PAINWeek Journal Vol. 4, Q1 by PAINWeek

vol. 4 q 1 2016

BREAKTHROUGH VS CHRONIC PAIN: PAIN IN CANCERP.20 THE FORGOTTEN OPIOID: COULD LEVORPHANOL LEVITATE ABOVE METHADONE MISADVENTURE? P.28 INTO THE GROOVE: SEDUCING THE ANXIOLYTIC EFFECTS OF DANCE MUSIC P.38 IDENTIFYING AND UNLOCKING MYOFASCIAL PAINP.48

TW O SOURCES

OF PAIN

O NE SOURCE 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). NUCYNTA® ER is an opioid agonist indicated for the management of: • pain severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment options are inadequate

Not an actual patient.

• neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults 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 NUCYNTA® ER for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain • NUCYNTA® ER is not indicated as an as-needed (prn) analgesic

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

TIME TO DUAL

PRESCRIBE NUCYNTA® ER FOR ONE SOURCE OF RELIEF • Proven efficacy in chronic low back pain and DPN1,2 - Based on efficacy demonstrated in a prospective, randomized, double-blind, active- and placebo-controlled, multicenter phase 3 chronic low back pain study (N=981) showing significant change in mean pain intensity from baseline in Week 15 (Week 12 of the maintenance phase) vs placebo1 - Based on efficacy demonstrated in a double-blind, parallel-group, enriched-enrollment randomized phase 3 DPN study (N=977) showing significant change in mean pain intensity over the last week of the 12-week, double-blind, maintenance phase vs placebo2 • 5 dosage strengths: 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg3* Individualize dosing based on patient’s prior analgesic treatment experience and risk factors for addiction, abuse, and misuse; titrate as needed to provide adequate analgesia and minimize adverse reactions

COVERED FOR

94%

OF COMMERCIALLY INSURED PATIENTS.‡ PREFERRED FOR UNITEDHEALTH GROUP AND SILVERSCRIPT/ CVS CAREMARK PART D PLANS‡

• Administer NUCYNTA® ER ~q12h3

VISIT NUCYNTA.COM FOR MORE INFORMATION AND TO DOWNLOAD A NUCYNTA® ER SAVINGS CARD† • $0 co-pay for first prescription of NUCYNTA® ER with a $25 co-pay on each additional prescription if eligible†

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL 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) CONTRAINDICATIONS: Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment; known or suspected 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 within the last 14 days. *Please see full Prescribing Information for DOSAGE AND ADMINISTRATION. †Some restrictions and limitations apply. See full terms and conditions available at NUCYNTA.com. Available to commercially insured and cash-paying patients only. Patients covered by Medicare, Medicaid, or any other state- or federally funded benefit program are excluded. Patients must be 18 years of age or older. This promotion cannot be combined with any other programs, offers, or discounts. Depomed reserves the right to rescind, revoke, or amend this offer without further notice. ‡Source: MMIT 2.0, May 2015. References: 1. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase Ill study. Expert Opin Pharmocother. 2010;11(11):17871804. 2. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151-162. 3. NUCYNTA® ER [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse: NUCYNTA® ER contains tapentadol, an opioid agonist and a Schedule II controlled substance that can be abused in a manner similar to other opioid agonists, legal or illicit. There is a greater risk for overdose and death due to the larger amount of tapentadol present in NUCYNTA® ER. Assess risk for opioid abuse or addiction prior to prescribing NUCYNTA® ER. Addiction can occur in patients appropriately prescribed NUCYNTA® ER at recommended doses; in those who obtain the drug illicitly; and if the drug is misused or abused. Therefore, routinely monitor for signs of misuse, abuse, and addiction. Patients at increased risk (e.g., patients with a personal or family history of substance abuse or mental illness) may be prescribed NUCYNTA® ER, but use in such patients necessitates intensive counseling about the risks and proper use along with intensive monitoring for signs of addiction, abuse, and misuse. Life-threatening Respiratory Depression: Can occur at any time during the use of NUCYNTA® ER even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. To reduce the risk of respiratory depression, proper dosing and titration are essential. Overestimating the dose when converting patients from another opioid product can result in fatal overdose with the first dose. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Neonatal Opioid Withdrawal Syndrome: Prolonged use of NUCYNTA® ER during pregnancy can result in withdrawal signs in the neonate, which may be life-threatening and require management according to protocols developed by neonatology experts. Neonatal opioid withdrawal syndrome presents as poor feeding, irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, rigidity, seizures, vomiting, diarrhea, and failure to gain weight. Interactions With Central Nervous System Depressants: Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, tranquilizers, general anesthetics, neuroleptics, other opioids). When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. If the decision to begin NUCYNTA® ER is made, start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use in 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. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients in the lower range of recommended doses. Closely monitor these patients, particularly when initiating and titrating NUCYNTA® ER and when given concomitantly with other drugs that depress respiration. Use in Patients With Chronic Pulmonary Disease: Patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, should be monitored for respiratory depression particularly when initiating therapy and titrating with NUCYNTA® ER. Consider the use of alternative nonopioid analgesics in these patients. Hypotensive Effect: May cause severe hypotension. 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 for signs of hypotension during dose initiation or titration. Avoid use in patients with circulatory shock; may cause vasodilation that can further reduce cardiac output and blood pressure. Use in Patients With Head Injury or Increased Intracranial Pressure: Monitor patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Seizures: May aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures. Monitor patients with a history of seizure disorders for worsened seizure control during therapy. Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported with the concurrent use of NUCYNTA® ER and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system, and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome 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), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. If concomitant treatment with SSRIs, SNRIs, TCAs, or triptans is clinically warranted, careful observation of the patient is advised, particularly when initiating or titrating the dose. Use in Patients With Gastrointestinal (GI) Conditions: Contraindicated in patients with Gl obstruction including paralytic ileus; may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Avoidance of Withdrawal: Withdrawal symptoms (e.g., anxiety, sweating, insomnia, restlessness, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection) may occur: • After abrupt discontinuation or a significant dose reduction of NUCYNTA® ER in physically dependent patients. When discontinuing NUCYNTA® ER, gradually taper the dose. • If mixed agonist/antagonist (e.g., butorphanol, nalbuphine, pentazocine) and partial agonist (e.g., buprenorphine) analgesics are used in patients who have received or are receiving NUCYNTA® ER. Avoid use with mixed agonists/ antagonists and partial agonists. • If opioid antagonists (e.g., naloxone, nalmefene) are administered in physically dependent patients. Administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. Driving and Operating Heavy Machinery: 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. Hepatic Impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh Score 10 to 15). In patients with moderate hepatic impairment (Child-Pugh Score 7-9), initiate treatment with NUCYNTA® ER 50 mg no more than once every 24 hours, with a maximum dose of 100 mg per day. Monitor for respiratory and CNS depression when initiating and titrating NUCYNTA® ER. Renal Impairment: Use in patients with severe renal impairment (CLCR <30 mL/min) is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

DRUG INTERACTIONS Alcohol: See BOXED WARNING. Muscle Relaxants: Monitor patients receiving muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than otherwise expected. Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Anticholinergics: Use with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. USE IN SPECIFIC POPULATIONS Pregnancy/Nursing Mothers: Pregnancy Category C. NUCYNTA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. Observe newborns for symptoms of neonatal opioid withdrawal syndrome. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® ER is stopped. Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. Use in Elderly, Renal Impairment, and Hepatic Impairment: See WARNINGS AND PRECAUTIONS. DRUG ABUSE AND DEPENDENCE: See BOXED WARNING OVERDOSAGE: Institute supportive measures to manage respiratory depression, circulatory shock, and pulmonary edema as required. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression. ADVERSE REACTIONS: In clinical studies, the most common (≥10%) adverse reactions were nausea, constipation, vomiting, dizziness, somnolence, and headache. 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.

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 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) in adults 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, reserve NUCYNTA® ER for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • 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; AND INTERACTION WITH ALCOHOL 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) CONTRAINDICATIONS Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment; known or suspected 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 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. As modified-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. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA® 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 NUCYNTA® ER, and monitor all patients receiving NUCYNTA® ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) 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 modified-release opioid formulations 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. Opioid agonists such as NUCYNTA® ER 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. 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. Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA® ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with NUCYNTA® ER and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA® ER are essential. Overestimating the NUCYNTA® ER dose 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 signs 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. 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. 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. Interactions with Central Nervous System 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. Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin NUCYNTA® ER is made, start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant. Use in Elderly, Cachectic, and 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. Therefore, closely monitor such patients, particularly when initiating and titrating NUCYNTA® ER and when NUCYNTA® ER is given concomitantly with other drugs that depress respiration. Use in Patients with Chronic Pulmonary Disease: Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with NUCYNTA® ER, as in these patients, even usual therapeutic doses of NUCYNTA® ER may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible. Hypotensive Effect: NUCYNTA® ER may cause severe hypotension. 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 depressantdrugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose 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. Use in Patients with Head Injury or Increased Intracranial Pressure: Monitor patients taking NUCYNTA® ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA® ER. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. 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. Seizures: NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA® ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA® ER therapy. Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome 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) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. Use in Patients with Gastrointestinal Conditions: NUCYNTA® ER is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Avoidance of Withdrawal: Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (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. Driving and Operating Heavy 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. 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. 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 The following serious adverse reactions are discussed elsewhere in the labeling: • 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)] • Interaction with Other CNS Depressants [see Warnings and Precautions (5.4)] • Hypotensive Effects [see Warnings and Precautions (5.7)] • Gastrointestinal Effects [see Warnings and Precautions (5.11)] • Seizures [see Warnings and Precautions (5.9)] • Serotonin Syndrome [see Warnings and Precautions (5.10)] 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. 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. Postmarketing Experience: The following adverse reactions, not above, have been identified during post approval use of tapentadol. 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. Psychiatric disorders: hallucination, suicidal ideation, panic attack. Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA® ER. The psychiatric disorders end with panic attack. Advise patients how to recognize such reactions and when to seek medical attention. DRUG INTERACTIONS Alcohol: Concomitant use of alcohol with NUCYNTA® ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA® ER therapy. Monoamine Oxidase Inhibitors: NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events. CNS Depressants: The concomitant use of NUCYNTA® ER with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and NUCYNTA® ER for signs of respiratory depression, sedation and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced. Serotonergic Drugs: There have been post-marketing reports of serotonin syndrome with the concomitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when NUCYNTA® ER is coadministered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® ER with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Muscle Relaxants: Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than otherwise expected. Mixed Agonist/Antagonist Opioid Analgesics: Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonists (e.g., buprenorphine) may reduce the analgesic effect of NUCYNTA® ER or precipitate withdrawal symptoms. Avoid the use of mixed agonist/ antagonist analgesics in patients receiving NUCYNTA® ER. Anticholinergics: The use of NUCYNTA® ER with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. USE IN SPECIFIC POPULATIONS Pregnancy 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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly. Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. NUCYNTA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics 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. Nursing Mothers: 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 adverse reactions in nursing infants from NUCYNTA® ER, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® ER is stopped. 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. In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses. Renal Impairment: The safety and effectiveness of NUCYNTA® ER have not been established in patients with severe renal impairment (CLCR <30 mL/min). 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. Hepatic Impairment: Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The dose of NUCYNTA® ER should be reduced in patients with moderate hepatic impairment (Child-Pugh Score 7 to 9). Use of NUCYNTA® ER is not recommended in severe hepatic impairment (Child-Pugh Score 10 to 15). DRUG ABUSE AND DEPENDENCE Controlled Substance: NUCYNTA® ER contains tapentadol, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA® ER can be abused and is subject to misuse, addiction, and criminal diversion. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse and misuse. Abuse: 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. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving 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. Physicians 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 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. Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (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. If NUCYNTA® ER is abruptly discontinued in a physically-dependent patient, an abstinence 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. OVERDOSAGE Clinical Presentation: Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. 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. Rx Only

EXECUTIVE EDITOR KEVIN

L. ZACHAROFF MD, FACPE, FACIP, FAAP

PUBLISHER PAINWeek, 6

Erie Street, Montclair, NJ 07042

ART DIRECTOR DARRYL

FOSSA

EDITORIAL DIRECTOR DEBRA EDITOR HOLLY

WEINER

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

EDITORIAL BOARD

Steven D. Passik PhD Director of Clinical Addiction Research and Education Millennium Laboratories San Diego, CA

Peter A. Foreman DDS, DAAPM Consultant Rotorua Hospital and Private Practice Rotorua, New Zealand

Paul Arnstein RN , PhD, ACNS - BC , FNP-C, FAAN Clinical Nurse Specialist for Pain Relief Massachusetts General Hospital Boston, MA

Gary W. Jay MD, FAAPM , FACFEI Chief Officer AdviseClinical Raleigh, NC

John F. Peppin DO, FACP Director The Center for Bioethics Pain Management and Medicine University City, MO Medical Director The Infinity Center-Frankfort LLC , Frankfort, KY

Said R. Beydoun MD, FAAN Professor of Neurology Director of the Neuromuscular Program Keck Medical Center of University of Southern California Los Angeles, CA

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

Jennifer Bolen JD Founder Legal Side of Pain Knoxville, TN

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

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

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

Joseph V. Pergolizzi MD Adjunct Assistant Professor Johns Hopkins University School of Medicine Department of Medicine Baltimore, MD Senior Partner Naples Anesthesia and Pain Medicine 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 Executive Director Foundation for Ethics in Pain Care Bellevue, WA 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 © 2016, PAINWeek. 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.

8 | PWJ | www.painweek.org

Q4 | 2016

The national conference on pain for frontline practitioners.

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.

CONTENTS / PWJ / Q1 / 2016 14 | EXECUTIVE EDITOR’S LETTER

48 | MUSCULOSKELETAL PAIN

IDENTIFYING AND UNLOCKING MYOFASCIAL PAIN

by kevin l. Zacharoff

by hal s. Blatman

FEATURES

SHORT CUTS

20 | KEY TOPIC

BREAKTHROUGH VS CHRONIC PAIN: pain in cancer by srinivas Nalamachu / iwona Bucior / pete

Schmidt

28 | PHARMACOTHERAPY

THE FORGOTTEN OPIOID: could levorphanol levitate above methadone misadventure?

by courtney Kominek / abigail Brooks / jeffrey Fudin

38 | MUSIC THERAPY

INTO THE GROOVE seducing the anxiolytic effects of dance music by john f. Mondanaro

10 | PWJ | www.painweek.org

53 | CLINICAL PEARLS by doug Gourlay

54 | ONE-MINUTE CLINICIAN

with charles Argoff , sheena k. Aurora , jeannette Campos , arnold Weill

55 | PAIN BY NUMBERS 56 | OP-ED: THE DARK SIDE by gary w. Jay

58 | PUNDIT PROFILE

with bernd Wollschlaeger

Q1 | 2016

Get things moving with reliable and rapid relief. RELISTOR helps provide chronic non-cancer pain patients relief from opioid-induced constipation— without compromising analgesia.1,2 • 6 out of 10 RELISTOR® (methylnaltrexone bromide) patients (n=150) had at least 3 Spontaneous Bowel Movements (SBMs) per week (P<0.001)1,2 • One-third of patients taking RELISTOR (n=150) experienced an SBM within 4 hours of their first dose (P<0.001)1 IndIcatIons RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain. RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.

