pharmd, bcps, cpe

P.30

Courtney Kominek is a Clinical Pharmacy Specialist in Pain Management at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri. She coauthored her article with Abigail Brooks, pharmd, bcps, a Clinical Pharmacy Specialist in Pain Management at the West Palm Beach va Medical Center in Florida. Drs. Kominek and Brooks are Axial Healthcare consultants.

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Q4 | 2017

PWJ keeps you going all year long.”

—Michael R. Clark Md, mph, mba

SCULPTURE BY EMMA CASTER-DUDZICK

“Meetings come to an end, but learning never stops.

ACCeSS PAiNWeeK 365 DAYS A YeAR PAINWeek® is an innovative single point of access designed specifically for frontline practitioners, recognized as a trusted resource for the latest pain management news, information, and education. →Visit www.painweek.org to access key opinion leader insights expressed via the following sections: ❶ Expert Opinion ❷ Key Topics ❸ One-Minute Clinician ❹ Pundit Profile ❺ PWJ—PAINWeek Journal

TeCHNOLOGY

By Stephen F. Butler J. Michael Lacroix Simon H. Budman

One of the most frustrating aspects of a clinician’s work is getting patients sufficiently engaged in their recovery to comply with the recommended treatment. We present a case report describing the implementation of web-based pain assessment and pain management tools for use with short-term disability claimants. This case study reports on 89 short-term disability members/claimants with musculoskeletal clinical diagnoses who were offered the opportunity to access pain management programs (PainCAS and painACTION) previously found effective in pain management when used in doctors’ offices and at medical clinics. While the participation rate was negatively impacted by the trust deficit inherent in dealing with an insurance company, those patients who did participate fully had significantly shorter disability durations, higher return-to-work rates, and lower rates of progression to long-term disability compared with controls. These results suggest that some of the tools that are used successfully in doctors’ offices and clinics to engage patients can also be useful in engaging the more skeptical disability claimants, although they also point to the need for enhanced efforts in engaging these patients.

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Q4 | 2017

Convincing mistrustful patients to change their behaviors when many of them think the clinician’s only motivation is to close their claim as soon as possible--even if untrue--is a challenge. The answer, in principle, lies in patient education.

engaging patients in their recovery and recommended treatment. Research has demonstrated that even simply taking medications as prescribed is a stretch for many patients, let alone making behavioral changes, such as exercising or losing weight.1 Motivating patients becomes even more challenging when barriers are introduced between the patient and the clinician. One large barrier is the presence of an insurer in cases involving injuries or disabilities. When the clinician trying to assist the claimant works for the entity that decides on disability payments, trust is often a casualty. This is true, whether the patient-insurer relationship revolves around a workers’ compensation injury or a nonoccupational disability.2 One potential avenue for getting around this “trust deficit” is to strip the disability clinician of any decision-making power over disability benefits, and to preclude these clinicians from directing care. In the world of nonoccupational disability, disability clinicians are contractually precluded from directing care on disability claims: they may only advise. Convincing mistrustful patients to change their behaviors when many of them think the clinician’s only motivation is to close their claim as soon as possible—even if untrue—is a challenge. The answer, in principle, lies in patient education. Q4 | 2017

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TeCHNOLOGY

Patients who completed the PainCAS were more engaged in clinically relevant topics during clinic visits, such as substance abuse history and medication misuse, than those patients who did not complete the PainCAS program.

This case study recounts the experience of a pilot effort to implement a program intended to provide to disability insurance claimants access to web-based evaluation and educational tools about their conditions. The tools are suggested by an insurance company nurse and are designed to enhance patient engagement and may potentially alter disability outcomes. Two electronic tools were implemented, both of which had been extensively evaluated in studies on patient populations drawn from doctors’ offices and more general medical offices. The 2 programs were the PainCAS®: Clinical Assessment System and painACTION, a website. The PainCAS instrument and painACTION programs were developed through NIH grants and have been validated on patient populations recruited in medical offices and hospitals but never with disability claimants.

Materials and Methods

Patients

This case study presents administrative data on 89 claimants, 51 males and 38 females, average age 44 years, who were employed by United Parcel Service (UPS), and had applied for short-term disability benefits following a musculoskeletal injury. This sample reflects the population of UPS short-term disability claimants, which averages 43.85 years, and skewed 61.5% male. 54.5% were in occupations rated Heavy or Very Heavy (as against Light or Medium). Based on insurance company records, claimants had back, knee, or shoulder musculoskeletal diagnoses and a new claim opened between January 1 and August 31, 2016. The target

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diagnoses were selected on the basis that patients with these diagnoses often experience significant pain and commonly exceed disability guidelines durations. The specified complex diagnoses were: »» Cervical spondylosis with myelopathy »» Acquired spondylolisthesis

»» Spinal stenosis in cervical region

»» Spinal stenosis, lumbar region, without

neurogenic claudication

»» Lumbar spondylosis without myelopathy

»» Displacement of lumbar intervertebral disc without

myelopathy lumbago

»» Rotator cuff syndrome of shoulder and allied disorders »» Rotator cuff syndrome (not otherwise specified) »» Other affections of shoulder region

»» Tear of medial cartilage or meniscus of knee, current »» Sprain of cruciate ligament of knee »» Neck sprain

»» Lumbar strain

PainCAS and painACTION PainCAS is a systematic computer administered, patient self-report assessment for chronic pain patients that provides a succinct evaluation of the presenting pain complaint along with a comprehensive pain assessment, including quality of life evaluation, current medical status, medical, family, and treatment history, and opioid risk stratification. A shorter, follow-up version focuses on current pain, functioning and Q4 | 2017

emotional status, and ongoing opioid risk monitoring.3,4 In a controlled trial, significantly greater levels of chart documentation were observed for the PainCAS condition for a number of pain related individual chart elements, including pain description, treatment history, psychosocial factors, substance use history, and risk assessment. Patients who completed the PainCAS were more engaged in clinically relevant topics during clinic visits, such as substance abuse history and medication misuse, than those patients who did not complete the PainCAS program.4 Following completion of the PainCAS, the patient is given a tailored, patient oriented PainCAS report that links them to the painACTION website. painACTION is an interactive self-management website for people with chronic pain to assist with emotional management, coping, self-efficacy to manage pain, pain levels, and physical functioning—basically, a daily resource that shows patients how to manage chronic pain, step by step. The website provides skill based lessons to help people manage cancer pain, back pain, migraine pain, arthritis pain, and neuropathic pain, by helping them prepare for medical visits and manage their medications safely, and through engaging and targeted interactive tools, lessons, personal stories, a daily pain tracker, and articles on taking pain medications appropriately and safely. The content in painACTION is intended to increase positive cognitions (eg, pain self-efficacy), reduce negative cognitions (eg, pain catastrophizing), and increase frequency of self-management behaviors. painACTION has been shown in controlled clinical trials to improve outcomes for adult patients with back pain,5 headache pain,6 and arthritis pain.7 Q4 | 2017

Procedure The electronic tools (PainCAS and painACTION) were implemented by Aetna short-term disability plan nurse clinicians for use with ups employees on short-term disability who met the diagnostic criteria listed above. The pilot program was implemented between January 1 and August 31, 2016. Claimants who met the referral criteria were referred to an Aetna disability nurse clinician and were asked if they were interested in completing a web-based evaluation tool that might help them understand their condition better. The nurse clinician offered a PainCAS assessment to the members; went over participating members’ PainCAS profiles with them if/when completed; pointed them toward web-based painACTION disease management programs relevant to their profiles; forwarded the profile to the member’s primary care practitioner (with the member’s release); and offered the member to retake the PainCAS assessment every 2 or 3 weeks to evaluate progress as long as they continued on shortterm disability. As part of the implementation pilot, the nurses spent many hours with the PainCAS vendor to learn the specifics of the instrument as well as the associated disease management programs; formal training for the operational aspects of the pilot was then provided; and team meetings were held weekly initially and then bi-weekly as the study progressed. The data presented here are the status of these claims as of October 1, 2016.

Analysis Plan Patients who refused to participate in the pilot program were compared with those who agreed to participate. We further compared those who did agree to participate and followed through with those who initially agreed but failed to follow through. The possibility that willingness to participate may have co-varied www.painweek.org | PWJ

TeCHNOLOGY

…a clear difference: With respect to both means and medians, those members who fully participated [in PainCAS] required fewer disability days than their colleagues who agreed to participate but ultimately did not follow through.

with the patients’ actual diagnosis or related factors was investigated. This analysis compared patients in these 2 subgroups with matched “twins” from the 2015 ups short-term disability census. In addition to a having the same employer and operating under the same short-term disability contract language, “twins” were also matched on the basis of b primary diagnosis; c gender; d age (as close as possible but no more than 6 years difference); and e the presence or absence of any secondary diagnosis. Dependent measures included the number of disability days approved as well as disability claim closure code, ie, how the claim was ultimately disposed. As indicated above, approval/ denial/disposal was determined independently by Disability Benefits Managers, not the nurse clinicians.

Results A notable proportion of patients (34%) refused to participate outright; of the remainder who did agree to participate, only 38% complied fully with the educational program, reflecting the trust deficit referenced above. This is the first time that the PainCAS instrument was implemented in the context of disability insurance, and disability claimants turned out to be a less cooperative population than the pool of patients who are asked to complete the instrument by their primary practitioner or at a medical clinic. Among the reasons given for nonparticipation were some “good” ones, notably poor computer or English skills, or a sense that the measure would not be valid as they were either recovering from, or anticipating surgery. The largest proportion of refusals (42%) were simply because “I just don’t want to.” We compared this group with members who did agree to participate with respect to age, gender, and the proportion of cases in each group that performed Heavy or Very Heavy work, as opposed to Light or Medium work, on the possibility that this might correlate with

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education. None of the group comparisons were statistically significant: those who refused to participate were not statistically different from the others in any obvious way. Of the 58 members who did agree to participate, only 22 (38%) actually followed through with completing at least the initial PainCAS evaluation, despite encouragement from the nurses. Having acknowledged this less than stellar participation rate, we can still compare administrative outcomes of those who did fully participate in the process compared to those who did not participate. Table 1 reports on the number of disability days approved for members in the 2 groups, and suggests a clear difference: With respect to both means and medians, those members who fully participated required fewer disability days than their colleagues who agreed to participate but ultimately did not follow through. The mean difference of 28 disability days was substantial and statistically significant. Table 2 presents the disability claim closure codes for the 2 groups. Members who completed at least one PainCAS evaluation were twice as likely to have returned to work as of October 1, 2016. Those who did not follow through were more likely to have had their claim ultimately denied, and more likely to have their claim still open as of October 1, in keeping with their longer disability durations. These outcome differences were statistically significant. It is possible that those members who did participate fully in the process differed from those who did not, if not with respect to age, gender, or the “heaviness” of their premorbid occupational duties, perhaps in some other meaningful way related to their diagnosis. We evaluated this possibility by pairing each member as mentioned above in the Analysis Plan. Ten members could not be matched on all of these criteria, resulting in 21 and 26 “twin pairs” for the Fully-participating and Agreed-but-didnot-complete groups, respectively. Table 3 presents the mean disability duration data for the 4 groups. Q4 | 2017

Table 1. Average Disability Days for Members Who Agreed to Participate Outcome as of 10/1/16

Agreed but did not complete (N = 36)

Completed 1 or more PainCAS evaluations (N = 22)

Mean disability days

128.89

100.91

Approved (median)

(138.5)

(92)

Group differences significant: t (56) m= 2.1, P<.05

Table 2. Claim Closure Outcomes for Members Who Agreed to Participate Outcome as of 10/1/16

Returned to work

Approved for long-term disability

Claim ultimately denied

“Other”

Claim still active

Agreed but did not complete (N = 36)

36.1%

19.4%

13.9%

8.3%

22.9%

Completed 1 or more PainCAS (N =22)

72.7%

13.6%

4.5%

Group differences significant: X2 (4) = 9.75, P<.05

Table 3. Mean Disability Days Approved for Members Who Agreed to Participate vs 2015 “Twins” Matched on Specified Variables

Agreed but did not complete (N = 26) Completed 1 or more PainCAS (N = 21)

Current pilot

2015 “matched twins”

