PAINWeek Journal Vol 5, Q3 by PAINWeek

vol. 5 q 3 2017

the mirror has 2 faces p.20 the challenges of assessing pain in a busy emergency department p.32 why skin matters p.40 pain, drugs, and ethics—a delicate balance p.62

TIME TO DUAL

TW O O NE SOURCES SOURCE

OF PAIN OF RELIEF NUCYNTA® ER is the first and only FDA-approved long-acting opioid designed to control both nociceptive pain and the neuropathic pain associated with diabetic peripheral neuropathy (DPN). Not an actual patient.

Visit Nucynta.com for more information and to download a NUCYNTA® ER savings card

INDICATIONS AND USAGE Limitations of Use NUCYNTA ER is an opioid agonist indicated for the management of: • Because of the risks of addiction, abuse, and misuse with opioids, • pain severe enough to require daily, around-the-clock, longeven at recommended doses, and because of the greater risks of term opioid treatment and for which alternative treatment overdose and death with extended-release opioid formulations, options are inadequate reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate• neuropathic pain associated with diabetic peripheral release opioids) are ineffective, not tolerated, or would be neuropathy (DPN) severe enough to require daily, around-theotherwise inadequate to provide sufficient management of pain. clock, long-term opioid treatment and for which alternative treatment options are inadequate. • NUCYNTA ER is not indicated as an as-needed (prn) analgesic. NUCYNTA® ER IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.3). • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7).

Please see additional Important Safety Information, including BOXED WARNING, and Brief Summary on the following pages.

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product. • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extendedrelease products such as NUCYNTA 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 tapentadol present. 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 NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death. Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. 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. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA 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. Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. 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 NUCYNTA 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. Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA 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: NUCYNTA 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 NUCYNTA ER.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Alternatively, consider the use of non-opioid analgesics in these patients. Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs.Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range. See Warnings and Precautions in full Prescribing Information for a list of symptoms associated with Serotonin Syndrome. Discontinue NUCYNTA ER if serotonin syndrome is suspected. 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 NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA 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 (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA 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 NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA 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 NUCYNTA ER therapy. Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing NUCYNTA ER, gradually taper the dose. Do not abruptly discontinue NUCYNTA ER. Risks of Driving and Operating Machinery NUCYNTA 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 NUCYNTA ER and know how they will react to the medication. Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. ADVERSE REACTIONS In clinical studies, the most common (â&#x2030;Ľ10%) adverse reactions were nausea, constipation, vomiting, dizziness, somnolence, and headache.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Select Postmarketing Adverse Reactions Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA ER. Advise patients how to recognize such reactions and when to seek medical attention. Panic attack has also been reported. DRUG INTERACTIONS Alcohol See BOXED WARNING. Benzodiazepines and Other Central Nervous System (CNS) Depressants See BOXED WARNING. Serotonergic Drugs See Warnings and Precautions. Monoamine Oxidase Inhibitors (MAOIs) See Contraindications. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics May reduce the analgesic effect of NUCYNTA ER and/or precipitate withdrawal symptoms. Avoid concomitant use. Muscle Relaxants See BOXED WARNING and Warnings and Precautions. Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. NUCYNTA ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Labor or Delivery Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including NUCYNTA ER, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. Lactation Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER.

Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established. Geriatric Use Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient. 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 NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression. Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment is not recommended. In patients with moderate hepatic impairment, dosage reduction of NUCYNTA ER is recommended. Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended. DRUG ABUSE AND DEPENDENCE See BOXED WARNING OVERDOSAGE In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Please see Brief Summary, including BOXED WARNING, on the following pages.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use NUCYNTA ER safely and effectively. See full Prescribing Information for NUCYNTA ER. INDICATIONS AND USAGE NUCYNTA ER (tapentadol) 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 • neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Usage • 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), reserve NUCYNTA 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. • NUCYNTA ER is not indicated as an as-needed (prn) analgesic. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.3). • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7). CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product (see Adverse Reactions). • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see Drug Interactions). WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA 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 tapentadol present (see Drug Abuse and Dependence). Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA 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 NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death (see Overdosage). Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the

proper disposal of unused drug (see Patient Counseling Information). Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see Overdosage). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA 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 NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential (see Dosage and Administration). Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA 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, Patient Counseling Information). Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol (see Clinical Pharmacology). Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already 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 NUCYNTA 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 and Patient Counseling Information). Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA 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: NUCYNTA 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 NUCYNTA ER (see Warnings and Precautions). Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see Warnings and Precautions). Alternatively, consider the use of non-opioid analgesics in these patients. Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration (see Warnings and Precautions). Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic

antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see Drug Interactions). This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected. 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 NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA 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 (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA 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 NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA 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 NUCYNTA ER therapy. Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms (see Drug Interactions). When discontinuing NUCYNTA ER, gradually taper the dose (see Dosage and Administration). Do not abruptly discontinue NUCYNTA ER (see Drug Abuse and Dependence). Risks of Driving and Operating Machinery NUCYNTA 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 NUCYNTA ER and know how they will react to the medication (see Patient Counseling Information). Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment (see Dosage and Administration and Clinical Pharmacology). Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known (see Clinical Pharmacology). 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) • Life-Threatening Respiratory Depression (see Warnings and Precautions) • Neonatal Opioid Withdrawal Syndrome (see Warnings and Precautions) • Interaction with Benzodiazepine or Other CNS Depressants (see Warnings and Precautions)

• Serotonin Syndrome (see Warnings and Precautions) • Adrenal Insufficiency (see Warnings and Precautions) • Severe Hypotension (see Warnings and Precautions) • Gastrointestinal Adverse Reactions (see Warnings and Precautions) • Seizures (see Warnings and Precautions) • Withdrawal (see Warnings and Precautions) Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The most common adverse reactions (reported by ≥10% in any NUCYNTA ER dose group) were: nausea, constipation, dizziness, headache, and somnolence. The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA ER dose group for NUCYNTA ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively. Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients. Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The most commonly reported ADRs (incidence ≥10% in NUCYNTA ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache. Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients. Postmarketing Experience The following adverse reactions have been identified during post approval use of tapentadol. Psychiatric disorders: hallucination, suicidal ideation, panic attack 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 NUCYNTA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see Clinical Pharmacology). DRUG INTERACTIONS Clinically Significant Drug Interactions with NUCYNTA ER Alcohol Clinical Impact:

Concomitant use of alcohol with NUCYNTA ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Due to additive pharmacologic effect, the concomitant use of Impact: benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical The concomitant use of opioids with other drugs that affect Impact: the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.6]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical MAOI interactions with opioids may manifest as serotonin Impact: syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. Intervention: Do not use NUCYNTA 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 May reduce the analgesic effect of NUCYNTA ER and/or Impact: precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Tapentadol may enhance the neuromuscular blocking action of Impact: skeletal muscle relaxants and produce an increased degree of respiratory depression.

NUCYNTA ER (tapentadol) extended-release tablets, CII BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION (continued) Muscle Relaxants (continued) Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUCYNTA ER and/or the muscle relaxant as necessary. Diuretics Clinical Opioids can reduce the efficacy of diuretics by inducing the Impact: release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical The concomitant use of anticholinergic drugs may increase Impact: 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 NUCYNTA ER is used concomitantly with anticholinergic drugs. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions). The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. 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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see Warnings and Precautions). Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychphysiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor. Opioid analgesics, including NUCYNTA ER, can prolong labor. Lactation Risk Summary There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded. Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER. Clinical Considerations Monitor infants exposed to NUCYNTA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established. Geriatric Use Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients. Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function 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 NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see Warnings and Precautions). Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment (ChildPugh Score 10-15) is not recommended. In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), dosage reduction of NUCYNTA ER is recommended (see Dosage and Administration). Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended. DRUG ABUSE AND DEPENDENCE Controlled Substance NUCYNTA ER contains tapentadol, a Schedule II controlled substance.

Abuse NUCYNTA ER contains tapentadol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA ER can be abused and is subject to misuse, addiction, and criminal diversion (see Warnings and Precautions). The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. NUCYNTA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of NUCYNTA ER NUCYNTA ER is for oral use only. Abuse of NUCYNTA ER poses a risk of overdose and death. The risk is increased with concurrent use of NUCYNTA ER with alcohol and other central nervous system depressants. With intravenous abuse the inactive ingredients in NUCYNTA ER can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, 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. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. NUCYNTA ER should not be abruptly discontinued (see Dosage and Administration). If NUCYNTA ER is abruptly discontinued in a physicallydependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see Use in Specific Populations). OVERDOSAGE Clinical Presentation Acute overdosage with NUCYNTA 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. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

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 3 2017

20 32 40

key topic

the mirror has 2 faces

by michael r. clark

acute pain

the challenges of assessing pain in a busy emergency department

by sophia sheikh phyllis hendry

new frontiers

why skin matters

by frank l. rice phillip j. albrecht charles e. argoff

ethics

pain, drugs, and ethics—a delicate balance

by kevin l. zacharoff

69 70 71 72 74

pw next generation

with georgine lamvu

clinical pearls

by douglas gourlay

pain by numbers one-minute clinician

with michael schatman, ramon cuevas-trisan, peter pryzbylkowski, mel pohl, richard harris

pundit profile

with brett r. stacey

PWJ | www.painweek.org

Q3 | 2017

A treatment for opioid-induced constipation (OIC) for your adult patients with chronic non-cancer pain (CNCP) that may help them

GO LIKE CLOCKWORK RELISTOR tablets* deliver a reliable, rapid response, that may give your adult patients relief from OIC they can count on 1,2

% Achieved at least 3 SBMs† per week over 4 weeks

HOURS

vs 38% taking placebo (P=.005)1,2

4 4 HOURS

Patients experienced % relief within 4 hours of dosing

27% of dosing days vs 18% with placebo (P<.0001)2

HOURS

The only PAMORA not metabolized via the CYP3A4 pathway

PAMORA, peripherally acting mu-opioid receptor agonist; SBM, spontaneous bowel movement. * Three 150-mg tablets (450 mg total) once daily in the morning with water on an empty stomach at least 30 minutes before the first meal of the day.1 †

HOURS

No pharmacokinetic drug-drug interactions1

Defined as bowel movement without the use of any laxative in previous 24 hours.1

STUDY DESIGN

In a 4-week, randomized, multicenter, HOURS double-blind, placebo-controlled, phase 3 study, the efficacy of RELISTOR tablets was evaluated in 401 patients (200 RELISTOR tablets, 201 placebo) with CNCP for which they were taking opioids. All patients had OIC, defined as <3 SBMs per week and at least one additional symptom of constipation.1,2

INDICATION • RELISTOR is an opioid antagonist. RELISTOR tablets are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain.

IMPORTANT SAFETY INFORMATION - RELISTOR 150-mg tablets, for oral use • RELISTOR tablets are contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. • Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR tablets in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR tablets in patients who develop this symptom. • If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR tablets and consult their healthcare provider. • Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR tablets. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal. • Avoid concomitant use of RELISTOR tablets with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal. • In a clinical study, the most common adverse reactions for RELISTOR tablets (≥ 2% of RELISTOR patients and at a greater incidence than placebo) in patients with

chronic non-cancer pain were: abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%), hyperhidrosis (3%), anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%). • The use of RELISTOR tablets during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Advise pregnant women of the potential risk to a fetus. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR tablets. • A dosage reduction of RELISTOR tablets is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets is needed in patients with mild renal impairment. • A dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary for RELISTOR tablets on adjacent page and full Prescribing Information at relistor.com. REFERENCES: 1. RELISTOR [prescribing information]. Bridgewater, NJ: Salix Pharmaceuticals. 2. Data on file, Salix Pharmaceuticals.

Tablets

The safety of RELISTOR injection was evaluated in a double-blind, placebocontrolled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 2) included a 4-week, doubleblind, placebo-controlled period in which adult patients were randomized to receive RELISTOR injection 12 mg subcutaneously once daily (150 patients) or placebo (162 patients). After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR injection 12 mg subcutaneously was administered less frequently than the recommended dosage regimen of 12 mg once daily. The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR injection are shown in Table 5. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

BRIEF SUMMARY OF PRESCRIBING INFORMATION This Brief Summary does not include all the information needed to use RELISTOR safely and effectively. See full prescribing information for RELISTOR. RELISTOR (methylnaltrexone bromide) 150 mg tablets, for oral use. RELISTOR (methylnaltrexone bromide) injection, for subcutaneous use. 8 mg/0.4 mL methylnaltrexone bromide in single-dose pre-filled syringe. 12 mg/0.6 mL methylnaltrexone bromide in a single-dose pre-filled syringe, or single-dose vial. Initial U.S. Approval: 2008 INDICATIONS AND USAGE RELISTOR is an opioid antagonist. RELISTOR tablets and RELISTOR injection are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain. RELISTOR injection is also indicated for the treatment of OIC in adults with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Limitations of Use: Use beyond four months has not been studied in the advanced illness population. CONTRAINDICATIONS RELISTOR tablets and injection are contraindicated in patients with known or suspected mechanical gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Consider the overall risk benefit in patients with known or suspected lesions of the GI tract. Cases of gastrointestinal perforation have been reported in adult patients with OIC and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom. Severe or Persistent Diarrhea Discontinue if severe or persistent diarrhea occurs during treatment. Opioid Withdrawal Consider the overall risk benefit in patients with disruptions to the bloodbrain barrier. Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Monitor closely for adequacy of analgesia and symptoms of opioid withdrawal. 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 clinical practice. Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR tablets was evaluated in a double-blind, placebo-controlled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 12-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR tablets 450 mg orally (200 patients) or placebo (201 patients). After 4 weeks of double-blind treatment administered once daily, patients continued 8 weeks of double-blind treatment on an as needed basis (but not more than once daily). The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR tablets are shown in Table 4. Adverse reactions of abdominal pain, diarrhea, hyperhidrosis, anxiety, rhinorrhea, and chills may reflect symptoms of opioid withdrawal. Table 4: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Tablets in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 1) RELISTOR Tablets Placebo Adverse Reaction n = 200 n = 201 Abdominal Pain** 14% 10% Diarrhea 5% 2% Headache 4% 3% Abdominal Distention 4% 2% Vomiting 3% 2% Hyperhidrosis 3% 1% Anxiety 2% 1% Muscle Spasms 2% 1% Rhinorrhea 2% 1% Chills 2% 0%

*Adverse reactions occurring in at least 2% of patients receiving RELISTOR tablets 450 mg once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness.

