PAINWeek Journal Vol. 4, Q3 by PAINWeek

vol. 4 q 3 2016

THE PERTINENT NEGATIVE P.18 A PARADIGM SHIFT: COMBINED ELECTROCHEMICAL TREATMENT (CET) FOR NEUROPATHIC & OTHER REFRACTORY PAIN SYNDROMES P.32 TRANSFORMATIVE CARE FOR CHRONIC PAIN P.44 EXPOSED P.58

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 • neuropathic pain associated with DPN in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Not an actual patient.

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, including BOXED WARNING, and Brief Summary 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 withdrawal 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 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. ‡Data on file. Depomed, Inc. formulary data are sourced from MMIT. Transaction data are sourced from SHA Health. Data are current as of July, 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 depressant drugs (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 ahead 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. 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 Sr. Medical Director Endo Pharmaceuticals Malvern, PA

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

John F. Peppin DO, FACP Medical Director, US Medical Affairs Shionogi Inc. Florham Park, NY

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

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

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

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

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

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

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

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 / Q3 / 2016 12 | EXECUTIVE EDITOR’S LETTER by kevin l. Zacharoff

FEATURES

18 | CLINICAL CONUNDRUM

THE PERTINENT NEGATIVE by gary w. Jay

32 | INTERVENTIONAL

A PARADIGM SHIFT combined electrochemical treatment for neuropathic & other refractory pain syndromes by cynthia r. Cernak / robert h. Odell

44 | KEY TOPIC

TRANSFORMATIVE CARE FOR CHRONIC PAIN

by james Fricton / alfred Clavel / mark b. Weisberg

10 | PWJ | www.painweek.org

58 | PAIN&ADDICTION EXPOSED

by steven d. Passik

SHORT CUTS

62 | CLINICAL PEARLS by doug Gourlay

63 | ONE-MINUTE CLINICIAN

with donna Alderman , jeffrey Fudin , stephen Ziegler ,

roger Fillingim , kevin l. Zacharoff

64 | PAIN BY NUMBERS 65 | OP-ED: THE SILENT HEALTHCARE EPIDEMIC counterfeit medicine by jay Joshi

70 | PUNDIT PROFILE with Jeffrey Gudin

Q3 | 2016

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KEVIN L.

ZACHAROFF MD, FACPE, FACIP, FAAP

case: there’s more to successfully treating chronic pain than simply employing traditional biomedically directed treatment strategies. The authors discuss employing educational programs for healthcare professionals that stress the importance of self-management as an integral component of chronic pain treatment. Attention is paid to the role of early and multidisciplinary interventions to prevent the transition from acute to chronic pain, and assessment of the “whole patient” as opposed to solely the pain itself. These ideas are rooted in the basic principles that the patient has a role in successful pain treatment. Dr. Jay Joshi covers a subject we don’t often see discussed in healthcare: the variation among generic and brand name medications containing the same active ingredient. Dr. Joshi postulates that clinicians and patients alike may be unaware that when medication is prescribed, in some cases the accompanying substances in the medications (fillers) are allowed to vary, since they do not contribute to the pharmaceutical efficacy. Dr. Joshi discusses how counterfeiting of pharmaceuticals is a prevalent problem at a worldwide level, presenting significant danger to patients. This article is important, provocative, and the subject matter is worthy of the attention.

eptember is Pain Awareness Month and, for me, it is also PAINWeek Awareness Month. As the nation’s largest annual pain meeting approaches, I find myself taking stock of what has taken place in the world of pain and its management. Each year I seem to come to the same conclusion—there hasn’t been as much progress as I would have wished for, especially in the area of education. Nobody can deny that We also have a very rare treat: a piece by Dr. Steven Passik. I’ve this year there has been a particularly high degree of political involve- known Steve for many years now both professionally and personally, ment in pain management regarding opioid therapy, with much of this and have included much of what he has said in my own articles and debate necessary to try to find a way out of the “epidemic” that exists in symposia. His article, Exposed, gives us his perspective on the omniour country. On the other hand, though, there has been a comparatively present subject of an intimate relationship: pain, its management with low level of debate moving us towards what hopefully is ultimately the opioid analgesics, and addiction. In addition to being honest, open, common goal—safe and efficacious management of people who deal and pertinent, this piece is a must read for anyone who has tried to with chronic pain every day of their lives. If we are deficient in coming balance the ethical dilemma of undertreating pain patients and the up with innovative, cost effective, scientifically proven, and reimburs- specter of creating/facilitating addiction with opioids. This is often able treatment alternatives, patients are the ones who pay the price. not an easy task, and if there’s one thing I’ve learned from Dr. Passik, it’s that you are always going to need to evaluate that dilemma on a Dr. Gary Jay’s article about The Pertinent Negative reinforces some- case by case basis, and over the continuum of care. thing I was taught by my professors: “If you give the patient enough time, in many cases, they will tell you what is wrong with them.” Lastly, PWJ’s Pundit Profile focuses on my good friend and colleague, I make it a point to teach this to my medical students. Testing is Dr. Jeffrey Gudin. Rarely have I met someone with whom I share so intended to support what you consider to be the right diagnosis, not many values, both as a human being and a healthcare provider. I have to create the diagnosis. When the testing is “negative” it doesn’t always taught my medical students about the importance of the word mean that nothing is going on, it just means that you haven’t found “care” in health care. Dr. Gudin cares about what he does, who he is, the reasons. The types of cases Dr. Jay presents are one of the best and how he impacts people’s lives. Enjoy this profile, as I can personally ways to teach: utilizing real world clinical cases. I think you will find attest to its accuracy, his integrity, and our common tastes in music. them relevant and enlightening. Hold onto this article for future reference on a prn basis. This is not your average issue. Read it, enjoy it, let it provoke thought, and then discuss with your colleagues. One of my sessions at PAINWeek Drs. Cynthia Cernak and Robert Odell, Jr, have written a very interest- this year is about the role of communication in pain management. This ing article about shifting paradigms for the treatment of neuropathic Journal is communication. I hope to see you at the national PAINWeek and other refractory pain syndromes. They discuss an innovative meeting! Find me and come say hello. Let’s communicate together. approach—combined electronic signals and local anesthetics— that can help bring relief to a subset of chronic pain patients in a — KEVIN L. ZACHAROFF synergistic fashion, which, in their experience, has a higher degree of efficacy and safety than other available treatment regimens. This article should set the stage for further research. Kevin L. Zacharoff, MD, FACPE, FACIP, FAAP, is Pain Educator and Consultant and

In their article about transformative care for chronic pain, Drs. James Fricton, Alfred Clavel, and Mark Weisberg make a strong

12 | PWJ | www.painweek.org

Faculty, Clinical Instructor at SUNY Stony Brook School of Medicine, Department of Preventive Medicine, in Stony Brook, New York.

Q3 | 2016

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BiRMiNGHAM AL KANSAS CiTY MO N W ORL ANS LA BOSTON MA SOUTHFi LD MI MiNN APOLiS MN PiTTSBURGH PA CHARL STON SC

■ Cynthia R. Cernak DPM, FACFAS, FABPM, FAENS

P.32

■ James Fricton DDS, MS

P.44

■ Gary W. Jay MD, FAAPM, FACFEI

P.18

■ Jay Joshi MD, DABA, DABA-PM, FABA-PM

P.65

■ Steven D. Passik PhD

P.58

Cynthia Cernak is a podiatric surgeon at the Weil Foot and Ankle Institute and the Wisconsin Neuropathy Center in Kenosha. She is a founding member of the Institute of Peripheral Nerve Surgery. Dr. Cernak coauthored her article with Robert H. Odell, Jr, MD, PhD, DABA , DABPM, FIPP, who is the owner and Medical Director of the Neuropathy & Pain Centers of America in Las Vegas, Nevada. Dr. Odell co-developed and popularized the combined electrochemical technique (CET ).

James Fricton is a Professor at the University of Minnesota, and a Senior Investigator at HealthPartners Institute for Education and Research in Minneapolis. He is also a Pain Specialist at the Minnesota Head and Neck Pain Clinic in St. Paul. Dr. Fricton coauthored his article with Alfred Clavel, MD, a neurologist and pain specialist. He is Department Chair at the Pain Department in HealthPartners, and the Minnesota Head and Neck Pain Clinic; and Mark B. Weisberg, PhD, ABPP, a Clinical Health Psychologist at the Minnesota Head and Neck Pain Clinic, and Adjunct Community Professor in the Center for Spirituality and Healing, Academic Health Center, University of Minnesota.

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.

Jay Joshi is CEO and Medical Director at the National Pain Centers based in Illinois. He is Chairman of the Clinical Board of Directors at the National Pain Foundation..

Steven Passik is a pain psychologist who, after a 25 year clinical and academic career, has been working in the lab and pharmaceutical industries for the past 4 years. He has over 200 publications on issues related to pain and its interface with addiction. He is working with his long term collaborator, Kenneth L. Kirsh, PhD, on an upcoming book about opioids in the healthcare system..

Correction: In the last issue of PWJ (Vol. 4 Q2 2016) Dr. Hans Hansen’s affiliation information should have read: “Hans Hansen was the President of the American Society of Interventional Pain Physicians (ASIPP) from 2013 to 2014 and is currently Director Emeritus. He is a member of DABPM, AAPM, ASAM (addiction), FIPP, as well as an editor of Pain Physician. He is a practicing physician, operating a number of pain management clinics in North Carolina.”

14 | PWJ | www.painweek.org

Q3 | 2016

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CLiNiCAL CONUNDRUM

here."

20 | PWJ | www.painweek.org

abstract: For the purpose of this article, the Pertinent Negative is an essentially normal neurological and musculoskeletal examination. In other words, the diagnosis lies elsewhere, and, most commonly, there are no examination findings. Typically, the diagnosis may be uncovered by other aspects, sometimes even by simply asking the “right” question, sometimes by acceptance. The following 3 case histories were presented at PAINWeek 2015.

Q3 | 2016

patient #1: GH

CLINICAL CONUNDRUM

The first patient was in reality my very first hospital based consult in the first hospital I obtained privileges in decades ago. This consult was sent to me by a very well respected physician who didn’t understand what pain medicine was and who thought that someone who did “pain medicine” could answer any and all questions about pain, both quickly and easily. This occurred before pain medicine was an acknowledged medical subspecialty and before the birth of the first national pain organization, for which I was one of 30 founders.

The patient, GH, was a 68-year-old, right handed Caucasian woman admitted to the hospital with a chief complaint of substernal chest pain. She had received a very thorough evaluation of her cardiovascular status. After a week of tests and observation, and the acknowledgement that a cardiovascular event had not occurred, she continued to complain of substernal chest pain that had not been reduced an iota. All of her tests were negative. The consultation request noted briefly that the

patient had been admitted previously for this problem, but the pain had currently exacerbated. Her attending physician could find nothing to explain her pain, so he wanted a “pain medicine evaluation and diagnosis,” as he stated it. Obviously, this being my first consult in my first hospital, with the fact that I stated I did pain medicine, which no one really understood—I felt no pressure at all! ( NOT!)

She had truly had a full, very extensive work-up, all of it negative. After I took the history, I did a very thorough neurological examination, followed by a musculoskeletal examination and a general physical examination.

THE PERTINENT NEGATIVE for Patient #1:

The patient was a very nice older woman who gave a hisAll examinations were negative, tory of substernal chest pain beginning about 7 days earlier, but the patient’s pain level which she had reported to her attending physician, who had hospitalized her for work-up and to rule out a myocarwas a 7/10! dial infarction. She did note that she’d been in the hospital before for the same problem, but was not specific and stated that she could not remember exactly how many times; 2 or Everything was negative. There was no diagnosis I could give. This being my first ever hospital consultation request, I knew 3 was her statement on history.

22 | PWJ | www.painweek.org

Q3 | 2016

that if I was not helpful, I, and my appellation of doing “pain medicine,” could be ignored from then on. So, I did what I could: I ordered up her past medical records. She didn’t have 1 or 2 past hospitalizations—she had 7 thick charts from 7 prior hospitalizations. Superficial evaluation revealed them all to be secondary to substernal chest pain. I went through each chart, outlining subjective complaints and objective findings. They were all substantially the same. Now it was after 1 am and I was no closer to having a diagnosis than I had been before. Was I concerned? You betcha!! I sat thinking, reviewing the charts and my notes. Then I realized there was one thing that I hadn’t done, so I did it: I listed the dates of her hospitalizations. There were 2 a year, except for the first year, when there was one. And the dates were exactly the same each year! It was now 2 am, and the patient was still up, stating that her chest pain made it impossible for her to sleep. So I asked her again how many times she could remember being hospitalized for substernal chest pain. She told me, “4 or 5 times, maybe more.” Then I asked her if she knew that the dates of her hospitalizations were always the same. She looked at me and said, “Of course they were!”

treatment and/or counseling with her Rabbi. I received an incredulous call from her attending physician—he was amazed at my diagnosis and the fact that it ran so contrary to what he would have thought, ie, that it had to be something physiological—who discharged her with an appointment with a psychologist. He became a good referral source.

Conclusion: Patient #1 A negative neurological examination did not, in this patient’s case, mean that she had no diagnosis. Nor did it mean that she couldn’t develop a “real” cause of pain. While some might call it “imagination-induced pain coinciding with the death of her husband,” it certainly didn’t mean that she didn’t have any pain. Who can argue that her “brain hurt” with a good bit of limbic system input, rather than her heart—or did they both have the same etiology?

Figuring that I had it solved, I picked the first date and asked, “Why have you always been hospitalized in December of each year”? (It was December at that time.) She looked at me like I was crazy and said, “That’s the date my husband died!” When asked why she was hospitalized in June, she answered that it corresponded to when the headstone of her husband’s grave was unveiled. Finally, of course I had to ask her what caused her husband’s death. The answer, which should not be a surprise, was “a heart attack.”

DIAGNOSIS for Patient #1:

The diagnosis of this woman’s multiple episodes of severe substernal chest pain was: ANNIVERSARY REACTIONS.