132.9

109.59

97.05

124.19

Group differences significant: F (1, 46) = 4.48, P<.05

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TeCHNOLOGY

Table 3 shows that those members in the present implementation pilot who followed through with the PainCAS process had shorter disability durations, not only in comparison with those in the pilot who did not complete the process, but also when compared with employees matched for employer, primary diagnosis, gender, age, and presence or absence of a secondary diagnosis. The interaction was statistically significant, reinforcing the notion that involvement in the PainCAS process was likely the key factor responsible for the shorter disability durations, and not potentially confounding factors related to diagnostic severity or demographic variables. If involvement in the PainCAS process yields quantifiable improvement in outcomes, might the mechanism lie in greater engagement in the treatment process by the patient? While the N here is too small to yield a definitive answer to that question, we do have some indirect evidence that points in this direction. One of the statistics maintained by the nurses is the number of contacts made with the member. The correlation between disability days approved and the number of clinician contacts in the Agreed-but-did-not-complete group was close to zero (r = 0.16). On the other hand, the same correlation in the Fully-participating PainCAS group was moderately positive and significant (r = .42, P<.05). This more orderly relationship suggests that adding PainCAS to the member-nurse discussions might have focused the discussions a little more.

to be determined. It is clear that improvements in disability durations and return-to-work outcomes are not simply the result of having a nurse contact the patient, since a third of the patients refused to participate outright, and others failed to follow through. One can speculate that PainCAS facilitates in some way the patient-clinician interaction, resulting in a greater willingness to engage in the recovery and return-towork process. This conjecture is consistent with other findings suggesting that presence of the PainCAS assessment prompts increased discussion of key, pain-relevant topics during the clinical interaction.3 Perhaps the novelty of a web-based tool further enhanced this facilitative process. For those members who are willing to make the extra effort, the PainCAS evaluation and process resulted in shorter disability durations and a greater likelihood of a return to work, possibly through more focused and targeted discussions with the nursing staff (and conceivably also the treater). Acknowledgments Many thanks to Donna Morrison at ups, as well as MJ Harris and Marty Strang for helping bring ups to the project. We are enormously grateful to Pam Bloom-Pugliese and Grace Koch-Schoedinger, as well as our nurses, Jill Chatting, Jannette Lindo, Helene Newsome, and Virginia Wells, who gave unstintingly of their time and talent, as well as Director Evelyn Rodriguez for bringing this project to fruition. Disclosure

Conclusions As we surmised, the trust deficit in patients dealing with insurance company nurses was well in evidence, with a significant proportion of members refusing to participate with a webbased assessment of their pain, even when coached by a high credibility clinician, such as a nurse.8 However, the disability related outcomes were significantly improved for those who did participate compared with 1 claimants who did not participate fully, as well as 2 previous year claimants matched for employer, primary diagnosis, age, gender, and the presence/absence of secondary diagnoses. Comparisons suggested that those who utilized the electronic assessment and web-based educational program had disability durations that were almost a month shorter (22%); their return-to-work rates 30 days after the end of the program were 50% higher; and their migration rate from short-term to long-term disability averaged 30% lower. Although this was a small case study, it raises the possibility that such an intervention might save employers significant sums of money as well as improve disability and clinical outcomes. Clinicians have a difficult time getting patients engaged in the recovery process, and particularly so in the disability arena. These preliminary results suggest that some of the tools that have been shown to be successful in doctors’ offices and clinics in facilitating patient engagement can also be useful in engaging the more skeptical disability claimants, although they also point to the need for enhanced efforts in engaging these patients. The putative mechanism of action remains

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The implementation pilot and article preparation were funded internally by Aetna Group Insurance (Disability Unit). References 1. Vermeire E, Hearnshaw H, Van Royen P, et al. Patient adherence to treatment: three decades of research. A comprehensive review. J Clin Pharm Ther. 2001;26(5):331–342. 2. Kilgour E, Kosny A, McKenzie D, et al. Interactions between injured workers and insurers in workers’ compensation systems: a systematic review of qualitative research literature. J Occup Rehabil. 2015;25(1):160–181. 3. Butler SF, Zacharoff K, Charity S, et al. Electronic opioid risk assessment program for chronic pain patients: barriers and benefits of implementation. Pain Pract. 2014;14(3):E98-E105. 4. Butler SF, Zacharoff KL, Charity S, et al. Impact of an Electronic pain and opioid risk assessment program: are there improvements in patient encounters and clinic notes? Pain Med. 2016;17(11):2047–2060. 5. Chiauzzi E, Pujol LA, Wood M, et al. painACTION-back pain: a self-management website for people with chronic back pain. Pain Med. 2010;11(7):1044–1058. 6. Bromberg J, Wood ME, Black RA, et al. A randomized trial of a web-based intervention to improve migraine self-management and coping. Headache. 2012;52(2):244–261. 7. Trudeau K, Pujol L, DasMahapatra P, et al. A randomized controlled trial of an online self-management program for adults with arthritis pain. J Behav Med. 2015;38(3):483–496. 8. Gallup. Honesty/ethics in professions. Published 2016. Available at: www.gallup.com/poll/1654/honesty-ethics-professions.aspx

Q4 | 2017

By Courtney Kominek pharmd, bcps, cpe & Abig ail Brooks pharmd, bcps

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abstract: Gabapentin and pregabalin are nonopioid analgesics

used for various pain conditions and are collectively and commonly referred to as gabapentinoids. While structurally related to gamma-aminobutyric acid (gaba), gabapentin and pregabalin do not alter the uptake or breakdown of gaba, convert to gaba, or bind to gabaa or gabaB receptors.1–3 The proposed mechanism of both gabapentin and pregabalin is through binding at the α2-δ subunit of the voltage-gated calcium channel, which reduces the calcium-dependent release of pro-nociceptive neurotransmitters (such as glutamate, norepinephrine, and substance P).1,4 In recent years, there has been a growing prevalence of misuse and abuse associated with gabapentinoids, possibly related to the changes in chronic pain management focusing on nonopioid pharmacotherapy and push to reduce opioid doses for chronic nonmalignant pain. This article reviews the misuse and abuse of gabapentin and pregabalin, as presented at PAINWeek 2017.

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Q4 | 2017

Gabapentin is FDA-approved for both postherpetic neuralgia and as an adjunctive therapy in the treatment of partial onset seizures… Pregabalin…is FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, adjunctive therapy for adult patients with partial onset seizures, fibromyalgia, and neuropathic pain associated with spinal cord injury.

Role in chronic pain Gabapentin is fda-approved for both postherpetic neuralgia and as an adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatrics ≥3 years.5 Pregabalin, the newer agent of the two, is fda-approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, adjunctive therapy for adult patients with partial onset seizures, fibromyalgia, and neuropathic pain associated with spinal cord injury.6 The gabapentinoids are considered first-line treatment options for neuropathic pain by numerous guidelines.7–11 Outside of fda-approved indications, both gabapentin and pregabalin have various off-label uses for a variety of indications (see Table 1). While gabapentin and pregabalin share a similar mechanism of action and side effect profile, there are some nuances for use between the 2. Gabapentin is typically initiated at 300 mg at bedtime and titrated by 300 mg as aggressively as every 3 days, or more conservatively every week or few weeks, up to the lowest effective dose or maximum daily dose of 3600 mg, administered in divided doses. Gabapentin tends to have a higher pill burden and requires more frequent dosing compared to pregabalin. It is important to note that gabapentin requires renal dose adjustments for patients with creatinine clearance (CrCL) <60 mL/min. Dosage formulations include tablets, capsules, and oral solution. There are also extended-release formulations of gabapentin.3,4 Q4 | 2017

Table 1. Off-label use of gabapentinoids.1,7 Pregabalin

Gabapentin

▸▸ Bipolar disorder

▸▸ Insomnia

▸▸ Alcohol/narcotic withdrawal

▸▸ Neuropathic pain

▸▸ Anxiety

▸▸ Drug and alcohol addiction

▸▸ Attention deficit hyperactivty disorder (ADHD)

▸▸ Anxiety

▸▸ Restless legs syndrome

▸▸ Bipolar disorder

▸▸Trigeminal neuralgia

▸▸ Migraines

▸▸ Non-neuropathic pain

Pregabalin, a Schedule V controlled substance, can be initiated at 50 mg 3 times daily or 75 mg twice daily and titrated up to the target dose, depending on the specific indication for use. Outside of the target dose, the maximum daily dose of pregabalin is 600 mg, administered in divided doses. Similar to gabapentin, it requires renal dose adjustments for patients with CrCL <60 mL/ min. Dosage formulations include capsules and oral solution.3,4 Additionally, at the time of writing, a new extended-release pregabalin tablet had just been approved by the fda, though it does not share all the same approved indications as the original www.painweek.org | PWJ

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product.12 From a pharmacokinetics perspective, pregabalin has a higher bioavailability, a faster onset, and a higher affinity for the receptor compared to gabapentin.3,5,6 These pharmacokinetic properties may be responsible for the “liking” or “euphoria” some patients reported to experience after a dose of pregabalin, which will be discussed in more detail later.6 Concomitant use of gabapentin and pregabalin is not recommended or advised. Given the shared mechanism of action, use of both agents concomitantly would be considered duplication of therapy and increase the risk for adverse effects. However, some patients may respond better to 1 agent over the other so conversion between gabapentinoids is not uncommon. There are 2 different conversion methods published; a cross-titration method and a stop-start method. The cross-titration method involves reducing the gabapentin dose by 50% and initiating pregabalin at 50% of the equivalent dose and administering together for 4 days. After 4 days, gabapentin is discontinued and pregabalin is increased to the full equivalent dose. The stop-start method is just as the name implies—gabapentin is stopped and the equivalent dose of pregabalin is initiated.13,14 If converting from pregabalin to gabapentin, you could follow either method as outlined. In order to discontinue either gabapentin or pregabalin, the dose should ideally be tapered to discontinuation rather than abruptly stopped, to limit the potential for withdrawal symptoms. Outside of chronic pain, as noted in Table 1, there is a potential role for the use of gabapentinoids in the treatment of certain substance use disorders in addition to management of opioid withdrawal symptoms.1,7 Pregabalin has evidence for use in alcohol withdrawal, alcohol relapse prevention, and cocaine relapse prevention; gabapentin has evidence for use in opioid, marijuana, and alcohol addictions.1 While gabapentin and pregabalin can be used in this patient population, prescribers should proceed with caution due to the rising rate of abuse and misuse when it comes to these medications.

Prevalence First, let us compare the definitions of misuse and abuse. According to the Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (acttion) system, misuse is defined as “intentional therapeutic use of a drug product in an inappropriate way” while abuse is “any intentional, nontherapeutic use of a drug product or substance, even once, for the purpose of achieving a desirable psychological or physiological effect.”15 Specific studies may use varying definitions for these terms or even use the terms interchangeably, which is a potential limiting factor. An anonymous online survey of the general population examining the rates of misuse of gaba analogues (baclofen, gabapentin, and pregabalin) was conducted in the United Kingdom. Of the respondents, 49.1% of patients were male and 50.9% were female. Those aged 16 to 59 years were allowed to participate, with 9.1% aged 16 to 20 years, 40.5% aged 21 to 39 years,

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21.1% aged 40 to 49 years, and 29.3% aged 50 to 59 years. From the 1500 respondents, 1.1% (n=17) self-reported gabapentin misuse while 0.5% (n=8) self-reported pregabalin abuse. No definition of “misuse” was provided.16 Gabapentin abuse is more common in patients with opioid use disorder. An epidemiological study of 503 patients in Appalachian Kentucky currently using illicit prescription opioids and not in substance abuse treatments was completed. 15% of patients reported using gabapentin “to get high,” representing a significant rise from even the year prior (165% increase) and an even more profound increase from 2008 (2950% increase).17 A written questionnaire asking about the nonmedical use in the past of certain medications was given to 255 people living in a correctional community center with a history of substance use disorder. Prescription drug abuse was defined as “not having a prescription and obtaining the drug elsewhere, having a prescription but using too much, obtaining a prescription to use the drug for other than medical reasons.” Results showed that 16% of patients reported misusing gabapentin with rates differing based on comorbid opioid use disorder—26% of people with an opioid use disorder reported gabapentin misuse compared to 4% of patients without opioid use disorder.18 Rates of gabapentin abuse in patients with opioid use disorder has ranged from 15% to 22% and pregabalin abuse in patients with opioid use disorder ranges from 3% to 68%.19 A recent retrospective cohort analysis examined gabapentin abuse from an insurance claims database. To be included, patients had to be 16 to 64 years of age and have at least 2 pharmacy claims for alprazolam, gabapentin, pregabalin, zolpidem, or any opioid medication, with the exception of patch formulations or fentanyl products with at least 12 months of continuous enrollment. Potential abuse was identified by 3 or more claims exceeding the daily dose threshold (dose per dispensed day = total supply dispensed divided by the days’ supply) and 3 or more rolling quarters where the dispensed supply exceeded the threshold. Thresholds were determined to be 3600 mg/day for gabapentin and 600 mg/day for pregabalin. Overall, the study sample included 838,364 patients with 72,477 patients receiving gabapentin and 11,655 patients receiving pregabalin. Data showed that 3.2% and 4.9% of patients were potentially abusing gabapentin or pregabalin alone, respectively. Rates of gabapentin and pregabalin potential abuse increased in those also using an opioid with 24% of gabapentin patients on opioids and 28% of pregabalin patients on opioids meeting criteria for potential abuse.18

