The Pain Practitioner - Herbal Cannabis

american academy of pain management

Integrative Pain Management for Optimal Patient Care

Integrative Pain Management for Optimal Patient Care

The Pain Practitioner June/July 2016

a growing interest in herbal cannabis

+

Safe Use of NSAIDS Group Acupuncture Effectiveness The Sticky Problem of Dry Mouth

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: •p ain severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment options are inadequate

Not an actual patient.

• neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA® ER for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain •N UCYNTA® ER is not indicated as an as-needed (prn) analgesic

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

TIME TO DUAL

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

COVERED FOR

94%

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

• Administer NUCYNTA® ER ~q12h3

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

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning.

• NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3) • I nstruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) CONTRAINDICATIONS: Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (e.g., anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product; concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days. *Please see full Prescribing Information for DOSAGE AND ADMINISTRATION. † Some restrictions and limitations apply. See full terms and conditions available at NUCYNTA.com. Available to commercially insured and cash-paying patients only. Patients covered by Medicare, Medicaid, or any other state- or federally funded benefit program are excluded. Patients must be 18 years of age or older. This promotion cannot be combined with any other programs, offers, or discounts. Depomed reserves the right to rescind, revoke, or amend this offer without further notice. ‡ Source: MMIT 2.0, May 2015.

References: 1. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase Ill study. Expert Opin Pharmocother. 2010;11(11):17871804. 2. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151-162. 3. NUCYNTA® ER [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse: NUCYNTA® ER contains tapentadol, an opioid agonist and a Schedule II controlled substance that can be abused in a manner similar to other opioid agonists, legal or illicit. There is a greater risk for overdose and death due to the larger amount of tapentadol present in NUCYNTA® ER. Assess risk for opioid abuse or addiction prior to prescribing NUCYNTA® ER. Addiction can occur in patients appropriately prescribed NUCYNTA® ER at recommended doses; in those who obtain the drug illicitly; and if the drug is misused or abused.

Therefore, routinely monitor for signs of misuse, abuse, and addiction. Patients at increased risk (e.g., patients with a personal or family history of substance abuse or mental illness) may be prescribed NUCYNTA® ER, but use in such patients necessitates intensive counseling about the risks and proper use along with intensive monitoring for signs of addiction, abuse, and misuse.

Life-threatening Respiratory Depression: Can occur at any time during the use of NUCYNTA® ER even when used as recommended.

Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. To reduce the risk of respiratory depression, proper dosing and titration are essential. Overestimating the dose when converting patients from another opioid product can result in fatal overdose with the first dose. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.

Neonatal Opioid Withdrawal Syndrome: Prolonged use of NUCYNTA® ER during pregnancy can result in withdrawal signs in the neonate, which may be life-threatening and require management according to protocols developed by neonatology experts. Neonatal opioid withdrawal syndrome presents as poor feeding, irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, rigidity, seizures, vomiting, diarrhea, and failure to gain weight.

Interactions With Central Nervous System Depressants: Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, tranquilizers, general anesthetics, neuroleptics, other opioids). When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. If the decision to begin NUCYNTA® ER is made, start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use in Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients in the lower range of recommended doses.

Closely monitor these patients, particularly when initiating and titrating NUCYNTA® ER and when given concomitantly with other drugs that depress respiration.

Use in Patients With Chronic Pulmonary Disease: Patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, should be monitored for respiratory depression particularly when initiating therapy and titrating with NUCYNTA® ER. Consider the use of alternative nonopioid analgesics in these patients.

Hypotensive Effect: May cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor for signs of hypotension during dose initiation or titration.

Avoid use in patients with circulatory shock; may cause vasodilation that can further reduce cardiac output and blood pressure.

Use in Patients With Head Injury or Increased Intracranial Pressure: Monitor patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.

Opioids may also obscure the clinical course in a patient with a head injury.

Seizures: May aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures. Monitor patients with a history of seizure disorders for worsened seizure control during therapy.

Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported with the concurrent use of NUCYNTA® ER and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system, and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,

tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. If concomitant treatment with SSRIs, SNRIs, TCAs, or triptans is clinically warranted, careful observation of the patient is advised, particularly when initiating or titrating the dose.

Use in Patients With Gastrointestinal (GI) Conditions: Contraindicated in patients with Gl obstruction including paralytic ileus; may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Avoidance of Withdrawal: Withdrawal symptoms (e.g., anxiety, sweating, insomnia, restlessness, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection) may occur: • After abrupt discontinuation or a significant dose reduction of NUCYNTA® ER in physically dependent patients. When discontinuing NUCYNTA® ER, gradually taper the dose.

• If mixed agonist/antagonist (e.g., butorphanol, nalbuphine, pentazocine) and partial agonist (e.g., buprenorphine) analgesics are used in patients who have received or are receiving NUCYNTA® ER. Avoid use with mixed agonists/ antagonists and partial agonists.

• If opioid antagonists (e.g., naloxone, nalmefene) are administered in physically dependent patients. Administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

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

Hepatic Impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh Score 10 to 15). In patients with moderate hepatic impairment (Child-Pugh Score 7-9), initiate treatment with NUCYNTA® ER 50 mg no more than once every 24 hours, with a maximum dose of 100 mg per day.

Monitor for respiratory and CNS depression when initiating and titrating NUCYNTA® ER. Renal Impairment: Use in patients with severe renal impairment (CLCR <30 mL/min) is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

DRUG INTERACTIONS Alcohol: See BOXED WARNING. Muscle Relaxants: Monitor patients receiving muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than otherwise expected. Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Anticholinergics: Use with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

USE IN SPECIFIC POPULATIONS Pregnancy/Nursing Mothers: Pregnancy Category C. NUCYNTA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. Observe newborns for symptoms of neonatal opioid withdrawal syndrome. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® ER is stopped.

Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate.

Use in Elderly, Renal Impairment, and Hepatic Impairment: See WARNINGS AND PRECAUTIONS. DRUG ABUSE AND DEPENDENCE: See BOXED WARNING OVERDOSAGE: Institute supportive measures to manage respiratory depression, circulatory shock, and pulmonary edema as required. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression.

ADVERSE REACTIONS: In clinical studies, the most common (≥10%) adverse reactions were nausea, constipation, vomiting, dizziness, somnolence, and headache.

Select Postmarketing Adverse Reactions: Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA® ER. Advise patients how to recognize such reactions and when to seek medical attention. Panic attack has also been reported.

Please see Brief Summary, including BOXED WARNING, on the following pages. © July 2015, Depomed, Inc. All rights reserved. APL-NUCX-0029 Rev.2

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: • p ain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Usage • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA® ER for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• NUCYNTA® ER is not indicated as an as-needed (prn) analgesic.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning.

• NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3) • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) CONTRAINDICATIONS Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (e.g., anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product; concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: NUCYNTA® ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA® ER exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as NUCYNTA® ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA® ER and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA® ER, and monitor all patients receiving NUCYNTA® ER for the development of these behaviors or conditions.

Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression).The potential for these risks should not, however, prevent the prescribing of NUCYNTA® ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as NUCYNTA® ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA® ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of NUCYNTA® ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death.

Opioid agonists such as NUCYNTA® ER are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA® ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified release opioids, even when used as recommended.

Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA® ER, the risk is greatest during the initiation of therapy or following a dose increase.

Closely monitor patients for respiratory depression when initiating therapy with NUCYNTA® ER and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA® ER are essential. Overestimating the NUCYNTA® ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of NUCYNTA® ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Neonatal Opioid Withdrawal Syndrome: Prolonged use of NUCYNTA® ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Interactions with Central Nervous System Depressants: Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA® ER therapy. The co-ingestion of alcohol with NUCYNTA® ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol.

Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).

When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin NUCYNTA® ER is made, start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use in Elderly, Cachectic, and Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, closely monitor such patients, particularly when initiating and titrating NUCYNTA® ER and when NUCYNTA® ER is given concomitantly with other drugs that depress respiration.

Use in Patients with Chronic Pulmonary Disease: Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with NUCYNTA® ER, as in these patients, even usual therapeutic doses of NUCYNTA® ER may decrease respiratory drive to the point of apnea.

Consider the use of alternative non-opioid analgesics in these patients if possible.

Hypotensive Effect: NUCYNTA® ER may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressantdrugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of NUCYNTA® ER. In patients with circulatory shock, NUCYNTA® ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA® ER in patients with circulatory shock.

Use in Patients with Head Injury or Increased Intracranial Pressure: Monitor patients taking NUCYNTA® ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA® ER. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of NUCYNTA® ER in patients with impaired consciousness or coma.

Seizures: NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA® ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA® ER therapy.

Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal.

Use in Patients with Gastrointestinal Conditions: NUCYNTA® ER is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Avoidance of Withdrawal: Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA® ER. In these patients, mixed agonists/antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing NUCYNTA® ER, gradually taper the dose.

Driving and Operating Heavy Machinery: NUCYNTA® ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA® ER and know how they will react to the medication.