I spent the next hour talking with the patient, sharing experiences and discussing the feeling one gets on such an important anniversary. She appeared to understand, became tired, and drifted off to sleep. I wrote up my consult, with the above diagnosis and recommended psychological Q3 | 2016

www.painweek.org | PWJ | 23

patient #2: DZ

DZ was a 38-year-old, right handed Caucasian woman seen for chronic low back pain. She had complained of this pain for 3 years prior to my seeing her. She had seen 4 physicians for her pain in the past. She was essentially unable to do anything at home: per the patient and her husband, she laid on the living room couch during the day, rarely getting dressed or putting on make-up. Her husband had hired people to come in and clean the house. He did the food shopping. He noted that he had a good feeling when he took care of his wife. He also took the major responsibility for their 2 high school aged children. The patient noted that her low back pain (lbp) was

too great for there to be intimacy with her husband, and she “sort of felt bad about that”—a direct quote. Her pain had begun after a slip and fall outside of their home, in front of it, so there were no legalities. The patient complained of sciatic pain, with lancinating pain shooting down her right leg. The pain was exacerbated by walking, bending, and turning her body. In addition to her significant LBP, she also complained of pain when sitting, localized in her right buttock. She complained of a chronic daily tension-type headache with neck pain, a holocephalic headache described as aching, with occasional photophobia and sonophobia. She also Q3 | 2016

complained of difficulty with concentration, poor sleep, and feelings of isolation. She denied depression, suicidality, or sadness. Pertinent examination revealed: on neurological examination—normal cranial nerves, sensation, cerebellar testing; musculoskeletal examination—reflex testing showed a very slight right Achilles decrement, with no pathological reflexes, including Chaddock, Babinski, and Oppenheim. She had a significant cervical myofascial pain syndrome with multiple myofascial trigger points. Her cervical range of motion was diminished in all 4 realms. She had significant lumbosacral myofascial pain with myofascial trigger points www.painweek.org | PWJ | 25

CLINICAL CONUNDRUM

in that region. She had a decreased range of motion at the waist, with decreased bending, turning, twisting. Finally, she had a right piriformis syndrome.

neuromuscular relation and muscle re-education

relaxation on electromyographic testing. In psychology, she didn’t appear to know what she wanted: she was ambivalent regarding feeling better. She stated that she loved her husband and children and expressed that she felt bad that she hadn’t been more involved with them for the prior 3 years. It was felt by the interdisciplinary team that there was an underlying depression but the patient refused to admit it or deal with it. She stated that she appreciated her husband taking care of her. The medications were helping: she was sleeping well, and after 6 weeks I stopped the hydrocodone prior to physical therapy and maintained the other medications.

3 weeks, then changed to tizanidine 12 mg at night Venlafaxine 37.5 mg, increased to 150 mg over a month for its noradrenergic activity º Doxepin 25 mg PO at night to help with sleep

At these weekly meetings, the patient, who was invited to participate, frequently did not. When she was there, she spoke little and did indeed appear ambivalent; her facial expression was almost masked. It was decided by the treatment team to try more socialization work and to work harder to get her involved with group psychotherapy, which she had refused to participate in up to that time.

By this point in my career, I had established an interdisciplinary pain center. This patient was treated with multiple modalities in one place. Her treatment included:

▸ Physical therapy ▸ Relaxation therapy—biofeedback enhanced

▸ Psychotherapy ▸ Medications: º Ketoprofen 75 mg every 6 to 8 hours with food º Methocarbamol 750 mg 3 times a day for the first º

She complained of difficulty dealing with physical therapy, At a medical visit 7 weeks into treatment with the patient stating that it hurt too much, so I started her on hydrocodone and her husband, he said her sleep was greatly improved and 5 mg taken 1 hour prior to physical therapy, 3 times a week she had begun to eat more regularly as well as get dressed in (maximum). She was taking a bottle of acetaminophen 1 to “going outside clothes.” He also noted that she was shocked 2 times a week, and I asked her to stop that immediately. I also when one piriformis injection stopped her sciatic pain. She tested her hepatic enzymes, which were a bit high, but returned didn’t know how to react and didn’t seem particularly happy to normal 3 weeks after she stopped the acetaminophen. Other about it. (Editorial comment: this is itself a strange reaction). treatment included myofascial trigger point injections in physical therapy: .5 to 1 cc of 1% lidocaine without epinephrine, 1 to The patient spoke little at these meetings. I would ask her 2 times a week in different myofascial trigger points. more specific questions and she would ask her husband to answer them. When I asked her why she did that, she stated After 3 weeks of physical therapy being unable to end her either “I’m tired” or “He can explain better than I can.” piriformis syndrome, I injected the piriformis muscle with When I insisted that she answer the questions I posed to her, 100 units of onabotulinumtoxinA, with immediate release the patient would become upset and refuse to talk. of the piriformis muscle spasm and an immediate end of her complaints of sciatic pain. At 10 weeks, she denied headache; she had a full cervical range of motion. She continued to deny sciatic pain. Both After her first week of uncertainty, the patient began to her cervical and lumbosacral myofascial pain syndromes greatly enjoy and appreciate biofeedback therapy. were gone, with no palpable myofascial trigger points (active or latent). She stated that she felt better and that she was The doxepin greatly helped, especially in combination with glad, but I felt she was still uncertain. tizanidine; she was able to sleep through the night. Her neurological and musculoskeletal examinations were At the weekly interdisciplinary meeting, it was noted that: in within normal limits. She had finished her other treatments physical therapy, in combination with trigger point injections and her medications now consisted of nightly venlafaxine and exercise therapy, the patient’s cervical range of motion 75 mg and doxepin 25 mg. She was given a small prescription was markedly improving. When she received the piriformis of ketoprofen 75 mg to take one every 6 to 8 hours with injection, complaints of sciatic pain stopped; but, interest- food for pain. ingly, per the physical therapist, “The patient did not appear happy.” In biofeedback therapy, the patient was doing well The patient and her husband were seen 2 weeks later. She and enjoyed her biweekly visits. She was able to demonstrate continued to deny headache as well as LBP. She claimed to

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be sleeping well. Her husband noted that while she dressed and didn’t stay in her pajamas all day, she still sat on the couch and didn’t participate with the family when they tried to encourage her to go on outings with them. When I asked her why, for the first time I saw what I thought were tears, but she again denied depression, suicidality, or even sadness. Neurological and musculoskeletal examinations remained entirely negative. The patient had an excellent treatment outcome in most aspects. I suggested that she continue with the psychologist. I received a rather bland “Thank you” for the now selfproclaimed painfree patient. She also asked to be taken off all medications as soon as possible. I explained and wrote how to wean off of them. She stated that she would think about continuing to see the psychologist (who she stated she liked). The patient and her husband left the office.

THE PERTINENT NEGATIVE for Patient #2:

Totally normal neurological and musculoskeletal examinations with the patient stating total remission of all her pain! After the patient left that visit, I got busy seeing more patients until I was interrupted by a call from a local ED. On the way home from my office, the patient’s husband was driving, and she was sitting in the passenger seat. While stopped at a red light, their car was rear-ended. The patient and her husband were taken by ambulance to the nearest hospital ED. I was on staff at that hospital and the patient’s physician of record, so I was called. I saw the patient again about an hour or so later. In the ED, the patient’s husband stated that he was fine and was sitting at his wife’s bedside. She was complaining of severe headache, severe neck pain as well as LBP; essentially the same symptoms she had complained of when I had initially seen her. As she described her pain to me, her husband was telling her that he would take care of her and of course she could stay on the couch. What was new, unlike anytime during our past interactions, was that she was broadly smiling as she described her pain. She stated that she would think about further treatment. She did not call the office again. Q3 | 2016

DIAGNOSIS for Patient #2:

Possible “masked” depression, but more likely: secondary (the patient) and tertiary (her husband) GAIN!!! I could better understand the patient’s feelings then: as we treated her and she got better, we were taking her farther and farther away from her comfort zone which was, for whatever reason, doing nothing but being taken care of, with absolutely no expectations. Could she have been depressed? Certainly. Although all the psychological testing she had undergone, as well as the psychotherapy, did not reveal it. I think it was that she would have been expected, at least eventually, to DO something with/for her husband and children, and she didn’t want to, for whatever reason.

Conclusion: Patient #2 What puzzles me is that she let us get rid of her pain to begin with. Judging by her smile and essential happiness, the reinjury was, most likely to her, a gift. The secondary gain was hers: she could continue to be a literal “couch potato” and just be taken care of, with no expectations. At all. The tertiary gain was her husband’s: he got to take care of the woman he loved. It made me unexpectedly sad to see this, but it was not my job to fix what now appeared to be a deep-seated need to be in control of herself and her family.

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patient #3: ST

ST was a 59-year-old, right handed Caucasian woman with a 32-year history of severe chronic headache that had kept her, for the prior 15 years, essentially bedbound. The patient was seen in the presence of her husband. He noted that since his wife had become bedbound because of her pain, he worked a full time job and was also responsible for shopping and keeping the house clean, as well as generally taking care of things. The patient noted that she had seen “at least 8 physicians,” the last one 5 years prior to her seeing me. When asked what had brought her in to my clinic at that time, as there did not appear to be any changes, the husband stated “Hope!” At the same time his wife rolled her eyes. The patient described a holocephalic headache that

They had had no children. There was no intimacy in the was constant, aching, occasionally throbbing, that could be relationship. They slept in separate bedrooms. associated with nausea, very occasional vomiting, photophobia, and sonophobia. Per old records, she had previously been The patient was intense. She met my eyes and spoke with diagnosed with “muscle contraction headache.” On a 0 to 10 certainty to me, stating that things were what they were. NRS scale, the patient stated that her pain was a constant Her husband was much less intense. He was appropriate and 8.6/10 and that it never changed. a “nice guy” and it appeared that he really cared about his wife. It was also obvious that the patient had come to the She had fixed up her bedroom so that she was either in bed clinic at her husband’s behest. While he looked for “hope,” or sitting on “my chair,” which had a small table next to it, his wife was certain that nothing would ever help her heada light behind it, and a television. Her husband brought all ache pain. of her meals into the bedroom for her. According to both the patient and her husband, she had not left the bedroom Her description, agreed to by her husband, was that she for months. She stated that she was on no medications, as demonstrated essentially no functionality other than exist“they never help!” and she didn’t want any. ing/living in the bedroom. She stated that she had done Q3 | 2016

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CLINICAL CONUNDRUM

nothing for her husband or really for herself in “a long time,” but she didn’t mind it as her pain was just all too consuming. Examination was pertinent for a cervical myofascial pain syndrome with myofascial trigger points and a decreased cervical range of motion in all 4 realms. There were no focal neurological abnormalities: her examination was entirely normal. We discussed the headache program, which the patient felt would be a waste of time. Her husband implored her to give it a chance. She finally agreed to physical therapy— biofeedback enhanced neuromuscular relaxation and muscle re-education—with psychotherapy. I would see her weekly, and any medications used would be discussed thoroughly and she would need to agree. When they left, she shook my hand and told me that nothing I could do would decrease her pain.

I congratulated the patient on her achievements. She countered with the fact that her pain level had only dropped to an 8.5/10. Examination showed a good increase in total cervical range of motion. While the patient denied that her headache had changed at all (her pain level decreasing by only 0.1), she stated she was enjoying the pool and meeting with friends; she stated that she was “starting to get back into shopping.” Several more weeks passed. The patient and her husband consistently came to treatment, which at this time consisted of seeing me once a week, biofeedback once a week (at the patient’s request), and one visit with the psychologist a week. She had finished with her physical therapy weeks ago, and we continued with the weekly interdisciplinary team meetings to keep her engaged.

ST started her treatment program the next Monday. She attended all treatments for the first 3 weeks, including the It should be noted that I did not give the patient any mediweekly interdisciplinary meetings. During her third inter- cation whatsoever during her treatment. disciplinary meeting, I asked her if there were any sports or physical activity that she really liked. Her answer was swim- Just before her last team meeting, I examined her. Her ming. Her physical therapist agreed to take her swimming neurological examination continued to be normal. Her once a week if the patient found a pool she could and would musculoskeletal examination was normal, with no cervigo to. The next day, the patient decided to use an Olympic cal myofascial trigger points or decreased cervical range size pool in a local college that had open hours after classes. of motion. It should be noted that the patient had received The patient, along with her physical therapist, attended 4 sets of myofascial trigger point injections with 1% lido2 days later. The patient appreciated the physical therapist caine without epinephrine early in her treatment, given going with her. She started to tell this clinician more than while she was in physical therapy, so the therapist could she let on to others, including the psychologist. finish totally dealing with the myofascial trigger points.

The patient stated that she hadn’t driven in many years. She had had girlfriends, but had “given them up” when her pain became “all consuming.” The treatment team discussed these things and suggested to the patient the following week that she endeavor to call an old friend or 2 and see if they could meet to at least talk or have tea at her home.

The patient told the team that she was now able to swim 8 to 10 laps in the pool, and did so 2 to 3 times a week. Her husband proudly noted how much money she spent shopping with her girlfriends. He also told us that the prior weekend, he and his wife had gone out to dinner for the first time in 7 years.

The physical therapist noted that after the second visit to the pool, the patient was quite capable of swimming safely by herself.

The patient still insisted that her pain level was 8.5/10. I told her that it was unfortunate that it hadn’t gone lower but that physically she had made great gains, and her ability to function had markedly improved. I told her that I would accept her pain level of 8.5 if she would continue to be active, swim at least 3 times a week, go out with her husband and friends and continue, as she has started to do, to live her life rather than just exist. She insisted a second time that her pain remained an 8.5/10, and I acknowledged that, and told her that I was sorry that I was unable to bring her pain level lower. She stated that she would continue to do what she could. She was then discharged.

Three weeks went by and on her weekly visit with me, the patient’s husband shook my hand and proudly told me that “My wife has found her shopping gene!” She had indeed met with a friend, and then another, and the 3 women had gone out to the mall, shopping twice, the patient spending money that was not begrudged at all by her husband. On the physical therapist’s last visit to the pool, she watched the patient swim 3 full laps.

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THE PERTINENT NEGATIVE for Patient #3:

Totally normal neurological and musculoskeletal examinations in a patient who, for the first time in many years, had regained function enough to swim 10 laps in an Olympic size pool several times a week; get out of her bedroom; leave her house to go shopping with friends with whom she had regained a relationship; go out with her husband, who was ecstatic with her seemingly remarkable progress.

The gains she made were in spite of her continued complaints of headache pain, which were made irrelevant by her increasing functional and emotional abilities to do and feel and participate in life. Either way, I considered this patient’s treatment successful due to the work of the treatment team.

Conclusion: Patient #3 Two weeks later, according to my secretary, the patient actually drove herself to the clinic (another first, at least for us to see). She left a box for me. In it was a stone with 2 words etched into it: MIRACLES HAPPEN. Sometimes, being a pain physician is sublime work.

The fact that I had allowed her to “maintain her high pain level” without fault, telling her that I was unable to decrease her pain level, not her, but as long as she remained active and functional it was a wonderful trade-off, she continued to have a club to use indiscriminately, but she had yet to use it!

Diagnosis for Patient #3: While there were secondary gain issues in both the patient and her husband, it was more complex than that. The patient was able to regain significant function, including regaining a more adult relationship with her husband of many years. It appeared that the key to it all was accepting that the patient had pain, that it was a high level (8.5/10), and that I and my team were not going to insist on taking that from her. Q3 | 2016

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By Cynthia R. Cernak DPM, FACFAS, FABPM, FAENS / Robert H. Odell, Jr MD, PhD, DABA, DABPM, FIPP

Combined Electrochemical Treatment (cet ) for Neuropathic Other Refractory Pain Syndromes By Cynthia R. Cernak DPM, FACFAS, FABPM, FAENS / Robert H. Odell, Jr, MD, PhD, DABA, DABPM, FIPP

CET in the treatment of peripheral neuropathy… has been shown to be over 60% more effective than pregabalin in reducing discomfort and i mproving function in patients with diabetic peripheral neuropathy and was associated with o ver 95% fewer adverse events.

e e

iNT RV NTiONAL

abstract: Combined electrochemical treatment (CET ) uses local anesthetics combined with a computerized electronic signal treatment (EST) to mitigate or eliminate pain, allodynia, numbness, and other symptoms of neuropathic pain.1 Greater, faster, and longer lasting patient outcomes, especially in neuropathic pain, are achieved by first using a local anesthetic blocking agent prior to performing EST. While both bupivacaine and electrical stimulation have been well studied, here we describe the differences between electroanalgesia utilizing our advanced device and standard electric current devices. ¶ Use of CET in the treatment of peripheral neuropathy of all kinds has been shown to be over 60% more effective than pregabalin in reducing discomfort and improving function in patients with diabetic peripheral neuropathy (DPN) and was associated with over 95% fewer adverse events.2 It has been argued that there is a serious ethical issue going on: Medicare will pay for treatment with pregabalin at $7,000 per year, but disallows payment for the use of CET in the treatment of neuropathy, which, over a 2 to 3 month treatment period, costs somewhat less than $7,000. This policy is inhumane, narrow minded, and lacks economic sense.