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. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Symptoms consistent with opioid withdrawal, Important safety InformatIon including hyperhidrosis, chills, diarrhea, RELISTOR® (methylnaltrexone bromide) abdominal pain, anxiety, and yawning have Subcutaneous Injection is contraindicated in patients with known or suspected gastrointestinal occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain obstruction and patients at increased risk of barrier may be at increased risk for opioid recurrent obstruction, due to the potential for withdrawal and/or reduced analgesia and gastrointestinal perforation. should be monitored for adequacy of analgesia Cases of gastrointestinal perforation have been and symptoms of opioid withdrawal. reported in adult patients with opioid-induced constipation and advanced illness with conditions Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for that may be associated with localized or diffuse additive effects of opioid receptor antagonism reduction of structural integrity in the wall of and increased risk of opioid withdrawal. the gastrointestinal tract (e.g., peptic ulcer RELISTOR may precipitate opioid withdrawal in disease, Ogilvie’s syndrome, diverticular disease, a fetus and should be used during pregnancy infiltrative gastrointestinal tract malignancies only if the potential benefit justifies the potential or peritoneal metastases). Take into account the risk to the fetus. In nursing mothers, a decision overall risk-benefit profile when using RELISTOR should be made to discontinue nursing or in patients with these conditions or other

discontinue the drug, taking into account the importance of the drug to the mother. In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills. In clinical studies in adult patients with opioid-induced constipation and advanced illness, the most common adverse reactions (≥ 5%) were abdominal pain, flatulence, nausea, dizziness, and diarrhea. Please see Brief Summary of full Prescribing Information for RELISTOR on the adjacent page. references 1. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562. 2. RELISTOR® (methylnaltrexone bromide) Prescribing Information, Salix Pharmaceuticals, Inc.

Product under license from Manufactured for: Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024 RELISTOR is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates. All other product/brand names are trademarks of their respective owners. ©2015 Valeant Pharmaceuticals North America LLC. All rights reserved. Printed in USA. REL-US-0152 v.1 www.salix.com

The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain. Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Limitation of use: Use of RELISTOR beyond four months has not been studied in the advanced illness population. CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at risk of recurrent obstruction, due to the potential for gastrointestinal perforation. WARNINGS AND PRECAUTIONS 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 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 If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider. Opioid Withdrawal Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients. ADVERSE REACTIONS 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 clinical practice. Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 4-week, double-blind, placebo controlled period in which adult patients were randomized to receive RELISTOR 12 mg 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 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily. Adverse reactions in adult patients with opioid-induced constipation and chronic non-cancer pain receiving RELISTOR are shown in the following table. The adverse reactions in the table below may reflect symptoms of opioid withdrawal. Adverse Reactions* in 4-Week Double-Blind, PlaceboControlled Period of Clinical Study of RELISTOR in Adult Patients with Opioid-Induced Constipation and Chronic Non-Cancer Pain RELISTOR Placebo 12 mg once daily n = 162 n = 150 Abdominal Pain 21% 6% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% < 1% Chills 1% 0% * Adverse reactions occurring in ≥ 1 % of patients receiving RELISTOR 12 mg once daily and at an incidence greater than placebo. During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature Adverse Reaction

change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR 12 mg 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 1) 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 was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 2). Patients were allowed to administer RELISTOR 12 mg 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 1. Additionally, in Study 2, 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 was evaluated in two, double-blind, placebo-controlled trials in adult patients with opioid-induced constipation and advanced illness receiving palliative care: Study 3 included a single dose, double blind, placebo-controlled period, whereas Study 4 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common (≥5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR are shown in the following table. Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness* Adverse RELISTOR Placebo 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 ≥ 5 % of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo. The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1%) and placebo (2%). Postmarketing Experience The following adverse reactions have been identified during post-approval use of RELISTOR. Because they 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. Gastrointestinal Perforation, cramping, vomiting General Disorders and Administrative 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 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day. RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether RELISTOR is present in human milk. However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, 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 have not been established in pediatric patients. In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions,

tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals. Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs. Geriatric Use In the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended. Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault). Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment. OVERDOSAGE A study of healthy volunteers 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. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia. PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Administration Advise all patients to: • Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites). • Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use. • Be within close proximity to toilet facilities once RELISTOR is administered. • Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued. Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to: • Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days. • Inject one dose every day. • Inform their healthcare provider if their opioid regimen is changed, to avoid adverse reactions, such as diarrhea. Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to: • Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period. Gastrointestinal Perforation Advise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain. Severe or Persistent Diarrhea Advise patients to discontinue RELISTOR if they experience severe or persistent diarrhea. Opioid Withdrawal Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning. Pregnancy Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier. Nursing Advise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024. Manufactured for: Under License from:

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591

REL-RALAB56-102014

Live conference

SAN Di GO CA* February 20–21 SCOTTSDAL AZ* February 27–28 D NV R CO March 5 INDiANAPOLiS IN* March 5–6 LOS ANG L S CA March 19 BiRMiNGHAM AL March 19 SOUTHFi LD MI April 2

e e

e credits

6.0–12.0 C /CM

RAL iGH-DURHAM NC* April 2–3 OKLAHOMA CiTY OK April 9 ATLANTA GA* April 9–10 SALT LAK CiTY UT April 30 ST. LOUiS MO* April 30 – May 1 FT. LAUD RDAL FL May 14 KANSAS CiTY MO* May 14–15

CHiCAGO IL May 21 TAMPA FL* May 21–22 DALLAS TX June 4 NASHViLL TN* June 4–5 COLUMBUS OH June 11 N W ORL ANS LA* June 11–12 PiTTSBURGH PA June 25

This activity is provided by Global Education Group for 6.0–12.0 AMA PRA Category 1 Credits™. *2 day meeting = 12.0 AMA PRA Category 1 Credits™. This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard.

HOUSTON TX* June 25–26 S ATTL WA October 8 MASHANTUCK T CT October 8 BALTiMOR MD* October 15–16 SHORT HiLLS NJ November 12 HONOLULU HI December 3

KEVIN L.

ZACHAROFF MD, FACPE, FACIP, FAAP

t here is so much in this issue to discuss that affects us daily in the care we provide for people with chronic pain. Let’s take a closer look.

Our first article, by Dr. Srinivas Nalamachu, Iwona Bucior, and Pete Schmidt, focuses on breakthrough pain in patients with cancer-related chronic pain. With a prevalence of 50% to 95% in cancer patients, this phenomenon is obviously something we need to consider when formulating a pain treatment plan for these patients. The authors discuss important differences between chronic cancer and breakthrough pain as well as assessment tools that can better help identify the most appropriate course of treatment. Attention is also paid to common pharmacologic treatments, strategies, and, most importantly to me, practical considerations that we all should consider when treating patients with cancer-related breakthrough pain.

“The fascia ensheaths all bones, connects every muscle and organ, and is all one net with no separation from head to toe.” Dr. Hal S. Blatman intelligently points out that with its intimate involvement with the rest of the body, the fascia is actually an antenna of sorts to the brain, especially when it covmes to pain and pain perception. A number of nonpharmacologic, physical approaches to treating myofascial pain are described in a cogent and thoughtful manner. This would be one of those articles (like others I have identified in previous issues) that should be nearby for future reference and consideration. Just a quick note about Dr. Gary Jay’s personal piece; we are lucky to have him. His personal anecdote reminds us that we healthcare providers are human, too, and have a past, present, and future— hopefully rooted like Dr. Jay in devoting our professional lives to helping those in pain. Lastly, there is nothing I could say about this issue’s Pundit Profile of Dr. Bernd Wollschlaeger except that I will not forget it for a long time and I’m sure you won’t either. I’m not sure we spend enough time self-reflecting about how each one of us has gotten to the place we are in our careers. For me, this profile was a true catalyst in that regard. Each article in this issue should resonate with each of us. I think it’s fair to say that, unfortunately, we probably all have a relatively close relationship to someone who has some type of cancer, and also some degree of cancer-related pain. It seems to me that many of us have been so focused on issues swirling around regarding treatments for chronic noncancer pain that we may inadvertently not pay adequate attention to chronic cancer pain. I also don’t think anyone would dispute the frequency with which they see people with myofascial pain. Anyone who has been involved in helping people manage their chronic pain knows that any pharmacologic treatment option that is old or new is worthy of discussion. Coincidentally, at the PAINWeekEnd meeting in San Diego in February, someone asked me about levorphanol, so what good timing for us to focus on this medication! Lastly, anyone who read my Pundit Profile might recall that my favorite language is music, so I’m particularly thrilled about an article on that subject. These topics, along with that personal piece by my good friend and colleague Dr. Gary Jay, and the Pundit Profile, make for an issue that is truly relevant for all.

Levorphanol may very well be the forgotten opioid, and Drs. Courtney Kominek, Abigail Brooks, and Jeffrey Fudin adeptly summarize their session from the PAINWeek 2015 National Conference pointing out that in many cases, levorphanol may be a safer and more viable option than methadone when treating opioid dependence and chronic pain. Pros and cons of levorphanol are considered along with a clinically relevant and easy to digest comparative analysis to methadone. For those of you who missed this session last year, this is a must read— especially with mounting safety concerns regarding methadone use I am confident that you will enjoy this issue, and it will valuable both in frontline situations. professionally and clinically. Think Spring and think about attending a PAINWeekEnd regional conference near you (visit painweekend.org John F. Mondanaro’s article on music, groove, and pain management to see upcoming cities). strikes a particular “chord” with me—sorry for the pun. I am a firm believer in the positive aspects of music therapy, and one only needs to — KEVIN L. ZACHAROFF look to witness the benefits that music has on people around us. Why not in patients with chronic pain? Why not electronic dance music? I cannot remember the last time I saw someone dancing in an animated Kevin L. Zacharoff, MD, FACIP, FACPE, FAAP, is Pain Educator and Consultant and fashion who didn’t look pleased in some way, shape, or form. I’m sure Faculty, Clinical Instructor at SUNY Stony Brook School of Medicine, Department of that you wouldn’t dispute that music touches a part of our brain that Preventive Medicine, in Stony Brook, New York. is somewhat “different”—maybe above and below the conscious level of thinking. Read this article and give it some thought. Music might be right behind laughter as the best medicine.

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■ Hal S. Blatman MD, DAAPM, ABIHM

P.48

■ Gary W. Jay MD, FAAPM, FACFEI

P.56

■ Courtney Kominek PharmD, BCPS, CPE

P.28

■ John F. Mondanaro MA, LCAT, MT-BC, CCLS

P.38

■ Srinivas Nalamachu MD

P.20

Hal Blatman is Medical Director of the Blatman Health and Wellness Center in Cincinnati, Ohio. He is expert in treating chronic and acute pain by locating injury to fascia and promoting healing of these injuries. He has training in orthopedic surgery and occupational medicine, has offices in Cincinnati and New York City, and is coauthor of the book Winners’ Guide to Pain Relief.

Gary W. Jay is Chief Medical Officer of AdviseClinical, in Raleigh, North Carolina, and is in consultative practice in Davie, Florida. He has served as a principal investigator, KOL, and pharmaceutical industry advisor/consultant. Dr. Jay was one of the 30 founding members of the American Academy of Algology (now the American Academy of Pain Medicine), which helped develop the subspecialty of pain medicine. He has written over 130 articles in peer-reviewed journals dealing with headache, pain, autonomic nervous system, and mild traumatic brain injury; 5 textbooks; and third-party medical textbook chapters. He is currently Immediate Past President of the Eastern Pain Association.

Courtney Kominek is a Clinical Pharmacy Specialist in Pain Management at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri. Dr. Kominek cowrote her article with Abigail Brooks, PharmD, BCPS, a Clinical Pharmacy Specialist in Pain Management at the West Palm Beach VA Medical Center in West Palm Beach, Florida, and Jeffrey Fudin, BS, PharmD, FCCP, FASHP, Adjunct Associate Professor of Pharmacy Practice, Western New England University College of Pharmacy, in Springfield, Massachusetts, and Albany College of Pharmacy & Health Sciences in Albany, New York.

John F. Mondanaro is a doctoral student at NYU, and the Clinical Director for the Louis Armstrong Music Therapy Department at Mount Sinai Beth Israel in New York. He holds licensure in New York as a mental health practitioner in Creative Arts Therapy, board-certification in music therapy, and certification in Child Life Practice. He has published numerous articles on the arts in health care and has composed and produced 2 full-length recordings of original music.

Srinivas Nalamachu is Clinical Assistant Professor at Kansas University Medical Center in Kansas City, Kansas, and President and Medical Director of the International Clinical Research Institute in Overland Park, Kansas. Dr. Nalamachu coauthored his article with Iwona Bucior and Pete Schmidt of Depomed.

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BREAKTHROUGH VS CHRONIC PAIN: Pain in Cancer

Srinivas Nalamachu MD Iwona Bucior Pete Schmidt

Pain is the most feared symptom in cancer patients.

K Y TOPiC

Pain is the most feared symptom in cancer patients. It is associated with distressing psychosocial discomforts and often debilitates quality of life more than the disease itself.1,2 It may be present at any stage of the disease process: it is often the first complaint made by patients prior to the diagnosis of cancer, and it may be present long after treatment.1 Pain in cancer can be divided into 2 distinct components: 1) chronic, persistent, long-lasting pain, and 2) transient exacerbations of acute, severe pain called breakthrough pain, as the pain “breaks through” the background pain medication. The different pathophysiology of chronic vs breakthrough pain is not well recognized, and because breakthrough pain does not respond to the usual medications used to control background pain, control of breakthrough pain is suboptimal in a sizeable proportion of patients with cancer.1,3 abstract:

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INTRODUCTiON

Most chronic pain is caused by the disease process itself, when a growing tumor changes or puts pressure on nerves, bones, or organs, and by some treatments such as chemotherapy or radiotherapy which can produce painful conditions that persist long after treatment has ended.4,5 The prevalence of cancer pain varies depending on the type of cancer and stage of the disease. In a meta-analysis of 52 studies over a 40 year period, the highest prevalence—70%—was reported by patients with head and neck cancer, followed by 60% in gynecological, 59% in gastrointestinal, 55% in lung/bronchus, 54% in breast, and 52% in urogenital cancer.6 In a Pan-European survey, pain due to pancreatic, bone/muscle, and brain cancer were at the highest incidence at 90% to 93%; followed by non-Hodgkin’s lymphoma, lung, squamous cell carcinoma of the head and neck, bowel, and testicular cancer at 82% to 87%; blood borne, gynecological cancer, and lymphoma at 75% to 77%; and breast, leukemia, and prostate cancer at 53% to 66%.1 e

BR AKTHROUGH PAiN Many definitions of breakthrough pain have been proposed over the years, and even the term “breakthrough” has not been universally accepted, with some clinicians using such terms as end-of-dose failure, incident pain, pain flare, and transient or transitory pain.7,8 This lack of consensus has led to difficulties in comparing clinical studies and recommending assessment and management strategies. Therefore, the following definition of breakthrough pain9 has been recommended: Q1 | 2016

“Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.”