Hepatic Impairment: A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA® ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA® ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA® ER. Renal Impairment: Use of NUCYNTA® ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interaction with Other CNS Depressants [see Warnings and Precautions (5.4)] • Hypotensive Effects [see Warnings and Precautions (5.7)] • Gastrointestinal Effects [see Warnings and Precautions (5.11)] • Seizures [see Warnings and Precautions (5.9)] • Serotonin Syndrome [see Warnings and Precautions (5.10)] Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The most common adverse reactions (reported by ≥10 % in any NUCYNTA® ER dose group) were: nausea, constipation, dizziness, headache, and somnolence.

The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA® ER dose group for NUCYNTA® ER- and placebo-treated patients were nausea (4 % vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively.

Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The most commonly reported ADRs (incidence ≥ 10% in NUCYNTA® ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache.

Postmarketing Experience: The following adverse reactions, not above, have been identified during post approval use of tapentadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Psychiatric disorders: hallucination, suicidal ideation, panic attack.

Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA® ER. The psychiatric disorders end with panic attack. Advise patients how to recognize such reactions and when to seek medical attention.

DRUG INTERACTIONS Alcohol: Concomitant use of alcohol with NUCYNTA® ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA® ER therapy.

Monoamine Oxidase Inhibitors: NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

CNS Depressants: The concomitant use of NUCYNTA® ER with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and NUCYNTA® ER for signs of respiratory depression, sedation and hypotension.

When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.

Serotonergic Drugs: There have been post-marketing reports of serotonin syndrome with the concomitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when NUCYNTA® ER is coadministered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® ER with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Muscle Relaxants: Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than otherwise expected.

Mixed Agonist/Antagonist Opioid Analgesics: Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonists (e.g., buprenorphine) may reduce the analgesic effect of NUCYNTA® ER or precipitate withdrawal symptoms. Avoid the use of mixed agonist/ antagonist analgesics in patients receiving NUCYNTA® ER. Anticholinergics: The use of NUCYNTA® ER with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

USE IN SPECIFIC POPULATIONS Pregnancy Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.

Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. NUCYNTA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

Nursing Mothers: There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded.

Because of the potential for adverse reactions in nursing infants from NUCYNTA® ER, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® ER is stopped.

Pediatric Use: The safety and efficacy of NUCYNTA® ER in pediatric patients less than 18 years of age have not been established.

Geriatric Use: Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA® ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients.

In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses.

Renal Impairment: The safety and effectiveness of NUCYNTA® ER have not been established in patients with severe renal impairment (CLCR <30 mL/min). Use of NUCYNTA® ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

Hepatic Impairment: Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The dose of NUCYNTA® ER should be reduced in patients with moderate hepatic impairment (Child-Pugh Score 7 to 9).

Use of NUCYNTA® ER is not recommended in severe hepatic impairment (Child-Pugh Score 10 to 15).

DRUG ABUSE AND DEPENDENCE Controlled Substance: NUCYNTA® ER contains tapentadol, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA® ER can be abused and is subject to misuse, addiction, and criminal diversion. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse and misuse.

Abuse: All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

NUCYNTA® ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution.

Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

NUCYNTA® ER should not be abruptly discontinued. If NUCYNTA® ER is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.

OVERDOSAGE Clinical Presentation: Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.

Treatment of Overdose: In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

Rx Only

© 2015 Depomed, Inc., Newark, CA 94560 USA NUCYNTA® ER is a registered trademark of Depomed, Inc. All rights reserved.APL-NUCX-0041 Rev.2

The Pain Practitioner

American Academy of Pain Management

www.aapainmanage.org JUNE / JULY 2016

To access the virtual magazine, go to newsstand.aapainmanage.org

11 NOTES FROM THE FIELD What’s in a Name?

By Bob Twillman, PhD, FAPM, Executive Director 12 MEMBERSHIP Academy Announces New Corporate Council Program

By Robert Twillman, PhD, FAPM, Executive Director 13 MEMBER PROFILE The Importance of Interdisciplinary Care in My Professional Life

By Lucy Whyte Ferguson, DC 14 ANNUAL MEETING 27th Annual Meeting: The Only Clinical Meeting Dedicated Exclusively to Integrative Pain Management

PAGE 34

18 PROFESSIONAL DEVELOPMENT Academy Shared Interests Groups 20 ADVOCACY Alphabet Policy Soup: Add an F (for Federal) to SPPAN, and Sprinkle with NPS

By Amy Goldstein, MSW 26 The Resurgence of Herbal Cannabis

By Seddon Savage, MD 34 Safe Use of NSAIDs

By Christine Rhodes, MS 36 Is Group Acupuncture Effective for Chronic Pain?

By Benjamin Kligler, MD, MPH 43 Xerostomia: The Sticky Problem of Dry Mouth

By Shauna S. Pittman, PharmD 46 On Gratitude: A Conversation with Robert Emmons

By Bruce F. Singer, PsyD

PAGE 43

50 Co-prescribing of Naloxone in Conjunction with Opioid Therapy —A Statement from the American Academy of Pain Management —Response to the Academy Statement By Jennifer Schneider MD; Bennet Davis MD; Amy Kennedy PharmD; and Kathy Davis ANP-C —Academy Response to Clinician Comments By Joanna Katzman, MD, MSPH

And More, on the Web...

OVERVIEW Biofeedback for Chronic Pain Patients

Learn how biofeedback can be useful in chronic pain treatment, as explained by Rauof Gharbo, DO. http://goo.gl/Zlyecw PATIENT STORY Treating a Cancer Patient with

Sleep Apnea and Chronic Pain Watch our interview with Ashwin Mehta, MD, OTR, to hear how he helped a chronic pain patient by treating her sleep apnea using integrative methods. https://goo.gl/LQVAiU LEARN Can Pharmacogenetic Testing

Improve the Treatment of Pain?

Genetic testing may be able to predict patient response and avoid potential medication failures. Take this new 1-hour CME activity in our Pain Care Learning Center – which is always free for Academy members! https://goo.gl/G3FoaZ EXTRA CONTENT CLICK TO DOWNLOAD

GET MORE! Get the Digital Edition of the Pain Practitioner

Have you seen the digital editions of our magazine? They’re interactive and include additional content such as videos, slideshows, and more. http://goo.gl/lLcrV0 Subscribe to The Pain Practitioner even if you are not a member... you can still get this bi-monthly publication for just $50 annually!

Send your check to the American Academy of Pain Management, 975 Morning Star Drive, Ste. A, Sonora, CA 95370

8

| T H E PA I N PRACT ITION ER | J U N E / J U LY 2 0 1 6

ACADEMY BOARD OF DIRECTORS President Joanna Katzman, MD, MSPH Past President Robert A. Bonakdar, MD, FAAFP Vice President W. Clay Jackson, MD, DipTh Secretary Paul Christo, MD, MBA Treasurer Kevin T. Galloway, BSN, MHA, Colonel, US Army (Retired) Directors-at-Large Alfred V. Anderson, MD, DC John Garzione, DPT Christian D. González, MD Gerald Q. Greenfield, Jr., MD Michael Kurisu, DO, ABIHM Arthur S. Roberts, DDS, MD Liaison to the Board Maggie Buckley ACADEMY STAFF Executive Director Robert Twillman, PhD, FAPM Director of Education and Credentialing Debra Nelson-Hogan Director of the State Pain Policy Advocacy Network (SPPAN) Amy Goldstein, MSW Accounting Director Kristin Taylor Assistant Director of Education Cathleen Coneghen SPPAN Assistant Director for Legislative and Regulatory Affairs Katie Duensing, JD Account Managers Rosemary LeMay, Sheila Miller Professional Development Project Manager MacKenzie Davis Office Manager Karen Hebert

THE PAIN PRACTItiONER STAFF AND CONSULTANTS Editor Debra Nelson-Hogan Advertising and Sales Sheila Miller Managing Editor Cathleen Coneghen Clinical Editor Christine Rhodes, MS Art Director Amy Bothwell Copy Editor Rosemary Hope The Pain Practitioner is published by the American Academy of Pain Management, 975 Morning Star Drive, Ste., A, Sonora, CA 95370, P: 209-533-9744, F: 209-533-9750, Email: aapm@aapainmanage.org, website: www. aapainmanage.org. Copyright 2007 American Academy of Pain Management.

All rights reserved.

Send correspondance to: Debra NelsonHogan at dhogan@aapainmanage.org.

For advertising opportunities, media kits, and prices, contact: Sheila Miller at 209533-9744, or smiller@aapainmanage.org The Pain Practitioner is published by the American Academy of Pain Management solely for the purpose of education. All rights are reserved by the Academy to accept, reject, or modify any submission for publication. The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of the Academy or individual members. The Academy does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. The American Academy of Pain Management does not assume any responsibility for injury arising from any use or misuse of the printed material contained herein.

The printed material contained herein is 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 the Academy to accept, reject, or modify any advertisement submitted for publication. It is the policy of the Academy to not endorse products. Any advertising herein may not be construed as an endorsement, either expresed or implied, of a product or service.

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

ONCE daily with

EVENING MEAL

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.

© March 2016, Depomed Inc. All rights reserved. APL-GRA-0295 Printed in U.S.A.

Relief Uninterrupted

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.

© March 2016, Depomed Inc. All rights reserved. APL-GRA-0298 Printed in U.S.A.

notes from the field

What’s in a Name?