Table 5: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Injection in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 2) RELISTOR Injection Placebo Adverse Reaction n = 150 n = 162 Abdominal Pain** 21% 7% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% <1% Chills 1% 0%

*Adverse reactions occurring in at least 1% of patients receiving RELISTOR injection 12 mg subcutaneously once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness. During the 4-week double-blind period, in patients with OIC and chronic non-cancer pain that received RELISTOR every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR injection 12 mg subcutaneously every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 2) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%). The safety of RELISTOR injection was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with OIC and chronic non-cancer pain (Study 3). Patients were allowed to administer RELISTOR injection 12 mg subcutaneously less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 2. Additionally, in Study 3, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR. Opioid-Induced Constipation in Adult Patients with Advanced Illness The safety of RELISTOR injection was evaluated in two, double-blind, placebo-controlled trials in adult patients with OIC and advanced illness receiving palliative care: Study 4 included a single-dose, double-blind, placebo-controlled period, whereas Study 5 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common adverse reactions in adult patients with OIC and advanced illness receiving RELISTOR injection are shown in Table 6 below. Table 6: Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR Injection in Adult Patients with OIC and Advanced Illness* (Studies 4 and 5) RELISTOR Injection Placebo Adverse Reaction n = 165 n = 123 Abdominal Pain** 29% 10% Flatulence 13% 6% Nausea 12% 5% Dizziness 7% 2% Diarrhea 6% 2%

*Adverse reactions occurring in at least 5% of patients receiving all doses of RELISTOR injection (0.075, 0.15, and 0.3 mg/kg) and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness. The rates of discontinuation due to adverse reactions during the double-blind, placebo-controlled clinical trials (Study 4 and Study 5) were comparable between RELISTOR (1%) and placebo (2%). Postmarketing Experience The following adverse reactions have been identified during post-approval use of RELISTOR injection. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Perforation, cramping, vomiting. General Disorders and Administration Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported. DRUG INTERACTIONS Other Opioid Antagonists Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal. Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.3 mg/kg of RELISTOR did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. USE IN SPECIFIC POPULATIONS Pregnancy The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier and should be

used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Advise pregnant women of the potential risk to a fetus. Lactation Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR. In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of RELISTOR tablets and injection have not been established in pediatric patients. Geriatric Use In clinical studies of RELISTOR tablets, no overall differences in effectiveness were observed. Adverse reactions were similar; however, there was a higher incidence of diarrhea in elderly patients. In clinical studies of RELISTOR injection, no overall differences in safety or effectiveness were observed between elderly patients and younger patients. Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dosage adjustment based on age is recommended. Monitor elderly patients for adverse reactions. Renal Impairment In a study of subjects with varying degrees of renal impairment receiving RELISTOR injection subcutaneously, there was a significant increase in the exposure to methylnaltrexone in subjects with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault) compared to healthy subjects. Therefore, a dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets or RELISTOR injection is needed in patients with mild renal impairment (creatinine clearance greater than 60 mL/minute as estimated by Cockcroft-Gault). Hepatic Impairment Tablets In a study of subjects with varying degrees of hepatic impairment receiving a 450 mg dose of RELISTOR tablets, there was a significant increase in systemic exposure of methylnaltrexone for subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment compared to healthy subjects with normal hepatic function. Therefore, a dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). Injection There was no clinically meaningful change in systemic exposure of methylnaltrexone compared to healthy subjects with normal hepatic function. No dosage adjustment of RELISTOR injection is needed for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions. OVERDOSAGE A study of healthy subjects noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate. If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. NONCLINICAL TOXICOLOGY Carcinogenesis Oral administration of methylnaltrexone bromide at doses up to 200 mg/kg/day (about 81 times the subcutaneous maximum recommended human dose (MRHD) of 12 mg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the subcutaneous MRHD of 12 mg/day) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the subcutaneous MRHD of 12 mg/day) for 104 weeks did not produce tumors in mice and rats. Mutagenesis Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test. Impairment of Fertility Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the subcutaneous MRHD of 12 mg/day; about 3.3 times the oral MRHD of 450 mg/day) was found to have no adverse effect on fertility and reproductive performance of male and female rats. Animal Toxicology and/or Pharmacology In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone caused concentration-dependent inhibition of hERG current. PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Patient Information). To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Based on 9502500, Rev. 07/2016 Salix Pharmaceuticals 8510 Colonnade Center Drive Raleigh, NC 27615 www.salix.com Manufactured for:

Under license from:

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591 U.S. Patent Numbers: 6,559,158; 8,247,425; 8,420,663; 8,524,276; and 8,956,651 Relistor is a trademark of Salix Pharmaceuticals or its affiliates. RELO.0036.USA.16

e DUCaTiON iS THe BeST aNaLGeSiC. 2018

SePTeMBeR 4—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.

treating patients (with medication based therapy) who present with chronic pain in Pain Awareness Month, and the month in a moral and ethical way that is similar to Kevin L. Zacharoff which the PAINWeek National Conference the methods we use with patients with occurs. It’s the largest and, in my opinion, other medical conditions. Additionally, I most clinically relevant annual pain conference there is. I have said it wanted to make the point that, while we may subconsciously utilize many times before: chronic pain lies on the doorstep, and lives in the all or some of these principles from time to time, we probably should, waiting rooms, of frontline practitioners across the country. Never has in every case, consider them in a balanced way. I don’t think any of us meaningful pain education and its management been more important. would dispute that patients have a right to make informed decisions so The role of this journal is to complement the annual conference and that benefits outweigh risks, harm is avoided or minimized, and care is regional PAINWeekend meetings,* and to continue to build a good and delivered fairly and equitably. In the myriad of guidelines and treatment solid educational foundation. This issue of PWJ does not disappoint. recommendations, I hope this article sheds some light. Our first article, by Dr. Michael Clark, discusses the important subject of chronic pain and comorbid depression. With a prevalence at least more than double that of patients without chronic pain, depression—which may affect 33% to 50% of chronic pain patients—should be top of mind when assessing a patient. Dr. Clark vividly presents a pertinent case study, and then adeptly deconstructs the assessment, and offers practical tips for development of a balanced treatment plan tailored to the context of a patient’s “life trajectory.” This article focuses on what we need to consider for each and every assessment of patients presenting with the complaint of chronic pain, and, with the author’s competent and skilled approach, could not be more clinically relevant. Drs. Sophia Sheikh and Phyllis Hendry discuss something that is dealt with in every Emergency Department in the country today: how to assess pain in that specific institutional setting. Considering the fact that some estimate pain to be a contributor to as much as 78% of ed visits, we might expect that education and negotiation of potential barriers to adequate assessment and treatment of the 5th vital sign would have already been conquered. In fact, the authors point out that many existing policies, procedures, and tools developed for use in other clinic settings can’t be retrofitted to this urgent, often crowded, and high pressure environment. Lack of continuity is addressed as a significant challenge for a chronic medical condition, and a case is made for research and development of ed-specific tools. I couldn’t agree more. With skin being the largest sensory organ in the body, you would think it would be discussed frequently in the context of chronic pain. Drs. Frank Rice, Phillip Albrecht, and Charles Argoff provide an in-depth analysis of the skin’s role in different types of chronic pain, and how, from a scientific perspective, skin biopsies may play a significant role in determining targeted approaches to treating skin related pain pathologies. This article elucidates what we hear more and more in pain research: “personalized medicine” will likely shape therapeutic strategies for treatment of chronic pain in the future.

This issue’s Pundit Profile is devoted to Dr. Brett Stacey. As Medical Director, University of Washington Center for Pain Relief in Seattle, Dr. Stacey shares with me the critically important view that caring for patients is truly a privilege, and that trust and responsibility is paramount in that relationship. Once again, through the Profile we are given revealing and human insight about one of the important leaders of our pain community. The Next Generation profiles Dr. Georgine Lamvu, who is based in Orlando, Florida. Dr. Lamvu was trained as a gynecologist and sheds light on how she is often called upon to treat patients with chronic pelvic pain. She is devoted to being a mentor and helping foster the future generation of pain providers, and we are treated to finding out more about this thought leader. As we enter the final quarter of 2017, there is certainly no lack of issues in pain management for discussion, debate, and digestion. This edition provides much that may be relevant to your practice. Most importantly, the content contains things that you can implement into your clinic practice now, along with future technologies and strategies which are coming down the road, and closer than we might think. If just one topic makes you think a little differently about the patients you see in your clinic setting as a frontline practitioner, then the mission of this issue of PWJ has been accomplished. If you are attending the national PAINWeek conference in Las Vegas, please find me and say hello. I hope to see you there. —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.

Next is an article I have written about a topic that is personally important to me: Pain, Drugs, and Ethics—A Delicate Balance. I teach an elective course on this subject annually to 2nd year medical students; registration is limited and it never fails to fill quickly. The major goal of this piece was to present a reproducible approach to assessing and *Go to painweek.org for more information.

PWJ | www.painweek.org

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Michael R. Clark md, mph, mba

P.20

Michael R. Clark is Vice Chair, Clinical Affairs, and Director of the Pain Treatment Program, Department of Psychiatry & Behavioral Sciences at Johns Hopkins Medicine in Baltimore, Maryland. Dr. Clark specializes in disorders of the special senses such as chronic pain and vestibular & balance dysfunction. Dr. Clark is the Director of the Pain Treatment Program in the Department of Psychiatry & Behavioral Sciences and has joint appointments in the Departments of Otolaryngology/Head & Neck Surgery in the School of Medicine and Mental Health in the Bloomberg School of Public Health. He is a fellow of the Academy of Psychosomatic Medicine.

Frank L. Rice phd

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Frank Rice, cofounder, ceo, and Chief Scientist at Integrated Tissue Dynamics, llc (intidyn), taught for 30+ years at Albany Medical College. He holds an appointment in the Division of Biomedical Sciences, University at Albany in New York. Coauthor Phillip J. Albrecht, phd, is cofounder, vp, coo, and Director of the Neuroscience and Pain Research Group, intidyn. He has a bs in psychology and a phd in neuroscience from Penn State University. Dr. Albrecht taught at Albany Medical College for 10 years and holds an appointment in the Division of Health Sciences, University at Albany. Coauthor Charles E. Argoff, md, cpe, is Professor of neurology, Director of the Comprehensive Pain Center at Albany Medical Center.

Sophia Sheikh md, facep

P.32

Sophia Sheikh is Assistant Professor in the Department of Emergency Medicine, University of Florida College of Medicine-Jacksonville. Dr. Sheikh coauthored her article with Phyllis L. Hendry, md, faap, facep, is a Professor of Emergency Medicine and Pediatrics, and Assistant Chair, Research, Department of Emergency Medicine, in Jacksonville, Florida. They are investigators for the Pain Assessment and Management Initiative (pami), an educational and patient safety project for emergency healthcare professionals.

Kevin L. Zacharoff md, facip, facpe, faap

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Kevin Zacharoff is a Board-Certified Anesthesiologist with over 25 years of clinical experience in Anesthesiology and Pain Medicine. He is an active Faculty Member and Clinical Instructor at suny Stony Brook School of Medicine, the Executive Editor of pwj—PAINWeek Journal, Chairperson of the Ethics Committee at St. Catherine of Siena Medical Center in Smithtown, New York, and a member of the Anesthetic and Analgesic Drug Products Advisory Committee to the Food and Drug Administration.

PWJ | www.painweek.org

Q3 | 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

By Michael R. Clark md, mph, mba

“…the prevalence of depression is approximately 6% for those without chronic pain, compared to 16% of those with chronic pain.”

By Michael R. Clark md, mph, mba

KeY TOPiC

abstract:

PWJ | www.painweek.org

The association between chronic pain and depression is well accepted but remains poorly understood.1 In the general population, the prevalence of depression is approximately 6% for those without chronic pain, compared to 16% of those with chronic pain. These rates increase significantly in clinical samples and, using rigorous psychiatric diagnostic criteria, reach approximately a third to one-half of patients seeking care for chronic pain. Patients with chronic pain who also complain of depression experience greater pain intensity, use more passive coping skills, feel their lives are more out of control, report greater interference in activities due to pain, exhibit more pain related behaviors, have poorer outcomes from surgery, utilize more healthcare services, and retire from work earlier.

Q3 | 2017

patients with chronic pain would certainly be depressed. The argument makes intuitive, if not common, sense. Over time, the interactions between chronic pain and depression are supported by evidence of shared neurobiology and treatments for one condition often improving the other. Somatic symptoms occur in the majority of patients with depression, and individuals with documented affective (mood) disorders are at increased risk for developing chronic pain syndromes over a decade into the future.2 ¶ As we delve deeper into the phenomenology of patients’ experiences, we begin to see differences that distinguish them from one another.3 These variations play important roles in formulating an individual patient’s case with direct ramifications for their treatment. In this article, an approach to patients will be illustrated using cases that appear identical on first presentation but evolve with closer inspection such that unique plans of care are required.

The Usual Case

A common presentation begins with a 53-year-old woman who describes chronic low back pain and depression. Her pain is primarily in her legs (right greater than left) but she quickly adds, “I hurt everywhere.” Her mood is sad, frustrated, and angry because she “cannot do anything.” Over several years, she has undergone 3 lumbar spine surgeries for discectomy, laminectomy, and fusion. She experienced no prolonged benefit and is now unable to work. She notes that her husband has become distant and her friends have “moved on.” She is taking opioids on a variable schedule to “make the pain less horrible.” Intermittent injections with epidural steroids for inflammation and local anesthetic agents for trigger points have provided no relief. Multiple medications have been prescribed and “nothing works.” She cannot tolerate physical therapy due to increased pain and she remains at home except for healthcare appointments. Her primary care physician started a selective serotonin reuptake inhibitor (ssri) for depression but her symptoms are unchanged. Q3 | 2017

At this point, the next steps would usually include any/all of the following: ●● The surgeon considering removal of the hardware placed for her fusion or recommending extending the fusion ●● The anesthesiologist recommending a spinal cord stimulator or an intrathecal pump ●● Her primary care physician continuing the antidepressant and trying various medications for her symptoms such as muscle relaxants and sedative/hypnotics ●● The physical therapist urging a gym membership to initiate active exercise ●● The psychologist referring her to a support group and promoting better coping skills Meanwhile, the emergency medicine physician has banned her from returning, believing she is abusing medications, and her attorney is helping her file for disability as well as considering a malpractice claim against the surgeon. Also www.painweek.org | PWJ

KeY TOPiC

“Diseases are those conditions that patients ‘have’ that arise due to an abnormality in the structure or function of a bodily part that requires ‘fiixing’ to produce a cure.”” meanwhile, the Internet is providing an unlimited supply of theories, therapies, and horrible outcomes as the patient continues seeking the Holy Grail of causes and the Magic Bullet of treatment. As one would expect, her pain and depression persist and worsen. Her medications increase in number and dose. Her psychosocial condition deteriorates as her healthcare utilization increases. Eventually she receives disability income but is constantly challenged to prove that she remains unable to work. Periodically, she is referred for urgent psychiatry consultations for “suicidality” and she spends more time online telling her own horrible story. She feels unable to accept referral to an interdisciplinary pain rehabilitation program hoping that her current treatment might produce some small percentage improvement. The primary problem for this patient is that no one is sure whether she is sick with a disease, in trouble from unproductive behaviors, frustrated by personal vulnerabilities, demoralized by life stressors, or all of the above. The approach to patients with chronic pain should attempt to formulate their case from multiple perspectives making the contrast between the contributions of diseases, dimensions, behaviors, and life stories that are producing their symptoms and disability.4,5

The Disease Perspective

Diseases are those conditions that patients “have” that arise due to an abnormality in the structure or function of a bodily part that requires “fixing” to produce a cure. This broken part or etiology is generating a pathologic condition and

24 PWJ | www.painweek.org

the subsequent signs/symptoms define the clinical syndrome or diagnosis. Therefore, the approach to a disease begins with recognizing the clinical syndrome, suppressing the pathology, and fixing the broken parts with the goals of cure and minimizing new damage. The disease perspective would be helpful if our original case developed in the following ways. Upon further examination, the patient reports her pain follows the L5 dermatome on the right side and is characterized by a burning quality. Her depression is unresponsive to any positive life events and she exhibits anhedonia, or the inability to experience pleasure, in her usual activities. Since being on increased amounts of opioids, her depression has worsened. A low dose ssri improved her mood and motivation but waned over time. Trials of both gabapentin and pregabalin decreased her pain but caused intolerable sedation. In this variation, the patient is correctly diagnosed with major depressive disorder (mdd) and radicular neuropathic pain. Now, plans for further surgery and other interventions are placed on hold. Currently ineffective medications that lack specificity for her diagnoses are tapered and discontinued. She is started on a serotonin norepinephrine reuptake inhibitor (snri) and titrated to a recommended dose over several weeks. An anticonvulsant is added and gradually increased based on serum level monitoring for augmentation of the SNRI. Her husband becomes more supportive and encouraged upon seeing improvement and understanding her diagnoses. The patient begins to spontaneously increase her activities of daily living and returns to exercise as her symptoms lessen. As her condition improves, she initiates a conversation with her employer about possibly returning to part time work. Q3 | 2017

The important distinctions in this presentation focus on the specific diagnostic criteria of a major depressive disorder.6 Specifically, the criteria represent how the typical symptoms cluster together and focus on how the depressed mood is persistent and unresponsive to life events or that there is a sustained loss of interest or ability to experience pleasure. Usually, the patient’s self-image is negative with a loss of confidence in their ability to be successful. In addition, characteristic changes in bodily rhythms are typically present (eg, diurnal variations in mood, early morning awakening from sleep). Expressions of suicidality are typically linked to feelings of hopelessness or pessimism about the future and should not be considered a “normal” aspect of chronic pain.7 Similarly, neuropathic pain is recognized as a disease process that may involve multiple pathophysiological mechanisms producing burning or lancinating pain that occurs with an increased response or duration and is provoked by minimal or even absent stimuli suggesting a hyperactive and sensitized nociceptive system.8 Neuropathic pain is a common component of many disorders that affect neurological functioning. Pharmacological treatments are prescribed to counteract the loss of diffuse noxious inhibitory control, stimulation of nociceptors by norepinephrine, increased gain in signal processing, and loss of neuronal membrane stability. The most effective medications for both mdd and neuropathic pain are the antidepressants and anticonvulsants because of their direct pharmacological action on these pathophysiological processes.9 Multiple medications provide many options and unlimited combinations for treatment regimens. Emphasis is placed on using snris and tricyclic antidepressants because of their enhanced effectiveness in treating neuropathic pain that exceeds that of the ssris. However, they remain effective antidepressants and remission of mdd will improve the effectiveness of other therapies specific to neuropathic pain. Now the patient achieves a more optimistic outcome. Her depression goes into remission with the return of positive emotions, optimism, and energy. Her pain is decreased in intensity and the residual pain no longer interferes with her activities. As her activity increases, there is a gradual disappearance of myofascial pain, normalization of body mechanics, and increased strength. Her previous success at work provides the rationale for returning to work full time. With an active participation in the relationship, her marital stress and financial problems improve. Eventually, she increases her socialization with friends and reactivates a network of support. She no longer has time for Internet chat rooms and excessive healthcare visits.