However, the term “breakthrough pain’” is still being incorrectly used in both medical literature and clinical practice and is often used to describe any exacerbation of pain.10 Breakthrough pain is distinct from 1) exacerbations www.painweek.org | PWJ | 23

KEY TOPIC

“Barriers to the adequate management of BTPc are multifaceted and encompass inadequate education, communication, diagnosis, and utilization of available treatment options. They can be both provider and/or patient related.”

of the baseline pain (or background pain flares) in patients whose background pain is not well controlled, and 2) from end-of-dose failure pain that results from a reduction of analgesia due to a decrease in medication at the end of a dose interval, although some experts regard end-of-dose failure as a subtype of breakthrough pain.7,8,10 Furthermore, it has been postulated that BTPc—breakthrough pain in cancer—influences background pain, as it was shown to be associated with more intense and frequent background pain than occurs in patients without BTPc.11,12

Breakthrough pain is a heterogeneous condition, and clinical features vary from one patient to another, and even within the same patient over time. A typical episode of BTPc can occur several times a day, with a median of 1 to 4 incidents.14-16 The pain can be very intense, reaching a peak severity within 5 to 15 minutes, and has a duration of 30 to 60 minutes.7,10,14,16

ASS SSM NT TOOLS There are currently no validated assessment tools for clinBreakthrough pain is highly prevalent in cancer patients, ical use, and the diagnosis of breakthrough pain is usually but the prevalence rates vary widely, from 50% to 95% based on the criteria of exclusion of controlled background depending on the definition of breakthrough pain, meth- pain around the clock and various characteristics—locaods used to assess it, populations studied, stages of cancer, tion, severity, temporal characteristics, triggers, predictabiland on the time of day—generally, patients experience ity, and pathophysiology.7,8 The task group of the Science more episodes of breakthrough pain during the day com- Committee of the Association for Palliative Medicine of pared with at night.8,10 In a recent, systemic review and Great Britain and Ireland10 has also proposed an algorithm pooled analysis of published studies reported between for the diagnosis of breakthrough pain based on 3 questions: 1990 and 2012 in adults with cancer, breakthrough pain was reported in 59.2% of patients, with 39.9% prevalence ❶ Does the patient have background pain—pain in outpatients and 80.5% prevalence in a hospice setting present for >12 hours/day during the previous week patients.13 or would be present if not taking analgesia? Breakthrough pain can be classified into spontaneous ❷ Is the background pain adequately controlled— (idiopathic) and incident (precipitated, movement related) pain rated as “none” or “mild,” but not pain.8-10 Spontaneous pain occurs unexpectedly and is not “moderate” or “severe,” for >12 hours/day during related to an identifiable trigger, while incident pain is genthe previous week? erally predictable and related to a specific trigger (eg, treatment and/or comorbidities). Furthermore, incident pain is ❸ Does the patient have transient exacerbations subclassified into volitional (precipitated by voluntary act of pain? like walking), nonvolitional (precipitated by an involuntary act like coughing), and procedural (related to a therapeutic Breakthrough pain is considered present if the patient intervention like dressing change). responds “yes” to all the above criteria.

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TR ATM NT OF BR AKTHROUGH PAiN Various strategies are used to manage breakthrough pain in cancer, including 1) management of the factors leading to pain, 2) modification of the pathological processes/underlying causes, 3) nonpharmacological methods (eg, cognitive therapy, distraction and relaxation techniques, and acupuncture), 4) modification of the background, around-the-clock medication regimen, and use of “rescue medication.”8,10,17,18 The mainstay of management of breakthrough cancer pain is so-called “rescue medication”: treatment with an additional dose—5% to 20% of the total daily dose—of an analgesic medication already prescribed for managing chronic, background pain.17,19 These rescue medications include opioids such as immediate-release morphine sulfate, oxycodone, and hydromorphone.20,21 However, these immediate-release opioid formulations have pharmacokinetic profiles that do not correlate with the pattern of breakthrough pain, which is characterized by sudden onset, short time to maximum severity, and short duration.21,22 Molecules and formulations matching such profile would be characterized by a rapid elevation in plasma concentration and a short elimination half-life.17,22 To better match this pattern, transmucosal formulations of fentanyl have been developed and are the only medications approved by the Food and Drug Administration ( FDA) for treatment of breakthrough cancer pain.10,22,23

appropriate and potentially more successful in achieving the goal of reducing abuse, misuse, and addiction to TIRF medications. Furthermore, few physicians utilize the TIRF REMS Access Program because of its complexity; thus, the program can potentially burden the healthcare system and limit appropriate medical availability and patient access.25

Table. Transmucosal Immediate-Release Fentanyl ( TIRF ) Products Abstral® (fentanyl) sublingual tablets Actiq® (fentanyl citrate) oral transmucosal lozenge Fentora® (fentanyl buccal tablet) Onsolis® (fentanyl buccal soluble film) Subsys® (fentanyl sublingual spray) Lazanda® (fentanyl) nasal spray Approved generic equivalents of these products

PRACTiCAL CONSiD RATiONS TIRF REMS ACC SS PROGRAM Barriers to the adequate management of BTPc are multiIn 2011, the FDA approved a Risk Evaluation and Mitigation faceted and encompass inadequate education, communiStrategy program for Transmucosal Immediate-Release cation, diagnosis, and utilization of available treatment Fentanyl ( TIRF ) products ( TIRF REMS) that required options. They can be both provider and/or patient related. registration by healthcare providers involved with prescrib- Firstly, pain management should be considered integral to ing and dispensing fentanyl products.24 The goals of the treatment of cancer,1 and effective communication between TIRF REMS Access Program are to ensure patient access healthcare professionals—especially surgeons, oncologists, to important medications, and at the same time mitigate and pain specialists—is essential for continuous, quality the risk of misuse, abuse, addiction, overdose, and serious patient care. Furthermore, management of pain encomcomplications due to medication errors by 1) prescribing passes management of patient function, quality of sleep, and dispensing TIRF medicines only to appropriate patients, anxiety, depression, fatigue, and other aspects of quality including use only in opioid-tolerant patients; 2) prevent- of life26,27; thus it requires a multidimensional approach to ing inappropriate conversion between fentanyl products; assessing treatment outcomes. 3) preventing accidental exposure to children and others for whom TIRF medicines were not prescribed; and 4) educat- Additionally, education of both healthcare professionals and ing prescribers, pharmacists, and patients on the potential patients about BTPc (its burden, how it differs from backfor misuse, abuse, addiction, and overdose.24 TIRF products ground cancer pain, how to properly diagnose and manage used to manage breakthrough pain in adults with cancer it) and treatment options (risks associated with adverse include a nasal spray, a sublingual spray, buccal tablets, sub- effects vs benefits of improving quality of life) is paramount. lingual tablets, buccal soluble film, and oral transmucosal Poor patient-physician communication further contributes lozenges (Table). to suboptimal care, with many patients having misconceptions about pain as an unavoidable consequence of cancer. Although well intentioned, TIRF REMS Access Program has proven less effective in limiting inappropriate use of Fentanyl delivered by transmucosal systems would appear fentanyl products, primarily because it does not address to be the best option to cover the temporal pattern of BTPc, alternate aspects of abuse and misuse, outside of legiti- although the treatment should be individualized to address mate prescriber-patient interactions.25 As such, the pro- patients’ needs and balance clinical benefits with potential gram is isolated, and a multiagency approach seems more risks. Transmucosal fentanyl is a potent opioid that can

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KEY TOPIC

offer rapid pain relief for patients who experience BTPc, but serious side effects and deaths can occurred as a result of improper patient selection (use in opioid nontolerant patients) and/or improper dosing. However, the majority of fentanyl related deaths have been associated with misuse and abuse of transdermal fentanyl patches, which are prescribed for treatment of chronic pain due to its slow absorption.28-30 The TIRF REMS program should be considered an opportunity to educate providers, pharmacists, and patients about the safe usage of transmucosal fentanyl formulations and as a platform to make patients a part of the process, sharing responsibility and liability with physicians.

CONCLUSiONS The expertise of healthcare professionals, appropriate utilization of transmucosal formulations of fentanyl and the TIRF REMS program along with effective patient-physician and physician-physician communication, individualized care with a balanced risk-benefit ratio, and recognition of variations in patient experience are required for satisfactory treatment of BTPc. Because of the enormous impact of pain on many aspects of life quality, proper treatment of distinct chronic and breakthrough pain conditions should be a necessary counterpart to the treatment of cancer. References 1. Breivik H, Cherny N, Collett B, et al. Cancer-related pain: a panEuropean survey of prevalence, treatment, and patient attitudes. Ann Oncol. 2009;20(8):1420–1433. 2. Hanna M, Zylicz Z, eds. Cancer Pain. London, UK: Springer-Verlag London; 2013. 3. Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer pain: an observational study of 1000 European oncology patients. J Pain Symptom Manage. 2013;46(5):619–628. 4. Lee EQ. Neurotoxicity of radiation therapy and chemotherapy. In: Packer RJ, Schiff D, eds. Neuro-oncology. 1st ed. Oxford, UK: Blackwell Publishing Ltd.; 2012. 5. Glare PA , Davies PS, Finlay E, et al. Pain in cancer survivors. J Clin Oncol. 2014;32(16):1739–1747. 6. van den Beuken-van Everdingen MH, de Rijke JM , Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007;18(9):1437–1449. 7. Zeppetella G. Breakthrough pain in cancer patients. Clin Oncol (R Coll Radiol). 2011;23(6):393–398. 8. Wengstrom Y, Geerling J, Rustoen T. European Oncology Nursing Society breakthrough cancer pain guidelines. Eur J Oncol Nurs. 2014;18(2):127–131. 9. Davies AN, Dickman A, Reid C, et al. The management of cancerrelated breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain. 2009;13(4):331–338. 10. Davies AN . Breakthrough cancer pain. Curr Pain Headache Rep. 2014;18(6):420.

management in cancer patients. Cancer Manag Res. 2010;2:225–232. 12. Vissers DC , Lenre M, Tolley K, et al. An economic evaluation of short-acting opioids for treatment of breakthrough pain in patients with cancer. Value Health. 2011;14(2):274–281. 13. Deandrea S, Corli O, Consonni D, et al. Prevalence of breakthrough cancer pain: a systematic review and a pooled analysis of published literature. J Pain Symptom Manage. 2014;47(1):57–76. 14. Portenoy RK , Bruns D, Shoemaker B, et al. Breakthrough pain in community-dwelling patients with cancer pain and noncancer pain, part 1: prevalence and characteristics. J Opioid Manag. 2010;6(2):97–108. 15. Davies A, Zeppetella G, Andersen S, et al. Multi-centre European study of breakthrough cancer pain: pain characteristics and patient perceptions of current and potential management strategies. Eur J Pain. 2011;15(7):756–763. 16. Narayana A, Katz N, Shillington AC , et al. National Breakthrough Pain Study: prevalence, characteristics, and associations with health outcomes. Pain. 2015;156(2):252–259. 17. Caraceni A, Davies A, Poulain P, et al. Guidelines for the management of breakthrough pain in patients with cancer. J Natl Compr Canc Netw. 2013;11(suppl 1):S29-S36. 18. Zeppetella G, Davies AN . Opioids for the management of breakthrough pain in cancer patients. Cochrane Database Syst Rev. 2013;10:CD 004311. 19. Doulton B. Pharmacologic management of adult breakthrough cancer pain. Can Fam Physician. 2014;60(12):1111–1114. 20. Smith HS . Considerations in selecting rapid-onset opioids for the management of breakthrough pain. J Pain Res. 2013;6:189–200. 21. Hans GH . Treatment of breakthrough cancer pain: to titrate or to proportionate? Curr Med Res Opin. 2013;29(11):1523–1526. 22. Chen C, Gupta A. Clinical and pharmacokinetic considerations of novel formulations of fentanyl for breakthrough cancer pain. Pain Manag. 2014;4(5):339–350. 23. Meriggi F, Zaniboni A. Fentanyl for breakthrough cancer pain: where are we? Rev Recent Clin Trials. 2013;8(1):42–47. 24. Transmucosal Immediate Release Fentanyl ( TIRF ) Risk Evaluation and Mitigation Strategy (REMS) Program. Available at: www.tirfremsaccess. com/TirfUI/rems/about.action. 25. Pergolizzi JV, Gharibo CG, Gudin JA , et al. Development of federally mandated risk evaluation and mitigation strategies (REMS) for transmucosal immediate-release fentanyl products. Pain Pract. 2013;13(4):259–263. 26. Lintzeris N, Moodley R, Campbell G, et al. Sleep quality among people living with chronic non-cancer pain: findings from the Pain and Opioids IN Treatment (POINT ) Cohort. Clin J Pain. 2015 Jul 24. [Epub ahead of print] 27. Zoega S, Fridriksdottir N, Sigurdardottir V, et al. Pain and other symptoms and their relationship to quality of life in cancer patients on opioids. Qual Life Res. 2013;22(6):1273–1280. 28. Bakovic M, Nestic M, Mayer D. Death by band-aid: fatal misuse of transdermal fentanyl patch. Int J Legal Med. 2015;129(6):1247–1252. 29. Gill JR , Lin PT, Nelson L. Reliability of postmortem fentanyl concentrations in determining the cause of death. J Med Toxicol. 2013;9(1):34–41. 30. Martin TL , Woodall KL , McLellan BA . Fentanyl-related deaths in Ontario, Canada: toxicological findings and circumstances of death in 112 cases (2002–2004). J Anal Toxicol. 2006;30(8):603–610.

11. Leppert W. Role of intranasal fentanyl in breakthrough pain

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â&#x20AC;&#x153;Acquiring the Certified Pain Educator credential has been of benefit to me and has allowed me to bring more clout to the conversation.â&#x20AC;?

Kathryn Schopmeyer PT, DPT, CPE

the forgotten

could levorphanol levitate above methadone misadventure? by Courtney Kominek

PharmD, BCPS , CPE / Abigail Brooks PharmD, BCPS / Jeffrey Fudin BS , PharmD, FCCP, FASHP

PHARMACOTH RAPY

abstract: Although methadone has a role in the treatment of opioid dependence, its unique mechanism pharmacology, oral bioavailability, absence of active metabolites, and delayed withdrawal syndrome makes it a viable option for chronic pain management. With these benefits come multiple pitfalls, including variable pharmacokinetics, pharmacogenetic polymorphisms, potential for multiple drug interactions, QTc prolongation, and an extended titration period. Thus, the risks of methadone therapy may outweigh the benefits in some patients. Levorphanol, less commonly used or prescribed compared to methadone, shares all the benefits but avoids almost all of the pitfalls associated with methadone resulting in an overall more favorable risk-to-benefit profile for the treatment of chronic pain.