Demographics There is conflicting information regarding the role of gender with gabapentinoid abuse. Some studies have shown significantly increased rates of gabapentinoid abuse in females while case studies have shown higher rates of gabapentinoid abuse in males. Other studies have shown no difference based on gender. Average age in study samples ranges from 21 to 43 years while the mean age in case reports was 41 years.7 Q4 | 2017

Mechanisms for abuse As previously discussed, gabapentinoids do not bind directly to gaba but have gaba-mimetic properties. Other drugs with abuse potential like alcohol, benzodiazepines, or zolpidem exert their effects through altering gaba. Additionally, one theory proposes that gabapentinoids interact with the dopaminergic system, owing to their euphoric and dissociative effects.1,19

Characteristics of abuse Those misusing or abusing gabapentinoids may use a combination of sources to obtain the medications, and roughly 36.8% of people do just that. Similarly to opioids, the most common sources of gabapentinoids are healthcare providers (63.1%) and family or friends (57.8%). Other sources include the Internet (47.3%) and international purchase (7.8%).16 When purchasing gabapentin, the prices range from US$1 to US$7 per dosage formulation depending on the strength. Also, gabapentin may be traded for other drugs.7,19 In terms of doses, a broad range has been implicated. Those without a prescription for gabapentin are more likely to abuse doses of gabapentin within the therapeutic range (900 to 3600 mg/day) whereas those with a prescription are more likely to abuse supratherapeutic doses.7 From case reports, the median dose of pregabalin is 2100 mg/day with a range of 800 to 7500 mg/day. The median dose of gabapentin was 3600 mg/day Q4 | 2017

with a range of 1500 to 12,000 mg/day.19 When used therapeutically, gabapentinoids are administered in several divided doses throughout the day; however, when gabapentinoids are being misused or abuse, they are taken as a single large dose.19 Tolerance develops quickly leading to rapid escalation in gabapentinoid dose.19 Gabapentinoids are used through several common routes as well as some novel ones. Oral administration is the most common but gabapentinoids may also be used intravenously, by smoking, via inhalation, or rectally (plugging). A novel route of abuse associated with gabapentinoids is called parachuting. This involves opening the capsules or crushing the tablets to get powder. The powder is then put into a pouch or wrapped in paper to mask the taste then swallowed. Once the paper reaches the stomach, it dissolves quickly leading to a rapid bolus of a dose.19 The frequency of misuse and abuse of gabapentinoids also varies. In the general population, it was found that 36.8% of people abuse gabapentinoids less than once monthly, 50% of people abuse between once monthly and once weekly, and 13.1% of people abuse more than once weekly.16 As mentioned earlier, gabapentinoid misuse and abuse is more common in those with substance use disorder.19 Thus, gabapentinoids are often used in combination with other substances, www.painweek.org | PWJ

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including alcohol, opioids, benzodiazepines, z-hypnotics (eg, zolpidem, zaleplon), marijuana, amphetamines, lysergic acid diethylamine (lsd), baclofen, selective serotonin reuptake inhibitors (ssris), or quetiapine.7,19

Reasons and effects of abuse A variety of reasons have been identified for misuse and abuse of gabapentinoids. There are 3 common themes including recreational, self-medication, and self-harm. Gabapentinoids are used for the self-treatment of pain or mental health disorders as well as to prevent or treat withdrawal from other substances or even as a replacement for other substances.7 Self-treatment of withdrawal is listed as the primary reason for gabapentin abuse in its package insert.5 Furthermore, gabapentinoids are used to increase the effects of other drugs. Some use gabapentinoids due to an addiction.7 According to the pregabalin package insert, euphoria occurred in 4% of patients with pregabalin compared to 1% of placebo patients from a total of 5500 patients studied.6 Another study showed that a single 450 mg dose of pregabalin produced effects including “good drug effect,” “high,” and “liking” comparable to 10 mg of diazepam.1 Some of the effects of gabapentinoids are startling. Effects of gabapentinoid abuse have been compared to a marijuana-like high, cocaine-like high, euphoria similar to opioids, methylenedioxy-methamphetamine (mdma)-like high, and amphetamine rush.7 Other effects of gabapentinoids include improved energy and concentration, better sleep, and improved sociability.7 Gabapentin has been tied to “zombie-like effects” or a sedative/ opioid buzz. For pregabalin, dissociation has been reported, along with effects similar to those caused by alcohol, gamma hydroxybutyrate, and benzodiazepines.1

Patients experiencing gabapentinoid withdrawal may exhibit a variety of symptoms, some of which are very similar to those associated with opioid withdrawal (see Table 2). Withdrawal can set in anywhere from 12 hours to 7 days after last use of a gabapentinoid; most cases report onset within 24 to 48 hours.21 The treatment of gabapentinoid withdrawal is relatively limited; specifically, benzodiazepines, antipsychotics, and benztropine are ineffective compared to use of gabapentin and pregabalin themselves, which are effective.2,19,21–23 This can prove to be challenging in the management of patients with an addiction or dependence to gabapentin or pregabalin and require weighing the risks vs benefits of treatment based on the individual patient.

Table 2. Signs and symptoms of gabapentinoid withdrawal.2,21–23 Psychomotor agitation Confusion Craving Disorientation Arterial hypertension Tachycardia Tremor Insomnia Nausea Headache Diarrhea Diaphoresis

Overdose and withdrawal

Combating abuse

Gabapentinoid related overdose can begin soon after ingestion and last for several hours. Fatalities or intubation are rare as effects are usually mild to moderate in nature, including central nervous system (cns) symptoms. In fact, survivals have been reported with up to 11,500 mg of pregabalin and 91,000 mg of gabapentin. However, the use of gabapentinoids with other substances that result in an overdose can be more dangerous, with as many as 90% of fatalities associated with opioids. In fact, a recently published population nested case control study found that concomitant gabapentin and opioid exposure is associated with a 49% increased risk of death due to overdose, after looking at gabapentin use in patients who had died due to an opioid related cause. While more research is needed, findings such as these could signal a major change in the use of gabapentinoids in combination with opioid medications for chronic nonmalignant pain.20 Overdose is also more of a concern in patients with renal dysfunction, as this impairs the elimination of gabapentin or pregabalin from the body.19

In an effort to combat the outbreak of pregabalin abuse, clinicians can query their state’s prescription drug monitoring program (pdmp) database to assess for doctor-shopping. Pregabalin is a controlled substance, so these prescriptions are already reported to the database in some states. Because pregabalin is a Schedule V controlled substance, not all states require that it be reported. Though somewhat obvious, it should be noted that pdmp results will not detect illicit purchasing or use of pregabalin. Because gabapentin is not a controlled substance, some states—including Minnesota, Ohio, and Kentucky—have added it to their pdmp reports in an effort to improve patient safety.24–27 In fact, the state of Kentucky has officially declared gabapentin to be a controlled substance.25

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The use of pdmp databases will not be enough. Clinicians should monitor for the following indicators of abuse: requesting specific medications, requesting higher doses, doctor shopping, claims of lost or stolen medications, using multiple pharmacies, early refill Q4 | 2017

requests, and/or urine drug testing (though gabapentinoids are not part of a typical urine immunoassay drug test). In addition, as part of the clinical assessment and work-up, a patient’s substance abuse history, psychiatric history, and concurrent medications should be evaluated before prescribing a gabapentinoid. Clinicians may also want to consider establishing a protocol for gabapentinoid overdose and withdrawal treatment/prevention.19

Conclusion Until recently, gabapentinoids were thought to have minimal (pregabalin) or no (gabapentin) risk for abuse. Patients with a history of substance use disorders, particularly opioid use disorder, are at higher risk for gabapentinoid abuse. Therefore, it is imperative to assess a patient’s substance use disorder history, psychiatric history, and concurrent medications prior to initiating gabapentinoids. When a patient is on gabapentinoids, monitor for signs of misuse and abuse and keep an eye on early refills. Several states include gabapentinoids in their pdmps and likely more will follow. This will be a useful tool in risk mitigation for gabapentinoid abuse. Disclosure This article is the sole opinion of the authors and does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies mentioned or specific drugs discussed. It was not prepared as part of official government duties for Drs. Kominek or Brooks. REFERENCES 1. Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014;28(6):491–496. 2. Pittenger C, Desan PH. Gabapentin abuse, and delirium tremens upon gabapentin withdrawal. J Clinical Psychiatry. 2007;68(3):483–484. 3. Micromedex 2.0 Online. Available at: www.micromedexsolutions.com/ micromedex2/librarian. 4. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237–251. 5. Pfizer. Neurontin: highlights of prescribing information. 2017. Available at: labeling.pfizer.com/ShowLabeling.aspx?id=630. 6. Pfizer. Lyrica: highlights of prescribing information. 2016. Available at: labeling. pfizer.com/showlabeling.aspx?id=561.

12. Pfizer. U.S. FDA approves Lyrica® CR (pregabalin) extended-release tablets CV [press release]. 2017. Available at: www.pfizer.com/news/press-release/press-releasedetail/u_s_fda_approves_lyrica_cr_pregabalin_extended_release_tablets_cv. 13. Bockbrader HN, Budhwani MN, Wesche DL. Gabapentin to pregabalin therapy transition a pharmacokinetic stimulation. Am J Ther. 2013;20(1):32–36. 14. Ifuku M, Iseki M, Hidaka I, et al. Replacement of gabapentin with pregabalin in post-herpetic neuralgia therapy. Pain Med. 2011;122:1112–1116. 15. Smith SM, Dart RC, Katz NP, et al. Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. Pain. 2013;154(11):2287–2296. 16. Kapil V, Green JL, Le Lait M-C, et al. Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK. Brit J Clin Pharmacol. 2014;78(1):190–191. 17. Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry. 2015;172(5):487–488. 18. Bastiaens L, Galus J, Mazur C. Abuse of gabapentin is associated with opioid addiction. Psychiatr Q. 2016;87(4):763–767. 19. Evoy KE, Morrison MD, Saklad SR. Abuse and misuse of pregabalin and gabapentin. Drugs. 2017;77(4):403–426. 20. Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case-control study. PLoS Med. 2017;14(10):e1002396. 21. Mersfelder TL, Nichols WH. Gabapentin: abuse, dependence, and withdrawal. Ann Pharmacother. 2016;50(3):229–233. 22. Gahr M, Franke B, Freudenmann RW, et al. Concerns about pregabalin: further experience with its potential of causing addictive behaviors. J Addict Med. 2013;7(2):147–149. 23. Gahr M, Freudenmann RW, Hiemke C, et al. Pregabalin abuse and dependence in Germany: results from a database query. Eur J Clin Pharmacol. 2013;69(6):1335–1342. 24. State of Ohio Board of Pharmacy. Reporting gabapentin products to OARRS–Effective 12–1-2016. Available at: pharmacy.ohio.gov/Documents/Pubs/ Special/OARRS/Reporting%20Gabapentin%20Products%20to%20OARRS%20 %E2%80%93%20Effective%2012–1-2016.pdf. 25. Kentucky Cabinet for Health and Family Services. KASPER (Kentucky All Schedule Prescription Electronic Reporting). Available at: www.chfs.ky.gov/os/oig/ KASPER.htm. 26. Minnesota Prescription Monitoring Program. Available at: pmp.pharmacy.state.mn.us/. 27. National Council for Prescription Drug Programs (NCPDP). Implementation information for state prescription drug monitoring programs. Available at: ncpdp.org/ NCPDP/media/pdf/State_PMP_Tracking_Document.xls.

7. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160–1174. 8. Bril V, England J, Franklin 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(20):1758–1765. 9. American Diabetes Association. Microvascular complications and foot care. Diabetes Care. 2017;40(suppl 1):S88-S98. 10. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85(3 suppl):S3-S14. 11. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328–335.