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has been successfully used to treat diabetic and idiopathic neuropathy,3,4 chemotherapy induced peripheral neuropathy,5 spine pain, postherpetic neuralgia, phantom limb pain,6 occipital neuritis, and other refractory chronic pain conditions. Treatment of these chronic pain conditions is accomplished by serial interventions that may take 2 to 3 months. The protocol involves treating patients 3 times a week, with 1 or 2 CETs and 1 EST only. HOW iT WORKS

The device used in this study incorporates both AM, frequency modulation ( FM ), and AM / FM modes of stimulaThe electronic signal generating device uses sophis- tion to prevent accommodation. (Devices used in this study: ticated communications level technology to produce and NeoGen SLV and SLV-2, manufactured by Sanexas, GmBH, deliver medium frequency signal energy (utilizing 2,000 to Germany.) A frequency range of 2,000 to 23,000 Hz with 23,000 Hz) in continually varying sequential and random an energy delivery of up to 100 mAmp is possible. This patterns via specialty vasopulse electrodes. This alternation allows for all of the benefits of medium frequency (defined of sequential and random signal delivery effectively elimi- as 2,000 to 100,000 Hz) stimulation, giving the patient the nates neuron accommodation. Most electric current devices best possible chance for pain relief. fall into a low frequency class with an amplitude modulation (AM ) output of <2,000 Hz and 20 mAmp power. In these EST has profound anti-inflammatory and other physiologic types of low-level machines, pain decrease is noted but there effects: cellular membrane repair, increase in intracellular is no prolonged relief of pain. metabolism, diffusion of hydrogen ion concentration to Q3 | 2016

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INTERVENTIONAL

reduce tissue acidosis, regeneration of axons, and support of the immune system. These effects occur by using the principles of physics rather than pharmacology.7,8

iN OUR

eXPeRieNCe: Peripheral Neuropathy

We have successfully utilized CET for all forms of peripheral neuropathy. CET uses a local anesthetic block (eg, ankle block for peripheral lower extremity neuropathy; intercostal block for thoracic level postherpetic neuropathy) plus EST. We have treated hundreds of peripheral neuropathic patients with an 80% success rate.4,5,9,10 Epidermal nerve fiber density testing has confirmed clinical benefits by showing that nerve regeneration is occurring.10 A-delta small pain fiber neurodiagnostic testing data also improves, which supports normalization of A-delta nerve function.10 In a 69-year-old man with idiopathic neuropathy, after 1 month of treatment with CET, there was objective proof as shown by measurement of A-delta nerve function that the intervention normalized some or all of the A-delta nerves. (There are 3 other nerves related to neuropathy—afferent c, efferent c, and A beta—so the correlation is not always 100%.) The first formal prospective study of CET for neuropathy was done by one of us (CC), 2008 to 2010. One hundred fourteen patients who had DPN-related pain were offered entry in this open-label trial. All study participants received a description of the treatment protocol and provided written informed consent to participate in the study. A total of 101 patients chose to complete the combined electric current and

local anesthetic therapy protocol. The first patient enrolled in the trial in May 2008 and the last in July 2010. The entry criteria for this study were pain symptoms related to DPN. Of the 101 patients enrolled, 67.6% had confirmed type 1 diabetes mellitus or type 2 diabetes, and 32.4% had prediabetes. The average improvement was an 81.8% reduction in symptoms.4 (Note: 31 of the 101 patients reported numbness as their primary symptom, entered as an N/A by staff. These results interpret all N/A answers as a “0” pain. If the 70 patients who did not report numbness as their primary symptom are evaluated, average pretreatment pain scores were 7.8 compared to average post-treatment pain score of 1.0, indicating an 87.2% reduction in pain symptoms.) At 1 year post-treatment, 23 of 101 patients were without relapse of pain symptoms. Each reported improved quality of life and that they were benefiting from therapy. When questioned 5 years later, 22 continued to be free of the neuropathic pain. As a group they lost weight and had reductions in their HbA1c levels. In addition to increased pain relief after CET treatment, DPN patients showed a trend towards improvement in motor nerve function using nerve conduction velocity/ EMG testing. They also demonstrated improvement in sensory nerve function. We concluded in this study that CET appeared to positively aid the reversal of sensory and motor nerve pathophysiology in DPN. We also concluded that CET is safe, with miniscule risk from the local anesthetic injections (such as a rare allergy) and no risk from the electrical signaling.

“

These effects [cellular membrane repair, increase in intracellular metabolism, diffusion of hydrogen ion concentration to reduce tissue acidosis, regeneration of axons, and support of the immune system] occur by using the principles of physics rather than pharmacology.”

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“

In addition to increased pain relief after CET treatment, DPN patients showed a trend towards improvement in motor nerve function using nerve conduction velocity/ EMG testing.”

In work done since 2010, patients with all kinds of periph- FOOT DROP (peroneal nerve motor dysfunction) eral neuropathies have shown significant symptom reduction and motor function improvement. Patients experience Approximately 5% of our neuropathy patients have prereduction of pain, paresthesias, dysesthesias, allodynia, sented with common peroneal nerve dysfunction, or foot and numbness; increase in strength and balance; and an drop. Common peroneal nerve dysfunction is damage to the improved quality of life. The most improvement occurs peroneal nerve leading to loss of movement or sensation in between 10 and 20 weeks.4,5 In some patients, improvement the foot and leg. Foot drop occurs due to partial or complete of positive and negative symptoms approaches 100%.4-6 paralysis of the dorsal extensor muscles of the foot and the Improvements in motor and sensory nerve function have toes (tibialis anterior, extensor digitorum longus, and extenalso occurred after treatment has stopped. For a subgroup sor hallicus longus), which are innervated by the deep perofrom one of our studies (CC), with follow-up for as long as neal nerve. Superficial peroneal innervation is sensory to 5 years, clinical improvement continued. the dorsum of the lower leg and foot. Symptoms of peroneal nerve injury thus may include inability to dorsiflexion the Long-term goals—decreased medication use; improve- toes, pain, weakness, numbness on the shin or top of the foot, ment of balance, sleep, overall function, and quality of loss of function of the foot, and a high-stepping walk (called life—have been realized in a plurality of patients. A ret- stoppage or foot drop gait). Damage to the nerve destroys the rospective study from one of our clinics ( RHO) showed myelin sheath that covers the axon (branch of the nerve cell), that over 51% of patients were maintaining symptom or it may destroy the whole nerve cell. There is a loss of feelimprovement.9 Longer-term benefits, such as prevention ing, muscle control, muscle tone, and eventual loss of muscle of infections and amputations have profound implications mass because the nerves are not stimulating the muscles. in preserving healthcare resources. The level of symptoms of patients seen at our clinics are varied and include 1) decreased sensation, numbness, or PHANTOM LiMB PAiN tingling in the top of the foot or the outer part of the upper or lower leg; 2) foot that drops (unable to hold the foot up); In a case report of a 73-year-old Hispanic man status post 3) toes that drag while walking; 4) weakness of the ankles right above knee amputation in 2006 and left below knee or feet; 5) loss of muscle control in the lower legs and feet; amputation in 2008, the potential for sophisticated and com- and 6) difficulty lifting up the foot and toes and making plex electric current applications (signaling) to treat pain of toe-out movements. central origin and reorganization of central processing was illustrated.6 The patient has experienced the elimination Nonsurgical treatment for peroneal nerve injury includes of the phantom limb pain over time. After treatment for orthotics, including braces or foot splints, which may several weeks, his pain was essentially extinguished. When be custom built into the patient’s shoe; physical therapy, the pain recurred a few weeks later, it was present only at including gait training; and surgery including decompresthe stumps, a more proximal location. This observation rep- sion surgery, nerve sutures, nerve grafting, or nerve/tendon resents a modification, or reorganization, of his presenting transfer. Up to this time, there is no known treatment that central pain (of which phantom limb pain is a classic exam- will reverse this nerve dysfunction. ple). With ongoing EST treatments, the patient progressed to manifestations of only limited intermittent stump pain. Treatment using EST has shown improved peroneal nerve His current exacerbations are confined solely to occasional function in about 85% of the cases. It can take several stump pain, and periodic maintenance treatment has easily months for the nerves to regenerate and mitigate the conmanaged any small exacerbations. dition. One patient, a retired Las Vegas anesthesiologist, Q3 | 2016

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INTERVENTIONAL

initially presented with no peroneal function (0/5 on motor testing) and a sensory toxic neuropathy. Happily, he experienced partial functional return (4/5 on motor testing) in 1 week and a full return (5/5) in 5 weeks. In refractory cases (patients suffering from long-term severe motor nerve damage), EST has alleviated the associated pain and restored at least 50% of the motor nerve function.

4. Cernak C, Marriott E, Martini J, et al. Electrical current and local anesthetic combination successfully treats pain associated with diabetic neuropathy. Pract Pain Manag. 2012;12:23–26.

CONCLUSiON

5. Carney PM . Effectively treating CIPN . J Clin Oncol. 2015;33(suppl): abstr e2069.

The use of CET for neuropathy is one of first instances of successful pathophysiological modifying and nonpharmacologic treatments of a chronic disease of which we are aware. We have utilized physics in conjunction with pharmacology to permit cell healing in manners that have not been seen before. Yet, while the science and technology behind this treatment is informative and interesting, the real benefits have been to our patients and their life changing experiences with improvement or eradication of lower extremity peripheral neuropathy. We trust that government and other third party payors will finally understand the public health and cost benefits of the CET approach.

2. Carney PM . Quantum theory treats neuropathy better than pharmacology. Pain Pract. 2014;Winter:28–31. 3. Odell RH, Sorgnard RE . Anti-inflammatory effects of electronic signal treatment. Pain Physician. 2008;11: 891–907.

6. Odell RH, Sorgnard RE, Milne RD, et al. Novel treatment device for phantom-limb pain. Pract Pain Manag. 2015; 3:3–6. 7. Milne RD, Sorgnard RE . Quantum theory underpins electromagnetic therapies for pain management. Pract Pain Manag. 2012;13(1):1–7. 8. Odell RH, Sorgnard RE . New technique combines electrical currents and local anesthetic for pain management. Pract Pain Manag. 2011;11(5):52–68 9. Odell RH, Chaya Z. Clinical outcomes utilizing the combined electrochemical treatment for peripheral neuropathy: a retrospective study from a western clinic. Submitted for publication February 2016. 10. Odell RH, Sorgnard RE, Carney PM , et al. Combined electrochemical treatment for peripheral neuropathy. Pract Pain Manag. 2015;15(8):47-56.

References 1. Odell R, Woessner J. The integrated nerve block: electrical + chemical. Poster presentation: 18th Annual International Spine Intervention Society Meeting. Las Vegas, NV. July 23–26, 2008.

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To learn more, visit XtampzaER.com INDICATIONS AND USAGE Xtampza™ ER (oxycodone) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Xtampza ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufﬁcient management of pain • Xtampza ER is not indicated as an as-needed (prn) analgesic IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse Xtampza ER exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Xtampza ER and monitor all patients regularly for the development of these behaviors or conditions. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Xtampza ER. Monitor for respiratory depression, especially during initiation of Xtampza ER or following a dose increase. Accidental Ingestion Accidental ingestion of even one dose of Xtampza ER, especially by children, can result in a fatal overdose of oxycodone. Neonatal Opioid Withdrawal Syndrome Prolonged use of Xtampza ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Cytochrome P450 3A4 Interaction The concomitant use of Xtampza ER with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving Xtampza ER and any CYP3A4 inhibitor or inducer. Please see additional Important Safety Information and accompanying brief summary of the full Prescribing Information. Xtampza ER is a trademark of Collegium Pharmaceutical, Inc. ©2016 Collegium Pharmaceutical, Inc. All rights reserved. PP-XT-US-0085

XTAMPZA ER (oxycodone) extended-release capsules, for oral use, CII BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see Full Prescribing Information and Medication Guide at XtampzaER.com.) WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse XTAMPZA ER exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing XTAMPZA ER and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of XTAMPZA ER. Monitor for respiratory depression, especially during initiation of XTAMPZA ER or following a dose increase [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of XTAMPZA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Cytochrome P450 3A4 Interaction The concomitant use of XTAMPZA ER with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving XTAMPZA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 4 CONTRAINDICATIONS XTAMPZA ER is contraindicated in patients with: - Significant respiratory depression [see Warnings and Precautions (5.2)] - Acute or severe bronchial asthma is an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)] - Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)] - Hypersensitivity (e.g., anaphylaxis) to oxycodone 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As extended-release products such as XTAMPZA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence (9)]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed XTAMPZA ER. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing XTAMPZA ER, and monitor all patients receiving XTAMPZA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as XTAMPZA ER, but use in such patients necessitates intensive counseling about the risks and proper use of XTAMPZA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death [see Overdosage (10)]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing XTAMPZA ER. Strategies to reduce these risks include prescribing the drug in the smallest

appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of XTAMPZA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of XTAMPZA ER. To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential [see Dosage and Administration (2)]. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of XTAMPZA 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. [see Use in Specific Populations (8.1), Patient Counseling Information (17)]. 5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of XTAMPZA ER with a CYP3A4 inhibitor, such as antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of XTAMPZA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in XTAMPZA ERtreated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using XTAMPZA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in XTAMPZA ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of XTAMPZA ER until stable drug effects are achieved [see Drug Interactions (7)]. Concomitant use of XTAMPZA ER with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using XTAMPZA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)]. 5.5 Risks Due to Interactions with Central Nervous System Depressants Hypotension, profound sedation, respiratory depression, coma, and death may result if XTAMPZA ER is used concomitantly with other central nervous system (CNS) depressants (e.g., benzodiazepines and other sedative-hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids). When considering the use of XTAMPZA 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 can cause CNS depression. If the decision to begin XTAMPZA ER therapy is made, start with 1/3 to 1/2 the usual dose XTAMPZA ER, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dose of the concomitant CNS depressant. Use an alternative analgesic for patients who require a dose of XTAMPZA ER less than 9 mg [see Drug Interactions (7)]. 5.6 Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of XTAMPZA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: XTAMPZA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of XTAMPZA ER [see Warnings and Precautions (5.2)]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating XTAMPZA ER and when XTAMPZA ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients. Use an alternative analgesic for patients who require a dose of XTAMPZA ER less than 9 mg. 5.7 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.8 Severe Hypotension XTAMPZA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of XTAMPZA ER. In patients with circulatory shock, XTAMPZA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of XTAMPZA ER in patients with circulatory shock. 5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), XTAMPZA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with XTAMPZA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of XTAMPZA ER in patients with impaired consciousness or coma. 5.10 Risks of Use in Patients with Gastrointestinal Conditions XTAMPZA ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The oxycodone in XTAMPZA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.11 Risk of Use in Patients with Seizure Disorders The oxycodone in XTAMPZA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during XTAMPZA ER therapy. 5.12 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including XTAMPZA ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing XTAMPZA ER, gradually taper the dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue XTAMPZA ER. 5.13 Risks of Driving and Operating Machinery XTAMPZA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of XTAMPZA ER and know how they will react to the medication.