At PAINWeek 2015, the authors took an unusual approach to reviewing the attributes and shortcomings of 2 important unique opioids. The session started with a broad overview by author Fudin followed by a moderated debate between authors Brooks and Kominek. This summary highlights the teaching points from that session.

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In an opioid naïve patient, the FDA approved starting dose of levorphanol is 2 mg every 8 hours with doses titrated no sooner than every 3 days. But, in the authors’ experience, a more reasonable starting dose for these patients is 1 mg (1/2 x 2 mg tablet) twice daily. Levorphanol is quite potent. For example, a single 2 mg levorphanol tablet is approximately equivalent to 15 mg of morphine or 10 mg of oxycodone. The levorphanol package insert indicates that levorphanol is 4 to 8 times as potent as morphine.8 For elderly patients, the initial dose of levorphanol should be reduced by 50%.2-3 Methadone is typically dosed 2.5 mg orally every 8 to 12 hours in an opioid naïve patient and titration of doses occurring every 5 to 7 days.5-6 Multiple conversion strategies are available for switching to methadone from other medications. Figure 1 demonstrates some of the approaches available for morphine to methadone conversions.9

evor ph a nol ,

or 17-methylmorphinan-3-ol, belongs to the phenanthrene class of opioids and is the enantiomer of dextromethorphan. In comparison, methadone, known chemically as (RS)-6-(dimethylamino)-4, 4-diphenylheptan-3-one, is classified as a diphenylheptane opioid. Levorphanol and methadone have several commonalities in their mechanism of action. They are both mu-opioid receptor agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, and serotonin and norepinephrine reuptake inhibitors. But levorphanol also has opioid agonist activity at the kappa and delta opioid receptors, whereas methadone alone opens ATP-sensitive potassium channels.1 Table 1 discusses the pharmacokinetics of levorphanol and methadone.2-7

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PRO L VORPHANOL One of the major advantages with levorphanol is that there are less associated drug interactions. Levorphanol undergoes phase II glucuronidation; therefore, cytochrome (CYP) P450 drug interactions are not a concern. Moreover, unlike methadone, levorphanol does not depend on p-glycoprotein for oral absorption or passage through the blood-brain barrier. The metabolite of levorphanol is excreted renally.1,3 Methadone, on the other hand, is metabolized through multiple CYPP450 enzymes leading to numerous drug-drug interactions, the major concerns of which are CYP3A4 and CYP2B6, plus minor metabolic pathways involving CYP2D6 and CYP2C19. As mentioned earlier, methadone is a racemic mixture. The R-enantiomer, responsible for analgesic activity, is primarily metabolized through CYP3A4. S-methadone, which is responsible for the adverse effects including corrected QT interval (QTc) prolongation, is metabolized through CYP2B6. In addition, there are genetic polymorphisms with CYP2B6.1 The potential consequences of drug interactions with methadone can range from opioid withdrawal, inadequate analgesia, adverse events, and opioid overdose.1,10 A serious concern with the use of methadone is QTc prolongation for which it carries a Black Box Warning. QTc prolongation occurs with methadone through inhibition of the human ether-a-go-go-related gene (h ERG) cardiac channels. Typically, QTc prolongation occurs before the development of torsades de pointes, which can lead to ventricular fibrillation and cardiac arrest.1,10 Risk factors for QTc prolongation include electrolyte abnormalities (hypokalemia or hypomagnesemia), reduced liver function, structural heart disease, genetic predisposition to prolonged QTc, family history of prolonged QTc, and concomitant QTc prolonging medications.10 Examples of QTc prolonging medications include macrolide antibiotics, antipsychotics, and tricyclic antidepressants to name a few. In 2014, the American Pain Society released guidance regarding methadone safety. See Table 2 for ECG monitoring recommendations for methadone.10 Conversely, levorphanol has no effect on the QTc interval and does not require ECG monitoring.3 Q1 | 2016

CON L VORPHANOL day vs 3 mg maximum/day in the lower dose group).16 SympOne of the major advantages of using methadone is the low toms included anger, irritability, mood change, and personcost of the drug, especially compared to newer long-acting/ ality change; the exact mechanism behind this reaction is extended-release drug products that can be cost prohibitive unclear, but the levorphanol 3-glucuronide metabolite may to the patient and/or institution for use. Based on data from be the culprit.16 Levorphanol has also been shown to be tera2007, levorphanol is nearly twice as expensive per tablet com- togenic in mice, which would be concerning for women who pared to generic morphine sustained-release and nearly 20 are pregnant or of child-bearing age on levorphanol therapy.3 times more expensive per tablet compared to methadone!3 In today’s cost-conscious healthcare climate, levorphanol There are no prospective clinical studies evaluating reliabilis obtainable only through limited commercial availability. ity of conversion ratios between levorphanol and other opiUntil recently, levorphanol was available generically only oids. While methadone conversions are no walk in the park from Roxane Labs. Many years ago, the original branded for clinicians, the conversion ratios have been studied and product from Roche Pharmaceutical was called Levo- adopted into clinical practice.9 Levorphanol also utilizes a less Dromoran and was patented in the 1950s.8 Roxane’s generic convenient dosing schedule (every 8 hours or 3 times a day) average wholesale price within the last several months, prior compared to methadone, which in some cases can be dosed to their discontinuation of the product, was $214 per 100 per every 12 hours or twice a day (or as every 8 hours or 3 times a tablets. At time of print, the new kid on the block is Sentynl Therapeutics, which is charging a whopping average wholesale price of $4650 per 100 tablets.11

“Levorphanol…shares all the benefits but avoids almost all of the pitfalls associated with methadone resulting in an overall more favorable risk-tobenefit profile for the treatment of chronic pain.”

While methadone may have numerous drug interactions, levorphanol is not without its own risks for drug interactions. Caution should be used with medications that affect glucuronidation as these are expected to elevate serum levels or decrease the effects of levorphanol.2-3 For example, tricyclic antidepressants, often utilized in neuropathic pain management, can inhibit glucuronidation, which could increase the effect of levorphanol, so dose adjustment(s) may be needed. Methadone’s drug interactions occur through a separate mechanism, via CYP2D6 and/or CYP3A4 inhibition, which day).3 Depending on the patient’s daily routine and adherence applies to a number of both opioid and nonopioid pain med- to his/her medication regimen, levorphanol may not be the ications but is well established in the literature. Levorpha- preferred choice. Simply put, providers are more experienced nol is also affected by classic inducers such as rifampin and with methadone use compared to levorphanol. In fact, levorcarbamazepine that may affect Phase II glucuronidation to phanol is considered by some to be “the forgotten opioid.”1,3 a lesser extent, which could minimally decrease the overall effect of levorphanol. Again, methadone can be impacted by induction or inhibition of cytochrome enzymes and also PRO L VORPHANOL R BUTTAL p-glycoprotein. See Table 3 to compare and contrast med- Another downside with methadone is the social stigma assoication interactions that can occur with either methadone ciated with it. Shah and colleagues conducted a survey of or levorphanol.12-15 Providers should also be cautious using 550 pain physicians identified through the American Pain monoamine oxidase (MAO) inhibitors in combination with Society’s membership list.17 Of these physicians, 111 physilevorphanol as this can result in hypertensive crisis. And cians responded that they use methadone in their practice. lastly, similar to other opioids, levorphanol should be used Fifty-five respondents stated that social stigma was the most with caution in combination with other central nervous common reason their patient’s refuse methadone. system (CNS) depressants to limit the potential for additive CNS effects.2-3 So, the argument that levorphanol has less In data released from the CDC , methadone accounted potential for drug interactions compared to methadone is for 4.5% to 18.6% of opioids prescribed per state, 31.4% not as clear as previously discussed. of opioid related deaths, and 39.8% of single drug opioid related deaths. Overall, methadone leads to a disproporDrug interactions aside, levorphanol, as with other opioids, tionate number of opioid overdose deaths in relation to the still has side effects that can occur at commonly prescribed amount prescribed.18 doses. Levorphanol carries some of the more typical opioid side effects, including but not limited to nausea, vomiting, sedation, pruritus, and constipation, as well as other more CON L VORPHANOL R BUTTAL specific adverse effects. Anticholinergic side effects and his- Methadone associated risk for QTc prolongation has mostly tamine release are some of the more problematic adverse been evaluated and studied in an opioid dependence treateffects that can occur. A clinical trial evaluating levorphanol ment setting. A recently published prospective pilot study in neuropathic pain demonstrated occurrence of neuropsy- found no statistically significant difference in QTc values chiatric events in the higher dose group (16 mg maximum/ between the methadone and control groups at 1, 3, and Q1 | 2016

www.painweek.org | PWJ | 31

PHARMACOTHERAPY

6 months in patients being treated for chronic pain. There was also no statistically significant difference in maximum change in QTc, and the study found a low rate of clinically significant changes in QTc.19 Levorphanol, similar to morphine which also undergoes glucuronidation, is reliant on the kidney to excrete the levorphanol 3-glucuronide metabolite. Accumulation of active metabolites may occur in renal disease and cause unwanted or dangerous side effects.2 Due to high affinity to plasma proteins, levorphanol is not affected by dialysis and may be hard to remove in the event of a patient complication.2 Patients on dialysis may do better on methadone, which does not require dose adjustment in renal or hepatic impairment.20,21 Finally, revisiting methadone and its association with opioid related deaths, the data in opioid dependence suggests that mortality benefits related to reduction in illicit drug use outweigh potential harms. While there is some evidence that recent initiation of methadone, psychiatric admissions, and concomitant use of benzodiazepines increases risk for overdose, risk stratification is important for all opioid prescribing. Similarly, the risk associated with concomitant benzodiazepine use also applies to other opioids and is not associated with methadone use only.22

CONCLUSiON While levorphanol and methadone are similar mechanistically, the respective profiles of each and nuisances associated with use of each drug leave much up for debate as to which opioid is more ideal for use in chronic pain depending on the patient presentation (see Table 4 for a brief comparison summary1-7). Methadone has an established role in the treatment of opioid dependence, and its oral bioavailability, absence of active metabolites, and delayed withdrawal syndrome makes it a viable option for chronic pain management. However, with these benefits come multiple pitfalls, including variable pharmacokinetics, pharmacogenetic polymorphisms, potential for multiple drug interactions, QTc prolongation, and an extended titration period. Thus, the risks of methadone therapy may outweigh the benefits in some patients. Levorphanol, which is less commonly used or prescribed and more expensive compared to methadone, shares all the benefits but avoids almost all of the pitfalls associated with methadone. Levorphanol does require dose adjustment and monitoring in renal impairment and carries its own risk for unique adverse effects, including neuropsychiatric effects and teratogenicity, but overall provides a much “cleaner” drug for use with less drug interactions and more predictable pharmacokinetic profile. The debate between methadone and levorphanol results in an overall more favorable risk-to-benefit profile for levorphanol in the treatment of chronic pain by clinicians educated and familiar with its use and nuances. References

2. Prommer E. Levorphanol: revisiting an underutilized analgesic. Palliat Care. 2014;8:7–10. 3. Prommer E. Levorphanol: the forgotten opioid. Support Care Cancer. 2007;15(3):259–264. 4. Prommer E. Levorphanol revisited. J Palliat Med. 2007;10(6):1228–1230. 5. Veterans Affairs/Department of Defense Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain. May 2010.Available at: www.va.gov/PAINMANAGEMENT/docs/ CPG_opioidtherapy_fulltext.pdf. 6. Toombs JD. Oral methadone dosing for chronic pain: a practitioner’s guide. Pain-Topics.org. 12 March 2008. 7. Fudin J, Perkins RJ, Lipman AG. Practical Pharmacokinetics of Opioids. In Cohen H. Casebook in Pharmacokinetics and Drug Dosing. New York, NY; McGraw-Hill: 2015:131–151. 8. Levorphanol tartrate [package insert]. Roxane Laboratories, Inc. Columbus, OH; 2011. 9. Fudin J, Marcoux MD, Fudin JA . Mathematical model for methadone conversion examined. Practical Pain Management. 2012:46–51. 10. Chou R, Cruciani RA , Fiellin DA , et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15(4):321–337. 11. McKesson software system via Auto-Rx-Net–Pricing Services. Available by contract purchase only. Available at: www.mckesson.com/pharmacies/independent-retail/ pharmacy-management-software-and-services/pricing-services/. 12. Sasu-Tenkoramaa J, Fudin J. Drug interactions in cancer patients requiring concomitant chemotherapy and analgesics. Practical Pain Management. 2013;13(4):50–64. 13. Leavitt SB . Methadone-drug interactions (medications, illicit drugs, & other substances). Pain Treatment Topics. January 2006. Reviewed but not revised June 2010. 14. McCance-Katz EF. Clinically relevant drug interactions: buprenorphine or methadone with other frequently prescribed drugs. Am J Addict. 2010;19(1):4–16. 15. Fudin J, Vanesta Fontenelle D, Fudin HR , et al. Potential p-glycoprotein pharmacokinetic interaction of telaprevir with morphine and methadone. J Pain Palliat Care Pharmacother. 2013;27(3):261–267. 16. Rowbotham MC , Twilling L, Davies PS, et al. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med. 2003;348(13):1223–1232. 17. Shah S, Diwan S. Methadone: does stigma play a role as a barrier to treatment of chronic pain. Pain Physician. 2010;13:289–293. 18. Morbidity and Mortality Weekly Report (MMWR ). Vital signs: risk for overdose from methadone used for pain relief— United States, 1999–2010. 2012;61(26):493–497. Available at: www.cdc.gov/mmwr/ preview/mmwrhtml/mm6126a5.htm. 19. Grodofsky S, Edson E, Huang S, et al. The QTc effect of low-dose methadone for chronic pain: a prospective pilot study. Pain Med. 2015;16(6):1112–1121. 20. Kreek MJ, Schecter AJ, Gutjahr CL , et al. Methadone use in patients with chronic renal disease. Drug Alcohol Depend. 1980;5(3):197–205. 21. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28(5):497–504. 22. Chou R, Weimer MB, Dana T. Methadone overdose and cardiac arrhythmia potential: findings from a review of the evidence for an American Pain Society and College on Problems of Drug Dependence clinical practice guideline. J Pain. 2014;15(4):338–365.

1. Pham TC , Fudin J, Raffa RB . Is levorphanol a better option than methadone? Pain Med. 2015;16(9):1673–1679.

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could levorphanol levitate above methadone misadventure?