The Dimensional Perspective

In contrast to what a patient has, dimensions represent who the patient “is” and are the various traits that compose a unique individual.10 These traits (eg, height, intelligence, temperament) are quantifiable and measurable along a

Q3 | 2017

spectrum that conveys inherent strengths and vulnerabilities based on the demands experienced by a person in a specific situation.11,12 The potential of the trait is evoked by the demand and either the individual is able to meet the demand, in which case the trait is a relative strength, or they are not, in which case they lack the capacity and the trait is a liability. Traits are personal features or attributes that can be described along a graded continuum like the classic normal distribution. While neither good nor bad, inherent vulnerabilities may be unmasked by the setting of the patient and the mismatch results in a negative reaction. The approach to patients who are distressed by these types of shortcomings is to define and quantify their trait composition for the purpose of guiding them into situations that evoke their strengths as well as provide remediation to address or compensate for any weaknesses. This process requires obtaining descriptions of the patient before their illness and looking for opportunities to “enhance skills” that will counter an evoked vulnerability. In addition, understanding the inherent strengths of a given composition or profile of traits can facilitate matching an individual with tasks that will allow their capabilities to be manifest with the resultant success of being able to meet the demands of the task at-hand. In another variation of our patient’s presentation, the pain is more of a dull ache with tightness that radiates from the hip down the outer thigh to the knee. In addition to pain and depression, multiple somatic symptoms are elicited in the review of systems. The character of her depression is more anger regarding her lack of progress and anxiety over her symptoms. She does not like taking medications because they result in side effects and she believes “they just mask the underlying cause” of her problems. She is spending excessive amounts of time cataloguing symptoms and trying to exercise to remain fit. In her efforts, she continues to request more consultations with experts who can find the broken part and fix it. For this particular presentation, the presence of an affective or anxiety disorder is ruled out. A detailed review of her pain and its work-up reveals a thorough consideration of the causes and that there are no new findings to warrant further investigation. In considering her case, it becomes clear that the patient has a premorbid temperament of an unstable introvert. As a result, it is explained to her that her usual strengths of attention to detail, organization, and fixing problems have become vulnerabilities that are provoking anxiety about having failed herself. Therefore, management begins providing a detailed formulation of why she is having persistent postoperative pain. She is directed to stop collecting more information for her healthcare practitioners because it is actually confusing the formulation, which is quite clear. She is referred to a psychologist for biofeedback and relaxation training to decrease anxiety and normalize focus on bodily sensations. And, the frequency of follow-up appointments is increased to more closely monitor her condition and limit the distractions of additional consultations. www.painweek.org | PWJ

KeY TOPiC

“In contrast to what a patient has, dimensions represent who the patient ‘is’ and are the various traits that compose a unique individual.” In this scenario, the patient’s disposition is the central issue affecting her symptoms. Because of who she ”is” there is a built-in tendency to respond in a certain manner under particular circumstances. These events are bringing to light her inherent and latent characteristics, which are stable aspects of her make up. Often these characteristics are not evident to practitioners unless extensive personal history on the patient is available, which usually comes from collateral sources of information.13 In this case, the patient is an introvert and thought-oriented as opposed to extraverts who are action-oriented.14 Similarly, introverts tend to seek depth of knowledge and influence when compared to the breadth of what extraverts are seeking. Introverts would rather have a substantial interaction as opposed to a more frequent interaction. And, introverts tend to recharge from stressful experiences by spending time alone in contrast to extraverts who are more likely to spend this time with others. Temperament determines how people are likely to be conditioned. For example, introverts are more responsive to negative reinforcements and very slow to extinguish a conditioned response. Extraverts are more responsive to rewards and forms of positive reinforcement but will decondition more quickly. Individuals with unstable temperament are more disrupted by negative reinforcements and have a greater potential for strong emotional reactions. The unstable introvert will be more prone to prolonged demoralization, anxiety over change with anticipation of the worst outcome, and get caught up in obsessional dithering and scrupulosity. The unstable extravert is more likely to explode in anger, blame others, engage in public

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depressive sulking, and become even more disruptive under the influence of alcohol or other disinhibiting substances. The introvert is more internally focused, reflective, analytical, and punishment averse. They often focus on the past and future rather than being in the moment, and it is easier for them to engage in solitary activities. When introverts are in pain, they are more likely to become preoccupied with somatic sensations, ruminate about what is wrong with them, suffer in silence, and ask, “What did you miss?” or “What will go wrong?” because they are worried about feeling bad. The unstable introvert is now much more likely to experience negative emotions with greater intensity and react poorly to any stressor. Their reactions become more difficult to predict as they become more easily threatened, sensitive to the withdrawal of attention, and then dramatically catastrophize about their expected outcome. The unstable introvert in pain exhibits all of these vulnerabilities amplified such that they become more distressed, more difficult to redirect, more prone to attack, and assume the worst outcome is a certainty. The approach to the introverted temperament tries to engage their strengths and avoid the provocation of their weaknesses. For example, they respond well to extra time to be completely heard and provide more detailed information. Likewise, they are more likely to be reassured and understand more detailed information about their condition. Then, they will feel less drive to seek out other sources of information, become more open to anxiety reduction techniques, and be reassured by careful physical examinations as opposed to distracting consultations. Introverts will appreciate the more comprehensive treatment plan with predictable follow-up and outcome Q3 | 2017

measures. The goal is for them to appreciate their own complex composition and shift from thinking that the body is just a machine that should be easy to fix.15 In particular, the unstable introvert should not be told speculative theories for why they are ill but given concrete facts and plans for how their care will be carefully planned out. Reminders that the worst has not occurred will reorient them to the present and limit their own speculation that a disaster is just around the corner. Because traits are immutable aspects of the person’s make up, practitioners can become discouraged that their patient cannot change. In fact, the claim that these patients are untreatable rests on mistaking the dimensional foundation of traits for the clinical issue that is a provocation of their trait vulnerabilities. The dimension cannot be changed but the response and their provocations can be addressed with remediation adding experience to enhance the patient’s skills at meeting challenges.16 The optimistic outcome for this case rests on the process of engaging the patient. For example, the patient was impressed by the referral to an “expert” in biofeedback with electronic equipment that could measure and provide detailed information about the functioning of her body. In addition, learning biofeedback engaged the patient’s desire to always perform a task perfectly without error. As they mastered this skill, their anxiety and somatic symptoms decreased. Scanning their body in a new fashion provided reassurance that nothing was “beyond normal operating parameters.” Now the patient was able to reject external sources of information as not specific to her problems and she was reassured by the more frequent appointments in which she could provide updates that her practitioners would review. As the more generalized pain and distress receded, her residual symptoms were more easily diagnosed as an iliopsoas tendinitis and an iliotibial band syndrome. Her physical therapist was now able to prescribe a tailored regimen of rest, stretching, and massage in contrast to the overexercising that was aggravating these conditions. The patient was greatly relieved to know that there was something wrong but it was fixable. Gradually, she asked to decrease the frequency of healthcare appointments because they were interfering with her ability to focus on work.

The Behavior Perspective

The actions of patients are motivated by design and purpose. These complex behaviors result from personal choices, which is why they are referred to as motivated behaviors with drives and reinforcers. For patients, some behaviors can be problematic such as abusing prescription opioids or seeking too much healthcare. As a result, the treatment of a behavioral disorder begins with pointing out the problematic behavior and stopping it to gain control over the situation and understand the contributions of its various components. As part of the process, the patient must begin taking responsibility for their choices to emphasize looking for options that will stop undermining their improvement. The practitioner serves the role of reinforcing

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good choices that result in productive behavior and positive consequences. The issue is not finding blame but appreciating the factors that facilitate and reinforce a lack of progress so as to implement new methods for achieving change. Applied to a variation of our patient: in this instance, the patient’s pain is centered in the low back and described as sharp with any movement. Her depression is better characterized as feeling scared and being fearful of injuring herself. She repeatedly notes that any attempt at trying to function makes the pain worse. And, any activity is followed by extended periods of rest and taking more medications. In general, her behaviors are marked by inconsistency and noncompliance. She acknowledges a sense of feeling overwhelmed and unable to cope. The approach to this patient’s treatment emphasized concern about the lack of a systematic treatment plan.17 The practitioner utilized motivational interviewing to initiate needed changes based on the patient’s own desire for making changes to reach desired personal goals.18 In addition, a plan was developed for stabilizing her medication use to avoid rebound symptoms, withdrawal syndromes, and inconsistent benefits. The diagnosis of opioid induced hyperalgesia was explained and the rationale for eventual tapering and discontinuing of these medications was accepted. Sleep hygiene techniques were instituted and the patient felt that she now had the tools to address her insomnia. Visual imagery and self-hypnosis were added to reduce anxiety and an active physical therapy progress focused on gradual desensitization to feared movements that increased range of motion and strength. And the patient was referred to an addiction medicine specialist for added support through group therapy with similar patients. Formulating addiction as a behavioral problem highlights that effected patients exhibit disordered functioning.19 The core features of their addiction are behavioral manifestations of losing control of something they are doing, being excessively preoccupied with something they are doing, and continuing to choose to do that something despite adverse consequences. Their impaired control over their behavior, often referred to as compulsive use, may manifest as not being able to take medications as prescribed and making frequent requests for early refills based on poorly substantiated reasons such as medications being stolen or prescriptions being lost. The excessive preoccupation with a particular pursuit such as seeing multiple consultants or following a recommended course of therapy will generally be met with staunch or unreasonable resistance with attempts to undermine the practitioner coordinating their care by interjecting more sources of opinion and treatment. The patient’s insistence of engaging in risky behaviors while their function deteriorates and negative consequences accumulate defines how their choices are unresponsive to feedback. The treatment of behavioral disorders must start with the recognition that the standard medical approach to changing behavior involves confrontation and persuasion of patients www.painweek.org | PWJ

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to adopt a prescribed plan of action prior to any readiness for change.20 This approach understandably fails because the practitioner is talking about their own reasons for the patient to change, which just provokes resistance. A paradigm shift is needed that emphasizes the practitioner listening rather than talking, coupled with a discussion about the patient’s own reasons for why change would be beneficial.21 Motivational interviewing is based on getting patients to explore their own values and how these may be served by the status quo or making a change in their behavior.22 The process seeks to instill knowledge, insight, skills, and motivation through practice and collaborative problem solving.23 The patient’s autonomy is recognized and maintained allowing them to choose whether, when, and how to institute change. The practitioner now is in the role of validating that the patient has what they need to change and exhibiting confidence in the patient’s desire and capacity to grow in positive directions.24 Motivational interviewing is directive but patient centered to elicit behavior change from them through a process of exploring and resolving their ambivalence about solving their current problems.25 The guiding principles of motivational interviewing include expressing empathy, developing the discrepancy between what is and what is wanted, rolling with resistance, and supporting self-efficacy.26 Therefore, the foundation is a strong relationship between patient and practitioner in which the current situation is accepted, ambivalence is understood as normal, and it is clear that the patient should be the one to express her/himself. As the patient talks more about where they are and where they might want to be with respect to the situation, resistance will arise but the practitioner does not engage it directly.27 Instead, the patient is asked to think about their values and goals related to the problem being discussed. No criticism is offered and the practitioner reinforces the idea that the solutions are within the patient’s capabilities. As the patient readies for attempts at change, the practitioner is now in the role of supporter, providing confidence in the patient’s ability to decide how to make the desired changes.28 In this patient example, she acknowledged wanting to change but that she did not have a plan or the necessary skills.29 A mutual process ensued where the patient decided that standing schedules of medication dosing should be adopted and that extended release/long-acting formulations of opioids should be utilized. The resultant decrease in medication related adverse events reinforced her ability to be successful and she increased her engagement with her practitioners. As she mastered relaxation techniques, her anxiety improved and she no longer needed medication to sleep. Her energy increased and her self-efficacy improved, which facilitated taking on new challenges in physical therapy. Group therapy with peers reinforced more productive behaviors through encouragement and the development of

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better coping strategies than taking medications. With additional progress, she was able to taper her medications and return to work.

The Life Story Perspective

The events of a patient’s life are meaningful to them. The various encounters of any life story follow a sequence that takes place with a given setting. The outcome of the story will be interpreted by the patient as having a conclusion with varying degrees of satisfaction. The accumulation of these personally meaningful events results in the patient having an understanding of “Why me?” Often the outcome of the story is dissatisfying because the consequences of one’s actions are unintentional, such as getting fired from a job or becoming sick with an illness. In these situations, a new interpretation must be reached by the patient to restore a sense of mastery and expectation for success in moving forward. The practitioner is helping the patient to find an answer to the question, “What good does life hold for me?” but they must recognize that there is not just one “true” story. The patient must generate an interpretation in which the meaning still makes sense but is one that they can appreciate without becoming demoralized.30 In another variation of the case, in-depth examination reveals that the pain is quite variable. At times, the patient is actually painfree. However, at other times, the pain is severe and associated with fatigue. The patient describes her depression as more episodic and accompanied by crying spells when she is remembering what it was like to be healthy. At her worst, the pain seems uncontrollable and her situation hopeless. As she become more distressed and intrusive with her friends, she has alienated her support and feels alone. Her husband states that she always “flies off the handle for no reason” and that she is no longer able to work, which was a source of great pride and validation of having a successful life. In designing a treatment plan, the practitioner explained the reactive state of demoralization and the grieving process. Negative feelings were normalized as legitimate and needing validation.31 The concepts of acceptance and value-based goals were introduced.32 As needed medications such as muscle relaxants, anti-inflammatories, sedative/hypnotics and tramadol were discontinued, the focus of her treatment shifted from suppressing symptoms to improving coping without becoming catastrophic.33 She was redirected to use her previous work skills in sales to learn about catastrophizing and how to take control of her behavior. She entered interpersonal psychotherapy to work on re-establishing relationships such as those with her husband and close friends. She developed a problem-solving approach that included self-talk for rumination and feelings of helplessness relying on her support network for reinforcement of those self-management skills. As she improved, she sought out an occupational therapist and vocational rehabilitation counselor to consider how best to return Q3 | 2017

“The essence of working on problems related to a patient’s life story is to renew a sense of potential or hope for what the patient wants out of life.” to the work force. She located and joined a support group for professional women who were changing careers midlife. The essence of working on problems related to a patient’s life story is to renew a sense of potential or hope for what the patient wants out of life.34 The distressed patient has experienced a series of events in which hopes have not been realized or potential has not been fulfilled. Demoralization occurs when the patient reaches a meaningful realization that some aspect of their personal life is a failure and thereby unfulfilling.35 Grief is a particular form of demoralization associated with loss and manifests in several phases with characteristic behaviors.36 The phases of grief are not hardwired but more fluid and likely to overlap with periods of reversal. In general, grief begins with a sense of numbness and disbelief. Next, patients describe pining for the lost object—such as a person, or their health—with feelings of apathy and anxiety. A period follows during which there is disorganization and despair with repetitive review of the events leading up to the loss with the expectation of finding a way that it could have been avoided. Finally, there is a gradual reorganization of the person’s life with a return of normal drives and goals. During these phases, a variety of common grief related behaviors can be observed. In the immediate phase, there is a searching for the lost object. Q3 | 2017

Over time, reminders of the loss evoke spontaneous, uncontrolled and generally intense wellings of emotion, which gradually wane but do not disappear completely. These are initially accompanied by a loss of drive and inactivity that is replaced by increasing efforts directed at understanding the loss and eventually accepting it. The grieving process is a balancing of urges to look back and look forward, ultimately exploring the world that emerges from the circumstances of loss to discover what can be carried forward from the past with social and cultural pressures influencing how the urges are expressed or inhibited. The outcome of grief is shaped by circumstances of the life-changing event. Factors such as being able to anticipate the change, experiencing multiple or massive changes, and whether the events are violent or brutal will influence how patients are affected. The patient’s own personality and previous experience with transitions, how successful they have been in resolving them successfully, and their confidence in being able to reach a successful resolution are important. After the event, the degree of social support and opportunities for new roles in one’s life help carry the patient through this process. The therapy for grief centers on reviewing the relationship to the lost object such as a person or one’s health.37 Negative feelings should be validated but also need to be worked through www.painweek.org | PWJ

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to allow not only an expression of sorrow, but to facilitate the planning of an acceptable future relationship to what has been lost and discover new opportunities for acquiring new patterns of conduct given the current circumstances. The therapy becomes a form of work as opposed to a passive process that must be tolerated. Denial of the loss must be rejected and a new reality accepted. Withdrawal from others must be avoided despite having to experience the pain of grief. Challenges must be engaged to adjust to a changed world without the lost object. And others must be embraced so as to redirect emotional energy and reinvest in future endeavors. The outcome of this case was enhanced as the work of grief was accepted. Rather than waiting out a series of predictable emotional transitions, the patient began reconstructing her personal life of meaning that had been challenged and disrupted by illness. While she accepted that change, she affirmed her life and worked on renewing herself to accomplish new achievements. In essence, she re-scripted her life story with a focus on a new potential for success. Specifically, she built a support network of professional women sharing techniques for changing careers. She started her own business and nonprofit resource center for patients with pain. In her marriage, she began working on strengths that complimented those of her husband. She settled her Workers Compensation claim to eliminate distractions and negative stress, stopped all medications citing more confidence in “doing it myself,” and developed a personal “toolkit for pacing” to avoid depleting her “gas tank.”