5.14 Laboratory Monitoring Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative”. Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: - Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] - Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] - Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] - Interactions with Other CNS Depressants [see Warnings and Precautions (5.5)] - Adrenal Insufficiency [see Warnings and Precautions (5.7)] - Severe Hypotension [see Warnings and Precautions (5.8)] - Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)] - Seizures [see Warnings and Precautions (5.11)] - Withdrawal [see Warnings and Precautions (5.12)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of XTAMPZA ER was evaluated in a Phase 3, randomized withdrawal, double-blind clinical trial involving 740 patients with moderate-to-severe chronic lower back pain. In the doubleblind maintenance phase, 389 patients were randomized and 193 patients were assigned to the XTAMPZA ER treatment group. The most common AEs (>5%) reported by patients in the Phase 3 clinical trial during the titration phase were: nausea (16.6%), headache (13.9%), constipation (13.0%), somnolence (8.8%), pruritus (7.4%), vomiting (6.4%), and dizziness (5.7%). The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing XTAMPZA ER with placebo are shown in Table 1 below: Table 1: Common Adverse Reactions (>5%) Adverse Reaction Nausea Headache Constipation Somnolence Pruritus Vomiting Dizziness

Titration XTAMPZA ER (n = 740) % 16.6 13.9

13.0 8.8 7.4 6.4 5.7

Maintenance XTAMPZA ER Placebo (n = 193) % (n = 196) % 10.9 4.6 6.2 11.7 5.2 0.5 <1 <1

2.6 4.1 1.6

1.5 1.5 0

In the Phase 3 clinical trial, the following adverse reactions were reported in patients treated with XTAMPZA ER with incidences of 1% to 5%: Eye disorders: vision blurred Gastrointestinal disorders: abdominal pain, upper abdominal pain, diarrhea, gastroesophageal reflux disease General disorders and administration site conditions: chills, drug withdrawal syndrome, fatigue, irritability, edema, pyrexia Injury, poisoning and procedural complications: excoriation Metabolism and nutrition disorders: decreased appetite, hyperglycemia Musculoskeletal and connective tissue disorders: arthralgia, back pain, musculoskeletal pain, myalgia Nervous system disorders: migraine, tremor Psychiatric disorders: anxiety, insomnia, withdrawal syndrome Respiratory, thoracic and mediastinal disorders: cough, oropharyngeal pain Skin and subcutaneous tissue disorders: hyperhidrosis, rash Vascular disorders: hot flush, hypertension In the Phase 3 clinical trial, the following treatment-related adverse reactions were reported in patients treated with XTAMPZA ER with incidences of less than 1% of patients. Investigations: increased gamma-glutamyl transferase, increased heart rate Nervous system disorders: lethargy, memory impairment, poor-quality sleep Psychiatric disorders: abnormal dreams, euphoric mood, restlessness Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: night sweats

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in XTAMPZA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)]. 7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with XTAMPZA ER. Table 2: Clinically Significant Drug Interactions with XTAMPZA ER. Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of XTAMPZA ER and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of XTAMPZA ER and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of XTAMPZA ER is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of XTAMPZA ER until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of XTAMPZA ER and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved [see Dosage and Administration (2.4)]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider XTAMPZA ER dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacological effects, the concomitant use of CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention:

Examples:

Consider dose reduction of one or both drugs. Monitor patients for signs of respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.5)]. Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids.

Serotonergic Drugs The concomitant use of opioids with Clinical Impact: other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue XTAMPZA ER if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of XTAMPZA ER and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of XTAMPZA ER and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when XTAMPZA ER is used concomitantly with anticholinergic drugs.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with XTAMPZA ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there was no embryo-fetal toxicity when oxycodone hydrochloride was orally administered to rats and rabbits, during the period of organogenesis, at doses 0.5 to 15 times the adult human dose of 160 mg/day, respectively. In a pre- and postnatal toxicity study, when oxycodone was orally administered to rats, there was transiently decreased pup body weight during lactation and the early post-weaning period at the dose equivalent to approximately 0.4-times an adult dose of 160 mg/day. In several published studies, treatment of pregnant rats with oxycodone hydrochloride at clinically relevant doses and below resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration of use, and severity of neonatal opioid withdrawal syndrome may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)]. Labor or delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. XTAMPZA ER is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including XTAMPZA ER, can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. 8.2 Lactation Risk Summary Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. The lactation studies did not assess breastfed infants for potential adverse reactions. Lactation studies have not been conducted with extended-release oxycodone, including XTAMPZA ER, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with XTAMPZA ER. Clinical Considerations Infants exposed to XTAMPZA ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2)]. 8.4 Pediatric Use Safety and effectiveness of XTAMPZA ER in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3)]. Of the total number of subjects entered into the titration phase of the Phase 3 study for XTAMPZA ER (740), 88 (12%) were age 65 and older. In this clinical trial with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received XTAMPZA ER. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. Use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease, and use of other drug therapy. Respiratory depression is the chief risk in elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of XTAMPZA ER slowly in geriatric patients [see Warnings and Precautions (5.6)]. 8.6 Hepatic Impairment A study in patients with hepatic impairment demonstrated greater plasma oxycodone concentrations than those seen at equivalent doses in persons with normal hepatic function. A similar effect on plasma oxycodone concentrations can be expected for patients with hepatic impairment taking XTAMPZA ER. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg [see Dosage and Administration (2.3)].

8.7 Renal Impairment In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Follow a conservative approach to dose initiation and adjust according to the clinical situation. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg [see Clinical Pharmacology (12.3)]. 8.8 Sex Differences In pharmacokinetic studies with XTAMPZA ER, healthy female subjects demonstrate up to 20% higher oxycodone plasma exposures than males, even after considering differences in body weight or BMI. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages. In the Phase 3 clinical trial there was a greater frequency of typical opioid adverse events for females than males; there was no male/female difference detected for efficacy. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance XTAMPZA ER contains oxycodone, a Schedule II controlled substance. 9.2 Abuse XTAMPZA ER contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)]. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. XTAMPZA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of XTAMPZA ER XTAMPZA ER is for oral use only. Abuse of XTAMPZA ER poses a risk of overdose and death. The risk is increased with concurrent use of XTAMPZA ER with alcohol and other central nervous system depressants. Abuse Deterrence Studies Summary The in vitro data demonstrate that XTAMPZA ER has physicochemical properties expected to make abuse by injection difficult. The data from pharmacokinetic and human abuse potential studies, along with support from the in vitro data, also indicate that XTAMPZA ER has physicochemical properties that are expected to reduce abuse via the intranasal route. The data from the oral pharmacokinetic studies of manipulated XTAMPZA ER demonstrated a lack of dose dumping with no increase in oxycodone levels compared to intact XTAMPZA ER. Although the results of the oral human abuse potential study showed a difference in the Drug Liking endpoint, there was no statistically significant reduction in the response to Take Drug Again. Therefore, it cannot be concluded that XTAMPZA ER has physicochemical properties that are expected to reduce abuse via the oral route. However, abuse of XTAMPZA ER by injection and by the nasal route of administration, as well as by the oral route is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of XTAMPZA ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. XTAMPZA ER contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1)]. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. XTAMPZA ER should not be abruptly discontinued [see Dosage and Administration (2.5)]. If XTAMPZA ER is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation Acute overdosage with XTAMPZA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. Because the duration of reversal would be expected to be less than the duration of action of oxycodone in XTAMPZA ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. XTAMPZA ER will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or only brief in nature, administer additional antagonist as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of the usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. DEA ORDER FORM REQUIRED Healthcare professionals can telephone Collegium Pharmaceutical’s Medical Affairs Department (1-855-331-5615) for information on this product. Manufactured by: Patheon Pharmaceuticals, Cincinnati, OH 45237 Collegium Pharmaceutical, Inc. Canton, MA 02021 ©2016 Collegium Pharmaceutical, Inc. U.S. Patent Nos. 7,399,488; 7,771,707; 8,449,909; 8,557,291; 8,758,813; 8,840,928 and 9,044,398, and 9,248,195 This brief summary is based on Xtampza ER Prescribing Information, Revised 04/2016. PP-XT-US-0086

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

James Fricton DDS MS / Alfred Clavel MD / Mark B. Weisberg PhD, ABPP

“

A human systems approach provides a broader understanding of the role of diverse lifestyle risk factors which perpetuate chronic pain through recursive feedback cycles… A transformative care model is the clinical application of a human systems approach: it integrates risk factor assessments and robust personalized self-management training of patients, integrated with evidence based treatments.”

K Y TOPiC

Chronic pain conditions constitute the top reason for patients seeking health care, the most common reason for disability and potential addiction, and one of the highest drivers of healthcare costs. The personal impact of chronic pain in terms of suffering, disability, addiction, depression, conflicts, and other problems is incalculable. Although genetic factors may predispose one to chronic pain, there is much research suggesting that lifestyle and personal risk factors such as poor sleep and stress, are among the major factors leading to failed treatment and continued pain. If health professionals want to improve patient outcomes, they need to consider helping people identify and change the multidimensional risk factors that may contribute to delayed recovery and chronic pain. We can only do this by shifting our care model from a provider centric passive care model to an active patient centered transformative care model that educates, engages, and empowers patients to transform their lives from one of pain and suffering to one of health and well-being. abstract:

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hronic pain conditions are the most prevalent chronic conditions and the primary driver of health care, costing more than diabetes, cancer, and heart disease combined.1-4 With at least 100 million US adults suffering from chronic pain including headaches, back and neck pain, orofacial pain, and many others, pain has become the primary reason for seeking health care. Over half of all healthcare visits are attributed to some type of chronic pain.1-4 Chronic pain is also the most common cause of disability and decreased productivity at work. When opioid analgesics are used for chronic pain treatment, especially at high doses, there may be increased risk of abuse leading to unintended overdose related deaths, which now outnumber motor vehicle related deaths in some states.5-11 On a community level, the prevalence and economic burden of chronic pain is staggering; however, the personal cost of chronic pain can be even more devastating with loss of function, work loss, depression, addiction, and lower quality of life.12,13 The plight of the patient with chronic pain in seek- Prevalence and impact data as well as recommendations from

ing health care is profound. If initial efforts to improve pain the Institute of Medicine Report and the National Pain Stratfail, care may escalate to higher cost, higher risk passive egy show that more effort is needed in prevention and successinterventions such as on-going opioid analgesics, prolonged ful early intervention using a transformative care approach chiropractic treatment, polypharmacy, implantable devices, when caring for patients with pain conditions.1-3 injections, and surgeries.1-3,14-19 Unfortunately, many people with pain after 1 month still have persistent pain 5 years later despite these extensive interventions.16,17 Although TRANSFORMiNG CHRONiC PAiN TO H ALTH genetic factors may predispose one to chronic pain,18 there AND W LL-B iNG is also much research which suggests that repetitive strain, depression, poor sleep, stress, maladaptive postures, and To address the chronic pain problem, a new approach that ergonomics are among the contributing factors leading to conceptualizes chronic pain more broadly with a focus delayed recovery, failed treatment, and continued pain.19-24 on prevention and early intervention is recommended.29,30 Despite recognition that many of these factors can be A human systems approach provides a broader understanding improved with self-management strategies, they are often not of the role of diverse lifestyle risk factors which perpetuate addressed in routine care, which can lead to pain persisting for chronic pain through recursive feedback cycles that actuyears.1,2,25-27 Thus, chronic pain has become a major health- ally increase both peripheral and central sensitization.40-49 care problem when practitioners fail to engage, empower, and A transformative care model is the clinical application of a educate patients in reducing risk factors and enhancing pro- human systems approach: it integrates risk factor assesstective factors to help prevent pain from becoming chronic.26-39 ments and robust personalized self-management training

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KEY TOPIC

of patients, integrated with evidence based treatments. Risk factor assessment identifies both risk and protective factors that tilt the balance between pain/suffering and health/well-being. Self-management programs can then help train patients to reduce the identified risk factors, enhance protective factors, and reverse the perpetuation of chronic pain.1-3 This can best be implemented through an interdisciplinary integrative team approach that supports the patient in implementing lifestyle changes and long-term improvement in preventing chronic pain.

review the fundamentals of this new approach to care. In the first offerings of the course, the MOOC was quite successful, with almost all participants believing it made a positive difference in their lives and the care of their patients.

Human Systems Model

This human systems conceptual model assumes that people are complex, multidimensional, and dynamic and live within an ever-changing social and physical environment. In conThese changes, however, require transformation of the trast, the traditional biomedical model is based on a scientific healthcare system by changing the current conceptual model paradigm that is unidimensional, reductionist, and inflexible, of care and shifting to new clinical paradigms that could be based primarily on understanding underlying pathophysiolchallenging for even the most innovative healthcare profes- ogy (Table 1). Healthcare professionals often tend to see what sional. For this reason, additional training is recommended. they treat and treat what they see. If they see only the pathoOne example of a resource for transformative care are tool- physiology, the complex set of risk and protective factors in kits (available at www.preventingchronicpain.org) intended chronic pain will be missed. As a result, success of treatment for health professionals to integrate self-management train- can be compromised by limited approaches that only address ing along with evidence based treatments as part of routine part of the problem. For example, some systematic reviews pain care. In addition, the Massive Open Online Course of biomedical treatments for chronic pain have found that (MOOC, see www.courser.org) on preventing chronic pain even with the most efficacious treatments, the improvement (visit courser.org) presents a model for health professionals to occurs only slightly above placebo.37,38

Table 1. Comparison of the traditional biomedical model and a human systems model Concept

Biomedical Model

Human Systems Model

Conceptual basis

Reductionist, mechanistic, inflexible

Holistic, fluid, flexible

Application of scientific methods

Relies on objective physical measures, single brief interventions, and randomized controlled trials

Relies on objective and subjective measures, multiple interventions over longer periods, and pragmatic clinical trials

Etiology

Pathophysiologic etiology based on single static etiology (eg, infectious agent, structural change, cancer)

Multifactorial dynamic etiology of chronic illness (eg, influence of risk and protective factors on physical tissues)

Problem list

Identify chief complaint and diagnoses in the physical or psychiatric realm

Identify chief complaints, diagnoses, along with contributing factors in each aspect of life— body, mind, spirit, lifestyle, emotions, environment, and society

Treatment strategy

Unidimensional— encourages single sequential treatments

Multidimensional—integrates multiple interventions with self-management of risk and protective factors

Providers

Single clinician providing single intervention that is easy to implement. May lead to fragmented approaches

Interdisciplinary, integrative team of clinicians who address multiple levels of contributing factors. More complex to implement

Reimbursement

Well supported by traditional healthcare delivery system with an economic model that rewards procedures over process