Figure. Methadone Conversion Methods9 Ripanmontl et al, 1998

Morphine dose (mg/d)

30–90

91-300

301+

Morphine:Methadone EDR

3.70:1

7.75:1

12.25:1

Ayonrinde et al, 2000

Morphine dose (mg/d)

<100

101–300

301–600

601–800

801–1000

>1001

Morphine:Methadone EDR

3:1

5:1

10:1

12:1

15:1

20:1

Mercandante et al, 2001

Morphine dose (mg/d)

30–90

91-300

301+

Morphine:Methadone EDR

4:1

8:1

12:1

Fudin, 2012

Table 1. Oral Levorphanol and Methadone Pharmacokinetics2-7 Levorphanol

Methadone

Onset of analgesia

10 to 60 min

30 to 60 min

Half-life

Up to 30 hours

15 to 60 hours and up to 150 hours for polymorphic outliers

Duration of analgesia

6 to 15 hours

4 to 6 hours, increases with chronic use

Bioavailability

Well absorbed, limited data

80% of oral dose absorbed

Table 2. ECG Monitoring Recommendations for Methadone10

Q1 | 2016

ECG Considerations

ECG Results

Baseline EKG

»»Obtain ECG in patients with risk factors for QTc prolongation, history of prolonged QTc, or suggestive of prior ventricular arrhythmia »»An ECG within the past 3 months may be used »» Consider an ECG in patients if not know to have higher risk of QTc prolongation

»» QTc 450 to 500 msec: consider alternate medication »» QTc > 500 msec: avoid methadone

Follow-up EKG

»» Repeat ECG 2 to 4 weeks after initiation and following significant dose increases in patients with risk factors for QTc prolongation, history of prolonged QTc, or history of syncope »» Repeat ECG when dose reaches 30 to 40 mg/day and again at 100 mg/day in all patients »»Obtain new ECG when new risk factors present

»» QTc 450 to 500 msec: consider alternate medication »» QTc > 500 msec: switch medications or reduce dose

www.painweek.org | PWJ | 33

could levorphanol levitate above methadone misadventure?

PHARMACOTHERAPY

Table 3. Select Interactions With Medications Commonly Coprescribed in Pain Patients12-15 Medication

Interaction With Levorphanol

Interaction With Methadone

Tricyclic antidepressants (TCAs)

Elevate serum levorphanol through inhibition of glucuronidation

Elevate serum methadone through inhibition of 2C19 and 2D6 Weak inhibition of 3A4 with imipramine Also, prolongation of QTc interval

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) »» Duloxetine

None

»» Venlafaxine

None

Elevate serum methadone through inhibition of 2D6 Prolongation QTc interval

»» Milnacipran

None

Minimal to none

Selective Serotonin Reuptake Inhibitors (SSRIs)

None

Variable inhibition of CYP450 enzymes (for example, fluoxetine and paroxetine elevate serum methadone through inhibition of 2D6); QTc prolongation with high-dose citalopram

Carbamazepine, rifampin, phenytoin (classic inducers)

Reduce levorphanol effects Reduce methadone through induction of 3A4 through induction of glucuronidation

Fluconazole

None

Elevate serum methadone through CYP450 enzyme inhibition

Erythromycin, clarithromycin

None

Elevate serum methadone through CYP450 enzyme inhibition and prolongation of QTc interval

Efavirenz

None

Due to 3A4 and/or 2B6 induction, methadone withdrawal can occur and dose increase is usually required

Telaprevir

None

Elevate serum methadone through 3A4 inhibition and possible p-glycoprotein inhibition.

Boceprevir

None

Elevate serum methadone through possible inhibition of p-glycoprotein

Quetiapine

None

Elevate serum methadone QTc prolongation

Table 4. In Brief: Levorphanol and Methadone Compared1-7 Levorphanol

Methadone

Mechanism of action

»» Mu-opioid receptor agonist »» NMDA receptor antagonist »» Serotonin and norepinephrine reuptake inhibitor

Dosing (opioid naïve)

2 mg by mouth every 8 hours

2.5 mg by mouth every 8 to 12 hours

Kinetics

More predictable

Less predictable

Drug interactions

Less drug interactions

More drug interactions

QTc prolongation

Yes

34 | PWJ | www.painweek.org

Q1 | 2016

The Science of Less

With SoluMatrix Fine Particle Technology™, Iroko Pharmaceuticals, LLC has engineered nonsteroidal anti-inflammatory drug (NSAID) treatments that delivered effective pain relief at low doses.1-3

proven efficacy

rapid absorption

solumatrix fine particle technology™

low dose trusted molecule

low systemic exposure

VIVLODEX™ (meloxicam): The lowest FDA-approved dose of meloxicam available (5 mg)4* • VIVLODEX is FDA-approved at low 5-mg and 10-mg doses administered once daily1* • In a 12-week study, patients taking VIVLODEX 5 mg or VIVLODEX 10 mg experienced significant reductions in osteoarthritis pain1,5 • VIVLODEX was generally well tolerated in clinical trials1 - Most common adverse reactions in clinical trials (incidence ≥ 2%) include diarrhea, nausea, and abdominal discomfort *For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg.1

Indication VIVLODEX is a nonsteroidal anti-inflammatory drug indicated for the management of osteoarthritis (OA) pain. Important Safety Information Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. VIVLODEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Learn more about the Science of Less and low-dose SoluMatrix® NSAIDs at ScienceOfLess.com. Please see brief summary of full Prescribing Information on adjacent pages.

VIV-0040

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNINGS: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. VIVLODEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. INDICATIONS AND USAGE: VIVLODEX is indicated for management of osteoarthritis pain. DOSAGE AND ADMINISTRATION: Dosage - Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg. In patients on hemodialysis, the maximum daily dosage is 5 mg. Non-Interchangeability with Other Formulations of Meloxicam - VIVLODEX capsules have not shown equivalent systemic exposure to other formulations of oral meloxicam. Therefore, VIVLODEX capsules are not interchangeable with other formulations of oral meloxicam even if the total milligram strength is the same. Do not substitute similar dose strengths of other meloxicam products. CONTRAINDICATIONS: VIVLODEX is contraindicated in the following patients: known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product; history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients; and in the setting of coronary artery bypass graft (CABG) surgery. WARNINGS AND PRECAUTIONS: Cardiovascular Thrombotic Events - Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery - Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG. Post-MI Patients - Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of VIVLODEX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If VIVLODEX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including meloxicam, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with VIVLODEX. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation - Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration; Avoid administration of more than one NSAID at a time; avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs; remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy; if a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue VIVLODEX until a serious GI adverse event is ruled out; and in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding. Hepatotoxicity - Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flulike” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue VIVLODEX immediately, and perform a clinical evaluation of the patient. Hypertension - NSAIDs, including VIVLODEX, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema - The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately twofold increase in hospitalizations for heart failure in COX2 selective-treated patients and nonselective NSAID-

treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]). Avoid the use of VIVLODEX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If VIVLODEX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Renal Toxicity and Hyperkalemia - Renal Toxicity - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of VIVLODEX in patients with advanced renal disease. The renal effects of VIVLODEX may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating VIVLODEX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIVLODEX. Avoid the use of VIVLODEX in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If VIVLODEX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia - Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions - Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma. Seek emergency help if an anaphylactic reaction occurs. Exacerbation of Asthma Related to Aspirin Sensitivity - A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIVLODEX is contraindicated in patients with this form of aspirin sensitivity. When VIVLODEX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions - NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, StevensJohnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of VIVLODEX at the first appearance of skin rash or any other sign of hypersensitivity. VIVLODEX is contraindicated in patients with previous serious skin reactions to NSAIDs. Premature Closure of Fetal Ductus Arteriosus - Meloxicam may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VIVLODEX, in pregnant women starting at 30 weeks of gestation (third trimester). Hematologic Toxicity - Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with VIVLODEX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including VIVLODEX, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding. Masking of Inflammation and Fever - The pharmacological activity of VIVLODEX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring - Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms

or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically. 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. Adverse Reactions in Patients with Osteoarthritis Pain - Eight hundred sixty-eight (868) patients with osteoarthritis pain, ranging in age from 40 – 87 years, were enrolled in two Phase 3 clinical trials and received VIVLODEX 5 mg or 10 mg once daily. Fifty percent (50%) of patients were aged 61 years or older. Two hundred sixty-nine (269) patients received VIVLODEX 5 mg or 10 mg once daily in the 12-week, double-blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 1. Table 1 Summary of Adverse Reactions (≥2%) – 12-Week Phase 3 Study in Patients With Osteoarthritis Pain Adverse Reactions

VIVLODEX 5 mg or 10 mg N=269

Placebo N=133

Diarrhea 3% 1% Nausea 2% 0 Abdominal Discomfort 2% 0 Six hundred (600) patients received VIVLODEX 10 mg once daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of these, 390 (65%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 2. Table 2 Summary of Adverse Reactions (≥2%) – 52-Week Open-Label Study in Patients With Osteoarthritis Pain Adverse Reactions

VIVLODEX 10 mg N=600

Arthralgia Urinary Tract Infection Osteoarthritis Hypertension Diarrhea Headache Upper Respiratory Tract Infection Back Pain Nasopharyngitis Bronchitis Sinusitis Constipation Dyspepsia Nausea Edema Peripheral Pain in Extremity

6% 6% 5% 4% 4% 4% 4% 4% 4% 3% 3% 3% 3% 2% 2% 2%

Additional adverse reactions reported for meloxicam: Body as a Whole: allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase; Cardiovascular: angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis; Central and Peripheral Nervous System: convulsions, paresthesia, tremor, vertigo; Gastrointestinal: colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative; Heart Rate and Rhythm: arrhythmia, palpitation, tachycardia; Hematologic: agranulocytosis, leukopenia, purpura, thrombocytopenia; Immune System: anaphylactoid reactions (including shock); Liver and Biliary System: ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis, jaundice, liver failure; Metabolic and Nutritional: dehydration; Psychiatric: abnormal dreaming, alterations in mood (such as mood elevation), anxiety, appetite increased, confusion, depression, nervousness, somnolence; Respiratory: asthma, bronchospasm, dyspnea; Skin and Appendages: alopecia, angioedema, bullous eruption, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweating increased, urticarial; Special Senses: abnormal vision, conjunctivitis, taste perversion, tinnitus; Urinary System: albuminuria, acute urinary retention, BUN increased, creatinine increased, hematuria, interstitial nephritis, renal failure. DRUG INTERACTIONS: See Table 3 for clinically significant drug interactions with meloxicam.

Table 3 Clinically Significant Drug Interactions with meloxicam Drugs That Interfere with Hemostasis

Clinical Impact:

• Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Intervention:

Monitor patients with concomitant use of VIVLODEX with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding.

Aspirin

Clinical Impact:

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. VIVLODEX is not a substitute for aspirin for cardiovascular prophylaxis.

Intervention:

Concomitant use of VIVLODEX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers

Clinical Impact:

• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

Intervention:

• During concomitant use of VIVLODEX and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VIVLODEX and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function.

Diuretics

Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of VIVLODEX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects.

Digoxin

Clinical Impact:

The concomitant use of meloxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

Intervention:

During concomitant use of VIVLODEX and digoxin, monitor serum digoxin levels.

Lithium

Clinical Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of VIVLODEX and lithium, monitor patients for signs of lithium toxicity.

Methotrexate

Clinical Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

Intervention:

During concomitant use of VIVLODEX and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine

Clinical Impact:

Concomitant use of VIVLODEX and cyclosporine may increase cyclosporine’s nephrotoxicity.

Intervention:

During concomitant use of VIVLODEX and cyclosporine, monitor patients for signs of worsening renal function.

NSAIDs and Salicylates

Clinical Impact:

Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy.

Intervention:

The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.

Pemetrexed

Clinical Impact:

Concomitant use of VIVLODEX and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).

Intervention:

During concomitant use of VIVLODEX and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

USE IN SPECIFIC POPULATIONS: Pregnancy - Risk Summary: Use of NSAIDs, including VIVLODEX, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VIVLODEX, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of VIVLODEX in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent 1- and 10-times, respectively, the maximum recommended daily dose (MRDD) of VIVLODEX. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 116-times the MRDD. In pre- and post-natal reproduction studies, increased incidence of dystocia, delayed parturition, and decreased offspring survival were observed in rats treated with meloxicam at an oral dose equivalent to 0.12-times the MRDD of VIVLODEX. No teratogenic effects were observed in rats treated with meloxicam during organogenesis at an oral dose equivalent to 3.9-times the MRDD [See Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Clinical Considerations: Labor or Delivery - There are no studies on the effects of VIVLODEX during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data: Animal data - Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/ day (3.9-times the maximum recommended daily dose (MRDD) of 10 mg of VIVLODEX based on body surface area [BSA] comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (116-times the MRDD based on BSA comparison). The no effect level was 20 mg/kg/day (39-times the MRDD based on BSA comparison). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (1- and 10-times the MRDD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.12-times the MRDD based on BSA comparison). Lactation - Risk Summary: There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIVLODEX and any potential adverse effects on the breastfed infant from the VIVLODEX or from the underlying maternal condition. Data: Animal data - Meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. Females and Males of Reproductive Potential: Infertility – Females - Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including VIVLODEX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including VIVLODEX, in women who have difficulties conceiving or who are undergoing investigation of infertility. Pediatric Use - The safety and effectiveness of VIVLODEX in pediatric patients has not been established. Geriatric Use - Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects. Of the total number of patients in clinical studies of VIVLODEX, 291 were age 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment - No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Because meloxicam is significantly metabolized in the liver; use VIVLODEX in patients with severe hepatic impairment only if the benefits are expected to outweigh the risks. If VIVLODEX is used in patients with severe hepatic impairment, monitor patients for signs of worsening liver function. Renal Impairment - No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of VIVLODEX in subjects with severe renal impairment is not recommended. In a previous study, the free Cmax plasma concentrations following a single dose of meloxicam were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, the maximum VIVLODEX dosage in this population is 5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable. OVERDOSAGE: Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare. There is limited experience with meloxicam overdose. In four reported cases of meloxicam overdose, patients took 6 to 11 times the highest available dose of meloxicam tablets (15 mg); all recovered. Cholestyramine is known to accelerate the clearance of meloxicam. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a previous clinical trial. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). Manufactured (under license from iCeutica Pty Ltd.) for and Distributed by:

One Kew Place 150 Rouse Boulevard Philadelphia, PA 19112 VIV PBS-1 Jan 2016 References: 1. Full Prescribing Information for VIVLODEX. Iroko Pharmaceuticals, LLC; 2015. 2. Full Prescribing Information for ZORVOLEX. Iroko Pharmaceuticals, LLC; 2014. 3. Full Prescribing Information for TIVORBEX. Iroko Pharmaceuticals, LLC; 2014. 4. US Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. http://www.accessdata.fda.gov/scripts/cder/ob/. Accessed November 23, 2015. 5. Altman R, Hochberg M, Gibofsky A, Jaros M, Young C. Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week, phase 3 study. Curr Med Res Opin. 2015;31(12):2331-2343. SoluMatrix® is a registered trademark of iCeutica Pty Ltd., and is licensed to Iroko. SoluMatrix Fine Particle Technology™ is a trademark of iCeutica Inc., and the technology is licensed to Iroko for exclusive use in NSAIDs.

by John

F. Mondanaro MA , LCAT, MT-BC, CCLS

F. Mondanaro MA , LCAT, MT-BC, CCLS by John

…the groove in music has the potential of rendering positive, stress-releasing experiences to those receptive to its allure. Q1 | 2016

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abstract: The experience of pain is often debilitating and diminishing to the quality of life for those afflicted. Limited movement, restricted mood, isolation, separation, and loss drive most to seek medical treatment, particularly when chronic illness is the impetus. Assessment and pharmacological treatment of pain is central to best practice. Increasingly most individuals living with pain enter into treatment with a worldview shaped by a valued sense of agency and individualized expectations. Supported by integrative philosophy within the medical paradigm, individuals seeking pain treatment are encouraged to utilize integrative and holistic therapies that enhance wellness by addressing body, mind, and spirit. Music, music therapy, and the benefits of groove as the subject of recent compelling research, gives rise to a new frontier in integrative treatment with the utilization of self-resourcing afforded naturally through groove-based music. This article explores the genre of electronic dance music (EDM) and the growing trend in personal stereo use, a coupling that offers a viable choice to those seeking additional options for a potential treatment of pain symptoms.