Conclusion

The key to successful outcomes for patients with chronic pain and depression is an individualized formulation of each case. Many patients present with the same complaints and yet suffer for many different reasons. Evaluating the patient from different perspectives can organize information in a framework that will inform tailored treatments. If a patient has a disease, fixing broken parts should restore function to normal and eliminate symptoms. If a patient is unable to meet the demands of a situation, guidance and remediation can enhance trait strengths and avoid provoking weaknesses. If a patient is doing unproductive behaviors, interrupting those acts can repurpose drive and redesign goals. If a patient is dissatisfied with their life trajectory, they can reinterpret meanings to restore a sense of mastery and potential for fulfillment. The practitioner designs treatment emphasizing the proportions of each perspective contributing to the patient’s distress and disability. The best outcomes are achieved with the most accurate recipe.

2. Larson SL, Clark MR, Eaton WW. Depressive disorder as a long-term antecedent risk factor for incident back pain: a thirteen-year follow-up study from the Baltimore Epidemiological Catchment Area Sample. Psychol Med. 2004;34:211–219. 3. Clark MR. Psychiatry and chronic pain: examining the interface and designing a structure for a patient-centered approach to treatment. Eur J Pain. 2009;3:95–100. 4. McHugh PR, Clark MR. Diagnostic and classificatory dilemmas. In: Blumenfield M, Strain JJ, eds. Psychosomatic Medicine in the 21st Century. Baltimore, MD: Lippincott Williams & Wilkins: 2006:39–45. 5. McHugh PR, Slavney PR. Perspectives of Psychiatry. 2nd ed. Baltimore, MD: Johns Hopkins University Press: 1998:332. 6. American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013:947. 7. Fisher BJ, Haythornthwaite JA, Heinberg LJ, et al. Suicidal intent in patients with chronic pain. Pain. 2001;89:199–206. 8. Clark MR, Chodynicki PM. Pain management. In: Levenson JL, ed. Textbook of Psychosomatic Medicine. Arlington, VA: American Psychiatric Publishing; 2005:827–867. 9. Clark MR. Antidepressants. Pain Medicine and Management: Just the Facts. 2nd ed. Staats P, Wallace M, eds. New York, NY: McGraw-Hill Education; 2015:117–123. 10. Feist J, Feist GJ. Theories of Personality. New York, NY: McGraw-Hill; 2009:592. 11. Costa Jr PT, McCrae RR. NEO PI-R Professional Manual. Odessa, NY: Psychological Assessment Resources, Inc.; 1992:101. 12. Eysenck HJ. Dimensions of Personality. London, England: Routledge & Kegan Paul; 1947:308. 13. Briggs Myers I, McCaulley MH, Quenk NL, et al. MBTI Step III Manual: Exploring Personality Development Using the Myers-Briggs Type Indicator Instrument. Mountain View, CA: Consulting Psychologists Press; 2009:119. 14. Cain S. Quiet: The Power of Introverts in a World That Can’t Stop Talking. New York, NY: Crown Publishers; 2012:333. 15. Kuyken W, Watkins E, Holden E, et al. How does mindfulness-based cognitive therapy work? Behav Res Ther. 2010;48:1105–1112. 16. Chiesa A, Serretti A. Mindfulness based cognitive therapy for psychiatric disorders: a systematic review and meta-analysis. Psych Res. 2011;187:441–453. 17. Miller WR, Rose GS. Toward a theory of motivational interviewing. Am Psychol. 2009;64:527–537. 18. Simmons LA, Wolever RQ. Integrative health coaching and motivational interviewing: synergistic approaches to behavior change in healthcare. Glob Adv Health Med. 2013; 2:28–35. 19. Witkiewitz K, Bowen S, Harrop EN, et al. Mindfulness-based treatment to prevent addictive behavior relapse: theoretical models and hypothesized mechanisms of change. Subst Use Misuse. 2014;49:513–524. 20. Hettema J, Steele J, Miller WR. Motivational interviewing. Annu Rev Clin Psychol. 2005;1:91–111. 21. Day MA, Jensen MP, Ehde DM, et al. Toward a theoretical model for mindfulness-based pain management. J Pain. 2014;15:691–703. 22. Abramowitz SA, Flattery D, Franses K, et al. Linking a motivational interviewing curriculum to the chronic care model. J Gen Intern Med. 2010;25:620–626.

References

23. Apodaca TR, Longabaugh R. Mechanisms of change in motivational interviewing: a review and preliminary evaluation of the evidence. Addiction. 2009;104:705–715.

1. Clark MR, Treisman GJ, eds. Pain and Depression: An Interdisciplinary Patient-Centered Approach (Advances in Psychosomatic Medicine, Vol. 25). Basel, Switzerland: Karger; 2004.

24. Madson MB, Loignon AC, Lane C. Training in motivational interviewing: a systematic review. J Subst Abuse Treat. 2009;36:101–109.

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25. Lundahl B, Moleni T, Burke BL, et al. Motivational interviewing in medical care settings: a systematic review and meta-analysis of randomized controlled trials. Patient Educ Couns. 2013;93:157–168. 26. Benzo RP. Mindfulness and motivational interviewing: two candidate methods for promoting self-management. Chron Respir Dis. 2013;10:175–182. 27. Fu SS, Roth C, Battaglia CT, et al. Training primary care clinicians in motivational interviewing: A comparison of two models. Patient Educ Couns. 2015;98:61–68. 28. Dobber J, van Meijel B, Barkhof E, et al. Selecting an optimal instrument to identify active ingredients of the motivational interviewing-process. J Psychosom Res. 2015;78(3):268–276. 29. Rubak S, Sandbæk A, Lauritzen T, et al. Motivational interviewing: a systematic review and meta-analysis. Br J Gen Prac. 2005;55:305–312. 30. Shapiro SL, Linda E, Carlson LE, et al. Mechanisms of mindfulness. J Clin Psychol. 2006;62:373–386. 31. Hayes SC, Luoma JB, Bond FW, et al. Acceptance and commitment therapy: model, processes and outcomes. Behav Res Ther. 2006;44:1–25. 32. Cavanagh K, Strauss C, Forder L, et al. Can mindfulness and acceptance be learnt by self-help?: a systematic review and meta-analysis of mindfulness and acceptance-based self-help interventions. Clin Psychol Rev. 2014;34:118–129. 33. Carmody J, Baer RA, Lykins ELB, et al. An empirical study of the mechanisms of mindfulness in a mindfulness-based stress reduction program. J Clin Psychol. 2009;65:613–626. 34. Kahla KG, Wintera L, Schweiger U. The third wave of cognitive behavioural therapies: what is new and what is effective? Curr Opin Psychiatry. 2012;25:522–528. 35. Fjorback LO, Arendt M, Ørnbøl E, et al. Mindfulness-based stress reduction and mindfulness-based cognitive therapy – a systematic review of randomized controlled trials. Acta Psychiatr Scand. 2011;124:102–119. 36. Parkes CM. Bereavement as a psychosocial transition: processes of adaptation to change. J Soc Issues. 1988;44:53–65. 37. Thompson M, McCracken LM. Acceptance and related processes in adjustment to chronic pain. Curr Pain Headache Rep. 2011;15:144-151.

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www.painweek.org | PWJ

By Sophia Sheikh md, facep & Phyllis Hendry md, faap, facep

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abstract: Pain is a significant component of

emergency department (ed) chief complaints and by some estimates accounts for 78% of all visits.1 Managing pain in the ed and prehospital setting can be difficult due to a unique set of challenges and barriers compared to other healthcare environments. Emergency Departments treat an extremely diverse patient population, who present with a variety of acute and chronic pain complaints, accompanied by comorbidities from trauma to sickle cell crisis to diabetic neuropathy. Additionally, many ed patients have mental illness and or substance abuse histories. The ed can be an overcrowded high risk environment, especially during weekends, overnights, and holidays when primary care and pain clinics are closed. Further barriers adding to the complexity of ed pain management include: Limited clinician pain education (pharmacologic and nonpharmacologic) Lack of resources and time to verify patient histories and prescriptions Difficulty differentiating drug-seeking and drug-diverting behavior from true legitimate pain Balancing analgesia and sedation with adverse effects Differentiating pain from anxiety Pressure to rapidly disposition patients while decreasing readmissions and length of stay

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patient-clinician encounters are done in a segmented manner as opposed to outpatient settings where the patient-clinician encounter happens in one sitting. For example, while assessing a patient with low back pain in the ed, a clinician may be called to speak to radiology about a critical finding or to evaluate a more critical patient. Multiple interruptions during the patient-clinician encounter can affect the ability of the clinician to adequately recognize and assess pain. These inherent characteristics of ed and prehospital settings explain why traditional pain assessment tools may not be ideal nor realistic for use in these unique environments. During the “pain as a 5th vital sign” era there was a renewed focus on pain assessment in all healthcare settings. A reliance on unidimensional assessment tools was thought to have led to opioid overprescribing, adverse events, and oversedation incidents.2,3 ed physicians reported feeling pressure to prescribe opioids to avoid administrative and regulatory criticism for low patient satisfaction scores.4 However, despite the requirements and implementation in the electronic medical record, mandated pain assessments were not shown to improve pain management, patient outcomes, or time to analgesics administration, although documentation did improve.5–7 Interestingly, Press Ganey patient satisfaction scores in the ed were not associated with analgesic or opioid administration despite what ed physicians had perceived.8 Q3 | 2017

Despite implementation of the 2001 Joint Commission on Accreditation of Healthcare Organizations (jcaho) pain management standards, pain assessments in the ed setting were still lacking, particularly among patients with traumatic injuries.9,10 Patient acuity and clinical condition may provide a partial explanation. Patients are less likely to be assessed for pain as injury severity increases due to focus on management of life-threatening injury or condition. Additionally, those who are physiologically unstable are least likely to receive a standardized pain assessment or opioids.11 Numerous pain assessment tools are available but none have been created specifically for the ed. Emergency Department and prehospital pain assessment typically consists of measuring pain intensity only. Many ed providers are unfamiliar with the variety of pain scales www.painweek.org | PWJ

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available and typically follow the scale chosen for them by their institution and electronic medical record. Most eds use the Numeric Rating Scale (nrs), Visual Analogue Scale (vas), or the Verbal Rating Scale (vrs) because they are quick and easy to use.12 These unidimensional scales have limitations with most providing only a single snapshot and focusing on pain intensity rather than pain assessment. The vrs and vas were found to underestimate pain intensity in severe pain when used in the ed, while the NRS overestimated pain in the ed.12 All 3 scales require an alert and oriented patient and are not useful in the intoxicated or acutely impaired patient. For pediatric pain assessments, eds commonly use the Revised Face, Legs, Activities, Cry, Consolability (r-flacc) tool, Neonatal Infant Pain Scale (nips), or the Children’s Hospital of Eastern Ontario Pain Scale (cheops). However, these behavioral pain scales are open to clinician interpretation and bias. For example, clinicians may mistake behavior from a nonpainful condition, such as anxiety or hunger, as pain.13 A few pain assessment scales, such as the Pain Assessment in Advanced Dementia (painad) Scale, have been developed for cognitively impaired patients; however, use in the ed setting has not been tested. If validated for use in the ed, scales of this nature may be a potential tool to measure pain in acutely impaired patients. Even when the correct pain scale is selected, how the pain score should be interpreted and utilized in the management plan by emergency providers may not always be straightforward and brings up several questions such as what number requires treatment and what type of treatment? Is the score believable? What number is too high or unacceptable for discharge? Patients with the same injury may report widely different pain scores and seemingly unrelated patient factors may also influence the score. For example, higher pain scores have been associated with younger age, female gender, African American race, Medicaid insurance, multiple ed visits in the past year, and ed diagnoses of sickle cell pain, back/neck/shoulder pain, and headache.14 Additionally, anxiety and pain catastrophizing have been shown to be positively associated with pain scores in the ed, a finding that is rarely considered during ed pain assessment and treatment.15,16 Lack of context for pain scores using the nrs makes it difficult for the clinician to fully understand the patient’s degree of pain as a score of 8 out of 10 is subject to variable interpretation. Assessing physical functionality is another key component of the ed exam, especially in patients presenting with acute injuries or acute exacerbations of a chronic painful condition. Pain assessment tools that assess both pain intensity and functionality, like the Defense and Veterans Pain Rating Scale (dvprs) v 2.0, may be ideal for the ed and can be useful in patients with acute or chronic pain. The dvprs also contains questions assessing the biopsychosocial impacts of pain.17 These features are promising for ed use but have yet to be validated in the ed population and setting. Other important assessments to consider include screening for anxiety, pain catastrophizing, mental health, and substance abuse. Studies assessing risk Q3 | 2017

for opioid abuse and overdose, substance abuse, and anxiety and pain catastrophizing have been successfully performed in the ed.15,18–21 However, large scale studies are needed to replicate these findings and to provide guidance on which patients should receive these assessments. In an ideal setting, ed pain reassessments should be performed after an intervention and prior to discharge, just as a high blood pressure or glucose level would be managed and reassessed. Pain reassessments pose another challenge, as there are very few tools for ed clinicians to objectively measure improvement in pain during the relatively short ed visit. The currently available assessment tools were developed for outpatient settings and measure changes in pain over days to weeks to months—a time frame that is not amenable to the ed. Emergency Department studies have looked at the minimum clinically significant difference (mcsd) in pain to determine what change in pain intensity determines improvement for the most common pain intensity scales used in the ed.22–24 However, using only this measure for reassessment ignores pain’s influence on functionality and biopsychosocial effects. Tools to measure improvement in these areas during the ed encounter are needed; however, measuring changes on the biopsychosocial effects may not be possible due to the short timeframe of an ed encounter. Clinically stable patients presenting to the ed for pain should receive prompt pain assessment and treatment. None of the currently available pain assessment tools were created for the ed or prehospital setting and many would be prohibitive or inappropriate due to time of completion or clinical scenario. For example, the Brief Pain Inventory is an excellent tool but is too time consuming for a busy ed. On the other hand, the Pain Frequency, Intensity, and Burden Scale (P-fibs) is short but asks patients to evaluate their pain over the past week. Such a tool would not be useful in an acutely injured patient. The ed sees a variety of patients and painful conditions; the concept that one pain assessment tool will fit all ed patients may not be realistic. Instead, the approach may be a thoughtful consideration and selection of the tool that would best assess pain given the patient’s clinical picture and age. This dilemma highlights the need for validation of ed specific pain assessment “tools” or a toolkit. More research is needed to determine components of an assessment tool(s) for the ed that is rapid and sensitive; useful for pain reassessment and functionality; and can guide clinical decisions on treatment (considering substance abuse and adverse events risks) and disposition. ed validated tools could then be integrated into the electronic medical record allowing the ed physician or nurse to easily select which tool best suits the patient.

Conclusion

Pain assessment in the ed is vital as a significant number of patients present to the ed for pain. Although there is a plethora of available tools for pain assessment, few are applicable to the ed patient and environment. While adequate treatment of www.painweek.org | PWJ

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pain is a priority, it is important to realize the limitations of the ed and consider patient acuity to establish reasonable goals of care for every patient. References 1. Basic principles of pain management in the emergency care setting: introduction, recognition, and assessment. University of Florida College of Medicine-Jacksonville, Department of Emergency Medicine. Pain Assessment and Management Initiative (PAMI): a patient safety project. Available at: pami.emergency.med.jax.ufl.edu/. 2. Vila H, Smith RA, Augustyniak MJ, et al. The efficacy and safety of pain management before and after implementation of hospital-wide pain management standards: is patient safety compromised by treatment based solely on numerical pain ratings? Anesth Analg. 2005;101:474–480. 3. Mehendale AW, Goldman MP, Mehendale RP. Opioid overuse pain syndrome (OOPS): the story of opioids, Prometheus unbound. J Opioid Manag. 2013;9:421–438.