Supported by evolving healthcare delivery system with economic incentives for patient centered care

Outcomes

Good outcomes with acute conditions; poor outcomes with chronic illness due to fragmentation of multiple single treatments

Good outcomes with chronic illness due to use of transformative care model with self-management, biomedical interventions, and a team approach

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Table 2. Human systems theory provides an inclusive conceptual framework for transformative care and integrates multiple theories Concept Systems theory and ecology

Summary Quote “See the big picture”

All realms of an ecosystem are interrelated and impact each other

Neuroplasticity and “The brain can change pain” mind-body connections

We can learn to turn the volume up and down on pain and central sensitization

Positive psychology

“Positive wins over negative”

Strengthening protective factors, cultivating strengths, and encouraging what is best within a person has more impact than reducing the negative

Cybernetics

“What goes around comes around”

Each element of a system generates a change, which causes positive or negative feedback to the entire system and leads to 1st order reactive change, 2nd revelation change, or 3rd order transformative change

Chaos theory

“It’s the little things every day that matter”

Small differences in initial conditions may yield widely diverging outcomes within dynamic systems like humans. Thus, the influence of multiple small risk and protective factors can play a significant role in shifting the balance between health and illness

Social psychology

“Relationships matter to our health”

Our thoughts, feelings, and behaviors are influenced by the actual, imagined, or implied presence of others

Cognitive behavioral science

“We are what we repeatedly think, do, and feel”

How we think (cognition), how we feel (emotions), and how we act (behavior) all interact and can influence each other

Mindfulness

“Be here now”

By training our minds to be in the present moment and nonjudgmental, our health and well-being is enhanced

A broader conceptual basis is required for chronic pain, one that includes understanding how different realms of our lives can interact and contribute to chronic pain. Human systems theory ( HST ) stems from research in general systems theory and originated in ecology out of the need to explain the interrelatedness of organisms in ecosystems.41-48 A human systems approach integrating concepts—neuroplasticity, mind-body connectedness, positive psychology, cybernetics, chaos theory, social psychology, cognitive behavioral science, and mindfulness—to help explain the delicate balance between health and illness (Table 2).41-49 While many distinct pathophysiological mechanisms may occur in chronic pain conditions, HST suggests that it is the complex interaction of diverse factors discussed below which can initiate, perpetuate, or even protect people from the chronic pain progression and peripheral to central sensitization. HST views a person as a whole, with the interrelationship between different realms of their life contributing to this balance (Table 3). These realms are not static and independent but rather are dynamic, evolving, and interrelated processes that involve sets of risk and protective factors that can shift the balance between health and illness. The factors may be diverse and may include: Q3 | 2016

Description

●

Physical: comorbid conditions, physiologic, genetic, molecular

●

Behavioral: habits, repetitive strain, posture, diet, sleep, pacing

●

Emotional: depression, fear, anxiety, anger, guilt, shame

●

Social: conflict, relationships, abuse, isolation, social support, secondary gain

●

Cognitive: attitudes, resilience, expectation, understanding, automatic thoughts

●

Spiritual: compassion, purpose, faith, beliefs, direction

●

Environmental: safety, risk surroundings, disorganized, unclean, noise, pollution

Preventing chronic pain includes preventing the development of chronic pain, the progression from acute to chronic pain, and in some cases the progression from chronic to intractable pain. An illness such as a pain disorder often www.painweek.org | PWJ | 49

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Table 3. Description of the 7 realms (with the acronym BLESS ME ) in a human systems approach to preventing chronic pain Realm

Description

Protective Factors

Risk Factors

Body

Physical and physiologic aspects of the body

Balanced relaxed posture, stretching, Genetic risk, comorbid conditions, strengthening, and conditioning exercises poor posture, tight weak muscles, hypo- or hypermobile joints, poor conditioning, and injury

Lifestyle

Lifestyles and behaviors that we do regularly

Protective diet, steady pacing, being active, regular sleep, low risk behaviors, high energy, and compliance with protective actions

Poor diet, sedentary life, prolonged sitting, poor sleep, hurrying/rushed, repetitive strain, high risk behaviors, chemical use, low energy

Emotions

Positive and negative feelings we experience

Sustained positive emotions, such as joy, excitement, confidence, optimism, happiness, and contentment

Prolonged negative emotional experiences, anger, anxiety, sadness, fear, and depression

Society

Social relationships with the people around us

Positive relationships, social support, helping others, reward for recovery; eg, family, friends, colleagues, community, society

Poor relationships, conflict, abuse, posttraumatic stress, low social support, isolation, secondary and tertiary gain

Spirit

Higher beliefs and purposes that drive us

Purpose, direction, beliefs, faith, hope, self-compassion, and self-esteem

Stress, burnout, disbelief, cynicism, doubt, helpless, and hopelessness

Mind

Thoughts and attitudes

Whole understanding, resilience, self-efficacy, self-control, accepting responsibility, realistic expectations, and engaging in active coping

Ignorance of problem, low resilience, low self-efficacy/control, refuse responsibility, poor compliance, unrealistic expectations, and passive coping

Environment

Physical environment that surrounds us

Clean, organized, safe environment, and an approach that is protective, cautious, and careful

Living within an unclean, chaotic, and disorganized environment with activities that are negligent, dangerous, risky, and increase risk of injury, accident, and trauma

“

If a sufficient, even small, number of risk factors are present, it can shift the balance from the healing of acute pain to a delayed recovery and chronic pain. Strengthening protective factors and successful reduction of multiple risk factors in the cycle may have significant impact in healing the injured tissues.”

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“

When self-management training supplements treatments, the long-term outcomes can be dramatically improved while also reducing the patient’s dependency on the healthcare system.”

begins with initiating factors such as an acute physical injury treatments.1 Unfortunately, most health professionals lack of the muscles and joints. In most cases, this condition is the time and training to perform this role and find little transient and heals without complication or persistence. support and reimbursement from health plans for doing However, if a sufficient, even small, number of risk factors so. Transformative care is a new care model that integrates are present, it can shift the balance from the healing of acute robust self-management training with the best and safest pain to a delayed recovery and chronic pain. Strengthening evidence based treatments. Clinical trials of self-manageprotective factors and successful reduction of multiple risk ment strategies that activate the patient through exercise factors in the cycle may have significant impact in healing and cognitive and behavioral changes have equal or better the injured tissues. This strategy supports the concepts of efficacy than passive treatments in preventing or allevimultimodal and interdisciplinary team care that amplifies ating chronic pain.28-41 When self-management training the small effect of interventions by including self-manage- supplements treatments, the long-term outcomes can be ment training to achieve the best possible outcomes. To dramatically improved while also reducing the patient’s achieve these outcomes, several new strategies are needed dependency on the healthcare system. Thus, a transformaby the healthcare provider including recognizing their role tive care model can help transform not only the patient’s as agent of change, employing an inclusive problem list (see life but the healthcare system too. next page), determining the complexity of patient, following a decision tree for increasing the potential for successful The clinical application of transformative care involves management, and employing interdisciplinary and inte- identifying and reducing risk factors for chronic pain while grated treatment protocols to address the whole problem also training the patients in improving protective factors, list. When evidence based biomedical treatments are com- as illustrated in Table 3. Transformative care includes the bined with robust patient training to reduce risk factors and use of pain risk assessments to identify risk and protective enhance protective factors, the potential of transforming factors as part of a whole person problem list. Personala person’s life from one of illness to health and wellness is ized care strategies include integrative teams that can be enhanced.39-41 This is the basis for a transformative model supported by health coaches, social support networks, and of pain care. consumer based health information technology for both patient training and documenting outcomes. Since patients often expect to have a passive role in care, these new parTransformative Care adigms need to be conveyed to the patient as part of the evaluation (Table 4). Embracing patient centered healthcare The Institute of Medicine’s ( IOM ) monograph, Relieving paradigms such as self-responsibility, education, personal Pain in America: A Blueprint for Transforming Prevention, motivation, self-efficacy, social support, strong providerCare, Education and Research, emphasizes the need to trans- patient relationships, and long-term change will shift the form our current passive model of doctor centered care into balance of care from one of a passive, dependent patient to one that is patient centered.1 The document states, “Health an empowered, engaged, and educated patient.1,2 Ultimately, care provider organizations should take the lead in devel- this paradigm shift has potential to not only improve the oping educational approaches and materials for people quality of care and enhance pain and functional outcomes, with pain and their families that promote and enable but also will significantly reduce healthcare costs. In the self-management.” The IOM further states that health pro- process, the Institute for Health Care Improvement’s triple fessionals’ primary role in caring for chronic pain requires aim of improving population health, enhancing the patient guiding, coaching, and assisting patients with day-to-day care experience (including quality, access, and reliability), self-management in addition to evidence based biomedical and controlling or reducing cost of care will be achieved.51 Q3 | 2016

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Table 4. Clinical paradigms associated with transformative care and a human systems approach to preventing chronic pain New paradigm

Statement that shifts to the new paradigm

Understand the whole patient

Identify all diagnoses, risk factors, and protective factors in the 7 realms of life (body, mind, spirit, lifestyle, emotion, social, and physical environment) to shift the balance from illness to health.

Each patient is complex

Multiple conditions and interrelated contributing factors may initiate, result from, increase risk, or decrease risk of illness. Each need to be addressed as part of management strategy.

Self-responsibility is key to recovery

You have more influence on the problem than any treatment provided. Will you take ownership and control of the condition?

Self-care

You will need to make daily changes in order to improve your condition.

Education and training

We will teach you how to make these changes.

Long-term change

Change only occurs over time and it may take months for the changes to have a large impact on reducing pain and symptoms.

Strong provider-patient partnerships

We, as health professionals, will support you as you make the changes. We can be an agent to help you change.

Personal motivation

Will you be able to make the changes needed?

Social support

You may need help to make these changes.

Change process

Change will occur incrementally over time.

Fluctuation of progress

Expect ups and downs during the recovery process.

The Healthcare Provider as an Agent of Transformative Change

Determine the Complete Problem List

Human systems theory expands the traditional “probHealth professionals need to recognize their important role lem list” of the chief complaint and physical diagnosis to of not only providing treatments but also helping the people also include the list of contributing factors in each of the transform their health consciousness from being illness 7 realms—mind, body, emotions, spirit, lifestyle, social, centered and healthcare dependent to one of maintaining and physical environment. The physical diagnosis comprehealth and well-being on a daily basis (Table 5). As part of this, hends that a physical problem is responsible for the chief health professionals need to recognize the limits of biomed- complaint and associated symptoms, whereas, contributing ical treatments such as medication, interventions, and sur- factors include those that initiate, perpetuate, or result from gery that may in some cases lead to additional problems, like the disorder but in some way complicate the whole problem. adverse events, addictions, neuropathic pain, fibrosis from Multidimensional assessment will help determine which repeated surgeries, and secondary gain from care seeking contributing factors are present. Specific risk factors for to validate their illnesses. Rebound pain from medications chronic pain are included in Table 3 and may range from can actually be part of the patient’s pattern of problems and peripheral factors such as repetitive stress-strain and posgenerate self-sustaining chronic pain. If clinicians under- tural habits, or central mediating factors such as anxiety stand their integral role in tipping the balance from illness and depression, comorbid conditions, somatization, and to health, they can be an agent of transformative change and catastrophizing.44-50 Protective factors—level of coping, part of the long-term solution. They can help patients recon- self-efficacy, exercise, and patient beliefs such as perceived struct their world into one of health and well-being, and not control over pain and understanding that pain is a sign of illness. Clinicians can facilitate patients achieving the deep- strain or injury—reduce vulnerability to chronic pain.51 est most permanent order of change—a third order change, Social support can also affect outcomes. defined as the capacity to change their epistemology of health and illness, ie, how they understand of their own powerful role in developing illness, thereby learning how they can Matching Complexity of the Patient maintain health and well-being for their lifetime. Through With the Complexity of Care this third order of change, patients may see their world differently as enlightened and transformative wellness warriors. The level of care for patients can vary considerably from To do so, they first must understand each component of the simple to complex. Patients with complex chronic illness problem by establishing a complete problem list that includes often present with a frustrating medical and dental situaboth the physical problem and the contributing factors. tion, which may include persistent aggravation of symptoms,

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multiple clinicians, long‑term medications, repeated healthcare visits, and an ongoing dependency on the healthcare system. Thus, successful management is enhanced if the level of complexity is determined and matched to the complexity of the treatment strategy. Singular treatment strategies such as self-management, physical therapy, or medication can be quite successful with patients with few contributing factors but often fail in patients with complex contributing factors, due to the chronic nature of the disease and the long‑standing maladaptive behaviors, attitudes, and lifestyles. Thus, it is helpful to follow a decision-making process that can distinguish simple from complex patients and direct the treatment strategy. The Figure outlines the decision tree for sequencing evaluation and management for simple and complex cases. Once the complete problem list is developed, it can be used as criteria to distinguish simple and complex patients. Complexity of the patient increases with the presence of multiple diagnoses, persistent pain longer than 6 months, significant emotional problems, frequent use of healthcare services or medication, repetitive muscle strain, and significant lifestyle disturbances. In addition, there are some complex patients who warrant deferral of treatment until more complex problems are addressed. The criteria for not treating until these problems are resolved include primary chemical dependency, primary psychiatric disorder, significant litigation, and a patient unmotivated and/or overwhelmed with other concerns.

Interdisciplinary Individualized Integrative Care Multimodal treatments within an interdisciplinary integrative care model can best set the stage for a second or third level change in the patient’s life by addressing the physical diagnosis and all of its contributing factors. This model includes screening for pain risk assessment; implementing cognitive, emotional, and behavioral change; self-management; patient advocacy; and focus on a patient centered model. Once complexity is determined, simple chronic illness patients can be successfully treated using a single clinician and treatment to achieve resolution in 2 to 3 months. With more complex cases, it is recommended they be managed by an integrative team of clinicians to achieve the best level of improvement in the pain condition typically achieved in 3 to 6 months. Integrative care is the practical application of this model in clinical practice by combining the practices and care strategies of a team. Different aspects of the problem can be addressed by different health professionals, often including physicians, dentists, health psychologists, physical therapists, as appropriate, along with pain coaches, in order to enhance the overall potential for success. A pain coach may be an excellent addition to a busy primary care or specialty practice to help guide and support the patient in achieving their goals of reducing pain and its interference in life activities through learning self-management strategies. Teams can be interdisciplinary (one setting) or multidisciplinary (multiple settings). The use of a team helps

Table 5. Health consciousness. A person’s level of health and wellness consciousness determines the degree to which they take actions to maintain their optimal health and wellness and determine the amount of health care they require. The higher levels of health consciousness require less health care than lower levels.

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5th Level

Transformative Health Consciousness Wellness warriors live each day with maximum implementation of health and wellness actions in all 7 realms and actively act as evolutionary co-creators to help others achieve the same

4th Level

Enlightened Health Consciousness Health actives live each day mindful of the knowledge and decisions that determine their own health and well-being in all 7 realms and take active steps to maintain it

3rd Level

Informed Health Consciousness Weekend actives are informed of the importance of health and well-being and take some time each week to practice healthy actions in some realms but are not able to maintain this most days or in all realms

2nd Level

Illness Centered Health Consciousness Illness centered passives react to illnesses and take only limited short-term actions to help recover from the illness but often do not sustain the changes over time

1st Level

Medically Dependent Health Consciousness Medically dependent passives are continuously involved in passive treatment with a health professional and take little to no time and effort to take responsibility and actions to help their own health and well-being

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Figure. A decision tree for triaging patients and enhancing outcomes and successful care.