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aiting for coffee minutes before sitting down to write this article,

I was self-absorbed in the challenge I’d taken on in writing about groove and pain. Aware that the literature base intentionally linking the 2 topics is scant across their respective disciplines was central to my contemplation. Running a close second was the symphony of sound around me, comprised of the seemingly inconsolable crying of a toddler in a stroller with her young father in tow, the clatter of glassware and talking, and the sounds of milk steamers and espresso machines, all sounding to the landscape of other people waiting, including a middle-aged woman with a foot cast, physically straining to find her wallet while supporting herself on crutches, and a 20-something couple quietly exhibiting mutual irritation. Several minutes into this scene, the sounds of Michael Jackson’s 1979 hit “Don’t Stop ‘til You Get Enough” began to pour through the café speakers, and things began to change. The woman finding her wallet straightened her posture while subtly moving her body into slight rhythmic lateral movement. The young father, now crouched within eye contact of the toddler began bobbing his head to the rhythm while singing the lyrics to her, and she in turn shifted from crying to smiling as she started to move in sync with her father. The young couple had also transitioned to a casual embrace with mild gyration of their torsos paired with shared smiles. And I, too, was feeling the infectious groove of the music in my legs, from which ensued a lightness of being and reconciliation of my conviction to write about groove, its effect on the body and mind, and the potent role it plays as a resource in the treatment of pain.

GROOV , MUSiC, AND PAiN Research reveals that the quality of groove is most saliently identifiable by its undeniable capacity to elicit the desire to move, tap, shake, gyrate, head-bob, and to dance, each of which renders an overall feeling of pleasure.1-9 Notably, the pleasure factor is increased when the choice of music is individualized, leading toward a perception of the groove as internalized, and aesthetically stimulating but not overly complex.1,4,6 But what makes music “groove”? The idea of participatory discrepancies6,7—defined as human imperfection in balance with precision during music-making— is one theory about the genesis of groove. No matter how it occurs or is perceived, the groove in music has the potential of rendering positive, stress-releasing experiences to those receptive to its allure. These points are of considerable importance to most people, but may be particularly prudent as we consider those living with pain, where the experience of pleasure and enjoyment remain central to quality Q1 | 2016

of life, but are often paled.10-26 The assessment of pain and its impact on QoL is the focus of best practice in medical patients, and according to the World Health Organization, constitutes a vital point to patient care outcomes.27 The commitment to expanding efficacious treatment options has widened research efforts in pain medicine, with increasing emphasis given to mind-body practices and psychologically based strategies in movement to address the manifestations of traumatic stress and anxiety, such as Emotional Freedom Techniques ( EFT ) or tapping,28,29 and Eye Movement Desensitization and Reprocessing ( EMDR).30 Strategies such as these contribute to the buffet of pain treatment options for individuals living with pain. The use of music and music therapy to treat pain has been the subject of a growing body of disparate research, in which music therapy’s value of witness, human contact, and the tactile, creative, and aesthetic rewards of active music www.painweek.org | PWJ | 41

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Personal stereo use… provides the most tangible portal to self-treatment…

making within a therapeutic relationship12-15,18,21,22-26 has been juxtaposed to the rapid growth of music and medicine studies focusing on the effects of listening to recorded music.10,16,17,19,20,31,32 Multiple sources of research have contributed to a general acceptance that music in and of itself can bring about recognizable benefits in terms of both psychoemotional and physical symptoms related to pain. My intention in focusing on recorded music here is not to create further disparity or confusion in thought, but to suggest that the integration of well-established music therapy concepts with state of the art technology may very well open a window on understanding the expanding possibilities for individuals living with pain. That such individuals can become potentially active participants in their pain treatment through the resourcing of groove-based music is the focus here. The experience of pain can compromise quality of life by inhibiting movement, joy, and the autonomy of willful participation.12,14,15,22-25,33 The most basic and tangible portal to the benefits of groove in music and music therapy occurs through the act of drumming. Drumming is a primal form of communication, and as such offers archetypal meaning in its use communally, socially, recreationally, spiritually, and therapeutically.12,15,22,34-38 The tactile reward of striking a drum with one’s hand ensues not only from the conviction to do so, but is complemented by the immediate release of tension that follows. While this sense of power and conviction is hinged to the volitional act of drumming, it is not limited to it, but rather equally attributable to any form of coupling with musical groove that ensues, such as tapping, dancing,

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head-bobbing, and even rapping.1,2,5-8,21,26,39-41 The release of energy and emotion through the embodiment of rhythmic groove afforded in drumming is indisputably therapeutic, but is not necessarily a viable option for everyone. For those individuals whose lives are imbued with the opportunity to join a community drumming circle, or to engage in music therapy, or to even own a drum of their own whereby playing along with favorite music is easily accessible, the benefit is tangible. For those living outside of such ideal circumstances, the benefit of embodied rhythm may be accessed through music listening, dancing, hand-tapping, and other forms of coupling easily accessed through listening via personal stereo.17,42-45

e e e

ACC SSiNG TH GROOV EXP Ri NC Personal stereo use, having increased exponentially over the past 30 years, provides the most tangible portal to self-treatment, through the very tenets of individualized musical preference, personal scheduling, 24/7 accessibility, privacy, and controllability.42 The social phenomenon of personal stereo, from the introduction of the Sony Walkman in 1979 to the daily use of current technology, has given rise to an entire new paradigm of how music is perceived, understood, accessed, and actively implemented across the strata of our lives.21,22,39-42As a music psychotherapist working in a medical milieu, a point of assessment in patients across the lifespan is my understanding of the degree to which an individual regularly utilizes personal music resources, such as iPods and iPhones. Notably, the increased use of personal Q1 | 2016

the quality of groove is most saliently identifiable by its undeniable capacity to elicit the desire to move, tap, shake, gyrate, head-bob, and to dance, each of which renders an overall feeling of pleasure.

stereo systems correlates with increased accessibility to, and consumption of contemporary trends in pop music in the form of extended dance mixes. Reflecting the cultural shifts toward technology, DJ-produced dance mixes of pop music, for instance, are drawn from a larger movement categorized as electronic dance music ( EDM ). EDM is a broad genre of dance music that includes hip-hop, house, drum & bass, techno, and trance, to name a few. Popular artists such as Adele and Rihanna are enjoying greater crossover appeal because of their trending toward EDM. During a music therapy assessment, the ascertaining of patient preferences in music repertoire extends not only into what can be recreated together with live music, but also in the affordances of moments when he or she can access these resources on their own. Consequently, music therapists are charged with being familiar with various mixes of patient preferred music and in recognizing the therapeutic benefits of groove-based mixes and personal stereo use.40,41

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So, with both music therapy literature12,14,15,21-26 and research on the effects of groove1,4,8,9establishing personal preference as being a primary factor in delivering optimal experiences for individuals, the further assertion of groove-based music in the self-treatment of pain suggests a new unlikely frontier in EDM, where through extended mixes the familiar and the preferred may comfortably reside in the domain of groove.

seem disputable by those who would relegate the genre to one inextricably linked to the drug culture valued exclusively by teens and 20-somethings, but if we are bold enough to strip away such derogatory claims, we can see a genre that has evolved because of its emphasis on groove as the primary focus of production. Groove, as a feel-good experience,1,2,4-6 is a by-product of many other genres, but in EDM it is central to the art form. Therefore, I would offer that it is the emphasis on groove itself as an endorphin releasing,1,26, 34,44,45 feel-good experience that instills the genre with sustainability beyond the transient effect of recreational drugs. The exponential growth of the genre beyond the club and rave party circuits, drawing thousands of people worldwide on a nightly basis, to the caliber of stadium concert status that draws hundreds of thousands of concertgoers at any one time, is clearly attributable to something more profound than an artificially induced high. Perhaps it is the juxtaposition of electronic drums with the linear, melodic qualities of guitar, voice, winds, and strings that preserves the beauty of the aforementioned participatory discrepancy.6,7 Whether formulaic or creatively inspired, the groove experience of EDM is infectious and irresistible to thousands of listeners worldwide. The music being created, produced, and perfected in the studio has imbued current culture with a movement that is here to stay, and one that is as easily accessed through the technology of personal stereo as any other genre.

The growth of EDM as a unique genre is attributable to the skilled and artistic production of electronic beats to deliver groove experiences to its listeners. This latter point may

To further demystify EDM , it may be helpful to lend familiarity and perhaps tangibility by citing recognizable examples of the genre’s beginnings from as early as Donna www.painweek.org | PWJ | 43

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The trance-like space that is rendered when electronic groove is coupled with improvised linear melodies on acoustic instruments has effectively transported patients and medical staff alike beyond the stress and emotionally charged climate of painful medical experiences.

Summer’s 1977 “I Feel Love” to New Order’s 1988 mix and emotionally charged climate of painful medical expeof “Blue Monday,” Madonna’s 1990 “Vogue”, and Rozal- riences.21,22,46,47 Important and central to the efficacy of la’s 1992 “Are You Ready to Fly?” These songs heard today these interventions is the conviction to generating music can have the same palpable effect as the aforementioned experience according to the individually expressed preferMichael Jackson hit and succeed in creating a dichotomy ence of the patients involved. This point is worth repeating, of experiences—the visceral and temporal engagement of because while I have focused on EDM here as a prominent the body through steady, provocative groove, with vocal form by which to expose oneself to groove, groove occurs and synthesizer lines that engage the higher faculties to in many genres of music that are less stringent on bringing soar beyond the physical sense in a state of flow.46,47 This this particular component to the foreground. One needs effect of music across body, mind, and spirit46-48 can be only to listen to Pharrell Williams’ 2013 song “Happy” to poignantly experienced in the tracks of the German-based comprehend this point. recording project, Enigma, which juxtaposed such spiritual references as Gregorian chant and other world mantra-like The growth of EDM through the last 2 decades to include expression with provocative rhythmic groove and soaring the work of artists, DJ/composers and producers such as linear melodies rendered by voice, flute, or electric guitar. Moby, Empire of the Sun, Zedd, Nero, DJ Tiesto, Peter Lutz, Here again the effect is transporting, as one’s lower faculties Ryan Lewis and Macklemore, William Orbit, and David can become engaged in the groove itself, while the infinite Guetta, among many more is further testament to the genre’s imagery evoked by the melodic components inspires certain complexity, diversity, and tangibility. Simultaneous to the transcendence beyond the physical.11,48 trajectory of EDM has been a parallel movement of lounge music, which may prove more tangible to some because of Resourcing the positive effect of such multileveled experi- its attendance to subtle transitions as opposed to the build ences in my work has resulted in the amelioration of symp- and release momentum of EDM. To this end, record label toms ensuing from numerous procedural, acute, and chronic projects such as Café Del Mar and Café Ibiza49 have released pain experiences. The trance-like space that is rendered numerous volumes of ambient, groove-based mixes fusing when electronic groove is coupled with improvised linear pop and rock with jazz, world, and classical music, to render melodies on acoustic instruments has effectively trans- recordings that offer additional entry points to groove-based ported patients and medical staff alike beyond the stress music for listeners desiring a more “chill-out” experience.

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CONCLUSiON Individuals living with physical and emotional pain are most optimally served by empowerment of their personal agency in marshalling through their symptoms. The use of groove can in-and-of-itself deliver toward this point, and as a music therapist I can endorse groove-based music as a resource through its capacity to anchor one in the therapeutic benefits of embodied movement. Empowering another to resource the benefits of groove through listening does not translate as my abandonment of the value of music therapy nor the therapeutic relationship afforded in drumming. Rather it extrapolates from the metaphysical qualities of rhythm accessed in drumming to reinforce that the benefits of groove can offer equally rich therapeutic benefit through listening and through all other forms of coupling afforded by music based treatments. Socially, we live in a time where technology allows instant access to anything we so desire. Manners of self-treatment abound at the single request of any search engine, which can lead many astray, as the internet indiscriminately allows legitimate and purposeful treatment recommendations to sit side-by-side with unfounded and potentially harmful remedies. Favorably, a search on “music and groove” delivers an assortment of offerings most generally pertaining to community, dance, and movement, and herein lays the testament to groove as a universally shared experience that produces joy, fun, release of tension, and invites potential participation in a world of shared experiences.1-9,22,26,47 Add the word “pain” to the search, and a surprising number of community resources and testimonials about groove-based dance, aerobics, and of course drumming circles arise.50-52 Whether pursuing the use of groove through active drumming, personal stereo experiences with EDM, or through any of the many gradations that lie between the 2, there is choice afforded to those willing to explore. Finally, personal stereo as a means to accessing music as the mechanism of self-expression is status quo among current generations, and through its use we have generated a capability to make choices about how we orchestrate our lives at any point, day or night. Some speculate that the individualization of these choices is an isolating force, while others see the world as smaller and more unified in experiences across culture. Such technology provides an individual with undeniable control over the environment in which he or she lives. For the healthy, this is an expectation and a point of entitlement, and for those living with pain, it is a hard-won affirmation of identity, and an active portal toward living life proactively beyond the debilitating effects of a pain experience. References 1. Janata P, Tomic ST, Haberman JM . Sensorimotor coupling in music and the psychology of the groove. J Exp Psychol Gen. 2012;141(1):54–75.