19. Weiner SG, Griggs CA, Mitchell PM, et al. Clinician impression versus prescription drug monitoring program criteria in the assessment of drug-seeking behavior in the emergency department. Ann Emerg Med. 2013 ;62(4):281–289. 20. Weiner SG, Horton LC, Green TC, et al. A comparison of an opioid abuse screening tool and prescription drug monitoring data in the emergency department. Drug Alcohol Depend. 2016;159:152–157. 21. Broderick KB, Richmond MK, Fagan J, et al. Pilot validation of a brief screen tool for substance use detection in emergency care. J Emerg Med. 2015;49(3):369–374. 22. Bijur PE, Chang AK, Esses D, et al. Identifying the minimum clinically significant difference in acute pain in the elderly. Ann Emerg Med. 2010;56(5):517–521.e1. 23. Farrar JT, Berline JA, Srom BL. Clinically important changes in acute pain outcome measures: a validation study. J Pain Symptom Manage. 2003;25:406–411. 24. Lee JS, Hobden E, Stiell IG, et al. Clinically important change in the visual analog scale after adequate pain control. Acad Emerg Med. 2003;10(10):

4. Kelly S, Johnson GT, Harbison RD. “Pressured to prescribe” The impact of economic and regulatory factors on South-Eastern ed physicians when managing the drug seeking patient. J Emerg Trauma Shock. 2016;9(2):58–63. 5. Mularski RA, White-Chu F, Overbay D, et al. Measuring pain as the 5th vital sign does not improve quality of pain management. J Gen Intern Med. 2006;21:607–612. 6. Purser L, Warfield K, Richardson C. Making pain visible: an audit and review of documentation to improve the use of pain assessment by implementing pain as the fifth vital sign. Pain Manage Nurs. 2014;15:137–142. 7. Kaplan CP, Sison C, Platt SL. Does a pain scale improve pain assessment in the pediatric emergency department? Pediatr Emerg Care. 2008;24(9):605–608. 8. Schwartz T, Tai M, Babu KM, et al. Lack of association between press ganey emergency department patient satisfaction scores and ed administration of analgesic medications. Ann Emerg Med. 2014;64(5):469–481. 9. Silka PA, Roth MM, Morena G, et al. Pain scores improve analgesic administration patterns for trauma patients in the emergency department. Acad Emerg Med. 2004;11:264–270. 10. Herr K, Titler M. Acute pain assessment and pharmacological management practices for the older adult with a hip fracture: review of ed trends. J Emerg Nurs. 2009;35:312–320. 11. Spilman SK, Lechtenberg GT, Hahn KD, et al. Is pain really undertreated? Challenges of addressing pain in trauma patients during prehospital transport and trauma resuscitation. Injury. 2016. Available at: dx.doi.org/10.1016/ j.injury.2016.03.012. 12. Daghfous M, Jaafar M, Dziri C, et al. The pain assessment scales in the emergency departments: a meta-analysis and a systematic review. Eur J Anaesthesiol. 2010;27(47):193. 13. Welsh JT. Assessing pain in the ed including the use of pain scales (such as OSBD, FLACC, VRS, NRS, CRS, and Oucher). Curr Emerg Hosp Med Rep. 2016;4:19. 14. Marco CA, Kanitz W, Jolly M. Pain scores among Ed patients: comparison by ed diagnosis. J Emerg Med. 2013;44(1):46–52. 15. Kapoor S, White J, Thorn BE, et al. Patients presenting to the emergency department with acute pain: the significant role of pain catastrophizing and state anxiety. Pain Med. 2016;17(6):1069–1078. 16. Craven P, Cinar O, Madsen T. Pain anxiety may influence the efficacy of ed pain management. Am J Emerg Med. 2013;31:313–318. 17. Polomano RC, Galloway KT, Kent ML, et al. Psychometric Testing of the Defense and Veterans Pain Rating Scale (DVPRS): a new pain scale for military population. Pain Med. 2016;17(8):1505–1519. 18. Greene J. Amid finger-pointing for an overdose epidemic, emergency physicians seek pain control alternatives. Ann Emerg Med. 2016;68(2):17A-20A.

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Disclosures: Two of the authors (Albrecht and Rice) are owners of the for-profit company Integrated Tissue Dynamics, llc, (intidyn) mentioned in this article, which offers comprehensive immunolabeling skin biopsy evaluations using a proprietary ChemoMorphometric Analysis (cma)â&#x201E;˘ platform as part of their services. The authors have no current financial affiliations with any company that produces drugs or compounds mentioned in this article, and all authors declare no conflicts of interest in producing this work. Charles E. Argoff has nothing to disclose.

abstract:

NeW FRONTieRS

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is the largest sensory organ in the body and maintains the greatest contact with our external world. As such, skin acts as both an essential physical barrier and an exquisite detection system. Skin is highly adaptable, self-restorative, and provides structural and biochemical functions that participate in essential neural, vascular, endocrine, and immune system regulation. Furthermore, skin directly represents an external expression of internal functioning (eg, rash or blushing), and psychologically, when humans see themselves and others, the skin conveys an immediate impression of health (and attractiveness). Constant exposure to changing external and internal environmental conditions, including numerous physical, chemical, bacterial/viral, and uv insults can alter the complex functionality of skin, and many organic disorders and responses to exogenous substances result in a range of debilitating skin abnormalities and/or neurological afflictions, such as psoriasis or peripheral neuropathy. Importantly, intractable chronic pain conditions, pruritus (itch), and/or numbness are often accompanied by pathologies among the wide variety and dense distributions of skin neural innervation. Therefore, skin biopsy evaluations are becoming an important means of detecting pain-associated pathologies, particularly small fiber neuropathy, and identifying additional altered mechanisms which can be targeted to develop novel therapeutic strategies, including topical analgesics. This article reviews cutaneous (skin) mechanisms of chronic pain and highlights the emerging value of multimolecular skin biopsy analysis in patients with a variety of chronic pain conditions.

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Chronic pain, including that from arthritis, neuropathic pain (np), and idiopathic conditions, can be broadly characterized as maladaptive disorders of the peripheral and/or central somatosensory nervous system with known involvement of the immune, endocrine, and limbic systems. These disorders severely impair the health and quality of life in approximately 30% to 35% of the population, with np alone having an estimated economic impact at over $60 billion annually in the United States.1–4 Under normal conditions, painful sensations are beneficial and adaptive in that they serve to protect individuals from potentially dangerous or damaging tissue injury and promote healing by limiting use of injured body structures. Pain is a conscious sensation generated at the cortical level, but represents a culmination of direct stimulus detection processing (and physiologic response) regarding intensity, location, and quality, which is tempered with limbic (emotionality) activity regarding the situational context and environment. Pain is an individually unique sensation and can be qualitatively different across similar individuals, or even among the same individual at different times. This complex neural interplay makes treating chronic pain conditions notoriously difficult, despite having rather good control of acute pain treatment in the clinic.5 The pathways which are activated in response to stimuli that produce painful human responses (noxious stimuli) are termed nociceptive (noci = pain) pathways. The predominant theory is that some types of primary afferent sensory neurons of the dorsal roots and trigeminal ganglia, termed primary nociceptors, specifically respond to noxious stimuli and transmit the nociceptive signal from the periphery to the spinal cord. Nociceptors innervate nearly all tissues of the body as small caliber, thin, unmyelinated or lightly-myelinated axons and are particularly concentrated in the outermost layer of skin, the epidermis.6 These cutaneous nociceptive endings respond to extreme temperatures, mechanical stresses, chemicals, bacterial/viral proteins, and uv radiation stimuli to drive the sensation of pain (and/or itch). Acute pain occurs when stressors

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or ongoing tissue damage cause a high level of activity among these nociceptors. A variety of therapeutics can effectively treat acute pain by blocking different types of molecules (cytokines) released by traumatized and inflamed tissues that activate nociceptors, or by blocking different types of molecules that enable nociceptors to respond to cytokines and additional stimuli.2,7–10 Acute pain (by definition) lasts only for the “short” time that tissue damage requires to heal, presumably after which activity in the nociceptors decreases back to normal. However, many people develop chronic pains that last well beyond the time of normal tissue healing after disruption, or in some incidences without known provocation. Currently, the mechanisms underlying chronic pain development and maintenance remain obscure, despite much research. Q3 | 2017

“

Among the most important research to emerge over the last 15 years has been the discovery of small fiber neuropathy across a wide range of chronic pain conditions—indeed, a loss of the very axons that transmit noxious stimuli.”

Among the most important research to emerge over the last 15 years has been the discovery of small fiber neuropathy (sfn) across a wide range of chronic pain conditions—indeed, a loss of the very axons that transmit noxious stimuli. These findings indicate that many chronic pain disorders may fit the International Association for the Study of Pain definitions of being neuropathic pain (np) conditions with a known impairment of the nociceptive system. np arising from sfn associated with a loss of peripheral nociceptors may seem at first like a paradox. However, strong evidence indicates that increased spontaneous, nonevoked activity, as well as evoked hypersensitivity among remaining sensory innervation likely stimulates central nervous system (cns) nociceptive pathway activity via unpatterned input and/or deafferentation processes, particularly among spinal cord dorsal horn terminations.11–18 Although conceptually np may be driven by a prolongation or exacerbation of acute pain mechanisms causing aberrantly high nociceptor activity,12,13,15–18 therapeutics that effectively ameliorate acute pain provide only limited relief to a minority of np patients while eliciting deleterious side-effects among the majority.1,2,19–25 Currently, there remains a pressing need to develop novel chronic np therapeutics with improved efficacy and safety profiles.

Are nociceptors the answer?

Much research for new analgesic therapeutics continues to focus on molecular aspects of nociceptors. These “pain fibers” are classified by their thin axons and slower conductance rates (unmyelinated C-fibers and lightly myelinated Aδ fibers) which preferentially respond to noxious mechanical, thermal,

Q3 | 2017

chemical, uv, or polymodal stimuli.6–8,26 The wide range of functional response properties of primary afferent nociceptors are attributed to different relative expressions of signaling mechanisms. Nociceptors are complex neurons that express specific ion channels and receptors directly activated in response to noxious chemicals, low pH, extremely high or low temperatures, or mechanical membrane distortions. For example, nociceptors can express transient receptor potential channels (TrpV, TrpA), acid-sensing ion channels (asic), G-protein coupled receptors involved in numerous second messenger signaling interactions, such as endothelin receptor type A (eta), mu opioid receptors (µor), as well as specific voltage-gated sodium channels (Nav) required to generate action potentials. Nociceptors are also exquisitely sensitive to peripheral tissue growth factors (eg, nerve growth factor, brain derived neurotrophic factor, epidermal growth factor) and cytokines (eg, cytochrome oxidase, adenosine triphosphate, bradykinin, interleukins) that are known to increase in response to noxious stimuli and which are implicated as algesic signaling mediators.7,27–29 To date, several molecules targeting various nociceptor-specific mechanisms have shown promise in in vitro experiments and in vivo animal models, but have failed to translate to successful treatments in human clinical trials.21,23–25 Two critically important observations result from these failed translational platforms: 1) The mechanisms of chronic pain remain largely unknown and involve multiple factors such that no one specific molecular target will be identified as a universal therapeutic, and 2) Current endpoints used in standard preclinical pain models (mostly rodent) are insufficient to predict translational success in human clinical studies. www.painweek.org | PWJ

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“

Another common limitation with the use of biopsies in pain patients is that they are typically not collected from sites that are most relevant to the particular chronic pain affliction.”

With the discovery of the protein gene product 9.5 (pgp) antibody, immunochemical evaluations of skin biopsies from humans with a variety of np conditions have shown to be a powerful means of detecting pain-related pathologies within peripheral neural innervation, particularly sfn.30–34 More recently, the use of a wider array of antibodies, largely aimed at detecting additional neuronal characterizations of the small fibers in skin, has also determined the specific and regulated expression of many “neural-related” molecules among the cells of the innervation targets, for example epidermal keratinocytes or vascular smooth muscle. These multimolecular assessments have now shown that in a variety of human chronic pain conditions, target cell expression of neural signaling mediators are also significantly altered, most likely contributing to nociceptor activity and pain. We have postulated that these additional mechanisms are essential to the development of chronic np, and importantly, that targeting the function of these peripheral target-cell signaling mechanisms will lead to more effective and personalized therapeutic strategies. Clearly, the use of multimolecular skin biopsy evaluations holds enormous potential to identify novel targets, facilitate disease diagnoses, refine inclusion and exclusion criteria for enriched study designs, measure therapeutic efficacy, and to select the most relevant animal models for directed study. Furthermore, a very recent update from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (immpact) group, published in the July 2017, recommended skin biopsy analysis for multiple endpoint measures as one of the best techniques to advance the development of novel pain treatments.35

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The value of skin biopsies for chronic pain diagnosis and research

The recent immpact review highlights the use of skin biopsies in pain medicine, particularly for diagnostic, predictive, pharmacodynamic, and biomarker assessments in clinical trials.35 Importantly, that review remains focused on assessments of the nociceptor population, stresses that more research is needed to validate the ienf as a reliable measure, and specifically notes that “Although ienf density has been shown in some studies to be associated with neuropathic pain, a well characterized, direct relationship between ienf density and pain severity has not been established.”35 This statement clearly indicates that additional mechanisms are likely involved. However, no mention is made of target cells (ie, keratinocytes, vascular smooth muscle) or signaling interactions with small fibers, indicating that there continues to be an underutilization of comprehensive skin biopsy analysis. Small Fiber Neuropathy. The overwhelming use of skin biopsies in pain medicine to date has been primarily for sfn diagnostic purposes because routine clinical assessments commonly fail to detect evidence of pathology that explains the chronic pain symptoms experienced. The development of the pgp antibody, directed against a specific enzyme in the ubiquitin pathway (uchl-1), provided a means to label all neuronal elements and revealed previously undetected small caliber C and Aδ fibers in skin biopsies. Particularly important was the presence of numerous small fiber endings terminating among the epidermal keratinocytes (referred to as intraepidermal nerve fibers or ienf). Prior to this finding, the epidermis Q3 | 2017

was considered to be both avascular and uninnervated, and although it is the largest sensory organ, the role of skin was largely researched in the context of barrier function, wound healing, and immunology. However, a particularly surprising discovery that has received considerable attention is the seemingly paradoxical decrease of ienf in most patients with a variety of np afflictions, including postherpetic neuralgia (phn), painful diabetic peripheral neuropathy (pdpn), complex regional pain syndrome type 1, and even cns-localized poststroke pain.36–43 The detection of decreased ienf has become the accepted diagnosis for sfn associated with chronic np. Given that the ienf are widely regarded as nociceptor terminations, the paradoxical loss of innervation commonly associated with chronic pain has partly been explained by physiological evidence that remaining C and Aδ fibers have increased spontaneous activity and are hyperexcitable, referred to as “irritable nociceptors.”13,15–18,44 The authors of this article have long hypothesized that target cells play an essential role in maintaining nociceptor hyperexcitability, and recent optogenetic evidence has now demonstrated that keratinocytes directly signal to nociceptor endings.45,46 Personalized Medicine. Chronic pain is widely attributed to the induction and/or maintenance of hyperactivity within cns nociceptive pathways, a phenomenon referred to as central sensitization. However, central sensitization alone does not fully explain the varieties of symptoms associated with particular types of chronic pain afflictions, such as mechanical and thermal allodynia and/or hyperalgesia or spontaneous pricking and/or burning pain, which are presumably related to differential aberrations among the various functional types of peripheral nociceptors. Despite the increasing discovery of molecular mechanisms implicated in such symptoms, rationally designed therapeutics based on these findings have failed to translate to safe and effective treatments for human chronic pain afflictions. Key detailed mechanisms of chronic pain, on an individual basis, remain unknown. The vast number of potential pathologic mechanisms among the peripheral innervation and target cell signaling to nociceptors likely underlies the lack of predictable success in clinical trials, in part from the subtle differences among individual patients within a select disease population. The use of multimolecular skin biopsy evaluations, beyond a simple ienf density determination, should be considered more frequently to generate additional reliable criteria on which to match patients with appropriate single line or multimodal therapeutics, a much discussed objective of personalized medicine. Underutilization. While the use of human skin punch biopsies has become increasingly common for diagnosing sfn, virtually all of the analyses are limited to pgp9.5 immunolabeling of ienf. However, a simple ienf determination provides no insight into potential mechanisms or specific characteristics of each patient that could form a basis for personalized treatments. For example, it is generally true that a significant reduction of ienf occurs on average among patients suffering Q3 | 2017

from most chronic pain afflictions examined to date. However, it has been shown by us and others that ienf loss does not always occur in pain patients, and some nonpain subjects can show ienf loss. For example, we have demonstrated that select patients who developed chronic pain following an acute herpes zoster attack (postherpetic neuralgia, phn) have little if any ienf loss, while some others who resolved without pain had ienf loss that was just as severe as most PHN patients. Additionally, data from a recent human diabetic neuropathy study we conducted documented ienf loss that was statistically indistinguishable among those with painful diabetic peripheral neuropathy (pdpn) and diabetic patients with nonpainful neuropathy. These data support the idea that sfn, per se, is not the complete story of chronic np. Moreover, ienf loss also commonly occurs during normal aging without pain occurring.41,47–50 Based on the hypothesis that deafferentation is a significant contributor to chronic pain, therapeutic attempts at promoting reinnervation have yet to demonstrate significant efficacy for reducing pain, have been shown to increase inappropriate reinnervation, or are prone to other negative side effects.19,26,27,47,51 Therefore, the density of ienf is not in itself a predictor of the presence, severity, or type of chronic pain. Another common limitation with the use of biopsies in pain patients is that they are typically not collected from sites that are most relevant to the particular chronic pain affliction. Studies of phn have routinely biopsied painful dermatomes and contralateral nonpainful “control” sites, but have been mostly limited to thoracic dermatomes where innervation density is relatively low with little variety of sensory fiber types. The symptoms of most other painful peripheral neuropathy afflictions are commonly most severe in distal sites such as feet and hands (stocking glove) that have a high innervation density and a wide variety of neural innervation. However, biopsies are typically taken from a location on the distal leg a few centimeters above the lateral malleolus which has become the de facto international standard. This has the benefit of providing an increasingly large demographic reference for ienf quantification and diagnosing sfn. However, this site, like the thoracic skin, has a relatively low innervation density and limited variety of innervation, as compared to the glabrous (nonhairy) skin of the hands and feet where pain symptoms often originate. Of additional importance, unlike in the hands and feet, the skin of the distal leg and thorax has a much lower density of arterioles and vascular components, which have a high density of small caliber sensory and autonomic fiber innervation under normal, healthy conditions. Particularly, small fiber vascular innervation alterations are proving to be potential mediators of specific types of afflictions with chronic pain, including fibromyalgia and pdpn. Therefore, we recognize that the selection of skin biopsy location and the use of extensive multimolecular profiling beyond simple ienf determinations across individual skin biopsy samples creates a richer data set and a better characterized patient, greatly enabling the establishment of efficacious therapies. www.painweek.org | PWJ