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By David Cosio phd

BeHaViORaL

Pain management providers tend to be eclectic and flexible in their choice of modalities and attempt different treatments until they find something that suits the patient—similar to the idea that one has to “kiss a lot of frogs to find a prince.” In the Frog Prince fairy tale, a prince is rude to a witch-in-disguise who was asking for water. He is turned into a frog, and will remain a frog, unless he is bestowed true love’s kiss. A princess is told about the curse and in her kindness wants to help. One moral to the Frog Prince is how the power of kindness can bring about change. In reality, being authentic/genuine, having unconditional positive regard, and expressing empathy are necessary and sufficient conditions in a therapeutic relationship that are required for change to take place. Relationships are just one of 4 areas that are part of the “common factors” model, which also includes client factors, expectancy/placebo/ hope, and techniques/models. The purpose of this article is to explore the applicability of the common factors model to pain management.

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about the treatment of chronic, noncancer pain is that the results from research studies are disheartening. Of all the treatment modalities currently available, the best evidence for pain reduction averages around 30% in about half of treated patients.1 In other words, one could only expect a person suffering from chronic, noncancer pain reporting a 9 on the Numeric Rating Scale to see maybe a 3 point reduction in their severity score, half of the time. Clinical trials have indicated the comparable efficacy of numerous diverse treatment interventions—acupuncture, behavioral therapy, exercise therapy, and nonsteroidal anti-inflammatory (nsaids)—for chronic, noncancer pain.2 Overall, the current evidence provides little support for choosing one approach over another. Here is a brief look into each type of pain management modality and its corresponding research. Each section is followed by a case description that encourages the reader to question what else may be accounting for the change being witnessed.

Pharmacological Treatments. Medication management will on throughout the years and how he has repeatedly been able to continue to be the mainstay of chronic pain treatment in the “wean myself off” them. The patient is in the pain clinic hoping future. The classes of drugs most commonly used for the treat- that a 30 day supply of fentanyl patches could be prescribed for ment of chronic, noncancer pain are opioids, nsaid, antidepres- pain since he expects that the opioid should help considering sants, anticonvulsants, muscle relaxants, and topical agents. his past history. Meta-analyses concluded that opioids result in small improveIs it the medications alone that accounted ments in pain severity and function compared with placebo.3 for the outcome(s) in the past or is The efficacy of nsaid has been established for some patients something else happening in this case? with pain (arthritis, back), but has not been investigated in , others (neuropathic pain, fibromyalgia).4 5 Meta-analyses also Interventional Treatments. Interventional pain medicine suggested that antidepressants result in moderate symptom involves the application of various techniques, such as injecreduction and are superior to placebo.6 The best evidence sup- tions, surgery, and implantable devices. Epidural steroid and ports the efficacy of anticonvulsant drugs (gabapentin, pregaba- facet injections are the most commonly used in the US13; howlin, and carbamazepine) for the treatment of chronic, noncancer ever, the evidence for epidural steroid injection use as long-term pain.7–9 Muscle relaxants are typically recommended as adju- monotherapy is not clear.14,15 Facet injections have some evivant therapy and seem to have a restricted role in chronic dence for use with facet joint pain, but are not clearly effective pain.10,11 Topical agents have also been shown to effectively for other syndromes.16,17 In terms of surgery, evidence has rated reduce chronic pain in comparison to placebo.12 lumbar fusion as “fair,” and both discectomy and laminectomy as “good,”18 with the proviso that significant pain can persist even after spinal surgery.19,20 Several meta-analyses evaluated Sample Case the efficacy of spinal cord stimulation and concluded that there was moderate evidence for improvement in pain.21–24 A more A 68 year old, Caucasian man comes to the pain clinic for the recent systematic review evaluated the efficacy of epidural and first time reporting neck and lower back pain, which he has intrathecal drug delivery systems, and determined that there suffered from since the 1960s after several car accidents. The were moderate reductions in pain, but the long-term effectivepatient discusses at length all the various opioids he has been ness remains unclear.25

ONE:

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Even though a common factors model in pain management is not fully developed, such a model should be considered in order to further advance knowledge and practice in pain medicine.

Sample Case

TWO:

A 69 year old, Caucasian man comes to the pain clinic after having a medial branch block (mbb) for arthritis in the joints of his spine about 6 months ago. mbb is a diagnostic injection that temporarily—for a couple of hours—interrupts the pain signal being carried from a specific facet joint, providing relief. If the mbb proves to be successful, then a radiofrequency nerve ablation, where radio frequency waves are used to produce heat on specifically identified nerves surrounding the facet joints, may be performed. The patient reports that he continues to have relief from the MBB, which is similar to the outcomes he has had in the past with other injections. The relief from the mbb should have only lasted a couple of hours.

Was it the injection/procedure alone that accounts for the outcome or is something else happening in this case? Physical Medicine and Rehabilitation Approaches. Evidence suggests that exercise can effectively decrease pain and improve function, but no conclusions can be made about exercise type.26 Physical medicine approaches are commonly included as components of interdisciplinary pain rehabilitation programs—the embodiment of the biopsychosocial model.27 The reduction of pain after treatment at an interdisciplinary pain rehabilitation program has been reported to be significant.28–30 Sample Case

THREE:

A 68 year old, African American man suffering from the early stages of Parkinson’s disease comes to the pain clinic in a motorized wheelchair, accompanied by his son. Since he has been coming to the pain clinic, he has had physical and occupational therapy at home, which he and his son feel has made a significant improvement in pain, strength, and coordination. The patient

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has exhausted the 12 sessions covered by his insurance, but is now requesting further visits at home if it can be approved due to barriers including his son’s other responsibilities as a father.

Was it the physical and occupational therapy alone that account for the outcome or is something else happening in this case? Psychological Approaches. Psychological treatment as a whole results in modest improvements in pain and physical and emotional functioning, but there is insufficient evidence to recommend one therapeutic approach—behavioral therapy, cognitive behavioral therapy, psychodynamic therapy, stress management, emotional disclosure, biofeedback, and hypnosis—over another.31–36 Interestingly, the modest reductions in pain severity witnessed with psychological interventions were similar to those noted with pharmacological, interventional, physical, and rehabilitative approaches.37 Sample Case

FOUR:

A 58 year old, African American woman comes to the pain clinic diagnosed with pseudo-gout and fibromyalgia. She’s in a wheelchair and there is a cast on her right knee. She notes that she “hurt my knee so people would pay attention” to her verbal complaints. She completes a course of treatment, including cognitive behavioral therapy for pain and acceptance and commitment therapy, and seems to be coping with her pain better. Every time she sees her provider, she exclaims, “There is my favorite doctor” and goes in for a hug.

Was it the psychotherapy alone that accounts for the outcome or is something else happening in this case? Complementary and Integrative Health Approaches. Complementary and integrative health (cih), formerly known as

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Interestingly, the modest reductions in pain severity witnessed with psychological interventions were similar to those noted with pharmacological, interventional, physical, and rehabilitative approaches.

complementary and alternative medicine, is a group of medical and healthcare systems, practices, and products that can be categorized into 4 general groups: mind-body medicine (biofeedback, hypnosis, and yoga), natural-biological based (aromatherapy and herbs), manipulation-body based (chiropractor, massage, and spinal manipulation), and energy medicine (acupuncture and healing touch). There is promising scientific evidence to support the use of cih for noncancer pain conditions, such as low back pain (cognitive behavioral therapy, exercise, interdisciplinary rehabilitation, massage, spinal manipulation, yoga, acupuncture, and functional restoration); osteoarthritis (acupuncture, tai chi, self-management programs, and walking aids,); rheumatoid arthritis (omega-3 fatty acids, relaxation, mindfulness meditation, tai chi, and yoga); headaches (relaxation training, biofeedback, acupuncture, and spinal manipulation; dietary supplements are promising); preliminary for fibromyalgia (tai chi, qi gong, yoga, massage therapy, acupuncture, and balneotherapy); promising for irritable bowel syndrome (hypnotherapy and probiotics); and limited support for neck pain (acupuncture and spinal manipulation).38 Sample Case

FiVE:

A 62 year old, Caucasian woman has been coming to the pain clinic for about a year and tried all the different modalities available, without any relief. The patient has a history of multiple traumas and has suffered 2 strokes. The current provider introduces her to a nurse who is similar characteristically to her and who has been trained in healing touch. The patient returns a month later and notes that the healing touch is the only thing that has worked for her and that she enjoys working with the nurse.

Was it the healing touch alone that accounts for the outcome or is something else happening in this case? Q4 | 2017

Choosing a Treatment Providers may consider several factors when choosing a treatment for pain: 1. Pain related factors: type and intensity of pain, physical, cognitive abilities, and concurrent symptoms 2. Individual related factors: previous experiences, expectations for outcome, cultural and spiritual influences, patient preferences and coping styles 3. Environment factors: involvement of friends and family Thus, providers try different treatments until they find something that works, a phenomenon referred to as the “Goldilocks effect,” derived from another children’s tale of the Three Bears. In the story, Goldilocks wanders far from home and stumbles upon the house of the 3 bears. Trying all their chairs and tasting all their porridge, then lying in all their beds, she finds the baby bear’s the most suitable for her in all 3 cases. Research has shown that the overall treatment effectiveness for chronic pain remains inconsistent and fairly poor. The practice of psychotherapy confronted a similar issue, deciding which approach to choose over another, in the past. The field of pain management may be able to glean insight from the psychological research literature in “common factors.”

Common Factors Model References to the concept of “common factors” in psychotherapy began as early as 1936.39 At that time, research studies were concluding that all psychotherapies were effective, a verdict later termed the “Dodo bird effect,” referencing a scene from Alice’s Adventures in Wonderland.40 In the original story, in order to get dry after a swim, the Dodo bird proposes that everyone run a Caucus race where the participants run in patterns of any shape, starting and leaving off whenever they like, so that everyone wins and “all must have prizes.” It wasn’t until 1952, when Eysenck announced his refutation that psychotherapy

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Clinical Encounter

Pharmacology

Specific Interventions

Common Factors

Patient Effects

Interventions

Provider Effects

Rehabilitation

Relationships

Psychological

Expectations

CAM/CIH Modality

Pain Medicine

does not lead to improved patient outcomes, that research into the efficacy of psychotherapy witnessed a resurgence.41 Several meta-analyses illustrated the absolute efficacy of psychotherapy.40,42–45 Two important findings have been noted from those analyses: 1 Improved research methods did not increase the effects found, and 2 Effect sizes were comparable across all treatments. These conclusions led to the distinction of 2 possible mechanisms of psychotherapeutic change, “specific” vs “nonspecific” effects. Specific effects were associated with unique interventions to certain therapy approaches, while nonspecific effects were linked with contextual factors of the clinical encounter (see Figure).

and 2 factors to consider: expectancy/placebo/hope and the actual techniques/models we use. Which do you think accounts for the most variance in the remaining 2 factors? The research indicates that the percentage is equal between both variables: 15% is explained by expectancy/placebo/hope and 15% by the techniques/models we use. This research later inspired a book titled The Great Psychotherapy Debate, which concluded that nonspecific effects were responsible for more than 4 times the amount of variance in treatment outcomes across various interventions.47 Using models developed in other professions (in this case psychotherapy) to inform inquiry in another field is appropriate, and there is some precedence in the literature, specifically in physical medicine and rehabilitation.50 Is it possible that these nonspecific effects are responsible for some amount of variance in treatment outcomes in pain management?

Evidence from systematic reviews of diverse psychotherapy interventions indicate that factors common across therapies contribute more to treatment outcomes than effects associated with specific technical interventions.46,47 Meta-analytic studies Common Factors in then summarized psychotherapy outcome research and reduced Pain Management the factors into 4 areas: client factors, therapeutic relationship, “Common factors” speaks to pain management being an art form expectancy/placebo/hope, and techniques/models.48,49 Client in addition to a science. From a psychotherapy perspective, spefactors—the characteristics of the patient and his/her envi- cific interventions, such as techniques/models discussed previronment—were found to explain 40% of the variance in out- ously—pharmacological, interventional, physical medicine and comes. 30% of the variance in outcomes was attributed to the rehabilitation, psychological, and cih approaches—will not be therapeutic relationship, the characteristics of the provider and fully effective without the contribution from the other common the patient that facilitate change and are present regardless of factors. There is evidence to suggest that these same common facthe type of intervention. Which leaves us with 30% remaining tors may be responsible for general effects in pain management.51

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‘Common factors’ speaks to pain management being an art form in addition to a science. From a psychotherapy perspective, specific interventions… will not be fully effective without the contribution from the other common factors.