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2. Fairhurst MT, Janata P, Keller PE . Being and feeling in sync with an adaptive virtual partner: brain mechanisms underlying dynamic cooperativity. Cereb Cortex. 2013;23(11):2592–2600. 3. Collins T, Tillmann B, Barrett FS, et al. A combined model of sensory and cognitive representations underlying tonal expectations in music: From audio signals to behavior. Psychol Rev. 2014;121(1):33–65. 4. Madison G. Experiencing groove induced by music: consistency and phenomenology. Music Perception: An Interdisciplinary Journal. 2006;24(2):201–208. 5. McAngus Todd NP, Cody FW. Reply to “Embodied Rhythm” by Bruno Repp and “Do Preferred Beat Rate and Entrainment to the Beat Have a Common Origin in Movement?” by Laurel Trainor. Empirical Musicol Rev. 2007;2(3):110–112. 6. Keil C, Feld S. Music Grooves. Chicago, IL: University of Chicago Press; 1994. 7. Keil C. The theory of participatory discrepancies: a progress report. Ethnomusicoly. 1995;39(1):1–20. 8. Repp B. Embodied rhythm: commentary on “the contribution of anthropometric factors to individual differences in the perception of rhythm,” by McAngus Todd NP, Cousins R, Lee CS . Empirical Musicol Rev. 2007;2(1):14–16. 9. Trainor L. Do preferred beat rate and entrainment to the beat have a common origin in movement? Empirical Musicol Rev.1995;48B:129–141. 10. Macdonald R, Mitchell L, Dillion T, et al. An empirical investigation of the anxiolytic and pain reducing effects of music. Psychol Music. 2003;31(2):187–203 11. Gaynor ML . The Healing Power of Sound: Recovering from LifeThreatening Illness Using Sound, Voice, and Music. Boston, MA: Shambhala Publications; 1999. 12. Loewy J. Music therapy in cancer care. In: Barraclough J, ed. Enhancing Cancer Care: Complementary Therapy and Support. Oxford, UK: Oxford University Press; 2007:211–220. 13. Whitaker MH . Sounds soothing: music therapy for postoperative pain. Nursing. 2010;40(12): 53–54. 14. Edwards J. Developing pain management approaches in music therapy with hospitalized children. In: Loewy J, Dileo C, eds. Music Therapy at the End of Life. Cherry Hill, NJ: Jeffrey Books; 2005:57–76. 15. Loewy J. The quiet soldier: pain and sickle cell anemia. In: Hibben J, ed. Inside Music Therapy: Client Experiences. Gilsum, NH: Barcelona Publishers; 1999:69–76. 16. Schroter T. Medicine needs music! Music therapy for chronic pain. Revue Medicale Suisse. 2014;10(415):286. 17. Bellieni CV, Cioncoloni D, Mazzanti S, et al. Music provided through a portable media player (iPod) blunts pain during physical therapy. Pain Manag Nurs. 2014;14(4):e151–155. 18. Quentzel S. Music has charms to soothe a savage breast. In: Mondanaro J, Sara G, eds. Music and Medicine: Integrative Models in the Treatment of Pain. New York, NY: Satchnote Press; 2013:11–28. 19. Spintge, R. Thirty-five years of anxiolytic music ( AAM) in pain and aversive clinical settings. In: J Mondanaro J & G Sara G, eds. Music and Medicine: Integrative Models in the Treatment of Pain. New York: Satchnote Press; 2013:29–42. 20. Cepeda MS, Carr DB, Lau J, et al. Music for pain relief. Cochrane Database Syst Rev. 2006;(2):CD 004843. 21. Mondanaro J. Surgical and procedural support for children. In: Bradt J, ed. Guidelines for Music Therapy Practice in Pediatric Care. Gilsum, NH: Barcelona Publishers; 2013:205–251.

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22. Mondanaro, J. Music therapy based release strategies in the treatment of acute and chronic pain: An individualized approach. In: Mondanaro J, Sara G, eds. Music and Medicine: Integrative Models in the Treatment of Pain. New York: Satchnote Press; 2013:133–148. 23. Hartwig R. Music therapy in the context of palliative care in Tanzania. Int J Palliat Nurs. 2010;16(10):499–504. 24. Gutgsell KJ, Margevicius S, Harris M, et al. Music therapy reduces pain in palliative care patients: a randomized controlled trial. J Pain Symptom Manage. 2013;45(5):822–831. 25. Warth M, Kessler J, Koenig J, et al. Music therapy to promote psychological and physiological relaxation in palliative care patients: protocol of a randomized controlled trial. BMC Palliative Care. 2014;13(60):2–7.

Everyday Life. New York: Oxford; 2000. 43. Tomaino C. Using rhythmic auditory stimulation for rehabilitation. In: Berger J, Turrow G, eds. Music, Science and the Rhythmic Brain. New York: Rutledge; 2011:111–121. 44. Thaut M. Neurobiology of rhythmic motor entrainment. In: Avanzini G, et al. Neurosciences and Music. New York, NY: New York Academy of Sciences; 2003:313–321. 45. Thaut M. Rhythm, Music, and the Brain: Scientific Foundations and Clinical Applications. New York: Routledge; 2008. 46. Csikszentmihalyi M. Flow: The Psychology of Optimal Experience. New York: Harper & Row, Publishers, Inc;. 1990.

26. Aigen K. Playin’ in the Band: A Qualitative Study of Popular Music Styles as Clinical Improvisation. Gilsum, NH: Barcelona; 2005.

47. Fidelibus JF. Mindfulness in Music Therapy Improvisation: When the Music Flows. Doctoral Dissertation. New York: New York University; 2004.

27. Skevington S. Investigating the relationship between pain and discomfort and quality of life, using the WHOQOL . Pain. 1998;76(3):395–406.

48. Godwin J. Harmonies of Heaven and Earth: Mysticism in Music from Antiquity to the Avant-Garde. Rochester, VT: Inner Traditions International;1987.

28. Brattberg G. Self-administered EFT (Emotional Freedom Techniques) in individuals with fibromyalgia: a randomized trial. Integr Med Clin J. 2008; 7(4): 30–35. 29. Church D, Brooks A. The effect of a brief EFT self-intervention on anxiety, depression, pain and cravings in healthcare workers. Integr Med Clin J. 2010;9(4):40–44. 30. Karatzias T, Power K, Brown K, et al. A controlled comparison of the effectiveness and efficiency of two psychological therapies for post-traumatic stress disorder: EMDR vs. EFT. J Nervous Mental Dis. 2011;199(6):372–378. 31. Bernatzky G, Presch M, Anderson M, et al. Emotional foundations of music as a non-pharmacological pain management tool in modern medicine. Neurosci Biobehav Rev. 2011;35:1989–1999.

49. Café del Mar Music. Available at: www.cafedelmarmusic.com/ 50. The World Groove Movement. Available at: theworldgroovemovement.com. 51. Source News Room: Saint Louis University Medical Center. Older adults feel less hip and knee pain when moving to the grooving. Saint Louis University Medical Center. Available at: newswise.com/articles/ older-adults-feel-less-hip-and-knee-pain-when-moving-to-the-grooving. 52. Bilkey C. Elderly drum away the pain. Available at: www.nysun.com/ health-fitness/elderly-drum-away-the-pain/81750/.

32. Bradshaw DH, Chapman CR , Jacobson RC , et al. Effects of music engagement on response to painful stimulation. Clin J Pain. 2012;28(5):418–427. 33. Krampe J, Wagner JM , Hawthorne K, et al. Does dance-based therapy increase gait speed in older adults with chronic lower extremity pain: a feasibility study. Geriatr Nurs. 2014;35(5):339–344. 34. Friedman RL . The Healing Power of the Drum. Reno, NV: White Cliffs Media, Inc.; 2000. 35. Winn T, Crowe BJ, Moreno JJ . Shamanism and music therapy: ancient healing technique in modern practice. Music Ther Perspect. 1989;7:67–71. 36. Burt JW. Distant thunder: drumming with Vietnam veterans. Music Ther Perspect. 1995;13:110–112. 37. Slotoroff D. Drumming techniques for assertiveness and anger management in the short-term psychiatric setting for adult and adolescent survivors of trauma. Music Ther Perspect. 1994;12:11–116. 38. Valdesolo P, Ouyang J, DeSteno D. The rhythm of joint action: synchrony promotes cooperative ability. J Exp Soc Psychol. 2010;46:693–695. 39. Hadley S, Yancy G, eds. Therapeutic Uses of Rap and Hip-Hop. New York: Routledge Taylor & Frances Group; 2012. 40. Lightstone AJ . The importance of hip-hop for music therapists. In: Hadley S, Yancy G, eds. Therapeutic Uses of Rap and Hip-Hop. New York: Routledge Taylor & Frances Group; 2012:39–56. 41. Lightstone AJ . Yo, can ya flow! Research findings on hip-hop aesthetics and rap therapy in an urban youth shelter. In: Hadley S, Yancy G, eds. Therapeutic Uses of Rap and Hip-Hop. New York: Rutledge Taylor & Frances Group; 2012:211–252. 42. Bull M. Sounding Out the City: Personal Stereos and the Management of

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By Hal

S. Blatman MD, DAAPM, ABIHM

Every cell in the body is hooked into and responds to the tensional environment of the fascia. The fascia ensheaths all bones, connects every muscle and organ, and is all one net with no separation from head to toe.

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MUSCULOSK L TAL PAiN

MUSCULOSKELETAL PAIN

To the credit and suffering of our chronic pain patients, the source of their pain is rarely discovered. Indeed, this is part of the definition of chronic intractable pain for which chronic opioid medication is prescribed. When the source is identified and treated, much of the pain resolves with the treatment. When treatment does not help, it is due in part because the cause of chronic pain and injury has not been discovered and successfully treated. Many people with chronic pain find therapeutic benefit from various myofascial therapies outside of conventional procedure-based pain care. Modern dissection techniques have brought a new understanding of anatomy that leads to a more complete understanding of how injury leads to myofascial pain, and why it might not resolve with common invasive treatment options and medications. abstract:

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Our nervous system is so intimately intertwined with the fascia that pressure and shear forces along the lines of fascia transmit radiating pain, as the fascia is the antenna of the brain.

ANATOMY Every cell in the body is hooked into and responds to the tensional environment of the fascia. The fascia ensheaths all bones, connects every muscle and organ, and is all one net with no separation from head to toe. Core to a new understanding of anatomy is that tendons do not attach to bone. Instead, the fascia that permeates and defines our muscle fibers and muscles interweaves with the fascia (periosteum) that covers the bone, and then takes off in the next muscle with no end or separation of tissue. Author and bodyworker Tom Myers developed Anatomy Trains courses and books detailing a map of the anatomy of connection. He demonstrated several continuous lines of fascia that go through the body from head to toe. He defined a “superficial back line” of fascia that goes from the eyebrows, over the top of the head, and down the back to the soles of the feet to end under the toes. (This is easy to feel yourself by simply putting a stretch on the hamstring and then dorsiflexing the foot or forward flexing the neck. Either motion will tighten the superficial back line and can often be felt as additional tightening and discomfort in the stretched hamstring.) Three fascia layers are defined as superficial, intermediate, and deep. The layers merge at well-defined points, enabling coordination among muscle groups. One example is the coupling between the gluteus maximus and the contralateral latissimus dorsi by the posterior layer of the thoracolumbar fascia. In the other direction, the gluteus maximus inserts into the iliotibial band, fascia lata, lateral intermuscular septum, and femur.1 Q1 | 2016

Fascia takes many forms in the body. It can be loose and mobile as in the dorsum of the hand, or tight and dense as in the bottoms of the feet. The form of fascia relates to its function, and different morphologies of fascia are better suited to their specific locations in the body. For example, our upper and lower limbs have a different fascia structure, and also a correspondingly different function. The fascia of our upper limbs being more elastic is thought to facilitate movement. Lower limb fascia is thicker and stronger, and thus is more able to transmit tension at a distance, and thereby thought to connect the body for coordination.2 Superficial fascia is loose and absent in the palms, soles, and face. Deep fascia ensheaths all muscles, vessels, organs, and glands. Muscle related layers include epimysium, perimysium, and endomysium. This fascia encloses each muscle fiber, fiber bundle, and entire muscle. It is directly evolved in the play of tension between muscle spindles and Golgi tendon organs.3 Understanding this anatomical structure helps explain the transmission of forces from the thoracolumbar fascia to the knee, and brings a different explanation to radiating pain and what is often called sciatica. The nervous system has been thought to monitor tension and pressure within the fascia by way of Golgi tendon organs, Pacinian corpuscles, and Ruffini nerve endings. More recent information tells us that free nerve endings between the layers of fascia are much more numerous than these organs and corpuscles. These nerve endings primarily measure pressure and shear forces within the fascia. Our nervous system is so intimately intertwined with the fascia that pressure and shear forces along the lines of fascia transmit radiating pain, as the fascia is the antenna of the brain. www.painweek.org | PWJ | 51

MUSCULOSKELETAL PAIN

PAiN Healthcare providers are generally taught that there is meaning in the difference between symptoms/sensations of numbness, tingling, burning, aching, sharp, dull, and others. Ability to feel pain is related to the interaction of the nervous system and the fascia. Pain from fascia injury (myofascial pain) can present as any of these sensations. Our brain cannot distinguish between numbness, tingling, aching, stabbing, burning, radiating, or even itch and tickle. The origin of these sensations can be entirely myofascial and have nothing to do with nerve and disc related spine pathology. Acupuncturists, myofascial therapists, and others have found that a patient’s various symptoms of pain quality and location are generally misleading to treating providers, and they are not related to dermatomes. Symptoms are important, but do not accurately represent anatomy of pain causation as most providers are taught. More important: Where specifically is the patient tender? Specific tenderness in the muscle belly and ropey band represents a trigger point, and specific tenderness at an enthesis is consistent with fascia injury. More tenderness likely corresponds with a more severe injury.

iNJURi S When our bodies are injured the “strings” and sheets of fascia that hold us together get stretched and torn. Every muscle or ligament strain is a tearing or overstretching of the fascia that goes through or attaches the tissue to our periosteum. This is most easily described after a simple ankle sprain, but is often not considered by conventional providers after more complex trauma. More complex trauma may result in bone and organ injuries, and after these heal the resulting pain might be attributed to a “soft tissue” injury. Soft tissue sequelae are traditionally difficult to assess and difficult to document. They are also the most important injury leading to chronic intractable pain.

ee e

R L AS When fibroblasts within muscle and fascia are stressed, they secrete soluble mediators as part of the body’s repair process. These include interleukin ( IL)-6, insulin-like growth factors, fibroblast growth factors, and NO. When these stresses are modified by myofascial release, 90 seconds of osteopathic stretch/compression will modify the inflammatory changes caused by 8 hours of repetitive strain.4 In addition, myofascial release has been shown also to change bioengineered nontraumatized tendons. Physical manipulation can increase tendon weight, increase IL -3 and IL -8, and growth colony stimulating factor,5 suggesting that variations in manual therapies may differentially affect physiological responses in vivo.

improve proprioception and also increase muscular activation and coordination. Alpha smooth muscle actin has been demonstrated in fibroblasts, chondrocytes, and osteoblasts. Inasmuch as fascia can contract, sometimes it contracts pathologically. One example is Dupuytren’s contracture. In this condition the fibrous fascia tissue under the skin thickens and tightens abnormally. Another example may be scoliosis. When the longitudinal and spiral lines of fascia through the trunk (as described by Tom Myers) either tighten or fail to lengthen, the spine cannot grow vertically and instead grows in a spiral. In unreported work we have used needle surgery to percutaneously release the tight fascia cords of Dupuytren’s as well as to release scoliosis in children.