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Multimolecular profiling

Among nearly all human (or rodent) skin biopsy assessments are the capability to conduct integrated multimolecular profiling among many sections from the same biopsy. This type of complex evaluation provides greater insight into potential pain mechanisms and particular features specific to each type of affliction, but unique among each patient. Integrated Tissue Dynamics, llc (intidyn; senior author Rice is cofounder, ceo, and Chief Scientist; lead author Albrecht is cofounder) has developed a proprietary intidyn ChemoMorphometric Analyses (itd-cma)™ platform for maximizing the potential of multimolecular skin biopsy evaluations for discovery and to provide a personalized tissue profile. Comprehensive multimolecular analysis across chemical and morphologic parameters, coupled with clinical measures of pain, will drive discovery of peripheral mechanisms and direct novel personalized therapeutic strategies, including the use of compounded pharmaceutical preparations. Additionally, a major benefit of the itd-cma™ technology platform is that unused experimental study and collected human tissue is archived and remains viable for additional future research. Furthermore, the use of multimolecular skin biopsy profiling is equally amenable to the same types of analyses in nonhuman animal models, preclinical studies for research discovery and experimental testing, and clinical phase efficacy trials.

Innervation

The use of pgp combined with other neuronal markers detects disease-specific impacts of the multimolecular and structural properties, as well as the relative proportions of functional neuronal subtypes.36,42,52 Signaling receptors and/or ligands can be upregulated among inappropriate sensory endings, while other types of cutaneous endings may preferentially decrease expression, which can be characterized through multimolecular profiling. For example, some subtypes of innervation, such as those that express the inflammatory mediators calcitonin gene-related peptide (cgrp) and substance P (peptidergic) are preferentially spared in animal models of painful neuropathy targeting the TrpV1 channel.53 However, these peptidergic axons also appear to be preferentially vulnerable to loss in males from normal aging (think hypertension, see below), but have also been shown to be preferentially spared among pathologically reduced painful human skin innervation (Rice and Albrecht, unpublished observations). Despite the wealth of literature describing a substantial number of known molecular targets on peripheral sensory fibers associated with injury/disease, single molecular targets on nociceptors continue to be the focus of the pharmaceutical industry, with very limited success. Continued multimolecular expression and function evaluations of the numerous chemical and morphologic small fiber innervation changes associated with both normal aging and pathologic chronic pain processes is clearly needed. Data from comprehensive analysis of innervation will further our understanding of the multiple mechanisms (including non-neuronal) essential for pain generation,

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and importantly drive the concept that multiple mechanisms should be simultaneously exploited for pharmacotherapy and multimodal treatment regimen.

Novel neurovascular pathology

Recent analyses at intidyn were the first to detect a novel, major peripheral neurovascular pathology in the hands of female patients with fibromyalgia,54 which has a well-established central sensitization component associated with the disorder. The cns is the assumed location of bioactive efficacy for nearly all analgesics, including duloxetine (Cymbalta®) and milnacipran (Savella®), serotonergic/noradrenergic reuptake inhibitors (snri) approved by the fda for treating fibromyalgia. The research into potential peripheral vascular innervation alterations in fibromyalgia was a direct result from a prior multimolecular human biopsy evaluation study of ours which demonstrated noradrenergic sympathetic innervation intermingled with peptidergic (cgrp-expressing) sensory innervation expressing an inhibitory noradrenergic α2C receptor.55 This finding suggested that vasoconstrictive sympathetic regulation of cutaneous peripheral vasculature also likely involved direct inhibition of vasodilatory sensory peptide release. To investigate if this cutaneous vascular innervation could be a possible location of snri activity, we analyzed glabrous skin biopsies from fibromyalgia patients and compared them with age-matched controls. Importantly, we discovered a peripheral neurovascular pathology involving excessive innervation to cutaneous arteriole-venule shunts in the glabrous skin from fibromyalgia patients, particularly the cgrp-containing (peptidergic) sensory fibers. cgrp is a potent vasodilatory and proinflammatory peptide, and the significant neurovascular pathology implies functional alterations which provide a logical rationale for fibromyalgia symptoms of local tenderness in the hands, as well as widespread deep tissue pain, muscle fatigue, and cognitive dysfunction, all related to improper blood apportioning. The discovery of a cutaneous neurovascular pathology among fibromyalgia patients demonstrates a potential site of peripheral activity for snri compounds, but more importantly should reshape the prevailing belief that fibromyalgia is strictly a central sensitization syndrome.56–58 In contrast to the excessive sensory neurovascular pathology in fibromyalgia patients, our multimolecular skin analysis platform has also detected a loss of the sensory vascular innervation in patients with crps35 and among diabetic patients, as well as during normal aging in which the loss of the cgrpreleasing sensory fibers may contribute to hypertension (Rice and Albrecht, unpublished observations). These discoveries of chemical and morphologic neurovascular pathologies in human skin biopsies are providing new insights into chronic pain mechanisms and promoting the exploration of novel strategies to treat or prevent a range of disorders including fibromyalgia, complex regional pain syndrome type 1, pdpn, and age-related hypertension. Q3 | 2017

“

Continued multimolecular expression and function evaluations of the numerous chemical and morphologic small fiber innervation changes associated with both normal ageing and pathologic chronic pain processes is clearly needed.”

Novel keratinocyte neurochemical pathology

ienf terminate among the most external cutaneous structure, the epidermis, comprised of structurally-stratified keratinocytes that continually renew and terminally differentiate (ie, keratinization). Comprehensive multimolecular evaluations of skin biopsies have now documented numerous neuroactive signaling families that are differentially distributed in stratified patterns, and which are recapitulated among the keratinocyte stratum from deep to superficial during normal turnover of the epidermis.28,59–64 The signaling molecules include those implicated in both algesic and analgesic mechanisms, and exert excitatory or inhibitory modulation of ienf and upper dermal nociceptors. Our published and preliminary results on human patients with phn, crps-I and pdpn have revealed a recapitulating increase in algesic and decrease in analgesic molecular expression in the epidermis, which likely contributes to the hyperactivity of sensory endings in np conditions.61,63 Our multimolecular research is continuing to elucidate the prevalence of epidermal keratinocyte expression changes among former zoster patients who resolved with pain (phn) as compared to those without pain, and among type 2 diabetic patients with pdpn compared to nonpainful neuropathy. Q3 | 2017

Normal stratified neurochemistry of epidermal keratinocytes. The vital (“live”) epidermal layers are defined by the structural differentiation of keratinocytes: stratum basalis (deepest layer; location of keratinocyte progenitor cells), stratum spinosum (mid layer), and stratum granulosum (most superficial layer). The outermost surface of the skin is covered by the stratum corneum, which is composed of denucleated, nonvital (presumably “dead”) corneocytes. The patterned organization of immunolabeling for signaling molecules implies that vital keratinocytes participate in cutaneous sensory transduction and integration, and recent seminal work using optogenetic techniques has demonstrated direct nociceptor activation following keratinocyte-only activation.45,46 In normal human and rat glabrous skin, our comprehensive multimolecular research approach first discovered that stratum granulosum keratinocytes express analgesic opiate mechanisms involving β-endorphin release driven by endothelin-1 receptor B or cannabinoid receptor 2 activation.62,63 The pharmacological data revealed that keratinocyte release of β-endorphin inhibited the activation of peptidergic ienf (nociceptors) by binding to mu-opioid receptors (µor) leading to the opening of inhibitory potassium channels (girk2). Importantly, our research has also demonstrated keratinocyte-mediated algesic www.painweek.org | PWJ

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mechanisms involving voltage-gated sodium channel (Nav) expression among stratum granulosum keratinocytes.64 Activation of specific Nav channels in keratinocytes may stimulate the release of atp, which likely activates purinergic receptors expressed on nonpeptidergic ienf (nociceptors). Additional research from our group has also demonstrated, for example, that keratinocytes produce and release the β-isoform of cgrp at painful heat temperatures, as different from the α-isoform produced by sensory neurons implicated in neurogenic and inflammatory pain,61 and that histamine receptor 3 (H3R) expressed on stratum spinosum keratinocytes likely contributes to inhibitory modulation by blocking cgrp production and release from keratinocytes.60,65,66 Taken altogether, these results strongly implicate epidermal keratinocytes as essential modulators of nociceptor activation and likely participate in the generation of painful sensations.

to injury, disease, and/or normal aging (from uv exposure, etc) somehow alter the basal keratinocyte stem cells? Do dermal fibroblasts alter their signaling, permanently changing the keratinocyte differentiation program? These and many other questions remain unanswered and at the center of the debate over peripheral mechanisms of chronic pain.

Conclusions

In the absence of detectable evidence of peripheral pathologies, chronic pain conditions have been widely regarded as cns disorders, and most therapies for chronic pain have cns activity. However, treatments focused on systemic and/or intrathecal pharmaceuticals with cns delivery and activity are saddled with marginal efficacy and a high risk of undesirable side effects. The use of skin biopsies for simple assessments of ienf density among pain patients has now demonstrated sfn as a common feature; however, the ienf density alone remains unvalidated as a pain diagnostic. Current use of third-party reimbursable skin biopsy assessments are only performed as single marker (pgp9.5), and generate limited data. However, the increased use of comprehensive multimolecular immunochemical assessments of skin biopsies is providing a powerful technique to visualize/diagnose and explicitly characterize sfn and other neuropathy and target cell conditions, which are evident among nearly every type of human np affliction studied to date. Comprehensive multimolecular analysis of skin biopsies can be used to profile individual molecular and microstructural pathologies as peripheral sources of np in preclinical pain models and in the translational application to human studies and trials. Importantly, specific pain mechanisms among small fiber innervation and skin cells can be identified on an individual basis and exploited through the application of topical therapeutics with targeted and locally restricted activity, thereby significantly limiting negative side-effects. Indeed, there are numerous excellent comprehensive reviews of topical analgesic applications and relative benefits.68,69

Recapitulating pathologic neurochemistry of epidermal keratinocytes associated with NP. Complex multimolecular evaluations of crps-I and phn subject skin biopsies revealed major alterations of Nav channel subunit expressions among the keratinocytes compared with control nonpainful skin, particularly a profound increase in the immunolabeling intensity and distribution of Nav1.6, Nav1.7, and βCGRP. Furthermore, in these painful skin samples, keratinocyte immunolabeling for TrpV1 and TrkA1 was increased, as well as de novo immunolabeling for Nav1.1, Nav1.2, the acid sensing ion channel 1a (asic1a), and bradykinin receptor 1 (bk1) (Albrecht and Rice, unpublished observations). Moreover, human np skin and animal model skin can be simultaneously accompanied by a decrease in analgesic components, particularly β-endorphin. For example, our preliminary data has shown that skin opiate systems are significantly altered in human chronic pain states, but more importantly, the data demonstrate that skin opiate alterations very likely contribute to opiate prescription misuse/ abuse and addiction/relapse issues. Several other potential keratinocyte-mediated algesic contributors in human chronic pain conditions identified with multimolecular evaluations, include TrpV1, TrpA1, βcgrp, endothelin-1 receptor A, and the Currently, only 2 topical therapeutics have been approved by ngf high affinity receptor (TrkA).28,67 Any of these identified the fda for their significant, albeit partial, effectiveness in alterations could potentially contribute to hypersensitivity treating specific np conditions. These include 5% lidocaine of innervation in the epidermis and upper dermis, leading patch (Lidoderm®) and 8% capsaicin patch (Qutenza®), both to increased spontaneous activity and decreased stimuli approved for phn.70 Lidocaine blocks fast acting Nav chanthresholds among nociceptors. Yet, several essential questions nels involved in action potential propagation and capsaicin remain uninvestigated. In our opinion, particularly important strongly activates heat-responsive TrpV1 cation channels on to understanding chronic pain mechanisms will be the deter- nociceptors. Both types of ion channels are expressed in mination of signals that pattern the aberrant keratinocyte nociceptors innervating the epidermis, and are the presumed expressions.7,8,29 For example, in all the human chronic pain target of the analgesic effect. Lidocaine blocks action potential conditions investigated, several generations of keratinocytes generation in nociceptors, and capsaicin causes nociceptor have turned over through the process of keratinization, yet the defunctionalization through excessive hyperpolarization and altered patterns of signaling molecule expression appear to be “burn out,” leading to a loss of TrpV1 expressing nociceptor recapitulated over successive generations. Furthermore, even endings or preventing aberrant fiber proliferation.71 However, in animal models of proximal nerve injury-induced chronic keratinocytes also express both Nav and TrpV1 channels, and pain, where ienf are lost and gradually regained, aberrant the effects of topical lidocaine or capsaicin on keratinocyte keratinocyte patterning appears to remain concomitant with function involve stimulation of cytokine expression. Currently, hypersensitivity, despite ienf regrowth.61 Does the response both topical preparations are commonly used off-label to test

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their effectiveness in patients with other chronic np afflictions. For example, topical treatment with the adrenergic α2 receptor agonist clonidine has shown limited benefit in treating pdpn.72–74 However in late-stage clinical studies, the topical formulation failed to demonstrate significant effect.75 Additionally, topical diclofenac (Voltaren®), an nsaid, may have some benefit in treating phn and other conditions.76 More recently, the mixing of efficacious pharmaceuticals in topical formulations has gained popularity through the use of compounding pharmacies. A review of some of the preparations include a wide range of combinations, including up to 8 different active compounds, each in a variable percentage, and mixtures for different disease etiologies and/or types of pain.69,77,78 The effectiveness of these types of complex compounds remains debated, however the use of topical analgesics represents a largely untapped resource to exploit for therapy. Comprehensive multimolecular skin biopsy profiling will greatly enhance the utility of topical compounding by identifying mechanisms specific to each patient which can then be targeted directly with personalized medicine solutions. Skin pathologies among chronic pain conditions are not limited to only ienf, which are the presumed primary source of cutaneous pain, but also involve disease specific pathologies among the innervation to other skin components, like blood vessels, sweat glands, and/or hair follicles, as well as among cells of the skin itself, such as epidermal keratinocytes. The keratinocytes are especially intriguing because they have complex neural-signaling properties implicated in inhibitory (analgesic) and excitatory (algesic) mechanisms that can modulate the relative sensitivity of nociceptors. Keratinocyte excitatory properties can be upregulated and inhibitory properties downregulated in chronic pain afflictions, and the neurochemical balance of the epidermis may distinguish between different types of np afflictions, between the relative intensity of pain symptoms, and between therapeutic responses among patients with the same affliction. Furthermore, multimolecular skin biopsy evaluations have provided significant evidence of peripheral pathologies in patients with painful afflictions attributed primarily to central sensitization, including fibromyalgia, indicating that these conditions likely have a peripheral neuropathic component. Importantly, comprehensive skin biopsy profiling can provide a rational approach to topical compounding treatment protocols for individual patients.8,77,79 For example, expression of Nav channels and TrpV1 receptors on keratinocytes and α2C receptors on cgrp containing vascular sensory fibers, which are all increased under np conditions, demonstrate novel potential sites of action for topical applications with lidocaine, capsaicin, and clonidine, in addition to direct actions on ienf. Therefore, towards achieving the goal of personalized medicine in treating chronic pain, comprehensive multimolecular immunochemical evaluations of skin biopsies can provide a more effective means of diagnosing specific np afflictions, beyond simple ienf. These include identifying novel targets, developing a more rational basis for existing and future therapeutic strategies, defining inclusion and exclusion Q3 | 2017

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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 (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.