Patient Factors. Patient factors are characteristics of the patient and her/his environment. Several different themes were explored when investigating over 20 retrieved articles on patient factors: remission, inner strength, resiliency, goal directedness, purpose, motivation, personal agency, sense of control, fortuitous events, chance, social support, faith, life experiences, strengths and abilities, and readiness to change. Themes such as social support, faith, and strengths/abilities seemed to have more literature related to them than others like motivation, whose model of pain management was only recently developed. In summarizing the findings from the various studies,51 it would appear that treatment outcomes were better when the patient: →→ Was employed, which affected remission →→ Had high treatment outcome expectations →→ Was resilient and remained positive →→ Was engaged in activities that were purposeful →→ Was motivated to manage pain →→ Had an internal locus of control →→ Felt they had control over their pain →→ Perceived having social support →→ Believed in god or a spiritual power greater than themselves →→ Did not experience any recent/daily life stressors →→ Had positive beliefs and used coping strategies →→ Had an increased readiness for change Therapeutic Relationship Factors. The therapeutic relationship, or working alliance, is a psychotherapy common factor identified by Grencavage and Norcross (1990).52 Therapeutic relationship factors are characteristics of the provider and the Q4 | 2017

patient that facilitate change and are present regardless of the type of intervention. Several different themes were explored when investigating approximately 25 retrieved articles on therapeutic relationship factors—empathy, warmth, respect, genuineness, acceptance, encouragement and instruction, communication, and the patient-provider relationship. Themes such as the patient-provider relationship and encouragement/ instruction seemed to have more literature than other themes. In summarizing the findings from the many examinations,51 it would appear that: →→ Provider empathy plays a crucial role in pain treatment →→ Providers who are warm are more effective →→ Patients are more satisfied when they perceive they are respected by providers →→ Patient suffering may be affected by acknowledgment of genuineness of pain →→ Patients need to reframe treatment as acceptance of chronic pain →→ Patient encouragement and instruction decreases pain and increases satisfaction →→ The communication process influences self-management of pain →→ Patient-provider relationship is significantly associated with outcome Expectancy Factors. Expectancy factors are improvements that result from the patient and provider’s belief that treatment is effective. Several different themes were explored when investigating almost 20 retrieved articles on expectancy factors— expectations, placebo, noncompliance, relapse, optimism, hope, and credibility. Themes such as expectations seemed to www.painweek.org | PWJ

BeHaViORaL

have the most literature available. In summarizing the results from numerous investigations,51 it would appear that treatment outcomes were enhanced when:

an opioid use disorder. It is less likely that there is an impact from the therapeutic relationship since this patient is new to the pain clinic.

→→ Patients expect and believe treatment is potentially beneficial →→ Providers consider how placebo effects and regression to the mean improve outcomes →→ Providers consider the patient’s potential to be noncompliant and relapse →→ Patients are optimistic, have hope, and/or accept their pain →→ Patients feel providers believe their pain is credible

In Case 2, a 69 year old man comes to the pain clinic after having had a mbb for arthritis in the joints of his spine about 6 months earlier, and he continues to have relief from the procedure despite the fact that it was intended to last only a few hours. Again, one should consider the impact of the technique being used: the intervention or injection/procedure. However, one should also consider the impact of the expectations of the patient and the therapeutic relationship—the patient has had multiple injections/procedures in the past and has built a relationship with the pain clinic team.

Sociocultural Factors. Sociocultural factors are the larger scale forces within cultures and societies that affect the thoughts, feelings, and behaviors of individuals. Sociocultural factors related to the pain experience may include pain expression, pain language, lay remedies for pain, social roles, tangibles, and perceptions of the medical care system. In summarizing the findings from the examinations,53–56 it would appear that: →→ Dissimilarities in cultural views about the mind-body relationship affects patient’s pain →→ Tangibles can be barriers to patient self-management →→ The needs of pain management providers cannot be ignored →→ Using a patient-centered approach improves self-rated pain and physical mobility Ethical and Legal Factors. Effective pain management has been deemed a right to health according to international human rights law. Thus, inadequate pain treatment is considered a violation to protect against cruel, inhuman, and degrading treatment. In summarizing the findings from the examinations,57 it would appear that:

Case 3 involved a 68 year old man suffering from early stages of Parkinson’s disease, requesting additional home physical and occupational therapy sessions beyond what has been approved by his insurance company: an expectancy. Note: he came to the pain clinic in a motorized wheelchair accompanied by his son, both facts which indicate that the patient may struggle with independence—a patient factor. Physical therapy and rehabilitation exercises, the technique/model, have been shown to be effective but require that the patient continue them at home independently. Continuing to offer the technique at home may continue the dependence and be effecting the outcome. In Case 4, a 58 year old woman comes to the pain clinic diagnosed with pseudo-gout and fibromyalgia. She’s in a wheelchair, with a cast on her right knee. There are clear patient factors present in this case as there is evidence of characterological issues including self-harm (she hurt her knee to prove she’s in pain). The patient also appears to have developed a strong therapeutic relationship with her therapist, her “favorite doctor,” beyond the techniques. There is also clear evidence for the need to set appropriate boundaries in this case.

Throughout this article, a question was posed: Is it the (technique) alone that accounted for the outcome or “Is something else happening in this case?”

In Case 5, a 62 year old woman coming to the pain clinic for about a year and tried all the different modalities available without any relief, but then finds healing touch to be “the only thing that worked.” In this example, one should consider the impact of the technique being used: the CIH approach. However, one should also consider the impact of the therapeutic relationship with the provider, a nurse who is similar characteristically to the patient. The patient may have been more comfortable with this particular provider due to their similar interests and her history of traumas. There is also the possibility that the patient had hoped this technique would help since it was referred to her by the pain clinic team.

In Case 1, a 68 year old man is asking for a 30 day supply of fentanyl patches for his pain since it helped in the past. In this example, one should consider the impact of the technique being used: pharmacology. However, one should also consider the impact of the expectations of the patient and any patient factors, such as the potential that the patient is suffering from

Research studies in pain management have concluded that the diverse treatment interventions currently available all appear to be equivocally effective, a verdict this author proposes to be termed the “Manumea effect,”51 referencing Samoa’s endangered

→→ Narratives of patient perception note pain as being a “moral event” →→ Providers may alter their practice in response to patient expectations →→ It is difficult to support this position as a point of law or as a matter of ethics

Revisiting Case Samples

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Conclusion

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tooth-billed pigeon, similar to the dodo bird, which is apropos since it is a relative of this famously extinct dodo (like pain management and psychotherapy being relative) and its cryptic, almost invisible, nature (like the use of common factors model in pain medicine being obscure). Even though a common factors model in pain management is not fully developed, such a model should be considered in order to further advance knowledge and practice in pain medicine. The true causes of improvements in pain after treatment remain unknown in the absence of independently evaluated randomized controlled trials. Additional research is needed to more clearly define the common factors model in pain management, specifically in: →→ Defining common factor categories that are more aligned with the pain medicine environment (eg, sociocultural and ethical/legal) →→ Estimating the impact of common factors on outcomes in comparison to the specific pain treatments →→ Exploring the interrelationships of the common factors Only then will we be able to increase the effectiveness and quality of health services during pain medicine consultations. References 1. Turk D, Wilson H, Cahana A. Treatment of chronic noncancer pain. Lancet. 2011;377:2226–2235. 2. Keller A, Hayden J, Bombardier C, et al. (2007). 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 noncancer pain: a meta-analysis of effectiveness and side effects. Can Med Assoc J. 2006;174:1589–1594. 4. Roelofs PD, Deyo RA, Koes BW, et al. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev. 2008 Jan 23;(1). 5. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Supp. 1999;56:18–24. 6. Kroenke K, Krebs E, Bair M. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry. 2009;31:206–219. 7. 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-e88. 8. Dworkin R, O’Connor A, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc. 2010;85: S3-S14. 9. Finnerup N, Sindrup S, Jensen T. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150:573–581. 10. Arnold L, Keck P, Welge J. Antidepressant treatment of fibromyalgia: a meta-analysis and review. Psychosomatics. 2000;41:104–113. 11. See S, Ginzburg R. Choosing a skeletal muscle relaxant. Am Fam Phys. 2008;78:365–370. 12. 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. Brit Med J. 2004;328(7446):995. 13. Manchikanti L. The growth of interventional pain management in the new millennium: a critical analysis of utilization in the Medicare population. Pain Physician. 2004;7:465–482.

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14. 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. 15. 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. 16. Chou R, Atlas S, Stanos S, et al. Nonsurgical interventional therapies for low back pain. Spine. 2009;34:1078–1093. 17. 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. 18. 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. 19. 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. 20. Hornberger J, Kumar K, Verhulst E, et al. Rechargeable spinal cord stimulation versus non-rechargeable system for patients with failed back surgery syndrome: a cost-consequences analysis. Clin J Pain. 2008;24:244–252. 21. Chou R, Loeser J, Owens D, et al. Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain. Spine. 2009;34:1066–1077. 22. Frey M, Manchikanti L, Benyamin R, et al. Spinal cord stimulation for patients with failed back surgery syndrome: a systematic review. Pain Physician. 2009;12:379–397. 23. 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. 24. 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. 25. 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. 26. 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. 27. Townsend C, Rome J, Bruce B, et al. Interdisciplinary pain rehabilitation programs. In: Ebert MH, Kerns RD. Behavioral and Psychopharmacological Pain Management. New York, NY: Cambridge University Press;2011. 28. Guzman J, Esmail R, Karjalainen K, et al. Multidisciplinary rehabilitation for chronic low back pain: systematic review. Brit Med J. 2001;322:1511–1516. 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. 30. 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. 31. 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. 32. Henschke N, Ostelo R, van Tulder M, et al. Behavioural treatment for chronic low-back pain. Cochrane Database of Systematic Reviews. 2010;7.7. 33. Hoffman B, Papas R, Chatkoff D, et al. Meta-analysis of psychological interventions for chronic low back pain. Health Psychol. 2007;26:1–9. 34. Jensen M, Patterson D. Hypnotic treatment of chronic pain. J Behav Med. 2006;29:95–124.

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35. Montgomery G, DuHamel K, Redd W. A meta-analysis of hypnotically induced analgesia: how effective is hypnosis? Int J Clin Exp Hypn. 2000;48:138–153.

47. Wampold B. The Great Psychotherapy Debate: Models, Methods, and Findings. 1st ed. Mahwah, NJ: Lawrence Erlbaum Associates Inc.; 2001.

36. 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.

48. Hubble M, Duncan B, Miller S. The Heart and Soul of Change: What Works in Therapy. American Psychological Association; 1999.

37. 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.

49. Lambert M. Psychotherapy outcome research: implications for integrative and eclectic therapists. In: Norcross & Goldfried. Handbook of Psychotherapy Integration. 1st ed. New York: Basic Books; 1992.

38. National Center for Complementary & Integrative Health (2017). Complementary Health Approaches for Chronic Pain: What the Science Says. Available at: nccih.nih. gov/health/providers/digest/chronic-pain-science.

50. Miciak M, Gross D, Joyce A. A review of the psychotherapeutic ‘common factors’ model and its application in physical therapy: the need to consider general effects in physical therapy practice. Scand J Caring Sci. 2011;26:394–403.

39. Rosenzweig S. Some implicit common factors in diverse methods of psychotherapy. Am J Orthopsy. 1936;6:412–415.

51. Cosio D. A review of the common factors model and its application in pain management. Int J Complement Alt Med. 2016;3(2):1–14.

40. Wampold B, Mondin G, Moody M, et al. A meta-analysis of outcome studies comparing bona fide psychotherapies: empiricially, ‘‘all must have prizes.’’ Psychol Bull. 1997;122:203–215.

52. Grencavage L, Norcross J. Where are the commonalities among the therapeutic common factors? Prof Psychol Res Pr. 1990;21:372–378.

41. Eysenck H. The effects of psychotherapy: an evaluation. J Consult Psychol. 1952;16:319–324. 42. Andrews G, Harvey R. Does psychotherapy benefit neurotic patients? Arch Gen Psych. 1981;38:1203–1208. 43. Landman J, Dawes R. Psychotherapy outcome: Smith and Glass’ conclusions stand up under scrutiny. Am Psychol. 1982;37:504–516. 44. Shapiro D, Shapiro D. Meta-analysis of comparative therapy outcome studies: a replication and refinement. Psychol Bull. 1982;92:581–604. 45. Smith M, Glass G. Meta-analysis of psychotherapy outcome studies. Am Psychol. 1977;32:752–760. 46. Frank JD, Frank JB. Persuasion and Healing: A Comparative Study of Psychotherapy. 3rd ed. Baltimore, MD: Johns Hopkins University Press; 1991.