By Robert Twillman, PhD, FAPM, Executive Director

“What’s in a name? That which we call a rose By any other name would smell as sweet” —Romeo and Juliet,

by William Shakespeare

In this quote from the famous balcony scene, Juliet argues that the mere fact that Romeo’s surname is Montague does not mean that they can’t love each other, because Romeo would still be who he is if he had a different name. The notion that the essence remains the same even if the appellation changes is relevant as the American Academy of Pain Management becomes the Academy of Integrative Pain Management.

What we believe, what we do, the vision we have for the future— all remain the same even though our name may change.

If that’s the case, then why make the change at all? While I agree with Juliet’s assertion that changing names doesn’t change the essence of who we are, it is important for organizations to choose to call themselves by names that make their missions instantly recognizable. This is especially true in the realm of pain management, where multiple organizations with similar names compete for members, sponsors, and media attention as each tries to carry out its particular mission. “American Academy of Pain Management” has served us well for 28 years, but we think it’s time for a change, one that makes our identity unique and instantly flags us as the only pain management organization to have focused on an integrative model of pain care since its inception.

It has never been more relevant to be known as THE organization for integrative pain management, given the March 2016 release of the National Pain Strategy report by the US Department of Health and Human Services. That report repeatedly calls for an approach to pain care that incorporates a variety of treatments, provided by a variety of clinicians, in an effort to successfully address the various aspects of each patient’s pain

experience—an apt description of integrative pain management if there ever was one. That approach is precisely what the Academy has taught and advocated for since its first day of existence in 1988.

Calling out this vision in the Academy’s name not only serves to identify what we do, it also helps set us apart from other organizations, one of which has a virtually identical name and an identical acronym. I can’t tell you how many times I have had to explain the difference between these two organizations, and how

The American Academy of Pain Management has a new name: Academy of Integrative Pain Management. many times I hear our Academy referred to as “the other AAPM.” Yet, in many ways, these two organizations couldn’t be more different, and we need to highlight the positive aspects of those differences by putting it right out there in our name.

Of all the feedback I’ve received from members about this, the only really consistent complaint is the deletion of the word “American” from the name. I can say that this issue was a point of discussion when the Board decided to recommend the name change. The consensus was that, effectively, all the inclusion really served to do was to limit the geographic scope of our activities. The Academy has always had international members, primarily in Canada, so it’s not exclusively an American organization. Further, if we ever decide to expand regionally throughout North and South America, or even globally, retaining the term “American” would simply force us to repeat the process

of changing our name. The Board (wisely, in my opinion) decided not to take that risk, in order to gain no clear benefit.

So, where does all of this leave us? With an organization whose core values, mission, and vision are all reflected in its name, to an extent that has never been truer. The emphasis throughout health care institutions and regulatory agencies on using an integrative approach to provide topquality pain care is growing rapidly, and has never been more apparent.

A wave is building, and by calling that out in our new name, we can position ourselves right where we should be—riding the crest of that wave.

So, here’s to the Academy of Integrative Pain Management— long may she reign!

Bob Twillman, PhD, is the executive director for the American Academy of Pain Management. In that capacity, Dr. Twillman is responsible for overseeing federal and state pain policy developments and advocating for those supporting an integrative approach to managing pain. He also serves as Chair of the Prescription Monitoring Program Advisory Committee for the Kansas Board of Pharmacy.

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

11

MEMBERSHIP

Academy Announces

New Corporate Council Program

By Robert Twillman, PhD, FAPM, Executive Director

the Academy is pleased to announce a new tiered Corporate Council membership structure.

The American Academy of Pain Management greatly values its relationships with the commercial sponsors who make the products that enable members to provide the best pain care possible. These sponsors support the Academy and its programs through a variety of means, including by joining the Academy’s Corporate Council. (For a listing of our current members, go to: www.aapainmanage. org/about/corporate-council/.)

In the past, the program’s dues structure limited Corporate Council membership to commercial sponsors who had substantial budgets to cover such memberships. That means that many smaller companies, some of whom have exciting new products, have been unable to join and to avail themselves of the benefits of Corporate Council membership.

Recognizing this, the Academy is pleased to announce a new tiered Corporate Council membership structure, one that we believe will enable companies of all sizes to participate and to receive the benefits that accompany that participation. (See chart below.)

Note that many of the benefits of Corporate Council membership are the same across all levels, while others, primarily those involving financial benefits of mem-

bership, increase in value as the level of corporate support increases. In particular, the Academy is pleased to be able to offer a number of free memberships, free Annual Meeting registrations, and discounted advertising rates to Council members. Additionally, Council members are eligible for premium visibility opportunities in advertising positions, a number of enhanced opportunities related to participation in the Annual Clinical Meeting, and advance notice of new opportunities and programs.

In addition to these financial benefits, Corporate Council members are offered the opportunity to interact with Academy staff and Board of Directors members in a number of ways. Each month, members will receive an update from the Academy’s Executive Director about the Academy’s programs. At the Annual Meeting, members are invited to attend a networking reception with members of the Board of Directors, and to participate in an Issues and Strategies Executive Roundtable, where they can share their thoughts with Academy staff and Directors. These opportunities to interact can be invaluable, as members and Academy staff share information and discuss important current issues related to pain management.

Members also can take advantage of their relationship with the Academy by receiving executive summary reports of member and patient surveys undertaken by the Academy, and by providing input into additional surveys planned by the Academy. These surveys can provide invaluable information about clinicians’ and patients’ experiences as they navigate the tricky waters of pain management, and can guide companies’ decisions regarding new product development and enhancement of existing products.

Finally, Corporate Council members also receive prominent recognition for their support through the Corporate Council webpage, in ads in Academy publications, at the Annual Meeting, and through a wall display for the company’s offices.

The Academy welcomes all commercial supporters, and is eager to expand the variety of participating companies through this tiered membership structure.

We are excited to offer this new opportunity, and look forward to establishing new and enduring relationships with a wide variety of supporters.

2016 Corporate Council Membership Program For more information on our Corporate Council program, please contact Sheila Miller at smiller@aapainmanage.org, or at (209) 288-2204.

LeveLs of Corporate support

Benefits & Considerations

$20,000

$15,000

$10,000

$5,000

4 valued at $1,000

3 valued at $750

2 valued at $500

1 valued at $250

20% off

15% off

10% off

5% off

4 valued at $2,400

3 valued at $1,800

2 valued at $1,200

1 valued at $600

1st choice on all

2nd choice on all

3rd choice on all

4th choice on all

On Corporate Council Webpage with Logo & Link

X

X

X

X

In Print/Electronic Publications House Ads

X

X

X

X

At Annual Meeting on Signage, in Program, Corporate Council Ribbons for Exhibit Personnel

X

X

X

X

Annual Corporate Council Membership Wall Display

X

X

X

X

Monthly Council Executive Updates

X

X

X

X

Networking Reception with Board of Directors at Annual Meeting

X

X

X

X

Corporate Council Issues and Strategies Executive Roundtable at Annual Meeting

X

X

X

X

Executive Reports of Member and Patient Surveys

X

X

X

X

Advisory Input into Planned Surveys

X

X

X

X

Complimentary & Discounted Programs Complimentary Membership(s) for Designated Employee(s) Discounted Advertising in The Pain Practitioner, e Newsletter (off gross rate) Complimentary Registration(s) for Designated Employees to the Annual Meeting Premium Visibility Right of Refusal Premium Advertising Positions in The Pain Practitioner, e Newsletter Premium Booth Selection at Annual Meeting Hosting Satellite Symposium at the Annual Meeting Sponsorship Opportunities at the Annual Meeting Advance Notice of New Opportunities, Programs Acknowledgement & Recognition

Executive Information & Access

Research & Intelligence Access

12

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6 For further information, please contact: Sheila Miller, Commercial Support Programs

American Academy of Pain Management 975 Morning Star Drive, Suite A, Sonora, Ca 95370

MEMBER profile

The Importance of Interdisciplinary Care in My Professional Life

By Lucy Whyte Ferguson, DC

I have dedicated my professional life to furthering learning about the diagnosis and treatment of myofascial pain. I have always worked as part of an interdisciplinary care team, whether under one roof or spread out in a community.

My first interdisciplinary care team was fostered by Janet Travell, MD, and it included medical doctors, myofascial trigger point therapists (massage therapists), a psychologist, dentist, and me, a chiropractor.

We sent our most difficult cases to be evaluated by other members of the team, and we were often able to help these patients much more by collaborating. Dr. Travell understood that there was a relationship between muscle dysfunction and joint dysfunction. She also understood that manual care was needed as well as medical injection of trigger points. Medical doctors also help assess concomitant medical conditions, and they and other providers help to assess and address perpetuating factors—all important aspects of successfully treating patients with myofascial pain syndrome.

Some patients have simple myofascial disorders that I can care for without other help. But patients who have major injuries or complex medical conditions require that I make a very specific set of diagnoses and seek the help of others to address all of the factors that affect these diagnoses and to carry out the appropriate sequence of care.

My care team in my rural community includes chiropractic plus massage therapy including specific trigger point release and fascial release plus cold laser therapy, medical evaluation including trigger point injection and prolotherapy, and acupuncture. I also regularly refer patients to physical therapists for supervised exercise, to a Feldenkrais instructor, athletic trainers, a dentist, a certified orthotist, psychotherapists, and an interventional radiologist for epidural and/or facet injections. I regularly communicate with patients’ primary medical doctors and I refer to orthopedic surgeons or

neurosurgeons when necessary.