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 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 or conditions. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of MORPHABOND ER. Monitor for respiratory depression, especially during initiation of MORPHABOND ER or following a dose increase. Instruct patients to swallow MORPHABOND ER tablets whole; crushing, chewing, or dissolving MORPHABOND ER tablets can cause rapid release and absorption of a potentially fatal dose of morphine. Accidental Ingestion Accidental ingestion of even one dose of MORPHABOND ER, especially by children, can result in a fatal overdose of morphine.

CONTRAINDICATIONS

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

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 MAOIs within the last 14 days; known or suspected gastrointestinal obstruction, including paralytic ileus; and hypersensitivity (e.g., anaphylaxis) to morphine.

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.

WARNINGS AND PRECAUTIONS

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 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.

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

Life-Threatening Respiratory Depression

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.

Please see Important Safety Information on following pages.

AVAILABLE SOON

A single-agent, abuse-deterrent ER morphine with SentryBondâ&#x201E;˘ technology that is expected to deter abuse by injection and insufflation1 However, abuse is still possible by intranasal, intravenous, and oral routes For more information, visit MORPHABONDhcp.com

WARNINGS AND PRECAUTIONS (contâ&#x20AC;&#x2122;d) 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.

ER=extended release. Reference: 1. MORPHABOND ER [package insert]. Basking Ridge, NJ: Inspirion Delivery Sciences LLC; 2016.

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS AND PRECAUTIONS (cont’d)

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 (e.g., 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 (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.

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 (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including 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

Please see Brief Summary of full Prescribing Information, including BOXED WARNINGS, on adjacent pages. ©2017 Daiichi Sankyo, Inc. MORPHABOND ER and the MORPHABOND ER logo are trademarks of INSPIRION DELIVERY SCIENCES LLC. Other trademarks are the property of their respective owners. PP-US-MB-0255 08/17

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 post-approval use of morphine sulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Amenorrhea, asthenia, bronchospasm, confusional state, drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in 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. 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 psychophysiologic 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 non-randomized study design. Animal Data Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on a human daily dose of 60 mg morphine using a body surface area comparison (HDD). Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear. Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation

were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity. An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated. In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, 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

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 Kevin L. Zacharoff md, facip, facpe, faap

Competing prescribing guidelines, negative media attention, educational deficits, comorbid medical complexity, and fear of regulatory scrutiny (along with other factors) have increased the burdens, challenges, and anxiety facing clinicians caring for these [chronic pain] patients.

eTHiCS abstract:

The safe and effective management of chronic pain with prescription pain medications shares both similarities and differences with providing pharmacologic care for patients with other medical conditions. Many forces have recently come together to attempt to reshape the use of prescription pain medications, particularly opioid analgesics, in chronic pain treatment today. Commonly, medication based treatment may be just one component of a chronic pain management treatment plan. Caring for patients suffering from chronic pain, because of its high prevalence, falls largely on the shoulders of frontline healthcare practitioners, many of whom haven’t received adequate education in pain management, prescription pain medications, or substance abuse. Competing prescribing guidelines, negative media attention, educational deficits, comorbid medical complexity, and fear of regulatory scrutiny (along with other factors) have increased the burdens, challenges, and anxiety facing clinicians caring for these patients. Unfortunately, not much discussion is taking place regarding the dutiful, thoughtful, and consistent application of ethical principles to treating patients with chronic pain. This article provides a summary of generally accepted principles of medical ethics. It offers a framework for incorporation of these principles into the development of a medication based pain treatment plan for clinicians that can be clinically relevant, reproducible, ethically sound, and above all helpful towards achieving positive patient outcomes.

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Everything is negotiable…

Chronic pain—how different is it?

Everything is negotiable… maybe more so when healthcare providers are tasked with assessing and treating patients with chronic pain. So closely tied to the negotiation of quality of life and functional capability, chronic pain is one of the few medical conditions where the patient gets to have a significant level of input regarding what determines the success or failure of a treatment plan. The lack of easily available and objective markers for chronic pain contrasts those available for other common diseases such as diabetes and hypertension, where treatment efficacy can be gauged by laboratory results or vital sign assessment like serum hemoglobin A1c or serial blood pressure measurement. Ironically, while shared decision-making is considered to be a hallmark of healthcare today, paternalism continues to play a role in patient care, often confounding key principles of effective pain management. In many cases, patients want to be told what to do, and in many cases, healthcare providers want to tell patients what to do and just be done with it. These sometime hard and fast dynamics can often be difficult to abandon, and may ultimately lead to diminished communication and understanding, and the violation of patient’s rights to ethical delivery of care. One could argue that rarely is there more of a need for transparent patient-provider communication than in the case of a patient with chronic pain. If setting goals and expectations of treatment is a foundational step in the assessment process and treatment plan formulation including prescription pain medications, surely there is a need for a high level of dialogue among all stakeholders.

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www.painweek.org | PWJ

eTHiCS

Pharmacologic approaches are more often than not a component of a chronic pain treatment plan. In many cases, a trial of opioid analgesics may be considered one arm of a multidisciplinary pain treatment plan, especially when other treatment options have failed. Over the past 20 years, the simple and often paternalistic approach to default to opioid utilization in chronic pain treatment has been challenged by many for a variety of reasons—none more prominently than the national “opioid epidemic.”1 Controversies have swirled around the default use of opioids both acutely and chronically to treat chronic pain, with the list of participants in the debate continuing to swell and each with their own perspectives and arguments. Calls for solutions to the seemingly ever-growing number of unintended opioid related overdoses and deaths have become outcries, and a number of “silver bullets” have been implemented to try to stem this tide. As the list of stakeholders involved in the discussion seems to grow every year, so does the level of debate regarding what may or may not be other viable options for more appropriate management of chronic pain. Due to its high prevalence, the challenges of treating chronic pain largely live on the doorstep of frontline, nonexpert clinicians. With pain management education rarely intensively incorporated into the curriculum of medical training programs,2,3 often, healthcare providers are presented with frequently occurring challenging clinical dilemmas in the face of these educational deficits—not a good combination. Additionally, many other issues dramatically complicate this situation including: ●● A growing number of sometimes conflicting prescribing guidelines ●● Negative media attention ●● Comorbid medical complexity ●● State level prescribing mandates ●● Competing educational programs ●● Fear of regulatory scrutiny One needs to consider how all of this impacts the most important stakeholders: the patients.

A healthy dose of ethics…

The subject of prescription pain medications and chronic pain often triggers thoughts of regimented processes, monitoring, and documentation. This is where guidelines, treatment recommendations, and mandates typically focus. While this is appropriate, what seems to be often overlooked by even highly educated healthcare providers and organizations is the consideration of ways to implement reproducible approaches and methodologies. These could be employed as pain management

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strategies based on ethical principles that don’t deviate from those used when treating other medical conditions. There is little dispute that self-reported pain ratings are subjective, and patient needs and treatment responses should be highly individualized. Previous clinical responses to treatments utilized for other patients, “gut checks,” prior experiences, and anecdotal experience will likely not suffice when it comes to chronic pain. There is an abundance of recommendations to consider for safe and effective implementation of pharmacologic pain treatment strategies and for potential negative behaviors like abuse, misuse, and diversion. But what may often be missing is the clinically reproducible relevance of these recommendations for frontline practitioners. How can frontline practitioners relate to all of this in ways that are similar to the myriad of other medical conditions they assess and treat? Basic ethical principles and may help to fill this void, and also help clinicians determine another critically important variable: context. In the absence of context it might be very difficult to truly approximate what may be most likely to yield the best outcome of a pain treatment plan. Despite the fact that most if not all of us are familiar with the Hippocratic mandate to “Do No Harm,” generally, (consciously or not) our decision-making is often guided by the limitations of our knowledge base, previous clinical experiences, precognitive biases, and one or more of these 4 ethical principles4: ❶ Autonomy ❷ Justice ❸ Nonmaleficence ❹ Beneficence Even though this seems relatively straightforward, there may be challenges in trying to figure out how we can reproducibly utilize these principles to guide our decisions when managing patients with chronic pain, especially when prescription pain medications are used as a component of the treatment plan. These principles almost always overlap and may conflict, and there may be no obvious mechanism to resolve these conflicts: Weighing and balancing principles may not be clear. Despite these challenges, it is worth the effort to help determine a reproducible framework that is independent yet complementary to other forces at play.

Autonomy Respect for autonomy is defined as the acknowledgment and respect for the fact that a competent person has the right to make decisions regarding treatment based on his or her individual contemplation, including personal values and beliefs, and comprehension of potential risks and benefits. Interventions Q3 | 2017

…what seems to be often overlooked by even highly educated healthcare providers and organizations is the consideration of ways to implement reproducible approaches and methodologies

should not be imposed on competent patients, and shared decision-making should be employed through the provision of offering a choice of treatments that is as broad as possible. This does not mean that clinicians should concede and prescribe what a patient wants (eg, demanding an opioid prescription) irrespective of sound medical judgment. It means that education, discussion, and communication are essential to help patients participate in pain management decisions. Many (including this author) consider this to be the overarching and most important ethical principle, and give it significant weight in how treatments are selected. However, it takes time and effort to arm the patient with all of the necessary information to consider and participate in the decision-making process.

Justice Justice as an ethical principle might appear simplistic, but may actually be the most complicated principle of all. At its most basic level, justice refers to the fact that there is a legal duty to provide fair and equitable treatment for all patients, regardless of who they are, and regardless of what we may think of them on a personal level. One example of using the justice based principle in the context of pain management, and something that is more and more pertinent each day, is Q3 | 2017

the notion that prescription pain medications such as opioid analgesics should always be considered and offered to patients when appropriate. From a justice perspective, when aberrant drug related behavior or substance abuse is suspected or discovered, someone with a higher level of expertise in these areas may be called upon to prescribe or monitor in order to maintain the necessary harmony between safety, efficacy, and the law. What’s important here is that the process of consideration takes place for all patients in an even and reproducible way, fairly and without judgmental impact.

Nonmaleficence Nonmaleficence most closely aligns with the idea that harm should be minimized or avoided whenever possible. In today’s pain care climate, this will typically include adverse effects, along with the potential for or presence of behaviors like abuse, misuse, and risk of addiction. Importantly, when including prescription pain medications as part of the treatment plan, consideration is crucial for the safety of family, other household members, and members of immediate social circles. Discussion with the patient about responsibilities and education about prescription pain medications is critical to upholding this principle. www.painweek.org | PWJ

eTHiCS

Beneficence The principle of beneficence simply dictates that decisions should be made on the basis of what will likely provide the greatest benefit to the patient. This might be the most likely place where we may revert to a paternalistic role, and assume that we know “what’s best” for the patient. In addition to education and access to the literature, guidelines, mandates, and media attention, we need to factor in things like empathy, being open-minded to patients concerns and perceptions, and individual aspects of the patient’s context in their lives. In the absence of all of this information it may be impossible to truly estimate what is most likely to benefit the patient, but that is our duty to the best of our capability.

Communication All of these principles are founded upon the most powerful tool we have at our disposal—communication. Providers should inquire about the needs and desires of the patient, members of the family, social circle, and community.5 These principles are intended to provide a framework and guide regardless of the patient’s medical problems and to provide a routine to the decision-making process. In the context of chronic pain, healthcare providers need to consider the synergy of assessment recommendations, prescribing and treatment guidelines, and regulatory pressures, and balance them with the application of these ethical principles in order to ensure that safety, efficacy, and context based plans can be formulated and replicated despite patient individuality. In practical terms, whether or not prescription pain medications are considered, all of the following boxes should be checked when formulating a chronic pain treatment plan: ☑ A comprehensive assessment, including diagnostic testing, helping to yield a diagnosis ☑ An informed autonomous patient (or caregiver/health proxy) involved in potential treatment decisions, taking into consideration personal beliefs and understanding of risks and benefits

Conclusions

In the final analysis, our challenge is to determine how decisions we make about formulating a treatment plan can provide patients with chronic pain the most relief possible in the safest, effective, and thoughtful and compassionate way. This involves taking into account patient’s individual needs and feelings, their circumstances, and the context of their lives. The overarching benefit is providing an ethical framework reproducible from patient to patient.6 These steps may be much more likely to resonate with clinicians, as they apply to pretty much every medical condition, and every clinical scenario. Information gathered from assessments and testing may vary from patient to patient, but ethical duties remain fixed. Our obligation is to balance all guidelines, practice recommendations, and regulatory pressures with the ethical and moral responsibilities that come along with the medical care that we provide to patients. It’s a delicate balance, but something we need to do to defend our guidance to help patients make decisions about how to best manage their chronic pain, especially when considering prescription pain medications as part of the treatment.7,8 References 1. The opioid epidemic: by the numbers. Department of Health and Human Services. 2016. Available at: www.hhs.gov/sites/default/files/Factsheetopioids-061516.pdf. 2. Mezei L, Murinson B. Pain education in North American medical schools. J Pain. 2011;12(12):1199–1208. 3. Bradshaw YS, Patel Wacks N, Perez-Tamayo A, et al. Deconstructing one medical school’s pain curriculum: ii. partnering with medical students on an evidence-guided redesign. Pain Med. 2017;18(4):664–679. 4. Principles of ethics. Kennedy Institute of Ethics, Georgetown University. Available at: bioethics.georgetown.edu/?s=Principles. 5. Garrett TM, Baillie HM. Health Care Ethics: Principles and Problems. 5th ed. London, England: Pearson; 2009. 6. Kotalik J. Controlling and reducing misuse of opioids: ethical considerations. Can Fam Physician. 2012;58(4):381–385, e190–195. 7. Cohen MJ, Jangro WC. A clinical ethics approach to opioid treatment of chronic non-cancer pain. AMA J Ethics. 2015;17(6):521–529. 8. Ballantyne JC, Fleisher LA. Ethical issues in opioid prescribing for chronic pain. Pain. 2010;148(3):365–367.

☑ Care delivered with fairness, equity, and compassion ☑ Approaches chosen that minimize potential harm including risk of aberrant drug related behaviors ☑ Strategies selected and discussed on the basis of what is most likely to benefit the patient ☑ Mutual willingness to reassess all of the above frequently and as necessary

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SHORT CUTS

Georgine Lamvu md, mph, facog VA Medical Center

People do not think of me— a gynecologist— as a pain specialist, but I am.