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53. Bates M, Rankin-Hill L, Sanchez-Ayendez M. The effects of the cultural context of health care on treatment of and response to chronic pain and illness. Soc Sci Med. 1997;45:1433–1447. 54. Bair M, Matthias M, Nyland K, et al. Barriers and facilitators to chronic pain self-management: a qualitative study of primary care patients with comorbid musculoskeletal pain and depression. Pain Med. 2009;10:1280–1290. 55. Matthias M, Parpart A, Nyland K, et al. The patient-provider relationship in chronic pain care: providers’ perspectives. Pain Med. 2010;11:1688–1697. 56. Alamo M, Moral R, Pérula de Torres L. Evaluation of a patient-centered approach in generalized musculoskeletal chronic pain/fibromyalgia patients in primary care. Patient Educ Couns. 2002;48:23–31. 57. Vroman K, Warner R, Chamberlain, K. Now let me tell you in my own words: narratives of acute and chronic low back pain. Disabil Rehabil. 2009;31:976-987.

Q4 | 2017

Not only can you take our faculty home with youâ&#x20AC;&#x201D;now you can also bring them to the gym 365 days a year!

By Annas Aljassem md, mha Levi M. Hall pharmd, bcps

topical opioids for reducing systemic opioid exposure

KeY TOPiC

Topically applied opioids have provided effective analgesia without adverse effects in adult patients with painful inflammatory conditions. The presumed mechanism of action is by interaction with opioid receptors that are sited on sensory nerve terminals, which may be upregulated in inflammation. A topical solution may result in rapid reduction in patient reported pain scores without reported adverse effects or tolerance. This treatment modality has been a successful addition to our practice. We run the Functional Pain & Rehabilitation Service that treats pain for patients with complex pain syndromes with focus on functional restoration at a 1,000+ bed Level 1 trauma-accredited academic teaching hospital and outpatient services in Royal Oak, Michigan.

A 71 year old woman with a past medical history of stage 3 rectal cancer underwent robotic assisted abdominoperineal resection. Her postoperative course was complicated by perineal wound dehiscence and infection that required repeated washouts. Although the patient was admitted to the hospital with gabapentin 300 mg every 8 hours and oxycodone 15 mg every 4 hours as needed for severe pain (135 mg oral morphine equivalent prior to admission), postoperatively she was quickly titrated with intravenous hydromorphone at doses equivalent to 600+ mg of oral morphine equivalent per day. Despite significant dose escalation, the patient became more sedated with limited improvement in analgesia. At this time, we elected to start topical morphine applied directly to the surgical wound, which was roughly the size of a softball.

The recent increased use of topical opioids to improve pain control and decrease systemic opioid exposure has created a positive buzz on the benefits of this treatment modality for patients with painful wounds.

panel examining the nation’s opioid crisis advised President Trump to declare a state of emergency due to the opioid epidemic. This comes at a time when mass paranoia about the opioid epidemic has taken over, exerting pressure on state legislatures and congress to respond. Many of the well-known examples of commercially available over-the-counter topical analgesics have been used over the last several decades to provide relief locally at the site of injury. The recent increased use of topical opioids to improve pain control and decrease systemic opioid exposure has created a positive buzz on the benefits of this treatment modality for patients with painful wounds. Its mechanism of action is accomplished via transdermal delivery allowing drugs to solubilize in order to penetrate the layers of tissue. Gels form liposomes that carry the drug down between the cells of the dermis and epidermis to gain access to the sensory neurons. Topical application minimizes adverse effects by delivering drug to the site of injury, rather than systemic exposure. Excess sedation, respiratory depression, and pruritus are some of the adverse effects to monitor. The risk of systemic adverse effects is increased with topical opioid use on larger wounds (>10 cm in diameter) and with more lipophilic opioids (fentanyl, methadone).

Research confirms a peripheral site of action for many of these drugs. Many examples of medications that have been compounded for topical use exist, and include many of the commonly known anti-inflammatory drugs such as diclofenac and ketoprofen. This article will focus on topical opioids and how they may exert local relief, ultimately reducing the amount of systemic opioid requirements. Preliminary research examining topical opioids has suggested that they can be effective local analgesics. Topical opioid gels are not available commercially and need to be prepared by a pharmacy with compounding capabilities. Several small case Q4 | 2017

series have shown rapid relief using topical opioids in patients with pain due to skin infiltration of tumor, skin ulcers of malignant and nonmalignant origin, severe oral mucositis, knee arthritis, and other painful inflammatory conditions.1 The presumed mechanism of action for topically applied opioids producing analgesia is interaction with opioid receptors located on sensory nerve terminals. Researchers also acknowledge the belief that opioid receptors are upregulated in inflamed tissues. The insight that opioids exert a local analgesic effect is based on several observations: 1 Opioid receptors have been found on peripheral nerves and inflamed tissue; www.painweek.org | PWJ

KeY TOPiC

The results…indicated that topical opioids are clinically useful and safe for controlling inflammatory pain in wounds. Systemic absorption occurs at a minimal concentration making it a safe alternative to systemic opioids.

2 Morphine and its metabolites are largely undetectable systemically when applied topically to skin ulcers (suggesting the analgesic effect is local); and 3 Peripheral opioid injections for local analgesia, such as intra-articular morphine after knee arthroplasty, have been found to be effective in several trials.2 Similarly, reports of morphine in INTRASITE gel applied topically to painful ulcers have shown clinical improvement in pain management.3,4

Table 1. Absorbency of Dressings Dressing

Low

Hydrogel*

Low adherence dressings (Vasoline® gauze; 3M Tegaderm™)

Hydrocolloids†

Medium

High

Film dressings† * * Published literature examining the benefits of topical opioids to date is limited and at times Alginate powder (stoma powder) * * reveals inconsistent conclusions. This could be Hydrofiber technology (AQUACEL®) largely due to the design of many of the available * * publications, which are retrospective reviews or Foam dressing (ALLEVYN, Mepilex®) * * case series. There are a variety of existing small sample studies that use different formulations Calcium alginates (Kendall Curasorb™) * * and concentrations of opioid with different Capillary action dressings (Advadraw®) base solutions and dosing frequency. A system* * atic review of topical opioids by Graham et al *Topical opioid may be mixed with this dressing, serving as a vehicle of drug delivery examined topical opioids for painful cutaneous †May be useful in rehydrating desiccated wounds lesions.5 A total of 27 articles were included, with 170 patients total. The main limiting barrier to fully understanding the effects were the variations in size and etiology of the wounds, preparation and Many opponents to using a topical opioid solution state that application of the topical solutions, dosages, and frequency there is inconclusive evidence and potential harmful effects of application. The results of the review indicated that topical on wound healing. This topic remains somewhat controversial opioids are clinically useful and safe for controlling inflamma- in the current published literature. More recent publications tory pain in wounds. Systemic absorption occurs at a minimal are questioning the theory that opioids impair wound healing.5 concentration making it a safe alternative to systemic opioids.3 Since opioids are potent vasodilators, they promote blood flow The large amount of variability seen in the available data indi- to a healing wound. There seems to be more pronounced healcates the need for a systematic approach and evaluation, to ing after 4 weeks of morphine gel application to the affected establish effectiveness and dose-response relationships of area, and the wound under the gel healed more quickly than usual.5 The morphine gel is postulated to have an anti-inflamclinical opioids to inform clinical guidelines. matory effect within the wound and morphine may act as an Woo et al performed an evidence based review of wound treat- endothelial growth promoting and angiogenic growth factor.7 ments, providing an evidence based approach to manage persistent wound related pain. Using this information may help When considering a compound base for the solution, the clinistandardize the variability in application and use amongst cian should know what they are trying to achieve. For examclinicians, in order to fully appreciate the effects of topical ple, silicone wound dressings involving silicone adhesive or opioids. When considering wound dressings, one should self-adhesive polyurethane foam will remove less stratum corappreciate the selection of the product.6 Table 1 illustrates the neum. Wound dressings composed of composite hydrocolloid or polyurethane foam with acrylic adhesive adheres strongly variability of absorbency.

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to the wounds and may cause more damage to the periwound skin. Knowledge of these nuances will allow clinicians to more appropriately select solutions that work given each clinical scenario. At our institution, we have established a topical solution containing morphine, SOLOSITE (as an equivalent to INTRASITE), and lidocaine. Our final compounds are as follows in Table 2.

Table 2. Final Compounds Opioid

Vehicle

Additive

Total Volume unit-of-use

Morphine 10 mg (1 mL)

solosite 10 gm (0.1% w/w) (9 mL)

None

10 mL

Morphine 10 mg (1 mL)

solosite 10 gm (0.1% w/w) (9 mL)

Lidocaine 2% 300 mg (15 mL)

25 mL

Given the limited but growing evidence in favor of topical solutions, careful guidelines should be established to facilitate proper indications for use. Due to difficulty with medication procurement (resources needed for compounding), patients must be reviewed by a specialist. The following criteria was implemented at our institution with regards to patient selection8: →→ Terminal or palliative care patients only →→ Painful wounds <10 cm in diameter →→ Non-neuropathic, localized pain →→ Opioid-naïve patients →→ Patients with a history of addiction to drug or alcohol (only where the introduction of systemic opioids would be inappropriate or is refused by the individual patient) →→ Opioid-tolerant patients (only where the side effects prevent adequate dose escalation of the systemic opioid dose) The following patients should be excluded from use of topical opioids8: →→ Patients with hypersensitivity (eg, rash) to morphine or other opioid derivatives used in the topical formulation →→ Individuals younger than 18 years of age →→ Patients with wounds around or close to the eyes →→ Patients with wounds with excessive exudate or bleeding, because the gel will not adhere to the wound surface (topical morphine causes vasodilation leading to more bleeding) →→ Patients with acute respiratory depression →→ Patients receiving topical anti-infective treatment for infected wounds Q4 | 2017

Administration of topical solutions should be done carefully. The entire contents of the syringe containing the solution should be applied topically to each wound with each dressing change, up to a maximum of 3 times per day. The packaging into unit-of-use topical syringes facilitates medication application to the wound as the nurse will have more accurate guidance when placing the topical solution throughout the wound in a back and forth motion filling in the wound using a “squirt gun” application to the open wound, especially covering the wound edges (where many nerve endings are exposed). To reduce the risk of an administration error, it is important to dispense the unit-of-use topical syringe that does not interface with any intravenous systems your health system utilizes. The nurse or physician applying the medication must use a gloved hand to evenly distribute medication throughout entire wound. The glove and topical syringe should be disposed in the sharps container (in compliance with controlled substance disposal policy). Do NOT apply external heat to the wound. Apply ordered dressings to the wound following medication application as indicated. After application of the solution, patients should avoid showering, bathing, or washing application sites for at least 12 hours. Topical opioids should be used with caution in the following individuals: those with 1 Intolerance to the systemic side effects of morphine or other opioid derivatives; 2 Severe renal impairment (eGFR <30 mL/min) or severe hepatic impairment (used in preference to systemic treatments for this very reason); or 3 Severe impairment of the central nervous system, such as head injury or raised intracranial pressure (used in preference to systemic opioids to reduce the risks of adverse effects). Physicians should monitor carefully for signs of opioid accumulation and toxicity over time. Care should be taken in bleeding or exuding wounds due to reduced inability of the INTRASITE gel or chosen base to adhere to the wound surface. As indicated previously, morphine has a vasodilatory effect and may increase bleeding if hemostasis has not been achieved. Hydrogels have a propensity to macerate the wound if left on too long or if an excessive amount of the gel is applied. Alternatively, for wounds with excessive exudative drainage, dry medication powders such as methadone in alginate powder may be applied by blowing the compounded mixture into the wound using a powder duster.9 Very few side effects have been reported within the available literature regarding the use of etopical morphine. There is a potential for systemic absorption especially over large areas or with higher concentrations. Patients should be monitored closely for opioid side effects, especially if also taking systemic opioids concomitantly. Pruritus, burning, and discomfort at the site of application of the morphine gel has been reported when using INTRASITE/SOLOSITE gel which contains propylene glycol. To mitigate this, lidocaine can be added to reduce burning or discomfort. Alternatively, you could consider changing the solution base. Propylene glycol has been reported to be a potential irritant and sensitizing agent in a small number of patients.

www.painweek.org | PWJ

KeY TOPiC

With the growing knowledge base and use of topical opioid solutions, consideration of potential challenges is warranted. If use of these medications expands outside of palliative care services to include wound care teams or plastic surgery teams, additional resources would be needed to meet needs. Hospitals or treatment centers would need to be equipped with personnel in the inpatient and outpatient pharmacy settings to keep up with the patient and/or service demands. Compounding may require outsourcing. Additionally, once patients are discharged (either home or to long-term care facilities), knowledge of insurance coverage of these medications is necessary.

formulation and protocol. Despite inconsistent findings in the literature, this therapy appears to be very promising with positive outcomes observed with adoption of this treatment modality in our clinical service. References 1. Watterson G, Howard R, Goldman A. Peripheral opioids in inflammatory pain. Arch Dis Child. 2004;89:679–681. 2. Zeppetella G, Ribeiro MDC. Morphine in Intrasite gel applied topically to painful ulcers. J Pain Symptom Manage. 2005;29:118–119. 3. Ribeiro MDC, Joel SP, Zeppetella G. The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage. 2004;27(5):434–439.

conclusion of the usual patient case

With the use of topical morphine 10 mg in SOLOSITE 10 g (0.1%) 10 mL, applied directly to the surgical wound, the colorectal surgery service reported that the “morphine gel helped tremendously with dressing changes” to the extent that the patient began to tolerate the dressing changes and packing procedure at bedside without the need for conscious sedation or intravenous opioid. The surgical team further commented, “wound appears to be healing well” only 2 days into the use of the topical morphine. Following a short inpatient stay, the 71 year old woman was successfully discharged with a significantly reduced systemic opioid exposure including only hydrocodone/APAP 7.5/325 twice daily in addition to the topical morphine in SOLOSITE (14 mg oral morphine equivalent at discharge). The patient continued to use the topical morphine compound for an additional 2 months, until the surgical wound healed in its entirety. The patient never reported adverse effects of the topical treatment.