History and Examination

Determine Problem List

Simple Treat or Use Self-Care Only?

Complex Simple or Complex

Single Clinician

to understand and manage the whole patient, allows work on multiple aspects of the problem simultaneously, improves patient compliance and outcome, saves time, and is more economical and more enjoyable as the team works together. A consistent philosophy and message to the patient is needed including the importance of self-care, self-responsibility, and education using concepts of the human system approach and the transformative care model. Success is dependent upon communication and integration among clinicians, and proper patient selection.

CONCLUSiON There are several areas of focus for health professionals in implementing transformative care and managing and preventing chronic pain. These include:

1 Evaluating the person with chronic pain as a whole by identifying/understanding their risk and protective factors

» Chief Complaints » Physical Diagnosis » Risk Factors » Protective Factors

Treat Now or Later Team of Clinicians

3 Implementing a transformative model of health care through a team approach A transformative care model includes risk assessment, robust self-management training, and evidenced based biomedical treatments to improve the outcomes of pain management while reducing the patient’s dependency on the healthcare system. Teams of healthcare professionals that may include a patient centered pain coach will play a growing role in training and supporting patients in self-management, particularly since they are also supported in most health reform efforts.

4 Continuing medical/dental education courses that review fundamentals of this new approach to care Make use of online and other CE courses and transformative care toolkits to implement online self-management training with evidence based treatments as part of the new routine of care.49

Unaddressed risk factors may lead to biomedical treat- 5 Supporting resources to help implement transformative care ment failure. Thus, using a broader conceptual basis with a human systems approach and a shift in patient centered Organizations like the International MYOPAIN Society clinical paradigms implicit in the clinician-patient relation- (www.myopain.org) through their Campaign for Preventing ship will be the key to success. Chronic Pain and Addiction50 have goals to increase research; develop strategies; expand education of both patients and 2 Improving safety of treatments to minimize development of health professionals on how to prevent chronic pain using chronic pain as an adverse event online training toolkits to implement a transformative care model; increase advocacy and awareness; provide media This is particularly true of adverse events from different toolkits to health plans, businesses, government agencies, types of surgery, dental procedures, chronic opioid use, and and communities to improve their efforts in preventing side effects related to drug-drug interactions. chronic pain.

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By accomplishing these goals, we will address the Institute for Health Care Improvement’s triple aim of improving the experience of care, enhancing health, and reducing the cost of health care for patients with pain conditions.51

19. Bigos SJ, Battie MC , Spengler DM , et al. A longitudinal, prospective study of industrial back injury reporting. Clin Orthop. 1992;279:21–34.

References

21. Bigos SJ, Holland J, Holland C, et al. High-quality controlled trials on preventing episodes of back problems: systematic literature review in working-age adults. Spine J. 2009;9(2):147–168.

1. Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. National Academies Press, Washington, DC; June 29, 2011. 2. Portenoy R, Zeltzer L. A call to revolutionize chronic pain care in America: an opportunity in health care reform. MayDayFund, Nov. 4, 2009. 3. National Pain Strategy. Available at: iprcc.nih.gov/National_Pain_ Strategy/NPS_Main.htm. 4. St Sauver JL , Warner DO, Yawn BP, et al. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc. 2013;88(1):56–67. 5. US Department of Health and Human Services. The 2005 Surgeon General’s call to action to improve the health and wellness of persons with disabilities. Washington, DC: US Department of Health and Human Services; 2005. Available at: www.cdc.gov/ncbddd/disabilityandhealth/ pdf/whatitmeanstoyou508.pdf. 6. Centers for Disease Control and Prevention (CDC ). Prevalence and most common causes of disability among adults— United States, 2005. MMWR Morb Mortal Wkly Rep. 2009;58(16):421–426. 7. Center for Disease Control and Prevention (CDC ). Prescription Drug Overdose in the United States: Fact Sheet. Available at: www.cdc.gov/ homeandrecreationalsafety/overdose/facts.html. 8. Jones CM , Mack KA , Paulozzi LJ . Pharmaceutical overdose deaths, United States, 2010. JAMA . 2013;309(7):657–659. 9. Berland D, Rodgers P. Rational use of opioids for management of chronic non-terminal pain. Am Fam Physician. 2012;86(3):252–258.

22. Pincus T, Burton AK , Vogel S, et al. A systematic review of psychological factors as predictors of chronicity/disability in prospective cohorts of low back pain. Spine. 2002;27(5):e109-e120. 23. Turk DC , Okifuji A. Psychological factors in chronic pain: evolution and revolution. J Consult Clin Psychol. 2002;70(3):678–690. 24. Turner JA , Holtzman S, Mancl L. Mediators, moderators, and predictors of therapeutic change in cognitive-behavioral therapy for chronic pain. Pain. 2007;127(3):276–286. 25. Gensichen J, von Korff M, Peitz M, et al. Case management for depression by health care assistants in small primary care practices: a cluster randomized trial. Ann Intern Med. 2009;151(6):369–378. 26. Cote P, Cassidy JD, Carroll LJ, et al. The annual incidence and course of neck pain in the general population: a population-based cohort study. Pain. 2004;112:267–273. 27. Aggarwal VR , Macfarlane GJ, Farragher TM , et al. Risk factors for onset of chronic oro-facial pain-results of the North Cheshire oro-facial pain prospective population study. Pain. 2010;149(2):354–359. 28. Coleman EA , Parry C, Chalmers S, et al. The care transitions intervention: results of a randomized controlled trial. Arch Intern Med. 2006;166(7):1822–1828. 29. Foster G, Taylor SJ, Eldridge SE, et al. Self-management education programmes by lay leaders for people with chronic conditions. Cochrane Database Syst Rev. 2007;17(4):CD 005108.

10. Centers for Disease Control and Prevention (CDC ). Vital signs: overdoses of prescription opioid pain relievers— United States, 1999–2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487–1492.

30. Bair MJ, Matthias MS, Nyland KA , et al. Barriers and facilitators to chronic pain self-management: a qualitative study of primary care patients with comorbid musculoskeletal pain and depression. Pain Med. 2009;10(7):1280–1290.

11. Dunn KM , Saunders KW, Rutter CM , et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010; 152(2):85–92.

31. Macea DD, Gajos K, Daglia Calil YA , et al. The efficacy of Webbased cognitive behavioral interventions for chronic pain: a systematic review and meta-analysis. J Pain. 2010;11(10):917–929.

12. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA . 2011;305(13):1315–1321.

32. Wantland DJ, Portillo CJ, Holzemer WL , et al. The effectiveness of Web-based vs. non-Web-based interventions: a meta-analysis of behavioral change outcomes. J Med Internet Res. 2004;6(4):e40.

13. Centers for Disease Control and Prevention. Injury Prevention and Control: Data & Statistics ( WISQARS). 2010. Available at: www.cdc.gov/ injury/wisqars/fatal.html.

33. Paul CL , Carey ML , Sanson-Fisher RW, et al. The impact of web-based approaches on psychosocial health in chronic physical and mental health conditions. Health Educ Res. 2013;28(3):450–471.

14. Fricton J. The need for preventing chronic pain: the “big elephant in the room” of healthcare. Glob Adv Health Med. 2015;4(1):6–7.

34. Lau PW, Lau EY, Wong del P, et al. A systematic review of information and communication technology-based interventions for promoting physical activity behavior change in children and adolescents. J Med Internet Res. 2011;13(3):e48.

15. Deyo RA , Mirza SK , Turner JA , et al. Overtreating chronic back pain: time to back off? J Am Board Fam Med. 2009;22(1):62–68. 16. Hestbaek L, Leboeuf-Yde C, Manniche C. Low-back pain: what is the long-term course? A review of studies of general patient populations. Eur Spine J. 2003;12(2):149–165. 17. Magnusson T, Egermark I, Carlsson GE . A longitudinal epidemiologic study of signs and symptoms of temporomandibular disorders from 15 to 35 years of age. J Orofac Pain. 2000;14(4):310–319. 18. Diatchenko L1, Slade GD, Nackley AG, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14(1):135–43.

Q3 | 2016

20. Deyo RA , Cherkin D, Conrad D, et al. Cost, controversy, crisis: low back pain and the health of the public. Annu Rev Public Health. 1991;12:141–156.

35. Hayden JA , van Tulder MW, Tomlinson G. Systematic review: strategies for using exercise therapy to improve outcomes in chronic low back pain. Ann Intern Med. 2005;142(9):776–785. 36. Eaton LH, Doorenbos AZ , Schmitz KL , et al. Establishing treatment fidelity in a web-based behavioral intervention study. Nurs Res. 2011;60(6):430–435. 37. Chou R, Huffman LH, American Pain Society, American College of Physicians. Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med. 2007;147(7):492–504.

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38. Kroenke K, Krebs EE, Bair MJ . Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry. 2009;31(3):206–219. 39. Devineni T, Blanchard EB . A randomized controlled trial of an internet-based treatment for chronic headache. Behav Res Ther. 2005;43(3):277–292. 40. Lorig KR , Sobel DS, Stewart AL , et al. Evidence suggesting that a chronic disease self-management program can improve health status while reducing hospitalization: a randomized trial. Med Care. 1999;37(1):5–14. 41. Engel GL . The need for a new medical model: a challenge for biomedicine. Science. 1977;196(4286):129–136. 42. Mansour M. Systems theory and human science. Ann Rev Control. 2002;(26)1:1–13. 43. Bailey B. Living systems theory and social entropy theory. Syst Res Behav Sci. 2006;22:291–300. 44. Bateson G. Mind and Nature: A Necessary Unity: Advances in Systems Theory, Complexity, and the Human Sciences. New York, NY: Hampton Press; 1979.

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45. Rolland JS . Chronic illness and the life cycle: a conceptual framework. Fam Process. 1987;26(2):203–221. 46. Dym B. The cybernetics of physical illness. Fam Process. 1987;26(1):35–48. 47. Fricton J. Preventing chronic pain: a human systems approach. Coursera. University of Minnesota. Available at: www.coursera.org/ course/chronicpain. 48. Fricton JR , Anderson K, Clavel A, et al. preventing chronic pain: a human systems approach—results from a massive open online course. Glob Adv Health Med. 2015;4(5):23–32. 49. Flor H, Braun C, Elbert T, et al. Extensive reorganization of primary somatosensory cortex in chronic back pain patients. Neurosci Lett. 1997;224(1):5–8. 50. International Myopain Society. Preventing Chronic Pain. Available at: preventingchronicpain.org/drupal/pcpnet/about. 51. Institute for Healthcare Improvement. IHI Triple Aim Initiative. Available at: www.ihi.org/offerings/Initiatives/TripleAim.

Q3 | 2016

You see recovery. Your patients may see OINV. Opioid-Induced Nausea and Vomiting

â&#x2030;&#x2C6;40% of patients receiving opioids experience OINV1-5 Is OINV disrupting more recoveries than you realize?

References: 1. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372-380. 2. Chang DJ, Desjardins PJ, Bird SR, et al. Comparison of rofecoxib and a multidose oxycodone/acetaminophen regimen for the treatment of acute pain following oral surgery: a randomized controlled trial. Curr Med Res Opin. 2004;20(6):939-949. 3. Daniels S, Casson E, Stegmann JU, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009;25(6):1551-1561. 4. Park YB, Ha CW, Cho SD, et al. A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement. Curr Med Res Opin. 2015;31(1):75-84. 5. Musclow SL, Bowers T, Vo H, Glube M, Nguyen T. Long-acting morphine following hip or knee replacement: a randomized, double-blind, placebo-controlled trial. Pain Res Manag. 2012;17(2):83-88. ÂŠ2016 Daiichi Sankyo, Inc. DSNA16102590 06/16

learn more at KnowOINV.com

By Ste

ven D. Pa

ss i k P

Stinky died of AIDS. He contracted the disease in the â&#x20AC;&#x2DC;80s after years of intravenous drug use. Sunny committed suicide in the middle of a drug-induced paranoid episode that followed years of a descent into madness much like that of his schizophrenic older brother. Bobby, too. His drug use led to him jumping off the roof of the high rise apartment buildings in which we grew up. Skinny and Prez became highly regarded, successful teachers. Harry, a sanitation man. Me, a clinical psychologist.

PAiN&ADDiCTiON

we all pretty much did the same stuff. We were a half generation removed from our older siblings and their friends who came back from Woodstock and led us into our own period of drug experimentation. The line-up on the previous page was the mixed bag of results in my peer group from the last time we as a society decided to expose a large swath of our population to potentially abusable drugs. Tune in, turn on, drop out. We all tuned in and turned on. Only some of us dropped out. And given that we were a young cohort we were at particular risk for developing problems. the experience of muh..muh…muh…my generation

elimination of exposures is at the heart of most drug fighting illustrated that Burroughs was wrong. The famous heroin rationales and attempts to keep kids and others off drugs. addict and author of Junkie cataloging his experience And we all know how well that has turned out. declared that addiction is “a disease of exposure.” I disagree. Exposure is necessary but not sufficient to create addiction. It’s tempting and a bit too easy to just say no to the complexity of addiction and decide that the way to attack it is to cut off, discourage, and try to eliminate all addiction hen it comes to pain management, the elimby eliminating all exposures. Drug experimentation and/ ination of all exposures is a recipe for cruelty and ensured or the use of anything to escape the mundane, enhance suffering for sufferers. Because unlike me and my band of creativity, heighten spiritual activities, and/or self-medicate brothers who were experimenting to escape the angst of a the vicissitudes of teenage wasteland is as old as the hills. For lower middle class fairly pampered upbringing, people with every complex problem there is, inevitably, a simple solution pain need the exposure to something that will at least take that is wrong but appealing because it’s, well, simple. The the edge off or hopefully eliminate a lot of their pain.

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“

To create addiction you do indeed need to have an exposure to a potentially abusable drug. That exposure has to occur in a vulnerable person at a vulnerable time. Pain patients are almost always at a vulnerable time when starting opioid therapy.”