Monthly I see patients at the University of New Mexico Pain Center, where I serve as the myofascial expert and also identify the accompanying joint dysfunctions that need to be treated. I coordinate with medical doctors, including a neurologist, an internist and a family practice doctor; physician assistants, some of whom perform trigger point injections; psychologists; physical therapists; pharmacists; interventional medical doctors; and neurosurgeons. We meet regularly and discuss our difficult cases.

I also participate in Project ECHO through the University of New Mexico, an online grand rounds that teaches practitioners around the state and around the country about the management of complex pain conditions.

Once we took a call from a military base in Germany. They had a patient who had felt a pop while performing sit-ups and had developed very severe pain in his testicles and groin that had lasted over a year. They wanted advice about medication management, which we provided, but the neurologist moderating the ECHO session suggested that the patient might have a myofascial disorder and asked two of us myofascial experts to consider whether myofascial pain might be a contributing factor. I also suggested the most common joint dysfunctions that might contribute.

These forms of collaborative care are very rewarding for me. I can only touch and care for a limited number of patients in my lifetime, but I can pass on what I have learned to the next generation just as Janet Travell mentored me. For this reason, I have dedicated part of my professional life to teaching, and it is most important to me to teach in interdisciplinary settings such as the courses offered through the University of New Mexico Continuing Medical Education and the courses offered through the American Academy of Pain Management, because all of the members of the care team need to be able to share a common ground and common skills

to identify and treat myofascial pain syndrome.

By assessing and treating myofascial pain and related joint dysfunctions and fascial dysfunction, I have learned an amazing amount about how to treat the pain of adults with scoliosis, young people who have severe pain after scoliosis corrective surgery, and how to treat the pain of adolescents who appear to be developing scoliosis, and often reduce scoliotic curvatures and rib humps.

I have published two papers on my work in the Journal of Bodywork and Movement Therapies and am revising for future publication the third article in this series regarding my treatment of 22 children and adolescents over the last 15 years who appeared to be developing scoliosis. After publication of this third article, I will hopefully embark on a new collaboration to perform research to verify the value of what I have learned about the treatment of scoliosis. And I will also teach my approaches in an interdisciplinary setting. Imagine if I could materially contribute to the care of adolescents with scoliosis and the understanding of this complex condition! I feel so grateful to have been taught the tools to help others and to benefit from working with teams to improve the care of patients with pain and individuals with scoliosis.

Lucy Whyte Ferguson, DC, (below right) was the first chiropractor to receive AAPM’s Janet Travell MD Soft Tissue Pain Management Award (1996). She is a faculty member of the UNM Pain Center and a consultant with Project ECHO.

At the Academy’s Annual Clinical Meeting, September 22, 2016

3 Experts, 13 Muscles: How to Treat and Diagnose Myofascial Pain A 7-hour course with Lucy Whyte Ferguson, DC; Ben Daitz, MD; and Victoria L. Magown, CMTPT, LMT. Sign up today!

For more information: meeting.aapainmanage. org/registration/.

ANNUAL MEETING

The 27th Annual Meeting

The ONLY Clinical Meeting dedicated exclusively to Integrative Pain Management WHO should attend?

All pain clinicians who embrace a person-centered, integrative model of pain care.

KEYNOTE SPEAKERS: Linda Porter, PhD; Seddon Savage, MD; Robert Alan Bonakdar, MD, FAAFP; M. Catherine Bushnell, PhD

Learning Objectives

for All pain clinicians who embrace a personcentered, integrative model of pain care.

After attending this educational program, you will be better able to: • Describe the benefits of using team-based care to manage pain.

• Explain how research is supporting integrative pain management techniques.

• Manage pain using a variety of strategies.

• Create a treatment plan for the patient with chronic pain that incorporates complementary, lifestyle, and mind-body therapies when appropriate.

Continuing Education Credit

For CEUs, total credits may vary according to discipline. Main meeting registrants can earn up to 56 CME/CEU credits: live (21 credits) + online post meeting (35 credits). Pre-conference attendees can earn an additional 6-15 CME/CEU, depending on the course.

The Academy is applying for accreditation for the following disciplines: • Acupuncturists • Chiropractors • Family Physicians • Naturopathic Physicians • Nurses • Nurse Practitioners • Nurse Anesthetists • Pharmacists • Physical Therapists • Physicians • Psychologists

T H E 2 7t h a n n u a L m eet i n g The ONLY Clinical Meeting dedicated exclusively to Integrative Pain Management S eptember 2 1 - 2 5 , 2 0 1 6 S an A ntonio , T e x as J W M arriott H I L L C O U N T R Y R E S O R T & S PA

14

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

For more information regarding the disciplines, accreditors, or CE hours/credits listed, please visit: www.aapainmanage.org/annual-clinical-meeting or contact: Cathleen Coneghen Assistant Director of Education, (919) 890-5215, cconeghen@aapainmanage.org.

headache management by the United Council for Neurologic Subspecialties. Dr. Bonakdar is one of the country’s primary thought leaders on integrative pain management. He also recently co-edited the book Integrative Pain Management published

by Oxford University Press.

Keynotes

Non-Pharmacological Modulation of Chronic Pain M. Catherine Bushnell, PhD, holds a doctorate

The National Pain Strategy: Balancing Care and Risks Linda Porter, PhD, joined the National Institute

for Neurological Disorders and Stroke (NINDS) in 2003. Dr. Porter holds a BS. in physical therapy from McGill University and a PhD in neuroscience from Boston University School of Medicine. She trained in neurophysiology at the Rockefeller University. She was on the faculty of the Uniformed Services University of the Health Sciences for 15 years, where she directed an NIH-funded research program aimed at elucidating mechanisms of sensory-motor integration. As a program director at NINDS, Dr. Porter was responsible for managing the institute’s pain research portfolio.

She participated in the efforts of the NIH Pain Consortium, a trans-NIH entity whose mission is to advance the NIH pain research agenda. In 2012, Dr. Porter became the director of the newly established Office of Pain Policy, for which she supports the activities of the NIH Pain Consortium and the activities of the Interagency Pain Research Coordinating Committee. She co-chaired the development of the National Pain Strategy and the ongoing development of the Federal Pain Research Strategy.

The Multi-dimensional Nature of Pain: Implications for Treatment and Recovery Seddon Savage, MD, is a clinician, educator,

and advocate in the fields of addiction medicine and pain medicine. She is medical director of the Chronic Pain and Recovery Center at Silver Hill Hospital in Connecticut, is an associate professor of anesthesiology on the adjunct faculty of the Geisel School of Medicine at Dartmouth College, and works as an advisor to the Dartmouth-Hitchcock Substance Use & Behavioral Health Initiative.

Dr. Savage served as president of the American Pain Society from 2010 to 2012 and as president of the New Hampshire Medical Society in 2007.

Integrative Pain Management: Global Perspectives On How We Can Improve Pain Care Robert Alan Bonakdar, MD, FAAFP, is director

of pain management at the Scripps Center for Integrative Medicine, La Jolla, California, a member of the Scripps Green Hospital Pain Management Committee, and immediate past president of the Academy. His clinical and research interests include lifestyle and self-management approaches to pain and headache, including the use of nutrition. He is a fellow of the American College of Nutrition and certified in the subspecialty of

in experimental psychology from American University and received postdoctoral training in neurophysiology at the National Institutes of Health (NIH). She then spent 12 years at the University of Montreal and 16 years as the Harold Griffith Professor of Anesthesia at McGill University before returning to NIH in 2012. She has been president of the Canadian Pain Society, treasurer and press editor-in-chief of the International ººAssociation for the Study of Pain, and is currently a councilor for the Society for Neuroscience.

Among her honors are the Lifetime Achievement Award from the Canadian Pain Society and the Frederick Kerr Basic Science Research Award from the American Pain Society. Her research interests include forebrain mechanisms of pain processing, psychological modulation of pain, and neural alternations in chronic pain patients.

Poster Abstract Submission and Continuing Education

For information, call (209) 533-9744, Ext.112, or email: cconeghen@aapainmanage.org.

Hotel JW Marriott San Antonio Hill Country Resort & Spa

23808 Resort Parkway San Antonio, Texas 78261 Phone: (210) 276-2500 Discounted Room Rates

Room Rate: $224/night Room rates shown do not include local Occupancy Tax, currently 16.75%, and an optional $15.00 daily Resort Fee. You can book, modify, or cancel your hotel reservations online at resweb.passkey.com/go/AAPainManagement or call reservations at (877) 622-3140.