4. Zeppetella G, Paul J, Ribeiro MDC. Analgesic efficacy of morphine applied topically to painful ulcers. J Pain Symptom Manage. 2003;25:555–558. 5. Graham T, Grocott P, Probst S, et al. How are topical opioids used to manage painful cutaneous lesions in palliative care? A critical review. Pain. 2013;154(10):1920–1928. 6. Woo KY, Abbott LK, Librach L. Evidence-based approach to manage persistent wound-related pain. Curr Opin Support Palliat Care. 2013;7:86–94. 7. Ondrovics M, Hoelbl-Kovacic A, Fux DA. Opioids: modulators of angiogenesis in wound healing and cancer. Oncotarget. 2017;8(5):25783–25796. 8. Northamptonshire Healthcare. Guidelines for the use of topical morphine for painful skin ulcers in palliative care. Version 1, November 2012. Available at: www. neneccg.nhs.uk/resources/uploads/files/use%20of%20topical%20Morphine.pdf 9. Gallagher R. Management of painful wounds in advanced disease. Can Fam Physician. 2010Sep;56(9):883–885.

conclusion There is a clear need for more prospective studies designed with power, adequate sample size, and a standardized treatment

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SHORT CUTS

Kate Schopmeyer pt, dpt, cpe Physical Therapy Program Coordinator San Francisco VA Healthcare System

I believe that my most meaningful contribution to patient care is imparting hope in people who may think there is no reason to expect it…

GPS San Francisco, ca Typical Day “Each day is different from the last, but all have a combination of direct patient care, program development, and collaborating with my colleagues.” Persona “My lifestyle preference is to remain constantly in motion, with occasional binge watching of a TV show to counterbalance the hectic weeks, and carving time out to read for leisure each week.” Social Media Habits “I most use Facebook, followed by Instagram. Most of my fb friends and I are connected because we share professional interests, primarily that of improving treatment approaches for and reducing stigmas toward persistent pain. Instagram is a source of creative inspiration and a means of seeing what those in my personal life are up to. I don’t tweet. I may never tweet.” Contribution “Contrary to most attitudes I encounter (‘You work in chronic pain? That must be so difficult and depressing….’), I am fascinated by neuroplasticity and the science of pain, which means I have genuine enthusiasm for my work. Because my passion is palpable, I believe that my most meaningful contribution to patient care is imparting hope in people who may think there is no reason to expect it; I am big on giving permission to laugh and laugh often, despite living with pain.” People “Edmund Burke has been quoted saying, ‘All tyranny needs to gain a foothold is for people of good conscience to remain silent.’ In the global social climate of 2017, I admire those who take a stand against hate, suppression, and nationalism, despite potentially significant consequences for speaking up. Malala Yousafzai is one example. Justin Trudeau, Angela Merkel, and Bernie Sanders in the political arena; Samantha Bee and Steven Colbert in the entertainment sector.” Words “Everyone should spend time reading novels—any novel, from any period, about any subject matter. Regular reading of fiction also provides a playground for the imagination, which can strengthen problem-solving abilities and creative thinking. I would take a good book over a good movie any day of the week.” Popcorn “Watching E.T. when I was in the 3rd or 4th grade must have had a strong influence. After having watched that film, I recall internally processing the notion of welcoming ‘otherness’ and overcoming fear of the unknown. I think E.T. was the first film to have sparked my affinity towards science fiction, which has been one of my favorite film genres for some time.” PAINWeek “In addition to the fabulous artwork and jazzy framework that hugs the corridors and session halls during the conference, PAINWeek offers the chance to meet and get to know other professionals from different disciplines who are all interested in improving healthcare for people with one of the most difficult conditions to treat. The interdisciplinary nature of this conference is unique, and invaluable. Dr. Sean Mackey is famous in my mind for saying, ‘treating chronic pain is a team sport.’ If we never have the chance to engage in meaningful discourse (particularly the kind that challenges our own beliefs) with our team mates out there, we are not likely to win many games.” Q4 | 2017

www.painweek.org | PWJ

SHORT CUTS

By Doug Gourlay md, msc, frcpc, fasam

Have you ever noticed that people who fall through the cracks seem to hang out around the cracks? Some patients, no matter how hard everyone tries, always seem to miss their appointments with medical referrals. Or someone misplaces their urine drug sample… It’s never their fault that the udt didn’t get done. Accepting responsibility for one’s own actions is a very healthy sign of patient stability.

58 PWJ | www.painweek.org

Q1 | 2017

SHORT CUTS

Repeat injections

common surgical interventions for anterior cruciate ligament (acl) injury are equally effective at repair, but equally ineffective at prevention of re-injury, which occurs in

up to

30%

of intra-articular triamcinolone provided no significant reduction in pain from knee osteoarthritis compared to placebo over a

2-year evaluation period,

younger active patients.

patients

The study examined

were randomized to receive

315 patients

40 mg/mL triamcinolone or

who were assigned to

1 of the 3 surgical approaches, with postsurgical follow-up at 3 and 6 months, and again at

1 mL of 0.9% sodium chloride. Assessments taken at baseline,

1-year, and 2-year intervals showed no significant difference in pain scores.

1-, 2-, and 5-year intervals. A 32-item questionnaire

found no significant differences in

acl quality of life.1

Researchers concluded that a regimen of

4 corticosteroid injections per year was not clinically useful for pain.3

may be associated with

accelerated cognitive decline and dementia.

10,000

over

To evaluate

the anesthetic efficacy of a

vibrating cold device (vcd),

251

a study examined outcomes in

A population of

adults,

median age 73 years,

children

aged 4 to 18 years

underwent 2 interviews 2 years apart.

who received IV injections

% who reported The persistent pain at baseline were observed to experience

during their emergency room admission.

10.9

accelerated memory decline

9.2% dementia 7.7%

more often,

and

more often over the ensuing 12 years than patients who did not report such pain.2

patients

who suffered head injury were screened for inflammatory biomarkers at

1 4 12 72 -,

- , and postinjury.

- hours

In comparison to a control group of uninjured volunteers, the tbi cohort were found to present with 3 specific biomarkers that could be useful predictors of secondary injury events.5

Mothers who breastfed their caesarian-delivered babies for at least 2 months were found to experience

less chronic pain

Does pain age the brain? Chronic pain in older adults

Blood samples from

according to a recent study.

140

A study

has isolated inflammatory biomarkers that may improve prediction of secondary effects from traumatic brain injury (tbi).

Patients were randomized to receive

from their surgery.

185

women

who underwent C-section in 2015 and 2016 were interviewed about their pain levels, their breastfeeding practice, and their anxiety state at

24 hours, 72 hours, and 4 months postdelivery.

either 4% topical lidocaine or VCD prior to IV insertion. Self-report scores of pain and anxiety showed that

VCD was

equally effective as the more typically used topical lidocaine.4

% Only of women who breastfed reported pain at the 4-month interview vs

of mothers who did not.6

1. http://bit.ly/2xaGhT0 2. http://bit.ly/2xazvkX 3. http://bit.ly/2yEmg8b 4. http://bit.ly/2g5JihM 5. http://bit.ly/2xb3LHt 6. http://bit.ly/2hIukBL

Q4 | 2017

www.painweek.org | PWJ

SHORT CUTS

Opioid Induced Respiratory Depression: Risks and Assessment Tools

Jeffrey Fudin bs, pharmd, fccp

In terms of who may end up with opioid induced respiratory depression, unfortunately many think of patients who are abusing these medications. That’s a small part of the people that are dying from opioids. Legitimate patients on a regular dose of opioids for months or years have risks that are unpredictable. One risk would be drugdrug interactions that were not anticipated. For example, a patient has been on a regular dose of oxycodone and the clinician really doesn’t think it’s too much of a problem, which is probably correct. But then the patient develops pneumonia and is given a prescription for clarithromycin or erythromycin, which blocks the metabolism of the oxycodone. Now you’ve got an active drug that’s starting to build up in the system, which could potentially lead to respiratory depression. And then the patient is started on an antibiotic that elevates the blood levels but not enough to push the patient over the edge. But the patient was given a prescription for cough syrup that is diphenhydramine, a sedating agent. And then the patient takes alprazolam because their back starts to hurt because they’re coughing so much. This person now could run into trouble and die. You can’t possibly know this when the patient leaves the office. When qualifying the patient for take home naloxone, there is a validated risk tool, which is a multivariate regression model. The tool identifies certain items that would elevate risk and will actually predict a percent of risk of opioid induced respiratory depression for a patient. But one of the biggest problems for clinicians is the lack of extensive documentation. I developed a software application that’s basically a point and click. It’s very comprehensive. The doctor spends one or two minutes checking boxes and now they have a comprehensive record of their evaluation, and they can select Evzio or Narcan or whatever naloxone they want. You can also generate a prior authorization that goes to the insurance company.

Integrative Pain Management and the Role of Nutrition: Address the Causes, Not Just the Symptoms Heather Tick md

Integrative medicine brings to pain management the culture change that the Institute of Medicine has called for. It is the change in focus

60 PWJ | www.painweek.org

of what our medical system does. We don’t really have a real healthcare system: we have a disease management system. What we’re seeking to do is put health first. Let’s try and see what we can do that’s health promoting, that’s health creating, because in fact between 70% and 80% of our health outcomes are actually dictated by what we do, not by our genetics. We have a lot of power to change our health outcomes based on what we eat, drink, think, feel, and do. And that’s really the approach of integrative medicine, to look at all the things we can do to improve our health. Today’s model of healthcare focuses on disease, and it comes from a silver bullet model. We had a dread disease like pneumonia that killed 50% of the people who got it, even if they were young and healthy. We developed antibiotics and suddenly that didn’t happen anymore. Then there were anesthetics and the surgeries that we could do because of them, and there were these miraculous changes that happened in healthcare as a result. For certain acute things, that model works. But most of medicine now is about chronic disease and that model doesn’t work for chronic disease. We’re still thinking of ourselves as gunslingers with a silver bullet, but the silver bullet doesn’t hit the target anymore and there’s a lot of collateral damage as a result of some of the things that we do. Patients with pain are extremely complex and far too often we’re settling for simple solutions that aren’t adequate for the complex problems that they have. Pain scores I think are virtually useless. They really reflect function very poorly. And what we really want to know is how our patients are doing, not what number do they choose. People will choose a number based on their distress at that moment and it may reflect function or it may not. Pain scores have also encouraged more use of drugs, more opioid treatment, in order to bring scores down to a particular level.