So how do you turn a pain sufferer into a drug addict? How you are pretty close to death already. The initial trivializado you turn anyone into a drug addict? For this alchemy to tion of risk and intellectual dishonesty that unfortunately occur, you need 3 elements and they need to come together accompanied the increase has been met by a backlash of in perfect harmony. To create addiction you do indeed need equally dishonest rhetoric, not to mention well intended to have an exposure to a potentially abusable drug. That and earnest efforts by lawmakers and others alarmed at the exposure has to occur in a vulnerable person at a vulnerable carnage but who in my view are all too often opting for time. Pain patients are almost always at a vulnerable time shortcuts rather than real solutions. when starting opioid therapy. By the time a person with chronic pain sees a physician they are usually months into a What have we learned? Something fundamental about opidownward spiral of pain, withdrawal from activities, inability oids and how minimally helpful and terribly harmful they to work and financial stress, depression, family strife, and are? I think not. I believe that opioid exposures exposed all loss of role. If that same person is also genetically, psychiat- of the inherent weaknesses in the healthcare system when it rically, or demographically vulnerable you have the recipe comes to complex, chronic medical and psychiatric condifor addiction, especially if the vulnerabilities have not been tions—from how we educate physicians to how we schedassessed and opioid therapy altered to include safeguards ule, pay for, and administer care. The healthcare system is when these people are to be exposed to these medications. broken in this regard. Opioids were simply the canary in the coal mine, like antidepressants and even proton pump In pain management, we decided in the mid to late ‘90s that inhibitors before them. Minimally monitored drug-only the suffering of people with pain had gone on long enough. therapy for complex conditions employed in a large scale The tertiary care cancer pain experience had illustrated fashion usually results, years later, in endpoints that lie on a that some people at least seemed to be able to take opioids spectrum from bewilderment to catastrophe. And then the for their pain and use them to good effect with minimal wonder drugs are seen as villains. The doctors are, too, as are abuse, tolerable side effects, stabilized function, and relief. the drug makers and the patients themselves. My contention It was then reasoned that at least some subsets of chronic is that the healthcare system itself is the villain. With its perpain patients could also benefit in similar fashion. A social/ verse incentives and constant insistence on faster, more facmedical movement started that led to dramatically increas- tory-like care fueled by overriding concerns about costs over ing the number of exposures to opioids in those suffering care, public health disasters such as what occurred around with chronic noncancer pain encompassing a much more opioids are virtually guaranteed. I would like to point to diverse group in many ways—demographically, psychiat- an alternative way forward, one that does not depend on rically, and medically for starters. And the exposures didn’t elimination of exposures but improving the quality of those end there: because of diversion of drugs and leakage out of exposures that do occur. It is not a simple, elegant solution. the medical system, these people’s friends, family members, It involves changing the entire healthcare system. The 70 to plumbers, and realtors were exposed too. 100 million people with chronic pain deserve no less. So do the earnest efforts of those who have hung in there and still The result of this exponential increase in opioid exposures want to care for people in pain. Opioids in our healthcare has been that while many benefited, many were harmed. system can be rendered safer. We must, though, tune in and And today, opioids are once again being viewed as power- turn on once again to our desire to help while the temptafully addictive pain-KILLERS that are to be avoided unless tions of dropping out are everywhere around us. Q3 | 2016

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By Doug Gourlay MD, MSc, FRCPC, FASAM

“I’m philosophically opposed to drug testing!” When approached in a respectful, patient-centered fashion, the vast majority of patients have no trouble with providing a urine specimen for drug testing. Never mislead a patient about what you are doing. Let them know you are looking for things that should be there (prescribed medication) and things that shouldn’t be there (unprescribed licit/illicit drug use). Explain that this is part of an overall strategy for risk management. Patients who acknowledge using marijuana should still be tested. In many cases, patients disclose part, but not all, of their drug use. Cocaine use is a particularly high-risk behavior that may make prescription of controlled substances particularly unwise. Urine drug testing is easily done and should be used to assist in managing patient care, not limit it.

Q4 | 2015

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1 |

3 |

Prolotherapy: Low Risk, High Reward for Musculoskeletal Pain and Tissue Injury

Roger Fillingim, PhD

Chronic pain affects all segments of the population, but of course older adults are more likely to be impacted, particularly by joint pain and other forms of musculoskeletal pain. In some studies, up to 50% of the older population reports clinically significant pain. Those numbers go even higher in nursing home residents, where the reported rate is as high as 80%. So, given that the population as we know is aging, we need to be prepared to manage pain in this segment of the population. When we think about how our bodies perceive pain and handle pain signals, we have one system to amplify pain to let us know and take corrective action, and balancing that we have a pain inhibition system to diminish the amount of pain that we experience. In healthy, younger adults, those systems are in balance so that we can feel pain when we need to, but we can also control our own pain and move on with our lives. What is seen with age is we get better at increasing the pain and we get worse at decreasing the pain, which puts older adults at risk for experiencing higher levels of pain given the same type of injury or extent of injury. This pain modulatory imbalance can be a problem that we need to address in pain management for older adults.

Donna Alderman, DO

Simply defined, prolotherapy—short for proliferation therapy—is an injection treatment that stimulates repair of musculoskeletal injuries. The body is a stimulus response machine that is programmed to heal, but with chronic musculoskeletal pain there’s no continuing stimulus to provoke healing. What prolotherapy does is trick your body to go to those areas that haven’t healed and get them healing by irritating the affected area in a directed and specific manner that creates an overresponse which stimulates healing. Prolotherapy can definitely be done in primary care offices, but some doctors aren’t really that interested in learning it or don’t have time to learn it. In those cases at least if they know about it they can refer. In terms of contraindications, I would just say the person has to be healthy. For instance, they can’t have an underlying condition that would prevent them from healing, such as uncontrolled diabetes. But as long as those conditions are under control, and the patient is healthy, has a desire for improvement, and understands the process, he/she is a good candidate

2 |

State Dosage Thresholds—Are They Effective? Jeffrey Fudin, PharmD, FCCP; Stephen Ziegler, PhD, JD

Fudin: It’s been said that patients who are on higher doses of morphine equivalence per day are at higher risk of opiate induced respiratory depression and death. But the truth is that patients who are on very high doses of opioids may be very much sicker and they may be at a higher risk of death for other reasons. It’s really important that the prescribing is tailored to individual patients. In my mind, to have dose thresholds is maddening because there are no uniformly accepted guidelines as to what constitutes “morphine equivalent.” Also, some patients may be ultrarapid metabolizers of a drug, some may be poor metabolizers, others are in between. And if we could account for that variability, there’s still the problem of drug interactions. All these factors are largely, if not completely, ignored by all the states who have these dosing thresholds. Ziegler: States have tried to respond to the opioid overdose epidemic, and one of the more recent innovations has been a focus on dosage thresholds and subsequent triggers. For example, once a chronic pain patient reaches 120 mg morphine equivalency per day, it triggers a particular action or recommendation. The concern about these models is that they’ve not been evaluated and they are very much focused on this idea of preventing overdose, while at the same time there’s another huge epidemic—that of undertreated pain. When it comes to science and politics oftentimes politics trumps science. So when we’re dealing with dosage threshold policies, instead of making mandatory rules, there should be at least advisory guidelines until these models can be evaluated for their efficacy and their impact on pain patients. Q3 | 2016

Understanding the Older Patient With Pain

4 |

When Acute Pain Becomes Chronic Kevin L. Zacharoff, MD, FACIP, FACPE, FAAP

One of the things that can be difficult with respect to people who have acute pain is the practitioner not thinking about the possible situation 1 or 3 months out. Every so often patients deviate from the norm, which is healing and resolution of acute pain. And it’s very easy, with an acute pain patient—maybe someone who’s been in an automobile accident and had surgery—to use a cookbook kind of formula to treat them, and then to gauge all of their progress by a reduction in their pain score. I call that a reductionist approach. But there is also a psychosocial dimension that needs to be considered. What was happening to the patient before this acute pain-causing event? What’s going to be happening to them while it’s going on, and what’s going to happen to them from a psychosocial perspective if the acute pain doesn’t resolve? These factors can set the stage for a subacute pain period, between 1 month and 90 days, and that middle 60 days is probably our best opportunity to forestall the transition from acute pain to chronic pain. Because the longer it goes on, the better the human body is at adapting to that scenario and the tougher it could be to treat. There are things that people in primary care can do to forestall the transition from acute to chronic pain, and one is actually asking the patient how they’re doing outside of the envelope of their pain. We need to consider everything else about the person that’s going on—work, social influences, sleep, appetite, and function. I would love for primary care to be able to claim greater success in pain treatment. I would love for the definition of pain treatment to be recast as the negotiation of pain and function, and I think the primary care clinician is the best suited to lead that negotiation, because presumably they know the patient better than anybody else, certainly way better than a consultant. www.painweek.org | PWJ | 63

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A procedure familiar to many plastic surgeons may be an effective treatment option for chronic temporal headache. A modified version of the Gillies incision, applied to the temple behind the hairline, achieved

50%

or better reduction in headache symptoms in 16 of 19 patients on which it was performed. These patients reported an average Migraine Headache Score of

52 points postprocedure, compared to 132 points presurgery.1

People with chronic migraine experience

at least

headaches

per month. Chronic migraine affects about 1% of the US population with fewer than 5% receiving correct diagnosis and appropriate treatment. But a justcompleted phase 2b trial of a new medication for migraine prevention found it reduced the number of headache days by

1.3

at 675/225 mg dose and

1.5

at 900 mg dose, after just 2 weeks of treatment.2

Persistent Post-Surgical Pain (PPSP)

Medical and prescription records of

450

is reported in about

1 8

veterans

with chronic pain were examined.

patients

following surgery, with

of the vets died from accidental opioid overdose, and

rating their pain as severe. Findings from a pilot study of

1/3

patients

did not overdose.

appear to support a meta-analysis of data from 8 prior studies in suggesting that Ketamine may be a safe and cost-effective intervention against PPSP. Patients who received Ketamine were only

On average, the cohort who overdosed had been prescribed a dosage that was

71% higher than those who did not.

1/2

as likely to report PPSP as were those who received placebo.4

Current guidelines for opioid prescribing = a maximum daily dose of

100 morphine-equivalent milligrams (MEM) However, the study found that the average prescribed dose in the overdose cohort was

98 VS 48M

M MMEM

Approximately

200,00 0

Americans experience a torn ACL each year, with over

50%

requiring surgery. Research on dogs found that the traditional screw fixation procedure was successful in only 4 of 6 cases, and none of the grafts fully integrated into the bones like a native ligament. But a newer suspensory system for ligament reattachment produced full functional restoration and natural healing in

M MMEM

among those who did not.3

100 % 6 of

procedures.5

1. http://bit.ly/1XeAiag 2. http://ow.ly/Zatku 3. http://bit.ly/29Ef16p 4. http://bit.ly/1thGAJC 5. http://bit.ly/1XkNdYe

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y J

D, DA B

DA B

A-

,F AB

A-

*Disclaimer: the opinions expressed herein are those of Dr. Joshi, a practicing clinician. They do not represent the opinions and views of the PWJ—PAINWeek Journal editorial board or PAINWeek faculty.

Q3 | 2016

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patient who I’ve been taking care of for about 8 years came in for his routine monthly medication visit. He was there to obtain another prescription for a brand name opiate medication produced by a well known and well respected pharmaceutical company. That night he refilled his medication. The next morning after ingesting a pill from the new bottle he started having difficulty breathing, with swelling and other angioedema-like symptoms. Fortunately, his wife was home and took him to the ER. It is likely that most people reviewing this case would conclude that the patient was allergic to the medication, despite tolerating it previously. Those who are not fans of chronic opioid analgesic therapy may be quick to conclude that he is a drug-addicted pain patient who overdosed on his medication. The reality may be quite different. The medication he received may have been a counterfeit. “Russia dabbles big time in fake pharma” “Beware of fake prescription drugs smuggled from China” these are really serious headlines1,2 designed to

Counterfeit pharmaceuticals are a multibillion dollar induscapture our attention. However, here in the United States, try. Many companies make far more money producing it can all seem distant and irrelevant to us. We think that it counterfeit products than branded pharmaceutical comdoesn’t really impact us. But the headlines are continuing, panies make selling legitimate products. It is these deep more frequently and closer to home. For example, the head- pockets that have managed to convince physicians and the line “The fake drug industry is exploding, and we can’t do general public that generic and counterfeit medications are anything about it”3 or the ABC News report, “Counterfeit the same as the real, authentic item. Ironically, the healthdrug operation found in the United States.”4 There’s more: care providers who patients trust to watch out for them and “Unapproved drugs prompt FDA alert to 5 Connecticut doc- take care of them may be ignorantly placing them in danger. tors.”5 And the Fox News report, “A new synthetic drug U-47700 has states rushing to stop the spread of the new There are some clinicians and patients who have an idea that fake drugs.”6 “allegedly” identical medications, obtained from different

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sources, can yield widely different efficacy and tolerability since the current regimen is not working—and even death. profiles, but are unsure as to why. Prevailing reasoning attri- Years of research, thousands of trials, countless meetings, butes it to the patient’s biological variability, but the reality and FDA approvals are required to produce FDA approved may be something completely different. According to the medications, but counterfeit medications fall outside of this. FDA , “Counterfeit medicine is fake medicine. It may be contam- So when a patient uses a counterfeit medication, all of the inated or contain the wrong or no active ingredient. They could research, safety, and efficacy data may not apply. When a have the right active ingredient but at the wrong dose. Counterfeit practitioner writes a script, s/he may ultimately not know drugs are illegal and may be harmful to your health.”7 In 2011, what the patient will actually receive. Thus the practitioner the World Health Organization ( WHO) proposed the use becomes an involuntary vehicle for the counterfeit. of the term “substandard/spurious/falsely labeled/falsified/ counterfeit drugs” or SSFFC .8 Counterfeiting of almost anything you can think of has become a big business, with staggering numbers: In 2012, Types of counterfeit medications more than 5% of wines sold on the secondary markets were counterfeit. Counterfeit auto parts accounted for $4 billion In the current pharmaceutical market there are 5 types of in the US and $12 billion globally; counterfeit electrical medications available—legitimate brand names, legitimate parts exceeded $15 billion; and aerospace/defense accounted generics, counterfeited brand names, counterfeited (yet for 520,000 counterfeit parts in the US.9 All estimates place legal) generics, and illegal counterfeit generics. global counterfeiting at over $1 trillion/year. According to Business Action to Stop Counterfeiting and Piracy 1&2 ( BASCAP), the annual global value of the counterfeit indusLegitimate brand names and legitimate generics contain try could be as high as USD $1.7 trillion.9-11 exactly what they advertise, and they contain the same fillers used in the studies submitted to the FDA for approval.

Counterfeit brand names are fake/“knock-off” medications produced by counterfeiters (individuals or pharmaceutical companies) but packaged identically to the legitimate brand name medication and are sold as such. They penetrate the legitimate supply chain, leaving distributors, pharmacies, physicians, and patients with no idea that they are working with counterfeit drugs.

Counterfeit generics are generic medications that are made by recognized manufacturers and sold through legitimate channels but don’t necessarily contain the same active ingredients as the brand name medication and may be manufactured with inexpensive, and sometimes harmful, filler substances that are not considered to be the “active ingredient.” Many generics may fall into this category, and since the active ingredient is the same as the brand name or other generics, it’s completely legal.⁸

Illegal counterfeit generics are medications made by counterfeiters that are fakes/knock-offs of legitimate generic medications, yet packaged and sold as the same.