Registration

ONLINE www.aapainmanage.org

By PHONE (209) 533-9744, Ext.100 By mail

American Academy of Pain Management 975 Morning Star Drive Suite A, Sonora, CA 95370

ANNUAL MEETING

Pre-conference programs Wednesday, September 21 and Thursday, September 22 7:00 AM – 4:00 PM Advanced Credentialed Pain Practitioner (ACPP) Curriculum Review Course (15 credits) Faculty: George D. Comerci, Jr., MD, FACP, ADAAPM; Brian M. Shelley, MD, ADAAPM; Daniel J. Duhigg, DO, MBA, ADAAPM

Thursday, September 22 9:00 AM – 4:30 PM Hands on Workshop: 3 Experts, 13 Muscles: How to Treat and Diagnose Myofascial Pain (7 credits) Faculty: Ben Daitz, MD; Lucy Whyte Ferguson, DC; Victoria L. Magown, CMTPT, LMT, RMTI Eating for Healing: Evidence-Based Nutrition, Supplements, and Lifestyle Choices for Pain Patients (6 credits) Faculty: Robert Bonakdar, MD; Nancy Cotter, MD, FAAPMR, FABIHM, FACN; Bryan White, PhD; Victor S. Sierpina, MD, ABFM, ABIHM Best Practices for Opioid Prescribing in the Current Regulatory Environment (6 credits) Faculty: Paul Christo, MD; Brett Badgley Snodgrass, FNP-C, CPE, FACPP; Gary Reisfield, MD, Jennifer Bolen, JD Osteopathic Approach for Chronic Musculoskeletal Pain (6 credits) Faculty: Roger Mignosa, DO; Michael Kurisu, DO

Thursday, September 22 Meeting Kick-off Activities 5:00-5:30 PM President’s Welcome

Joanna Katzman, MD, MSPH

1.

Keynote

The National Pain Strategy: Balancing Care and Risks Faculty: Linda L. Porter, PhD

6:30-8:30 PM President’s Reception in the Exhibit Hall

Friday, September 23

2. Wake-Up Call: Morning Movement Faculty: Roger Mignosa, DO

6:00-7:00 AM

6:30-8:00 AM

5. Update on CRPS Faculty: Paul Christo, MD 6. Trauma and Pain: An Evidence-Based Connection

Between the Emotional and Physical States Faculty: Donald D. McGeary, PhD

10:00 AM Exhibit Hall Grand Opening 10:15-11:15 AM Best Poster Awards and Poster Session Exhibit Hall 11:20 AM-12:20 PM 7. Myofascial Pain: A Brief History of the Present Illness & Trigger Point How-To Faculty: Ben Daitz, MD

conference sessions

5:30-6:30 PM

9:10-10:10 AM 4. Multidisciplinary Back Pain Faculty: Christian Gonzalez, MD

Sunrise Symposia

8:05-9:05 AM 3. Keynote

Integrative Pain Management: Global Perspectives on How We Can Improve Pain Care Faculty: Robert Bonakdar, MD, FAAFP

For full program descriptions, visit www.aapainmanage.org/annual-clinical-meeting

8. Controlled Substance Prescribing: Steps You Can Take to Avoid Getting Voted Off Pain Island Faculty: Jennifer Bolen, JD

9. Group Medical Visits 12:20-1:50 PM Advocacy Supported Lunch From Policy to Practice: How the CDC Guidelines

Play out in Primary Care (non-cme)

Faculty: Robert Twillman, PhD; Cindy Steinberg; Robert Rich Jr, MD, FAAFP 1:55-2:25 PM Short Shots: 30-Minute, Targeted Sessions

10. Osteopathic Pearls of Movement Faculty: Roger Mignosa, DO

11. Laughter is the Best Medicine Faculty: Jay Sandweiss, DO

12. Food for Thought: Can Diet and Nutrition Approaches Influence Pain?

Faculty: Robert Bonakdar, MD, FAAFP 2:30-3:00 PM Short Shots: 30-Minute, Targeted Sessions

13. Osteopathic Bits of Movement Faculty: Roger Mignosa, DO

14. Laughter is the Best Medicine Faculty: Jay Sandweiss, DO

15. Food for Thought: Can Diet and Nutrition Approaches Influence Pain?

Faculty: Robert Bonakdar, MD, FAAFP CONTINUED THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

15

ANNUAL MEETING

CONFERENCE SESSIONS CONTINUED 3:05-4:05 PM 16. Keynote The Multidimensional Nature of Pain: Implications for Treatment and Recovery Faculty: Seddon Savage,

MD 4:10-5:10 PM 17. PLENARY Plenary: Non-Pharmacological Modulation of Chronic Pain

Faculty: M. Catherine Bushnell, PhD

5:00 - 7:00 PM Exhibitors’ Reception in the Exhibit Hall

Saturday, September 24 6:00-7:00 AM 18. Wake-Up Call: Group Morning Meditation Faculty: Bruce Singer, PsyD 6:30-8:00 AM Sunrise Symposia 8:05-9:05 AM 19. How I Learned to Stop Worrying and Love the Migraine Brain Faculty: Duren Michael Ready, MD, FAHS, ADAAPM

11:50 AM -1:20 PM Supported Lunch 1:25 - 1:55 PM Short Shots: 30-Minute, Targeted Sessions

28. Can Yoga Help Back Pain as Much as Physical Therapy?

29. Integrating Massage Therapy into the Pain Practice Faculty: Nancy Porambo, MS, LMT

30. Guided Imagery for Pain Faculty: Bruce Singer, PsyD 2:00- 3:30 PM Exhibit Hall Closing Reception 2:00- 3:30 PM Shared Interest Groups (SIGs) 3:35 - 4:05 PM Short Shots: 30-Minute, Targeted Sessions

31. Can Yoga Help Back Pain as Much as Physical Therapy?

32. Integrating Massage Therapy into the Pain Practice Faculty: Nancy Porambo, MS, LMT

33. Guided Imagery for Pain Faculty: Bruce Singer, PsyD

20. How to Interview your Patients with Complex Emotional and Physical Pain Faculty: Jeff Katzman, MD

4:10 – 5:10 PM

21. Interdisciplinary Treatment for the War on Comorbid CRPS and PTSD Faculty: Benjamin M. Keizer, PhD

35. Fibromyalgia: Diagnosis and Treatment of a Prototypical Mind-Body Disorder Faculty: Catherine Vriend, PhD

22. Refractory Migraine: Alternatives to Cursing God

and Dying (When what you’re doing isn’t working) Faculty: Duren Michael Ready, MD, FAHS, ADAAPM

36. Do’s and Don’ts: Safe Prescribing of OTC Analgesics Faculty: Shauna Pittman, PharmD

9:10-10:10 AM

23. The Whole Story: Biopsychosocial Approach to the Assessment, Treatment, and Prevention of Chronic Pain Faculty: Robert J. Gatchel, PhD, ABPP

24. Taking the Haunt Out of the Phantom: Interdisciplinary Phantom Limb Pain Treatment Faculty: Benjamin M. Keizer, PhD

34. Musculoskeletal Pain: Is the Issue in the Tissue?

Faculty: John E. Garzione, DPT

5:15-6:15 PM 37. Lessons Learned: Group Acupuncture in Primary Care Faculty: Melissa Diane McKee, MD, MS; Arya Nielsen, PhD

38. The Evolution of Fibromyalgia Faculty: Jay B. Higgs, MD

10:00-10:45 AM Coffee Break, Exhibits, and Hall Drawings

39. Protecting Your Patients from Drug Interactions Faculty: Shauna Pittman, PharmD

10:45-11:45 AM 25. The Elephant in the Room: Managing Pain Patients with Substance Use Disorders Faculty: Michael Sprintz, DO, FASAM

Sunday, September 25

26. Incorporating Pain Management into Nursing Practice Curriculum Faculty: Jackie S. Rowles, DNP, MBA, CRNA, ANP-BC,

FAAPM, FAAN

27. Managing Patients’ Expectations: SI Joint and Low Back Pain Faculty: Ron Andrews, PT, PhD

6:00-7:00 AM 40. Wake-Up Call: Group Morning Meditation

Faculty: Bruce Singer, PsyD 7:00-8:00 AM Breakfast 8:00-9:00 AM 41. Integrative Pain and Symptom Management Strategies for the Cancer Patient Faculty: Larry C. Driver, MD

42. Community-Based Integrative Treatment Programs for Veterans and Military with Post-Traumatic

Stress and Chronic Pain Faculty: Bob Deschner, MS, and Dottie Goodsun, MEd,

EFT II 8:00 AM -1:25 PM 43. The Perfect Storm: Chronic Pain, Inflammation,

and Dysfunctional Sleep (5 hours) Faculty: Art Roberts, DDS, MSc; Joseph Matthews,

DDS; Juan F. Yepes, DDS, MD, MPH, MS, DrPH 9:05 AM-1:25 PM 44. Hands-On Workshop: Management of Amplified Pain Using Biofeedback (4 hours) Faculty: Raouf S. Gharbo, DO; Jay P. Ginsberg, PhD;

Melanie E. Berry, MS, BCB, OMC, FAIS

45. Auricular Therapy (4 hours) Faculty: Dean H. Hommer, MD, MBA, FAAPMR, FAANEM

16

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

Chronic Pain & Recovery Center A treatment program with proven results for patients with chronic pain and co-occurring mental illness or addiction. â&#x20AC;˘ 80% of patients who completed our program were either completely off opioids at discharge (63%) or on agonist therapy (17%) â&#x20AC;˘ Patients reported a 24% mean reduction in reported pain To get more information about our treatment outcomes, please call 866.542.4455.

www.silverhillhospital.org

PROFESSIONAL DEVELOPMEnT

Academy Shared Interest Groups This year, the Academy’s shared interest groups (SIGs) will convene during the Annual Clinical Meeting in San Antonio. Although each group has specific goals and objectives defined below, they all will play a role in creating annual meeting content, providing content for Academy publications, and driving our integrative pain management mission. Join us in San Antonio on Saturday, September 24, 2016, at 2 pm!