GPS Orlando, Florida Typical Day “I spend most of my time educating people on how to evaluate, treat, and research pelvic and vaginal

pain. I also spend a good deal of time building collaborative research networks and obsess a lot about how to create the next generation of pelvic pain providers and be a good mentor.” Persona “People do not think of me— a gynecologist— as a pain specialist, but I am. I focus on teaching patients and providers what they need to know about chronic pain physiology and put it all in the perspective of the pelvis and genitalia, so that we can overcome the stigma and isolation that our patients experience and promote treatment of this type of pain like we do for other chronic pain syndromes. I spend a good deal of time teaching folks that not all pain in the pelvis is endometriosis.” Social Media Habits “I am a Facebook® and Twitter® person. The truth is my favorite type of communication is face-to-face. I just don’t think the complexities of chronic pain can be effectively communicated without face-to-face interactions.” People “I most admire Marie Curie, the first woman to win the Nobel prize and whose work eventually went on to develop the X-ray. She was a fabulous scientist whose discovery changed medicine. ’Nuff said!” Words “My most recent favorite read is Drug Dealer, MD.* It really emphasizes how providers can do just as much harm (unintentionally) as good. But I also like to unwind and read geeky sci-fi stuff like my favorite the Mistborn trilogy. In those worlds, nothing is impossible, and pain is just a state of mind.” Popcorn “I am definitely a Star Wars geek! I was born and raised in Romania, so the first time I saw it was in a small outdoor theatre with Romanian subtitles. Even so, I thought it was the coolest movie ever, and I was a Princess Leia fan all the way. Pretty much anything that has to do with strong warrior women is right up my alley.” PAINWeek “I like collaborating across specialties, so during PAINWeek I really enjoy getting exposure to chronic pain from a perspective other than the pelvis. It’s the mixture that makes PAINWeek unique and the perfect combination between science and clinical practice. It’s also a great place for novices and experts alike.” *Drug Dealer, MD: How Doctors Were Duped, Patients Got Hooked, and Why It’s So Hard to Stop by Anna Lembke

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By Doug Gourlay md, msc, frcpc, fasam

“Abandon the molecule not the patient!” In any trial of therapy, some patients will do brilliantly while others may fail to meet previously agreed upon therapeutic goals. In those cases, it may be necessary to stop prescribing controlled substances while continuing to provide other pharmacologic as well as nonpharmacologic support. In some cases, the use of opioids may need to be suspended until further assessment around concurrent substance use disorders has been made. Alternatively, continued prescription of these medications should be contingent on something like participation in a urine drug testing program or attendance at 12 step mutual support programs as part of an ongoing plan for recovery.

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SHORT CUTS

In the search

for more treatment options for the

2 million Americans suffering from

inflammatory bowel disease,

the microRNSA miR-223 may be the key.

In research on mouse models, the introduction of synthetic miR-223 caused a reduced expression of the inflammasome component NLRP3, effectively protecting them from experimentally

induced colitis.1

The Behavioral Pain Assessment Tool (bpat) considers

readily observable behaviors associated with pain. A study of its effectiveness examined

3,850 patients who underwent 4,800 procedures in

192 icus worldwide.

Among the

66%

of the study population who could communicate their pain, the bpat score was found to be comparable to the standard

10-point score

in identifying patients in severe pain.2

Both

excessive weight and underweight are risk factors for migraine, per a meta-analysis of

Better prescribing guidance is needed for clinicians treating pain from minor injuries.

studies of body mass index and headache incidence.

A study of

53,000

Surveying

288,981

patients, the analysis found those with BMI >30 were

patient records of emergency department visits for ankle sprain in 2011 and 2012 found

1.6

27% more likely

% of patients in Delaware received opioids,

and those with BMI <18.5 were

but % of patients in Mississippi received them.

to experience migraine

13% more likely

than were patients of normal weight.3

Rural dwellers experience

Although the median prescription quantity was 20 pills, % of prescriptions were for 60 doses or more.

High quantity patients were

✗more likely to subsequently fill a second prescription.5

more diabetes and receive worse treatment than their urban counterparts. Nationally, up to

Patients with osteoarthritis

of patients with diabetes also develop painful diabetic neuropathy.

A study of

111

average years on medications before undergoing total knee arthroplasty (TKA), and

25% are prescribed opioids. But a review

patients seen at a rural South Carolina clinic found that

suffered from diabetic neuropathy, and

only

50 20

of those had been properly diagnosed.

patients received treatment, but at insufficient dosing levels to satisfy accepted treatment guidelines.4

156

of patients who underwent TKA between 2011 and 2013

found that the % who received opioids in the

years prior to their surgery reported an average postsurgical pain score of

17 .

Patients who did not use presurgical opioids reported an average score of

following their TKA procedure.6

1. http://bit.ly/2rprB3W 2. http://bit.ly/2qrtSX6 3. http://bit.ly/2qrIRAA 4. http://bit.ly/2qrvIaz 5. http://bit.ly/2r5R29L 6. http://bit.ly/2r5MdNM

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SHORT CUTS

MEDD Myths: The Dangers for Research and Practice Michael Schatman phd, cpe, daspe

There are 2 big problems with morphine equivalent daily dose, and one is in research, where the concept of medd as a dependent variable has been empirically established as invalid — my 10 mg of morphine is not necessarily the same as your 10 mg of morphine, due to a variety of differences including the pharmacogenomics differences. So, the research that uses medd as a dependent variable will be invalid. This research, of course, is very important in that it is going to inform practices. With respect to the cdc prescribing guideline, the writing committee’s use of medd, focusing on nothing other than getting that medd down, was disingenuous, because it is an invalid concept. The emphasis was on how much is prescribed rather than, more importantly, to whom we are prescribing. So the cdc guideline is really terrible. It doesn’t address important questions and focuses on how much you ought to be prescribing without taking individualized genetic makeup and other factors into account. An invalid guideline that’s agenda-based rather than empirically-based is certainly problematic. I think it’s important that primary care docs who are subject to the chilling effects of these medd-based guidelines write op-ed pieces to their local papers, that they speak to their state medical societies, and that they try to organize. I don’t think that individual states can afford to have a lot of disgruntled physicians, particularly primary care physicians. By 2025, in the United States we are expected to have a shortage of 66,000 primary care physicians, an astronomical number. And if this ends up pushing people away from family practice where most of the prescribing is done, then the primary care crisis is only going to worsen, and I think that is going to result in a lot more deaths than does the so-called opioid crisis.

Easing Joint Pain With Viscosupplementation

Ramon Cuevas-Trisan md

Approval for the first viscosupplement agent in the United States came 19 years ago. It has been used in different forms for well over 2 decades in multiple different medical fields ranging from cosmetics all the way to neurosurgery. It also has application to the management of disability and pain from osteoarthritis. It is approved in the United States for knee osteoarthritis specifically,

PWJ | www.painweek.org

but there are non-fda-approved joints that have been widely treated— hips and shoulders particularly, but also sacroiliac joints, facet joints, metacarpophalangeal joints and others. There are actually 8 products that are marketed and approved by the fda: 6 different products and 2 that are the same parent compound, but they are in a one-injection regimen as opposed to being multiple injection regimens like most of the others. In the sequence of treatment, viscosupplementation is usually tried after you have already exhausted more conservative management such as basic analgesics, as well as physical therapy. There are some potential adverse events, but they are very low in terms of their incidence. One that most widely raises concern is the appearance of pseudoseptic arthritis or pseudoseptic joints, which is an inflammatory reaction that occurs in the injected joint. It’s not really an infection or a septic joint, but an inflammatory response to a foreign entity that is usually self-limited to a day or 2. The evidence for effectiveness of viscosupplementation is actually quite controversial. There have been a number of different societies that have called into question its efficacy, most notably the American Academy of Orthopedic Surgery. However, there have been other publications, particularly a Cochrane database review that was published a couple of years ago, that shows their efficacy. One of the biggest challenges is choosing the patient appropriately. There are many different phenotypes of osteoarthritis that may have better or lesser responses to this therapy specifically. Clinicians should know that viscosupplementation represents another option for patients who have osteoarthritis, and pain and disability related to it, one that could have potentially a medication-sparing effect which could be helpful in keeping patients functional and avoiding the systemic side effects of medication therapy.

Platelet Rich Plasma: What, When, Where?

Peter Pryzbylkowski md

Regenerative therapy is on the forefront of new technologies being developed to help people with chronic pain. What you’re really trying to do is heal damaged tissue, which is kind of a novel approach. In our field, we’re used to giving a molecule to help with pain. And what we’re trying to do now with these biomolecules— which is basically what they are — is to restore, repair, and heal damaged tissues. Platelet-rich plasma (prp) is acquired via venipuncture with the patient. The whole blood is then centrifuged usually twice to get the PRP. It’s usually recombined with bovine or calcium serum to activate it before it’s injected. Typically, where we’re seeing it used is in orthopedics via injections into tendons that have been damaged, such as rotator cuff tears, acl tears, etc. It is usually done under direct ultrasound guidance to make sure we’re injecting into the tendon rather than into the joint space. In terms of application for chronic pain conditions, the data provide some support for its use for chronic tendinopathies. In terms of injection into spinal disc material, that’s still kind of on the forefront and we’re still making advances in that area. A lot of the data that’s coming out concerns injecting into disc material for patients with radiculopathy from disc bulges or disc herniations and seeing what the long-term effectiveness of that procedure is. Some contraindications to injection of PRP would be patients who have any thrombocytopenia, low platelet

Q3 | 2017

counts, history of active hematological cancers such as leukemia or lymphoma, and patients who are on anticoagulants, like heparin or Coumadin. Looking to future applications for prp, it’s really been shown to help with diabetic ulcers, nonhealing chronic ulcers, whether they be diabetic or venous stasis ulcers. Currently the Centers for Medicare & Medicaid Services has approved its use for patients with those conditions as long as they’re enrolled in an active clinical trial. As of right now it’s not covered by any major healthcare plan. It’s still considered investigational and acquiring it is time-consuming: the venipuncture procedure, drawing of the blood, centrifuging it, takes on average 20 to 30 minutes before you’re able to actually do the injections. And it is pricey with patients paying out of pocket currently.

Going Beyond Pharmacology for Better Outcomes Mel Pohl MD

Pain is really a mind-body experience. It’s unrealistic to think that the mind and the body are somehow separate, or that we can deal with a mind process with only pharmacology. With that underpinning, we need to figure out how to impact a person’s experience with pain. That’s really what this is about. It’s the experience of pain and the response of the person’s pain experience which is known as suffering. Our patients have narratives about their pain. “My head is going to explode.” “My back is killing me.” “My feet are on fire.” None of that is true. So helping people separate from that attachment is something every clinician can do. It’s talking about what their perceptions are, how their focus is drilled into a belief system, and then starting to loosen the ties to that belief. There’s cognitive behavioral therapeutic interventions and there’s dialectical behavioral therapy and there’s acceptance commitment therapy. These are all manualized therapies that have great evidence behind them of efficacy for pain reduction— evidence that they effect changes in different parts of the brain, the somatosensory cortex and the cingulate gyrus and the insula and thalamus. We can impact the neurophysiology of the pain experience in the brain by a variety of interventions. Besides the thought-related interventions, there are physical interventions. People tend not to move and we all know that lack of movement causes pain to be worse. How do we introduce movement into the life of the patient? Many patients are frightened of movement, and I stress the difference between hurt and harm. It will not harm you to move but it won’t feel very good. Graduated exercise is something that has to be introduced into any pain patient’s experience, and that could include yoga or tai chi or qigong, things that are known to stimulate circulation and immune system function while decreasing stress and anxiety. It’s also important to pay attention to nutrition. There are inflammatory foods that probably make pain worse, and foods that probably decrease pain. When we’re talking about toxins, the first toxin to deal with is smoking. Every clinician should instruct their patient to quit smoking if they smoke. On the positive side, hydration makes sense; flushing the system out and enhancing kidney function and helping the liver with its detoxification process. There are a variety of pretty easy interventions, and clearly you can’t talk about them all in one session, but to have them on the agenda, clinicians can help people to a better quality of life.

Q3 | 2017

Analgesia from Acupuncture— Is it Real? Richard Harris phd, ms, dipl ac

Acupuncture analgesia is a debated question. In the research on chronic pain, there is the issue of how to control for the intervention. With the typical drug, it’s easy to come up with a control. As long as the patient can’t tell the difference between a placebo pill and the actual pill in terms of taste or color or smell or whatever, you’ve got a nice control. But with acupuncture, you’re dealing with an intervention where you touch the person. That raises the question of how do you study the effect? Many sham-controlled studies of acupuncture have shown that sham treatments, ie, placing needles in nontraditional points, are similarly effective to traditional placements in reducing clinical pain. But we also know that if you compare acupuncture to standard care or acupuncture to waitlist control or acupuncture vs no treatment at all, the data is strong showing that acupuncture has a profound effect on chronic pain. Studies have compared sham acupuncture vs a placebo pill — 2 placebos basically — and the sham acupuncture was much more effective at reducing pain than a placebo pill. We have been studying the effect of sham acupuncture and traditional acupuncture on the opioid receptors in fibromyalgia patients using positron emission tomography, and have discovered that they exert the exact opposite effect. We found that sham acupuncture caused a reduction in the receptor-binding ability that we inferred was due to an increased release of endorphins. However, with traditional needling, we found an increase in the receptors’ binding ability. Either the receptors were able to bind stronger to the endogenous ligands or maybe there was an insertion in a translation of more receptors being expressed on the plasma membrane and thereby basically making it more effective at reducing pain, but they did it via different mechanisms. It looked like sham increased the neurotransmitter whereas real acupuncture was working on the receptors and modifying the receptor’s ability to bind. There are both clinical and basic science implications. The clinical usefulness of acupuncture seems to be there, and it’s very safe, cheap, and the effects last a long time. So clinically, we’re moving in the direction of combining acupuncture with other treatment modalities, such as cognitive behavioral therapy, exercise, massage, or even drugs. The basic science angle is asking, how does acupuncture mechanistically work, and there’s still a lot to be done there. I think the future of the research is going to be translational, combining work from animal studies and translating that into humans, doing a mechanistic study in humans who have a disease and then translating that back into animals while pairing it with new interventions as well.

www.painweek.org | PWJ

SHORT CUTS

with

brett r.

stacey

PWJ | www.painweek.org

Q1 | 2016

“As a medical student and resident I was surprised by the lack of understanding of what drove the chronic pain experience for patients…”

Q What inspired you to become a healthcare provider?

First, I liked the idea that being a doctor often leads to a personal, intense involvement in a patient’s life. There is an inherent trust and responsibility to do one’s best on all levels that goes with that relationship. Second, there is the ever-evolving science and knowledge that demands one’s intellectual engagement. These two aspects motivated me to go to medical school and still keep me going.

Why did you focus on pain management?

As a medical student and resident I was surprised by the lack of understanding of what drove the chronic pain experience for patients— this was intriguing. Patients always have bodies, minds, and life circumstances, and we must look at all of them to find meaningful answers to chronic pain dilemmas. Effective pain assessment and treatment requires one to be truly immersed in the biopsychosocial model to care for patients— I enjoy this. Finally, the variety of treatments that can be effective from intervention to medication to counseling to physical conditioning means that each patient requires a unique treatment plan. I really like sorting out a path for each individual toward better health and function.

Who were your mentors?

As a trainee at the University of Pittsburgh, I modeled myself after pain physician Michael Brody. His calm demeanor, compassion, and his

Q3 | 2017

advice “to be the doctor each patient needs you to be” still serves as a daily guide in my practice. Robert Dworkin furthered my interest in clinical trials and thinking about how to design better studies and have fun doing it. At ohsu, Jeff Kirsch taught me to be appropriately assertive in receiving recognition for my efforts. Finally, here at the University of Washington, John Loeser demonstrates weekly how to be effective as a clinician, researcher, and administrator while always smiling and loving your work.

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

Being a doctor is the right career for me. Most other careers that seem interesting to me would require an act of God to give me talents I lack—musical, artistic, or athletic. More realistically, I would be interested in public health policy as I had toyed with this career path when I was in college and there is so much to improve in this realm.

What is your most marked characteristic?

I would say it is being direct—some would say blunt—which is sometimes helpful, other times not!

Q What do you consider your greatest achievement?

In my work life — finding a way to survive in an academic environment while focusing on taking care of patients.

www.painweek.org | PWJ

PUNDi T PROFiLe/STaCeY

“I would say [my most marked characteristic] is being direct— some would say blunt— which is sometimes helpful, other times not!” Q

What is your favorite language?

Despite living in the “French house” in college, living in Quebec for most of a year, and years of French language education, the only language I can speak or communicate in is English, making it my favorite by default. I am confident that my foreign language cerebral cortex (along with my musical cortex) is grossly underdeveloped. So despite my longstanding love of French, I am stuck with an outsider’s knowledge of it.

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?

of Washington’s long tradition in pain medicine move to a new era of modern interdisciplinary care.

What is your motto?

My colleagues from Portland would say it is “Go! Go! Go!” Internally, I translate that to: “Let’s get moving and figure out what we can do to help.” Brett R. Stacey, md, is a Professor at the University of Washington, and Medical Director of the uwmc-Roosevelt Center for Pain Relief in Seattle.

I would be happy with any book by Michael Chabon or as an alternative Being There by Jerzy Kosinski. Michael Chabon can take on any theme or situation with eloquence and insight, while Being There satirizes what it takes to be viewed as a wise pundit in the world of politics (not much, unfortunately) which is still relevant today. In college I worked on the film series and learned to appreciate a wide variety of film. If I had to pick only one I would want an escape—action or sci-fi, but I am having difficulty picking one. For music, I would pick David Bowie’s album Heroes because it comes with an amazing Berlin vibe and collaboration with both Brian Eno and Robert Fripp.

What would you like your legacy to be?

Beyond having two healthy and happy children, it is important to me that the University

PWJ | www.painweek.org

Q3 | 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.