Why is this important? Simply stated, counterfeit medications can kill. The risks of counterfeit pain management medications include everything from decreased efficacy, resulting in decreased quality of life and decreased function, and other adverse effects such as seizures, overdose, pseudoaddiction—seeking more pills Q3 | 2016

Counterfeit medications accounted for $200 billion in sales in 2011 according to the World Economic Forum. More than 8% of the medical devices in circulation are counterfeit, and global sales of counterfeit products in the pharmaceutical industry alone accounted for $431 billion in 2012 according to WHO.11-13 As previously stated, counterfeit medications have been identified as a major cause for decreased wellness, increased morbidity, and even deaths. Worldwide, approximately 10% of drugs may be counterfeit. Antimicrobials—antibiotics, antivirals, etc—account for half of these and are a leading cause of antibiotic resistance. In addition, about 60% of the “legitimate” or “legal” antimicrobials have substandard or fraudulent quality.14-16 To give a greater sense of urgency and reality surrounding counterfeit medications, here are some of the compounds that people in the US and around the world are involuntarily and unknowingly ingesting17: Heavy metals: Mercury, aluminum, lead, cadmium, arsenic, chrome, uranium, strontium, selenium Actual poison: PCBs, benzopyrenes, rat poison, boric acid, antifreeze Common household items: Road paint, wall paint, brick dust, floor wax, sheet rock, paint thinner Drugs no one asked for: Aminotadalafil, homosildenafil, xanthoanthrafil, pseudovardenafil, hongdenafil, sibutramine, haloperidol No drugs at all: Dextrose, dextrin, lactose, starch, saline, salt www.painweek.org | PWJ | 67

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“The biggest reason we may not be seeing any action regarding counterfeit medications is that clinicians and patients aren’t demanding it, and pharmaceutical companies don’t change unless the FDA forces them. If there is no demand for anticounterfeiting solutions, there may be no incentive to control the supply of fully authenticated medications.”

Quite literally, people have no idea if the expensive purse they just bought, the fancy sunglasses they are wearing, the brake pads installed in their car, or the medication they are taking are counterfeit. That is the reality and it is not only very concerning, it’s life threatening.

Why is the conversation not bigger? One has to consider how this issue became so big and out of control, and why it seems that no one is doing anything about it? There are initiatives within various organizations to fight counterfeiting, but they are clearly not effective enough. Governments have failed to impose sufficient penalties. But the biggest reason we may not be seeing any action regarding counterfeit medications is that clinicians and patients aren’t demanding it, and pharmaceutical companies don’t change unless the FDA forces them. If there is no demand for anticounterfeiting solutions, there may be no incentive to control the supply of fully authenticated medications.

What can be done? Here are 3 things that we as healthcare providers and patients can start doing to help grow the conversation and generate awareness that will create change.

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First, practitioners must speak to their patients, friends, and community: communication and education are catalysts for change. Patients should be aware that they should keep prescribers informed if their pharmacist switched them to a generic. Again, in many cases, generics are legitimate. In other cases, however, generics may be “legal counterfeits.” Sometimes it is obvious; however, counterfeiters are quite good at creating pills that look legitimate.14 It is important to help patients and the community to understand the differences between generic and brand name medications. It is important to remember, especially with the proliferation of online pharmacies, that in some cases, the brand name could be counterfeit as well. It is important to help patients understand that if they’ve had success with a pharmaceutical treatment and suddenly the pill looks different—in color, shape, or texture—to be aware of the explanation for it, and report back if there is a change in how they are reacting to the treatment. People should be encouraged to be vigilant and engaged when taking prescriptions and to communicate with prescribers and staff. Second, insurance companies have a role in this story as well. Let them know about the importance of authenticated single doses for the protection of the patients. Insurance companies have a reputation for employing strategies to save money. Thus, it is important to communicate with them Q3 | 2016

on their level and show them that they can actually save money by offering a legitimate treatment by a legitimate clinician prescribing legitimate, authenticated medications. Intervening with medications that actually work will save money in the long run by significantly lowering morbidity and mortality. I’m not holding my breath but perhaps insurance companies may have some solutions for solving the problem of counterfeit pain physicians—those who claim to be pain specialists but really are either glorified drug dealers, uneducated about proper pain management, or just looking to bill excessively. Third, the manufacturing companies need to be held accountable. The conversation about counterfeits and the need for authenticated drugs needs to take place. Reporting back to them when patients have issues may help. Counterfeiters infiltrate supply chains: In July of 2014, FedEx was federally indicted for shipping counterfeit medications. They were facing up to $1.6 billion in fines.18 After 2 years, the case was dismissed by the judge because there was no evidence that FedEx was a co-conspirator or that they had any knowledge or intention to ship counterfeit drugs. In other words, the counterfeiters are so good at infiltrating the supply chain that FedEx and the government have no idea who they are or how to stop them. Manufacturers have to start authenticating their products so they can protect patients and protect their bottom line. Loss of revenue and perceived loss of confidence in their medications should be motivation for the manufacturers. Unfortunately, that is not enough. They need to know that there is a demand from the public. Only then will they implement a solution to a problem they have known about for years.

Conclusions Change may not be foreseeable unless the FDA forces pharmaceutical companies to implement anticounterfeiting technologies or patients and clinicians to start demanding authenticated medications. I remain hopeful that there are still people within pharmaceutical companies who believe in the “right thing to do” and will courageously be amongst the first to implement solid, unhackable, and unduplicable anticounterfeiting technologies. Counterfeiting is one of the leading sources of funding for terrorism. In fact, it has been reported that the terrorists behind the 1993 World Trade Center bombing raised money by selling counterfeit T-shirts on New York City’s Broadway.19 For this reason, it would seem that it is our patriotic duty to fight counterfeiting. We must be the change we want to see in the world. Until that change, buyers beware. References

2. Philipp J. Beware of fake prescription drugs smuggled from China. Available at: www.theepochtimes.com/n3/1129598-beware-of-fakeprescription-drugs-smuggled-from-china/. 3. Ossola A. The fake drug industry is exploding, and we can’t do anything about it. Newsweek. Available at: www.newsweek.com/2015/09/25/fakedrug-industry-exploding-and-we-cant-do-anything-about-it-373088.html. 4. McNiff E. ABC news investigation into counterfeit prescription drug operations in the US . ABC News. Available at: abcnews.go.com/Health/ abc-news-investigation-counterfeit-prescription-drug-operations-us/ story?id=31077758. 5. Stoller G. Unapproved drugs prompt FDA alert to 5 Connecticut doctors. The Hartford Courant. June 10, 2016. Available at: www.courant. com/health/hc-fda-drugs-letters-20160610-story.html. 6. New synthetic drug U-47700 has states rushing to stop spread. Fox News Health. Available at: www.foxnews.com/health/2016/06/07/newsynthetic-drug-u-47700-has-states-rushing-to-stop-spread.html. 7. U.S. Food and Drug Administration. Counterfeit medicine. Available at: www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/CounterfeitMedicine/. 8. World Health Organization. Substandard, spurious, falsely labelled, falsified and counterfeit (SSFFC ) medical products. Available at: www. who.int/mediacentre/factsheets/fs275/en/. 9. Stealth mark’s anti-counterfeiting technology ready for use in art galleries & museums. MSN . Available at: www.msn.com/en-us/news/ other/stealth-marks-anti-counterfeiting-technology-ready-for-use-in-artgalleries-and-museums/ar- BB cb08K. 10. Welcome to BASCAP. ICC International Chamber of Commerce. Available at: www.iccwbo.org/advocacy-codes-and-rules/bascap/ welcome-to-bascap/. 11. War on fakes. IBA International Bar Association. Available at: www.ibanet.org/Article/Detail.aspx?ArticleUid=02fb8505-e9c4– 4f23-b271-c5bf64a8326d. 12. Fighting the scourge of fake medicines. World Economic Forum. Available at: www.weforum.org/agenda/2014/09/ cracking-counterfeit-medicines-emerging-markets/ 13. Over 8% of medical devices in circulation are counterfeit: WHO. News Medical. Available at: www.news-medical.net/news/20100128/ Over-825-of-medical-devices-in-circulation-are-counterfeit-WHO.aspx. 14. NOVA NEXT. Cracking down on counterfeit drugs. PBS .org. Available at: www.pbs.org/wgbh/nova/next/body/uncoveringcounterfeit-medicines/. 15. Kitamura M. Fake antibiotics feed growing worldwide superbugs threat. Bloomberg. Available at: http://www.bloomberg.com/news/ articles/2014–06–17/fake-antibiotics-feed-growing-worldwidesuperbugs-threat. 16. Kelesidis T, Falagas ME . Substandard/counterfeit antimicrobial drugs. Clin Microbiol Rev. 2015;28(2):443–464. 17. The drugs you are taking may be fake. Asia One Health. Available at: http://health.asiaone.com/health/health-news/ drugs-you-are-taking-may-be-fake. 18. Lobosco K. FedEx indicted for shipping drugs sold online. CNN Money. Available at: money.cnn.com/2014/07/17/news/companies/ fedex-indictment-drugs/index.html. 19. Naim M. Illict: How Smugglers, Traffickers, and Copycats Are Hijacking the Global Economy. New York, NY: Random House; 2005.

1. Clark F. Russia dabbles big time in fake pharma. MSN Website. Available at: www.msn.com/en-ca/news/other/ russia-dabbles-big-time-in-fake-pharma/ar- BB kb0hw.

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with

Jeffrey A. Gudin MD

Jeffrey Gudin is Director of Pain Management and Palliative Care at Englewood Hospital and Medical Center in New Jersey. He is Clinical Instructor, Anesthesiology, at the Icahn School of Medicine at Mt Sinai, in New York.

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“Anyone who has spent time with me has witnessed the passion that I have for teaching others.”

What inspired you to become a healthcare provider? As a surgical intern, I found myself sitting on the edge of a patient’s bed—a 60-year-old school teacher crying in pain following a large abdominal surgery—trying to convince her to “hang in there and wait” for her next suboptimal dose of pain medication. Every-6-hour IM Demerol®/Vistaril® was the illogical norm, and I soon developed a passion for pain management and the relief of suffering. Why did you focus on pain management? I was always interested in the spine as a source of health and pain, and targeted my early training towards orthopedic surgery. I was doing spine surgery research in Albany as a medical student. In between surgical cases, I met the anesthesia-based pain management team who seemed to be having too much fun. Their schedule was filled with a whole day of various pain relieving injections. After interacting with them, hearing the patient stories, and seeing just what a remarkable difference these pain doctors made, I decided that my personality, knowledge, and talents were a great fit for the specialty. Who were your mentors? It started with…this may sound corny, but it started with my dad. He taught me the importance of family structure and values. As the son of poor immigrants, he wanted a better life for his family and always had the vision and drive to pursue success. As most elders do, he often reminded us of our heritage and just how poor we once were: that to support us he delivered and picked up cloth diapers during the day and pumped gas at night! He worked hard, was the ultimate salesman and jack-of-all-trades. He was an engineer who knew how to take things apart and make them work. He was also a true New Yorker (go Brooklyn!). I think with his engineering mind he would have made a great physician, but instead he became a great businessman. After losing his job following

Q3 | 2016

medical leave for an MI, he subsequently built and ran a large telecommunications company. He unfortunately died of CAD at the young age of 69. Clinically it started at Albany Medical College more than 25 years ago with an anesthesiologist and visionary in the world of pain. He saw my passion for pain management and recommended the program at Yale under the direction of another mentor, Dr. Lloyd Saberski, who still practices in New Haven. At Yale, I had the opportunity to train with worldrenowned pain clinicians and researchers, such as: Luke Kitahata, a famous Japanese neurosurgeon who survived numerous bombings while living in Tokyo during World War II to later become a surgeon, neurosurgeon, anesthesiologist, inventor, teacher, lecturer, author, and administrator. Although academically brilliant, Luke taught me the humanistic values of being a physician, that each patient deserved my utmost caring, attention, and respect. I also have to recognize Dr. Ann Berger, whose passion drove her from nursing to oncology to palliative care; she is a pioneer, and now chief of the world-renowned Pain and Palliative Care Service at the NIH Clinical Center. She taught me the utility of high dose opioids and would stop at nothing to give her patients relief. Ann’s patients always managed to smile no matter how bad their disease—she had that effect on people. Her clinical care demonstrated (or exemplified?) that it’s the doctor/patient interaction that means the most to successful outcomes of any disease state, even those with terminal illness. When Sir Isaac Newton paid homage to his intellectual predecessors he said, “If I have seen further than others, it was only by standing upon the shoulders of giants.” I am honored to have the shoulders of colleagues like Lynn Webster, Steve Passik, Mike Brennan, and Sri Nalamachu surrounding me. They have been great mentors to me over the years whether they realize it or not!

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PUNDIT PROFILE/JEFFREY GUDIN

“Life is 10% what happens to us and 90% how we react to it.”

If you weren’t a healthcare provider, what would you be? For most that is a difficult question, but for me, it’s easy: a teacher. Anyone who has spent time with me has witnessed the passion that I have for teaching others. It brings a sense of gratification that doesn’t always come from the clinical practice of medicine. What is your most marked characteristic? Probably my sense of humor. This will probably sound crazy but I crack myself up all the time! People in the hospital make fun of me that I’m always smiling. I sometimes wish it were contagious! I find it incredible to watch our 2 ½-year-old twins doing the same thing. I guess genetically we find life funny What do you consider your greatest achievement? Let’s see, a number of things come to mind: board certification in anesthesiology, then pain management, then addiction medicine, and then hospice and palliative care. Being a certified medical acupuncturist. The honor of having traveled to more than 20 countries as visiting professor and invited lecturer. But my greatest achievement is something most people take for granted: having children and being a father. It’s something I had always dreamed about, and having happened late in life it has given me a sense of purpose, meaning, and more enjoyment than I ever thought possible. What is your favorite language? Italian. 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 last book that I had time to read was Being Mortal by Atul Gawande. This is a must read for all clinicians, especially as we ourselves age. It certainly helps put life in perspective. The book describes the need to change the way we counsel

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patients to help them define and achieve what matters to them most. Being Mortal is a valuable contribution to the growing literature on aging, death, and dying. It certainly made me stop and examine how life (and death) often takes us by surprise and what I would want for myself, my patients, and my family. Gawande is a gifted storyteller, and there are some funny, stirring, and even tear-inducing passages that will change the way you think about life. Movie: Boy, that is a tough one. When I think back at the movies I will watch over and over again they include Gladiator and The Shawshank Redemption. There is always Goodfellas, The Godfather, The Silence of the Lambs, and Forrest Gump. I recently saw Life is Beautiful on an airplane, and then came home and watched it again. It must be that sense of humor thing. Roberto Benigni’s performance was incredible and it brings a tear to my eye just thinking of it. Music: Get a hold of my iPod and you had better be a fan of all music types! From Metallica to Manilow, and I’m not kidding. Being a drummer, guitar and wanna-be piano player, I listen to Stevie Ray Vaughn, Diana Krall, and lots of Zeppelin. My Sirius radio favorites include The Highway, The Coffee House, The Blues, and Classic Vinyl. (Okay, CNBC and Howard Stern are in there as well!) What would you like your legacy to be? Hopefully my friends and colleagues will think of me as a passionate educator who helped grow the specialty of pain management from its infancy, all while providing personalized pain, addiction, and palliative services to those in need. Although it sounds cliché, I hope that as our children grow they will use their hearts, minds, and talents to do what they can to make the world a better place. What is your motto? One of my last slides in my chronic pain presentation quotes: “People don’t care how much you know, until they know how much you care.” My dad would always tell us “Measure twice…cut once.” But I usually quote a sign hanging by my desk: “Life is 10% what happens to us and 90% how we react to it.”

Q3 | 2016

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.

Relief Uninterrupted