Federal Medicine Establishing a Network of Integrative Pain Care Champions

Chair: Kevin Galloway, BSN, MHA, COL, USA (Ret) Contact for more information: kgalloway@aapainmanage.org

Newly Credentialed Members

Fellow

Cara Herrmann, MS, APRN-BC, NP-C, FAAPM, Twin Cities Pain Clinic, Edina, Minnesota.

Diplomate

Robert D. Lesser, MD, DAAPM, Owner, Causeway Interventional Medicine, Metairie, Louisiana.

Michael A Pound, DC, QME, DAAPM, Owner, Michael Pound Chiropractic Corporation, Brentwood, California.

18

The Federal Medicine Shared Interest Group was established to allow practitioners from the Military Health System, Veterans Health Administration (VHA), Indian Health Service, and other federal medicine organizations to share information and enhance a sense of community for those caring for the pain needs of our service members, veterans, and others in the federal medicine care systems.

Topics will include a review of the Department of Defense/VHA Joint Strategic Plan for Pain Management, the Federal Medicine pain-related responses to the Presidential Memorandum, “Addressing Prescription Drug Abuse and Heroin Use,” Centers for Disease Control and Prevention Opioid Prescribing Guidelines, and new clinical practice guidelines. This SIG will also feature discussions related to building a community of practice among the federal medicine AAPM membership.

Join others who share your interest in implementing integrative pain care across federal medicine.

component of integrative medicine.

Goals of this SIG dedicated to nutrition in pain management include bringing attention to the concept of nutrition in pain management, understanding how members are utilizing nutrition in pain care, and networking with other members who have similar interests.

We hope to create a group email list for continuing the discussion and will also talk about how the group can create consensus documents in this area.

This is similar to the recommendations of other groups who have created publications based on their shared interest in nutrition in medicine.

Pain Rehabilitation Advancing Non-pharmacological Rehabilitation Techniques

Chairs: John Garzione, DPT; Roger Mignosa, DO Contact for more information: johngarzione@frontiernet.net The Pain Rehabilitation Shared Interest Group is dedicated to all practitioners who have a common interest in sharing and advancing their knowledge of non-pharmacological rehabilitation techniques. These modalities include electrotherapy, exercise, mobilization, manipulation, and bio-mechanical corrections, which have been shown to reduce pain perception, improve blood flow, and increase muscle tone to decrease disuse pain as well as help reset the nervous system using the concept of neural plasticity. This multidisciplinary SIG will pool a knowledge base of the “hands-on professions” for the distribution of current information.

Information will be shared through articles in The Pain Practitioner, quarterly email blasts of pertinent current research articles, and through social media such as Twitter and Facebook for patient education.

Nutrition In Pain Management

Palliative Care

Adequate Nutrition is a Basic Premise of Good Health and Pain Relief

Advancing the Quality of Life for those with Serious, Life-limiting Illness

Chairs: Robert Bonakdar, MD; Nancy Cotter, MD Contact for more information: bonakdar@me.com

Chair: W. Clay Jackson, MD, DipTh Contact for more information: mydocjackson@live.com; Twitter: @mydocjackson

Nutrition is a vital but often overlooked aspect of pain management and a core

The Palliative Care Shared Interest Group serves as a dynamic forum to

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

advance the quality of life for persons facing serious, life-limiting illness. Areas of particular focus include promoting best practices, fostering new research, and providing a supportive community to explore the meaning of caring when cure is not expected. At this year’s meeting, we plan to explore the interface between palliative care and chronic pain management (for example, in cancer survivors with residual pain).

Behavioral Health and Addiction Addressing Mental Health and Substance Use Disorders

Chairs: Dan Duhigg, DO; Alice Inman, PsychD Contact for more information: DDuhigg@salud.unm.edu; alice.w.inman2.civ@mail.mil Behavioral health is an integral part of chronic pain management. Untreated mental health and substance use disorders worsen the course and prognosis of chronic pain management. Members of the Behavioral Health and Addiction Shared Interest Group have the opportunity to define the professional, strategic, and research priorities needed to improve the quality of integrated chronic pain management for our most vulnerable patients. Everyone interested in shaping the strategic priorities of integrated behavioral health and addiction for the Academy is invited to participate.

MacKenzie Davis named Professional Development Project Manager of the Advanced Credentialed Pain Practitioner Program

In this new position, Ms. Davis will oversee the planning, implementation, and tracking of the Advanced Credentialed Pain Practitioner program. Ms. Davis, based in the Sonora, California, office, has worked as account manager for Credentialing for two years. If you have questions about the ACPP, please email her at mdavis@aapainmanage.org or call her at (209) 533-9744, ext.105.

Proven Clinical Solution for Neuropathy NEUROGENX TECHNOLOGY WITH 87% SUCCESS RATE COMBINED WITH SUCCESSFUL BUSINESS SYSTEM HELPS DOCTORS CREATE MILLION DOLLAR CASH PRACTICES! Today’s medical professionals need to provide expert care while simultaneously growing and managing a sound medical business. Neurogenx helps you deliver on both counts. The Neurogenx Solutions Program can transform your business and clinical operations and make yours a milliondollar practice in 12 months – guaranteed!

The Solutions Program provides a unique combination of a proven treatment for neuropathy and a comprehensive cash medical business system. To help you learn and implement our turnkey system, the program includes a special Jump Start Boot Camp where our team closes $40-50K in 5 Days for you in order to insure your Quick Start to $100K in 30 Days and One Million in 12 months!

The timing is right for a new medical business approach. Currently, neuropathy patients are underserved due to lack of viable treatment options. Accordingly, there is tremendous practice growth opportunity in offering Neurogenx, a proven treatment with measurable, long-term results. From a medical business perspective, the treatment is effective, the market need exists and the Neurogenx Solutions Program provides an exceptional way to “Before I came to Neurogenx, I had successfully implement medical marketing and cash pay integration. burning and numbness in my feet and legs. My hands had tingling, numbness PROVEN CLINICAL SOLUTION and swelling. I had difficulty walking, standing for a long period of time and at Effective For All Chronic Nerve Conditions times couldn’t pick up a piece of paper.

I couldn’t do my favorite past time – • Neuropathy • Fibromyalgia • We help you learn step-by-step with our sewing. After four weeks, the burning in • Neuritis • Radiculopathy • Migraines Proven TURNKEY Clinical and Business my legs is gone – most of the numbness • Multiple Sclerosis • Neuromas Solutions Program! is gone – I can go on walks with my • Restless Leg Syndrome husband – I can walk up and down stairs.

• Jump Start Boot Camp where our team closes • Complex Regional Pain Syndrome & collects $40-50K in 4 to 5 days for you!

I feel the bottoms of my feet and my • Tarsal and Carpal Tunnel Syndromes toes! Best of all, I can sew without my • Charcot Marie Tooth • Quick Start Program coaches you to close • Plantar Fasciitis hands hurting! I’m also looking forward and collect $100K in 30 Days and $1 Million in 12 months!

• Phantom Limb Syndrome to being pill free! Neurogenx has really helped me.” - Joan S.

PROVEN TECHNOLOGY

PROFIL

IC ANALGES ELECTROLOCK B E V ER N ts on an case repor gesic Theory and electroanal generation or reducing advanced e (EAD) in medical devic and/or chronic acute mitigating tions. pain condi intractable Sorgnard,

PhD; and

Hans Ulrich

May, MD

Richard l Jr., MD, PhD; d electrica H. Odell, controlle the use of atic generators for umented g electrost s involvin lecular range. currents from problem macromo ted During s medical ure and documen numerou dysfunction. t crostruct known and well circulatory Franklin also docd by this treatmen pain and n Some well of action employe l lgesic medical r-modsms the imitation that period, Benjami by using electrica lectroana use of computeimitate, mechani c resonance include n of includpain relief to involves the of ailments harmoni effects, activatio n umented c signals for a number the facilitatio ulated electronifunction of somatic of hormone/ligand currents edtion, and elecshoulder. s.3,4,5 The block the of electrom ing frozen fibers. An c processe cellular regenera exhaust or s and clinical use ic metaboli etic nerve ), utiliznt case rediagnosi Today, the both subseque or sympath medical device (EAD gy, is of enzymat in the basic dees in with unit used Neo GeneSys ical modalitiwell documented troanalgesic ications-level technolo e- EAD with refert is higher-fr was the Sanexas treatmen ing commun science replete and deliver lly ports effects and physical rating the positive convice. used to produceenergy in a continua pattern ences demonst a myriad of medical quency signal al and random s l Nerve for various electrode on patients Backgroundelectrical signals for s. These varying sequenti aneous Electrica electrode t is a wellmentioned ditions.7 Transcut anatomical use of via specialty ts has been algeTENS) treatmen shape, and used to ob- The man( ion size, treatmen y the earliest the Stimulat form of electroan pain of specific 1,2 g times with Elec- medical ted, mild can be effectivel provide effects. since ancient (2750 BC) discussin t po- documen been shown to placement, eutical electrical ishing has and treatmen urus sia that ering small believed t for accompl use made records tain pharmac administ treatmen properties It is es typically relief by electrical catfish, Malopter the skin. troanalgesic block procedur s (approx. tential of the Nile writings of Celsius, currents through physiological mechaelectrode nt nerve fiber 6 algesic Subseque s describe targeting via standard the primary electricus. very small other compiler fish by that of action achieved a direct count), while electroan tend to use Oribasius, and to ¾"-1.5" diameter treatments t with electricelse until nism on is due system in ditreatmen TENS applicatithe central nervous but little medical s (4" or more physical medicine of (420 BC) is consisRoman electrode er-irritation sm of action of Pain Hippocrates , at which time the much larger generAD introduced (CNS); the mechani Theory digitally about 46 s Largus, ameter). into Gate Control cally and , Scribonu of the fish le tent with the Wall.8,9 follows quarterThis electroni at at physician l capabilities and pattern also blocks, both for intractab with a pause for the electrica