Spinal Manipulative Therapy– What We Know, What We Don’t Steven George pt, phd

There’s a lot of interest in spinal manipulative therapy, partly because it’s been around for a long time. The debate has moved from whether it’s “legitimate” to what are the magnitude of the treatment effects and who is it beneficial for. The research has been interesting because obviously the debate hasn’t been resolved. It’s becoming refined enough now that I think there are some key bits of information that we can get a move on in future studies to help improve clinical practice and help us understand what type of benefit and who is going to benefit most from receiving spinal manipulative therapies. There’s little doubt that spinal manipulation is modulating nociception. But it is really important to differentiate between nociception and pain because when you measure clinical outcomes, there are plenty of trials where there are no differences between spinal manipulative therapy and comparison treatments. It’s an interesting paradox and something I think we can tease out because ideally, the modulation of nociception would have a bigger benefit clinically but that hasn’t been the case. Looking to future research, one of the things we need to consider is the type of endpoints that we’re using. Especially with back pain, there is usually pain while patients are moving, and if that endpoint isn’t teased out from the more spontaneous or resting pain, which is more commonly measured, that could be an issue. Another very foundational issue is that the adequate dosage has not been established. And some people just seem to respond better, and so

Q3 | 2017

we need to get better at identifying who the responders are. All of these things will help us to better understand who can benefit the most from this treatment approach.

Appreciating Patient Differences– The Key to Treating Vulvar Pain

Q3 | 2017

get an answer back saying “Yeah, I’ve actually been having a lot of pain with intercourse” or problems with libido. There are also screening questionnaires available for vulvodynia that patients can fill out in the waiting room just like any other questionnaire.

Risk Management for Prescribing Clinicians

Georgine Lamvu md, mph, facog

Michael Barnes jd, miep

I consider vulvodynia one of those hidden female pain syndromes that no one talks about. Patients don’t talk about it unless providers are astute enough to pick up the symptoms and signs, and to screen women. We know that vulvodynia, which is chronic vulvar pain and chronic pain with intercourse as well, affects about 14 million women in the United States. About 21% of the female population throughout their lifetime are reported as having some type of vulvar or vaginal pain syndrome—and we know that the majority of those women just live with that pain. The consequences of that are amazing. Women with vulvodynia have the same patterns of disability and psychiatric comorbidities and other comorbid pain syndromes such as IBS and fibromyalgia. There’s a huge interaction between these pain syndromes. Vulvodynia seems to be omitted because it’s hard to talk to a woman about her private parts, especially if you’re not trained to do that. The easiest way to screen a patient for vulvodynia is to do it when you are screening for other pain syndromes. When a patient shows up with a chronic pain syndrome such as fibromyalgia, ibs, painful bladder syndrome, migraines, chronic fatigue syndrome… at some point when you build up enough trust, you have to start asking about other parts of their quality of life, and one of those is sexual health. Ask them if they have pain elsewhere, including their pelvic region, their vaginal areas. It’s amazing how many times you’ll

It is possible to provide the best care for a patient and protect yourself from criminal and civil liability. In fact, when you do one right, you do the other right as well. Typically you want to look for 3 things as a prescriber of any controlled prescription medication, opioid or otherwise. You want to make sure there is a legitimate medical need. You should make sure that the person is actually enduring a condition that cannot be treated without the controlled medication that you know now is necessary to prescribe. You also need to make sure that you adhere to what is the ordinary course of your professional practice. And so, you look to guidance through prescriber education, through your professional associations and the training materials that are put out by them, as well as entities like the fda and labeling for medications. You pull all that together and do what is consistent with the standard of care. Thirdly, you take reasonable precautions to prevent harm from the controlled prescription medications. That includes things like checking the prescription monitoring program, counseling your patients on the risks and how to take the medication appropriately, store it safely, dispose of it properly, making sure that you do urine drug testing on occasion, and that if there is something that’s different from what was expected in those results, that you take action and adjust the treatment plan. With those 3 things adhered to—the legitimate medical need, ordinary course of professional practice, and reasonable steps to prevent harm—then you do thorough documentation, and make sure it’s all in the medical record, individualized to the person you’re treating, and you will be pretty solid in knowing that you’re giving the best care, and you’re safe from civil and criminal liability.

www.painweek.org | PWJ

SHORT CUTS

with

forest

tennant

md, drph, facpm, mph

PWJ | www.painweek.org

Q1 | 2016

“While administering care in [a methadone] clinic, I realized that some nonaddict, severe pain patients attended the clinic. These patients didn’t belong there, so I designed a special intractable pain and palliative care program…” Q What inspired you to become a healthcare provider?

Growing up in a rural Kansas community, I frequently heard my elders lament the ardent scarcity of family doctors in the area. When challenged by friends and family during an increased paucity of medical care, a discussion was initiated by my mother. “You should be a doctor” was her sole comment. My mother’s foresight was never questioned. I thank her for her encouragement, support, and pride.

Why did you focus on pain management?

In the early 1970s as a public health postdoctoral fellow at ucla, I assisted in developing their methadone clinic for heroin addicts. We became aware of a need for clinics throughout Los Angeles County. While administering care in the clinic, I realized that some nonaddict, severe pain patients attended the clinic. These patients didn’t belong there, so I designed a special intractable pain and palliative care program in West Covina, California. This program’s progress has been an opportunity to educate patients, doctors, pharmacies, and insurance companies.

Who were your mentors?

As one goes through a long career, many mentors from different fields are special gifts. I have been grateful for so many. I list a few here.

Q4 | 2017

Business: Hugh Moore, President, Mark Four Companies Medicine: Frank Frazier, MD, US Public Health Service, Lexington, Kentucky Achievement: Zig Ziglar, Motivational Speake and Author Public Relations: George Strachan, Executive Director, Chamber of Commerce, West Covina, California Real Estate: Forest S. Tennant, Sr., President, Jayhawk Realty, Co. I would be remiss if I didn’t mention my mentoring and caring wife of 51 years who taught me the joys of a balanced life, love, and simple fun.

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

Actually, I have a parallel, second career as a real estate investor. While I was serving as a US Army Medical Officer overseas during the Vietnam War, I started sending money home to invest in Kansas real estate. My original intent was to prepare for retirement or a time I couldn’t practice medicine. I’ve been blessed to have two avocations that I dearly love.

What is your most marked characteristic?

I have an innate need to be constantly physically and mentally active. I must always be pursuing goals and education.

www.painweek.org | PWJ

PUNDi T PROFiLe/TeNNaNT

“I want my legacy to be simple: ‘Service Above Self.’”

Q What do you consider your greatest achievement?

In looking back over a long medical career of over 50 years, my basic achievement has simply been to develop better diagnostic and treatment tools for the setting I was in—be it military, sports, public health, addiction, primary care, or pain. I suspect the medical achievement, for which I’ll be most remembered, will be the initiation of hormonal and neuroinflammatory treatments for severe, chronic pain problems.

What is your favorite language?

a In pain practice I would like to leave a legacy as one who sought to treat the underlying causes of severe, chronic and intractable pain rather than just throw symptomatic drugs at it. I especially hope to leave behind a solid understanding and treatment approach to adhesive arachnoiditis, which is often a horrible disease. In my local community of West Covina, California, I want to leave a legacy through the Tennant Foundation that supports philanthropic activities and some very special antique collections and museums. I want my legacy to be simple:

English is my sole language. However, I intensely studied Latin while in college. A continuous abundance of writing projects both professional and for enjoyment creates an impetus to expand understanding and usage of both languages.

What would you like your legacy to be?

“Service Above Self.”

What is your motto?

In business, don’t set big goals, but do a little something each day to improve your enterprise.

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?

As an old-time and older physician, don’t retire but give back part-time in a caring endeavor where you can pass on not only your medical experience but spirituality and life skills.

Book: The Bible Film: The Thomas Crown Affair (Pierce Brosnan) Song: Soft Summer Breeze by Eddie Hayward

Forest Tennant, md, drph, facpm, mph, is Editor of Practical Pain Management in West Covina, ca.

PWJ | www.painweek.org

Q4 | 2017

GRALISE® (gabapentin) tablets Rx Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use GRALISE safely and effectively. See full Prescribing Information for GRALISE. INDICATIONS AND USAGE • GRALISE is indicated for the management of postherpetic neuralgia. • GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. DOSAGE AND ADMINISTRATION • GRALISE should be titrated to an 1800 mg dose taken orally, once-daily, with the evening meal. GRALISE tablets should be swallowed whole. Do not crush, split, or chew the tablets. For recommended titration schedule, see DOSAGE AND ADMINISTRATION in full Prescribing Information. • If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). • Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 mL/min or in patients on hemodialysis. CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. WARNINGS AND PRECAUTIONS GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Table 1: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in GRALISE) in the Pooled Analysis

Indication Epilepsy Psychiatric Other Total

Placebo Patients with Events Per 1000 Patients 1.0 5.7 1.0 2.4

Relative Risk: Risk Incidence of Difference: Events in Drug Additional Drug Patients Patients/Incidence Drug Patients with Events Per in Placebo with Events Per 1000 Patients Patients 1000 Patients 3.4 3.5 2.4 8.5 1.5 2.9 1.8 1.9 0.9 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed, are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that GRALISE contains gabapentin, which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and pre-existing tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established. ADVERSE REACTIONS Clinical Trials 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. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness.

Table 2: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group) Body System – Preferred Term Ear and Labyrinth Disorders Vertigo Gastrointestinal Disorders Diarrhea Dry mouth Constipation Dyspepsia General Disorders Peripheral edema Pain Infections and Infestations Nasopharyngitis Urinary tract infection Investigations Weight increased Musculoskeletal and Connective Tissue Disorders Pain in extremity Back pain Nervous System Disorders Dizziness Somnolence Headache Lethargy

GRALISE N = 359 %

Placebo N = 364 %

1.4

0.5

3.3 2.8 1.4 1.4

2.7 1.4 0.3 0.8

3.9 1.1

0.3 0.5

2.5 1.7

2.2 0.5

1.9

0.5

1.9 1.7

0.5 1.1

10.9 4.5 4.2 1.1

2.2 2.7 4.1 0.3

The following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis, viral herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. Postmarketing and Other Experience with Other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain, and sweating. DRUG INTERACTIONS In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day). Hydrocodone Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of the interaction at other doses is not known. Antacid (containing aluminum hydroxide and magnesium hydroxide) An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by approximately 20%, but by only 5% when gabapentin immediate release was taken 2 hours after the antacid. It is recommended that GRALISE be taken at least 2 hours following the antacid (containing aluminum hydroxide and magnesium hydroxide) administration. Drug/Laboratory Test Interactions False positive readings were reported with the Ames-N-Multistix SG® dipstick test for urine protein when gabapentin was added to other antiepileptic drugs; therefore, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein. USE IN SPECIFIC POPULATIONS Pregnancy Category C: GRALISE should be used during pregnancy or in women who are nursing only if the benefits clearly outweigh the risks. See full Prescribing Information for more information about use of GRALISE in pregnancy. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCl between 15 and 30 or in patients undergoing hemodialysis. [see Dosage and Administration in full Prescribing Information]. DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies. OVERDOSAGE Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Relief Uninterrupted

Bring 24-hour relief into their routine

GRALISE is the only true once-a-day gabapentinoid that offers Night to Day control of PHN pain1

• Patients receiving GRALISE experienced significant pain reduction vs placebo beginning Week 1 and continuing throughout the 10-week study (P<0.05)2,3 •Average daily pain score reduction for GRALISE was -2.1 vs -1.6 with placebo (P=0.013)2 Study Design: Patients from 89 investigative sites participated in this randomized, double-blind, parallel design, placebo-controlled, multicenter clinical trial. The study period included a 1-week baseline period, followed by randomization and a 2-week titration to a once-daily dose of 1800 mg G-GR or matched placebo, followed by an 8-week maintenance-dose period, followed by a 1-week dose-tapering period. 452 patients were randomized, with 221 receiving 1800 mg of GRALISE and 231 receiving placebo.2 Primary endpoint: change in the baseline observation carried forward (BOCF) average daily pain score from the baseline week to Week 10 of the efficacy treatment period.2

Learn more today at www.Gralise.com INDICATIONS AND USAGE GRALISE is indicated for the management of postherpetic neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS The most common side effects were dizziness (10.9%) and somnolence (4.5%). USE IN SPECIFIC POPULATIONS Reductions in GRALISE dose should be made in patients with age-related compromised renal function.

WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

For more information about GRALISE, please see Brief Summary on the following page.

References: 1. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012. 2. Sang CN, Sathyanarayana R, Sweeney M. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281-288. 3. Argoff CE, Chen C, Cowles VE. Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview. Expert Opin Drug Deliv. 2012;9:1147-1160.