CONCLUSiON In addition to various hands-on and even mind-body techniques, trigger point injections, prolotherapy, prolozone, and platelet-rich plasma injection techniques have been shown to help heal injury to fascia and resolve pain. Healing from chronic pain is not generally about drugs, epidural steroids, radio frequency ablation, or spinal cord stimulators. Resolving chronic pain is more about restoring the body from the fascia injuries of a lifetime and the toxicity of a lifestyle. Successful treatment involves nutrition and various forms of body work. The more you are familiar with so-called alternative medicine, the more success and fun you will have in eliminating the chronic pain in your patients. References 1. Stecco A, et al. The thoraco-lumbar fascia. Presented at the 8th Interdisciplinary World Congress on Low Back and Pelvic Pain, Dubai Conference Proceedings, 2013. 2. Stecco C, Porzionato A, Lancerotto L, et al. Histological study of the deep fascial of the limbs. J Bodyw Mov Ther. 2008;12(3):225–230. 3. Stecco L. Fascial Manipulation for Musculoskeletal Pain. Italy: PICCIN; 2004. 4. Standley PR , Meltzer K. In vitro modeling of repetitive motion strain and manual medicine treatments: potential roles for pro- and anti-inflammatory cytokines. J Bodyw Mov Ther. 2008;12(3):201–203. 5. Cao TV, Hicks MR , Campbell D, et al. Dosed myofascial release in three-dimensional bioengineered tendons: effects on human fibroblast hyperplasia, hypertrophy, and cytokine secretion. J Manipulative Physiol Therapy. 2013;36:513–521.

Another issue is that fascia can contract independently of muscle. This contraction can increase fascial stiffness to

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By Doug Gourlay MD, MSc, FRCPC, FASAM

Who are “your” patients? “our” patients? “my” patients? All physicians should take time to assess their particular practice from the perspective of risk. The average primary care doctor might have ~10% of their practice complicated by substance use disorders of one kind or another. A practice that specializes in pain management is likely to have proportionately more. For those practices that specialize in pain management and addiction, this number may approach 100%. Know when to call for help. Know when to refer!

Q4 | 2015

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1 |

3 |

Our Emerging Understanding of Small Fiber Neuropathies Charles Argoff, MD, CPE

Over the last decade, it’s become very clear that many people who experience widespread pain or maybe first experience pain in their distal extremities, burning pain, difficulties with sweating, difficulties with bowel function, difficulties with urination, may be experiencing small fiber neuropathy. In fact, in 3 studies almost 50% of individuals who had been diagnosed with fibromyalgia as the reason for their chronic widespread pain actually had biopsy-proven changes consistent with small fiber neuropathy. With respect to what causes small fiber neuropathy, glucose intolerance or frank diabetes, even metabolic syndrome is the most common associated set of circumstances. Many autoimmune disorders—Sjögren’s syndrome, rheumatoid arthritis, lupus—are associated with small fiber neuropathy as well. B12 deficiency, hepatitis C, HIV can be associated. Celiac disease or even gluten intolerance can be associated with small fiber neuropathy. Typically, we would approach small fiber neuropathy with the kind of treatments that we would use for neuropathic pain. That might mean various antidepressants that have been used as analgesics, as well as various anticonvulsants. Examples of antidepressants would be duloxetine, tricyclics like amitriptyline, nortriptyline, similar medications. For anticonvulsants, gabapentin, pregabalin, carbamazepine have been utilized. Intravenous lidocaine infusions are another approach under investigation, as well as the use of intravenous gamma globulin since there seem to be in some instances an immune-mediated disorder associated with a small fiber neuropathy. In less common use would be plasma exchange (also known as plasmapheresis) where a person’s plasma is taken out and exchanged, cleaned and given back with clear plasma to remove any circulating antibodies or other factors that might be perpetuating the disorder.

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Migraine Education Sheena Aurora, MD

The Chronic Migraine Education Program introduces concepts: what to watch for in patients who may have frequent episodic migraine; risk factors for conversion to chronic migraine; the differences between episodic and chronic migraine and how chronic migraine patients are a lot more disabled. They present with comorbidities and might need a more comprehensive treatment approach involving both medication and behavior management. Patients with episodic migraine on analgesics for other pain conditions, such as back or ankle pain, may become more predisposed to chronic migraine. Onabotulinum toxin A was approved by the FDA for chronic migraine but, in general, primary care physicians are not administrating it. Some knowledge about this therapy is important nonetheless. In research trials, overall in 15 months, 80% of patients had more than a 50% reduction of migraine. Other components of a comprehensive interdisciplinary approach include behavior modification and lifestyle management— keeping a headache diary, diet and nutrition, and exercise and trigger management.

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Social Media: Tools for Patient Engagement and Education

Jeannette Campos, MS

Social media is the future of communications. You can use it for branding, for community outreach, and patient education. The fastest growing segment of social media consumers is populations over the age of 50, because they are looking for information on chronic pain and disease. For practitioners, there are also many opportunities to use social media to transform outreach and communications. What we see mostly is physicians or medical groups using platforms like Facebook or Twitter or YouTube to share information with patients and the community. Very simple mobile based devices like text messaging are convenient and powerful ways to convert 1-to-1 communication from physician to patient into 1-to-many communications from physician to patient populations. All of the platforms can be integrated to create a broad and compelling message from your office to your clientele. The tools offer tremendous opportunity and advantage for changing the way we communicate with our clientele

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Low Back Pain: Key Points of Diagnosis and Treatment Arnold Weil, MD

Back pain is one of the primary reasons patients end up seeing a physician, primary care doctors included. It’s important to realize that you have to be very tenacious in diagnosing the actual cause of the pain because we don’t want to just treat the symptoms. It’s important to understand the anatomy, and in particular the relationship between the segments of the spine, the bones themselves, the intervertebral discs, and also the nerve roots in the spinal cord and how closely aligned they are together. To have a better appreciation for a patient’s symptoms, it’s important to understand the relationship between the primary pain generating components of the spine. Getting a good history is one of the most important parts of the evaluation. You can really get so much information by talking to the patient and getting a good sense of when their back pain occurred, what caused it, and the kind of symptoms they’re having. And a thorough orthopedic and neurologic exam can tweak out the symptoms that may be pointing more toward a disk issue or more toward muscle spasm. The nonsurgical treatments are really the mainstay of treating back pain. This includes pharmacological interventions like muscle relaxants, anti-inflammatories, and analgesics for pain. We can also incorporate physical therapy, home-based exercises, and patient education on body mechanics. There are office-based procedures such as trigger point injections for muscle spasm. If the patient hasn’t improved with conservative treatment, we can perform epidurals or medial branch blocks or some of the more invasive types of injection procedures.

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Researchers examined

A study observed that of

107

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evaluated people aged 24 to 32,

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1. http://ow.ly/Zatwy 2. http://ow.ly/Zatku 3. http://ow.ly/ZatEe 4. http://ow.ly/ZatOO

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by gary w. Jay MD, FAAPM, FACFEI

It can be an amazing situation to participate in the development of important patient needed medications. During my first 25 years of work, I ran a large pain, headache, and neurorehabilitation center with 20 other clinicians. I was also a Primary Investigator (PI), Key Opinion Leader (KOL), and consultant to industry. For those who don’t know me, after seeing more than 36,000 patients 56 | PWJ | www.painweek.org

in 25 years, I joined pharma full time and currently maintain a consulting practice. Why do such a thing? Why go to the DARK SIDE? I realized that if I could get one really good drug developed and approved, I could help millions of patients, far more than I could ever lay hands on. Q1 | 2016

…if I could get one really good drug developed and approved, I could help millions of patients, far more than I could ever lay hands on. What made me realize this? Well, in the 1980s, among other things I did a rehab/pain spot on local TV. As a PI, I had participated in over a dozen studies when I was asked to be involved in a Phase II study (proof of concept) for a new migraine drug. I mentioned this on my weekly TV spot, noting that I was going to start a new study on a new drug for migraine headache—and for the next 2 days I had to close the clinic to patients as I received over 4000 calls from all over the US. (I hadn’t realized that the spot was played around the country. I thought it was just on my local channel.) All of the folks who worked in the clinic were taking phone calls. For 2 days, nothing else could be done.

receptors of various kinds, while a triptan was a specific 5HT1B/1D receptor agonist. It was like the difference between using a shotgun vs a .357 bullet. We continued to learn more. At one point, along with another headache specialist, I wrote a letter talking about what we were seeing in patients who used their triptans too frequently: vasoconstrictor rebound headache. Today, there are 7 triptans, some of which are fast acting (30 to 45 minutes to abort a migraine) vs slow acting (2 to 4 hours). The triptans have varying durations of action, with half-lives between 1/1.5 hours to 28 hours. We know how best to use the medication: it should be used as soon as symptoms appear.

When the time came to begin the study, there was no problem getting patients. This was the first triptan. The first major paradigm shift There are side-effects, the most common of which include in the treatment of migraine in decades. I can tell you that facial flushing (redness), heat sensations, numbness and tinthings were fascinating and difficult. As this was the first gling, and tightness in the jaw and upper chest. Some side of the triptans, there was a lot that had to be learned. I was effects such as dizziness, tiredness, and nausea are similar taken aback by the fact that patients could develop signifi- to migraine symptoms. None of these side effects are concant substernal pain. The drug company was very respon- sidered serious and all pass quickly. Since triptans work, in sible and ECG s were done per the protocol. No one wanted part, by causing the blood vessels to constrict, they may a patient to experience a cardiovascular issue. also cause the arteries of the heart to temporarily contract, and therefore they can present a risk for people with coroThis could’ve been an “Oh boy”—the “Oh boy” or “Uh- nary artery disease, hypertension, hardening of the arteries, oh” is the possibility of a CV event—and therefore, while or a history of heart attacks or strokes. Physicians should we were concerned about an event, the patients’ migraines examine their patients for cardiovascular risk factors, such were stopped. Fantastic! as high blood pressure or high cholesterol. Patients at risk sometimes take their first dose at their doctor’s office while I was lucky enough to continue work on this drug all the way their blood pressure, respiration, and ECG, if needed, can into Phase IV, after it was approved by the FDA . Initially, be monitored, as I did back in the Phase IV days. I would insist that for my practice, my patients would get their first dose of this medication either in my office or in And we keep learning. Next up on the migraine treatthe ED, just in case. No one with known coronary artery ment paradigm: calcitonin gene-related peptide. disease was given the medication. So, for those who continue to say that working in pharma is “Going to the Dark Side,” I can only answer that the ability to I would carefully explain that substernal pain MAY be a side develop and refine a new medication that can help millions of effect but it had not been found to really induce a myocar- patients is rather satisfying. While I’ve personally seen and dial infarction (MI ) in patients with normal cardiovascular treated a lot of patients in my life, I would never be able to work-ups. touch the millions of patients helped by a drug I had a part in helping develop—really, minimally for this drug when I Later, I would learn that while I didn’t see any adverse effects was just a PI, but more so when working in pharma (I got a on patients using this drug—or still later, when I worked as drug for breakthrough pain in cancer approved and launched a PI for another major triptan in development—all of the in the USA and 4 EU countries). triptans initially developed could induce such a problem. I also found that there were rare patients who did experience I smile now, when I hear that “Going to the Dark Side” stuff. cardiovascular issues, including an MI, but this was known It’s one thing to diagnose and prescribe a medication that to be rare, and I remained careful as to how I used the drug. helps patients, but another—far more so—when you help develop a medication that is used by millions of patients that Meanwhile, the patients were happy that their migraines you would never in a million years know. could be aborted and that they didn’t spend days in bed. Remember that Cafergot® was being used at this time so And then I get to prescribe that drug to my patients. it wasn’t like migraineurs had nothing else to use to help As my incredible daughter would say, in her younger days, themselves. However, Cafergot worked but it “hit” numerous “How cool is that!” Q1 | 2016

www.painweek.org | PWJ | 57

SHORT CUTS

with

Bernd Wollschaeger MD, FAAFP, FASAM, MRO

Bernd Wollschlaeger, MD, FAAFP, FASAM is board certified in family medicine and addiction medicine and is Clinical Assistant Professor of Family Medicine at University of Miami School of Medicine, Florida International, and Florida State University College of Medicine.

58 | PWJ | www.painweek.org

Q1 | 2016

“Against all odds change is possible.”

What inspired you to become a healthcare provider?

What do you consider your greatest achievement?

As a young boy I dreamed of becoming a dentist. I actually studied dentistry for 2 years in Germany but soon realized that I did not have the technical skill set necessary to be a dentist. I took a year volunteering as a nurse’s aide in a local university hospital and felt a growing compassion caring for people and studied medicine instead.

To stand up against my father, a highly decorated German WWII tank commander and Nazi officer involved in the killing of civilians. I rebelled, converted to Judaism, and emigrated to Israel.

Why did you focus on addiction and pain management? I am actually an addiction specialist and was motivated to understand the disease of addiction, which was so prevalent in my family and caused the early death of my sister. Who were your mentors? In 1983 I volunteered in a hospital in Israel and met an American surgeon who gave up a successful, well paid career in the US, emigrated to Israel, and dedicated himself to practicing medicine in a small community hospital. An addiction specialist in Miami who cares for his patients with neverending patience and compassion and who became my friend and mentor also inspires me. If you weren’t a healthcare provider, what would you be?

What is your favorite language? Modern Hebrew. If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be? Book: The Book of Abraham by Marek Halter. Film: Blade Runner. Music: Tangerine Dream album Optical Race. What would you like your legacy to be? That an individual can make a difference. What is your motto? Against all odds change is possible.

I actually thought about becoming a full-time writer and still have not given up the idea. What is your most marked characteristic? Perseverance and a healthy dose of stubbornness.

Q1 | 2016

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June 24 â&#x20AC;&#x201C; July 1, 2016

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Celebrity Constellation Venice, Italy Zadar, Croatia Kotor, Montenegro Civitavecchia (Rome), Italy Livorno (Florence/Pisa), Italy Florence, Italy Toulon (Provence), France Barcelona, Spain

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.

ONCE daily with EVENING MEAL

Bring 24-hour relief into their routine GRALISE is the only once-a-day gabapentinoid that offers Night to Day control of PHN pain1

ONCE daily with

EVENING MEAL

ONCE daily with

EVENING • Patients receiving GRALISE experienced significant pain reduction vs placebo beginning Week 1 and continuing MEAL 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.

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