by Melzak ated energy as a cure algesia nerve the lumbar symtal steps medicine a, joint inflamElectroan and clinical tone incremen c frequencies selected neuralgi of ace pain, stellate ganglion mechanisms specific harmoni ies headach and gout. s doc- the effects or frequenc physician mation, their desired of specific 1 European of tisselection In the 1700s, tion. This the initiationthe miy increases enon in effectivel 2006 e phenom MENT, April sue resonanc permission.

By Robert

E

Practical

©2006 PPM

with PAIN MANAGE Inc. Reprinted ons,

Communicati

ES IN EXCELLE

NCE 201 4

By Ellen

Neurog enx Get s High

R. Delisi

o

Marks for

Treatin g Nerve

Condi similar tions such as neurogenic periph for podiat out. The conditionseral neuropathy patients. rists and the are the by increa result is increa and other most In the sed cellula pain, numb past, faced painful and most frustrating ative if sed cAMP levels. r metab enough with patien discouraging olism practitioner ness, tinglin The body of what of what g for ts who is amazi measured it and often s knew their in their feet aged. A needs is added impedes is ngly for month have had only minim treatm wide . The body removed and restorent option form allow range of s or Now ally enough is engag frequencies s were years, with the numerous podiat successful. ed and nerve fibers for more limited and a NEUROGEN leverrists are bio-sim and concucommunicat vative seeing ilar wave“This ion with X standa rrently nal Treatm lone patentSolution, which dramatic more uptake all the ry result leads to rapid results variou ed, FDA-C ent s. Retest offers and s differe nerve a conse ing with restorative of energy.” leared ntially (EST) Techn fiber rology.

Electronic This minim -augmented post-dischar density testing nerve condu motor and The treatm sensoSigwith ally-in ction ge, and a Dr. Marily objectively , usually startin studies and local has vasive, targeta specific local ent may be valida grated n Butler g six month been coined ed appro anesth has treate Nerve -Murphy, tes these results ach pairin etic. d Block s in Comb one since the literat 150 DPM, (INB) person ined .” under of ure as g EST Treat ment Electrochem or her patien going trainin with the NEURManhasset, an InteN.Y., g in or Block ical t for 20 OGEN or CEB). pain, heavin X system years and March, a man (CET ess in have beenThe EST and who dreade his feet has CET used by and an d walking becau been cians in unstea physise cialties a number of one treatm dy gait. After of (such just ent, he as pain speageme to walk more nt) and was able now are manhailed comfortably “He by being life-changer podia trists said Dr. loves the result . as a Butle r-Mur s,” were resign for people after treatin phy, pain and ed to living who g the times. with limited “He’s walkin man six mobility.

He could “I’m g better not . tients ; happy for the wards to before walk backpato resum give them without his balanc hope losing e daily very rewar ness in e and the living numb his Jean Chen- ding,” said is have been toes is gone. I in practi of Middl Vitulli DPM, Dr. 30 years, ce for MS, etown so it’s treats , NY, somet nice when patien who hi NEUROGEN ts and trains along .” n g n e w c omes X device other resent she used Other appro podiatrists . Patien appro aches ts with concentratin ximately limited over the years neuropathicto use the 75 succes had “I’ve seen g on buildi percent of her s. ing vitam pain rep“I was patien ins, practi very positivng a base givts differe elderly pleme help enougprescription of home- ce and she patien nt supnts s, activit is bound h.” from taking ts,” Dr. e results when ies—and for neuro pathy patients.

The treatm Chenthey didn’t ; one, somet three Percoc Vitulli said. this is used ent protoc and is “One person with augme really imes none. et tablets ol usuall succes nted specifi a day to y begins s rate.” went I have c and target as neede somet with EST about anesth What sets ed low-d d early on an 85-to- imes just etic for a time alone ose local NEUROGEN ing to 90-per permeabilityaddresses James cent anesth with the pain Martellini, X apart is “This at the erates early and etic. “The locala exclus nerve the ive medic NEUROGEN the machine, quencies helps the heavy results,” accord membrane accord increa X al which se ing to It produ (40,000 Hertz) device sweep Program Direct with EST lifting and ces a s from the treatm Martellini, really accelto lower or. alone. more sophis with a frequencies higher freent protoc “but EST does In combi rapidticated body produ rise and a ol usuall (400 Hertz) symbiotic, nation EST ‘Bio-S slow-d y ends ces in and the . synerg ecay compaimilar’ wavef surface from the istic effect. local anesth form of the orm rable to larization the nerve memb of action No etic create the local local anesth potentials what the etic paired numbness rane,” anesth s pendent occurs at the duces etic to with EST is experienceda membranehe said. “Susta along the and the driven gateways open. and EST EST can delivers electro more condu ined depomainta in while ctive tissue; drives be used nic biolog what impedWhat the cell ining voltag from diabet to help e-deically-effecti it proneeds, es, fluid with es, insults energy and H , is among viral infection neuropathic ve signals. ions, are others like planta and mecha pain caused JUNE/ driven JULY 2014 r fasciit , along with nical/ inform inflam | PODIA ation from is, as well matory chemical TRY MANA condit NEUROGEN as vascul Circle #158 GEME NT X includ ar conditions. ions, es publis This hed studie s.

Many professional journals have documented the success of the technology.

www.p

Pain

odiatry

m.com

*87% reduction in symptoms is based on an April 2012 published medical study. Offices following these protocols have seen similar results. Individual results may be the same or different depending on your patient’s age, condition, treatment compliance, genetics, diagnosis and other factors. **Results may vary depending on size of patient population & market analysis as well as your ability to follow our Solutions Program.

“As a neurological surgeon I have been trained to fix things with operations. For me, it initially seemed like a crazy idea that electrical stimulus treatment would help the body to heal itself. I read all the scientific reports I could find and was still a skeptic. Then I saw how well some patients did. After treatment with Neurogenx, some people have been able to give up their wheelchairs and walkers because they regained varying degrees of sensation and pain relief.”

Steven Weinshel, JD, MD | Board Certified in Neurological Surgery “I am very excited about being part of the Neurogenx team. The start-up training gave me the tools and confidence to succeed with a new business and clinical program. Neurogenx is helping our patients! These are patients that had tried every other type of pain management treatment without success – but now with Neurogenx, their results and testimonials are amazing.

Patients are sleeping better, have increased their activity and have been able to reduce their medications.

Neurogenx delivers as promised!”

Billy R. Smith, MD | Diplomate American Board of Physical Medicine and Rehabilitation

“I’m 61 years old and my diabetic neuropathy made my toes feel as if the skin had been sanded off with 80-grit sandpaper.

During my 3rd Neurogenx treatment the muscles in my legs started tensing, flexing and moving - they came back to life! For the first time in years I could actually feel the rug under my feet!” (Todd W.) “Before I came to Neurogenx, my feet were swollen badly and I was in lots of pain. I had been suffering with neuropathy since the 1990s. It had gotten so bad that I couldn’t walk. Now the pain and swelling is all gone.” ( H. Lann)

InRESTORATIVE more than 4 out of 5 patients, treatment RESULTS with resolved or IN MORE THAN 4 OUT OF 5 PATIENTS ... significantly reduced neuropathy symptoms!

Learn more about becoming Neurogenx Provider or a NerveCenter at www.neurogenx.com/million-dollar-model or call 1-800-335-7624 to secure your geographical area now.

ADVOCACY

Alphabet Policy Soup Add an F (for Federal) to SPPAN, and Sprinkle with NPS

By Amy Goldstein, MSW

The National Pain Strategy (NPS) validates the approach to pain care that the Academy has been advocating for since 1988.

20

SPPAN, the Academy’s State Pain Policy Advocacy Network, has just turned four years old! As we usher in our fifth year, we are finding ourselves increasingly engaged on the federal policy scene, as opposed to the purely state focus for which SPPAN was created. This is due to various factors, including the fact that we’ve never seen bi-partisan members of Congress and federal agencies more aligned on any public health concern than they are with today’s opioid challenges. As a result, it is vital that we engage on the dozens of opioid and pain-related bills flying through Congress at record speed—in one fell swoop, a change at the federal level could wipe out years of hard-won positive outcomes achieved for people with pain through our state advocacy work.

On a positive note, there are multiple federal bills that have the potential to greatly help those living with pain. The recent passage of US Senate Bill 483, Ensuring Patient Access and Effective Drug Enforcement Act, requires that a report be submitted to Congress, no later than one year after the bill’s enactment, on the effects of law enforcement activities on patient access to medications.

It is rare that we are able to identify the actual unintended consequences of law enforcement activity, and even rarer that policymakers proactively identify the need to do so, so this report is a rare opportunity to gather information for legislators so they may quickly address and improve policies.

Further, the bi-partisan H.R. 4641, a response to the single-agency guideline recently published by the Centers for Disease Control and Prevention (CDC), establishes an interagency task force to review, modify, and update best practices for pain management and prescribing pain medication.

What’s more, for the past two years, SPPAN has been co-facilitating a task force of 16 consumer advocacy organizations unified with a goal to implement the National Pain Strategy (NPS).

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

Since the release of the NPS on March 18, a different level of advocacy has been immediately necessary in order to hold the US Department of Health and Human Services (HHS) accountable for the swift implementation of this long-awaited game-changer for the pain community.

The National Pain Strategy validates the approach to pain care that the Academy has been advocating for since 1988.

The NPS is the federal government’s first coordinated plan for reducing the burden of chronic pain affecting millions of Americans. Developed by a diverse team of experts from around the nation, the NPS is the first-ever, comprehensive, population-level strategic plan to advance pain research, education, care, and prevention, and was developed in response to the urgent need to transform how pain is perceived, assessed, and treated in America. The development process began after the 2011 Institute of Medicine (IOM) report, Relieving Pain in America, determined that more than 100 million American adults live with life-altering chronic pain, at an annual economic cost burden of $600 billion. This equals a national epidemic with costs far exceeding that of any other disease state or disorder in the US. The National Pain Strategy calls for:

• Developing methods and metrics to monitor and improve the prevention and management of pain.

• Supporting the development of a system of patient-centered integrated pain management practices based on a biopsychosocial model of care that enables providers and patients to access the full spectrum of pain treatment options.

• Taking steps to reduce barriers to pain care and improve the quality of pain care for vulnerable, stigmatized, and underserved populations.

• Increasing public awareness of pain, increasing patient knowledge of treatment options and risks, and helping to develop a better-informed health care

workforce with regard to pain management.

We’re all in this together

As a testament to the interest of many SPPAN stakeholders to see the NPS implemented quickly, 72 organizations recently joined together on a sign-on letter sent to the Senate Health, Education, Labor, and Pensions and House Energy and Commerce Committees.

The request urges these committees to ask the HHS to submit a written implementation plan and corresponding budget for the NPS within 60 days of the committees’ request. Although this may sound like a tall request so soon after its release, the NPS took an extremely long time to be completed and released when compared to the speed at which other efforts have been completed, such as the recently released CDC Guideline for Prescribing Opioids for Chronic Pain. We believe accountability, appropriations, and oversight are key factors in future implementation.

What can you do to help advance the NPS objectives?

• Contact your Member of Congress to make sure they are aware of the NPS, and further, to help them understand the value to our public’s health if it is swiftly implemented.

• To find your elected officials and easily send them a note through our automated system, visit SPPAN’s homepage at www.sppan.aapainmanage.org.

• Contact Amy Goldstein, SPPAN Director, at agoldstein@aapainmanage. org, to learn more.

Amy Goldstein, MSW, as the inaugural Director of the State Pain Policy Advocacy Network (SPPAN) for the American Academy of Pain Management, has developed a collective vision to shape person-centered pain policies. She continues to cultivate effective alliances among advocacy leaders, create needed resources to educate and promote action on timely state and federal policies relevant to pain care, and lead a team to implement SPPAN’s policy priorities.

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

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.

Discontinue 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

100+ million people have chronic pain.

They want the most up-to-date and compassionate care available.

Show them you can provide it.

The Advanced Credentialed Pain Practitioner (ACPP) —Demonstrates your understanding of best practices in pain management —Establishes your knowledge base in treating commonly encountered pain conditions —Now open to PAs and APRNs in addition to MDs and DOs

Save $150 when you sign-up for the

▲ ▲

ACPP Exam and the Curriculum Review Course At our Annual Meeting, Sept. 21 & 22, 2016 15 CME/CE credits JW Marriott Hill Country Resort & Spa, San Antonio, Texas

OR online in our Pain Care Learning Center 14 CME credits

Learn to —Identify and discuss fundamental concepts and key topics to successfully evaluate and treat patients with chronic pain. ­— Describe how that knowledge improves evaluation, diagnosis, and effective treatment of people with chronic pain.

Designed for Physicians, APRNs and physician assistants who are preparing for the ACPP exam, or who want an outstanding refresher course on best practices in pain management.

Expert faculty

George D. Comerci, Jr., MD, FACP, Professor of Internal Medicine at the University of New Mexico Daniel J. Duhigg, DO, MBA, Assistant Professor of Psychiatry, University of New Mexico Brian M. Shelley, MD, Director of Albuquerque Independent Medical Services, Clinical Associate Professor of the University of New Mexico’s Department of Family and Community Medicine

SIGN UP NOW! Register for both and save $150!

For more information, email credentialing@aapainmanage.org or call (209) 288-2205

ACPP Exam —To download your application, go to: www.aapainmanage.org/credentialing/advanced-credential/ Curriculum Review Course —Live course (15 CME/CE credits credits) To register, go to: meeting.aapainmanage.org/registration/ —Online course (14 CME credits) To register, go to: education.aapainmanage.org/

the resurgence of herbal cannabis

By Seddon Savage, MD

C

annabis is a powerful herb that, like opium, has been a valuable tool in the healing armamentarium of humans for millennia. Both herbs can have beneficial qualities when used with care and both can cause harm when misused. While cannabis is not commonly associated with overdose deaths, as opium and its derivatives can be, cannabis alters perceptions and sensorium and can seduce some users into a pattern of use that can impair development and performance and erode quality of life.

Over the last century, as herbal remedies in medical practice gradually were replaced with more precisely formulated medications with defined doses, contents, effects, and side-

26

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

effects, the herbal form of both cannabis and opium gradually fell out of favor. Cannabis was removed from the US Pharmacopeia in 1941. However, unlike opium from which numerous FDA-approved opioid medications have been derived and which is no longer used medicinally in herbal form, there has been increasing societal demand for access to herbal cannabis over the past few years. Currently 24 states and the District of Columbia have made cannabis available for clinical use in specific contexts although it remains illegal under federal law. In addition, many states have decriminalized possession of small amounts of marijuana for personal use, and four statesâ&#x20AC;&#x201D;Colorado, Washington, Oregon, and

the resurgence of herbal cannabis

Alaska—have legalized marijuana for recreational use.

What has driven this resurgence in demand for herbal cannabis in the United States? There are a number of intersecting currents: cynics might cite cannabis legalization politics and money interests as primary drivers of the wave of support for medical marijuana, while others would point to the valuable pharmacologic attributes of whole plant cannabis and the relatively slow pace of research on pharmaceutical cannabinoids (the active constituents of cannabis). Likely all these contribute.

Legalization Advocacy

Among the leading policy reform organizations supporting clinical cannabis is the Marijuana Policy Project (MPP), a cannabis advocacy organization that “envisions a nation where marijuana is legal and regulated similarly to alcohol”(1).

To that end, the MPP lobbies state legislatures, patients, clinicians, and the public first to adopt permissive state medical marijuana laws, then to decriminalize marijuana and, finally, to legalize cannabis for recreational use. The MPP claims responsibility “for most of the major state-level marijuana policy reforms enacted in the past decade ... .”

Money Interests

There is significant money to be made in the marijuana industry. A Wall Street Journal article in March estimated that the annual revenues from marijuana sales by 2,500 businesses in Colorado total $1 billion with $130 million paid to the state in taxes (2). An online CNBC article estimated marijuana revenues in the US in 2015 at $5.4 billion (3). In addition to direct sales, however, there is a huge support industry that profits from marijuana including grow products, such as lights and fertilizers, and user paraphernalia, such as vaporizers and scales. An article in Marijuana Business News in 2016 detailed a budget for a small-scale grow operation that occupies a 10 x 10 foot indoor space with five grow lights and estimated gross annual revenues of $118,000 minus $3,000 expenses for a net profit of about $115,000 (4).

Once investments are made and such profit lines established, growth opportunities are likely to be targeted, so MPP’s strategy of building initial investments in medical marijuana and working toward legalization seems well designed to achieve its aims.

However, this strategy is only effective because cannabis does in fact appear to provide relief of pain and palliation of a number of other symptoms in some persons. However, a relative dearth of research has resulted in few cannabinoid-based

medications being FDA-approved for clinical use.

Therapeutic Promise of Cannabis and Cannabinoids

Plant cannabis contains more than 70 cannabinoids and a total of more than 500 potentially active chemicals. The most studied of the naturally occurring cannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD). Most recreational cannabis in the US has been bred for higher THC content because this chemical is responsible for the euphoria and cognitive changes sought by recreational users.

THC content has risen from an average concentrations of about 4% in the 1995 to about 12% in 2014 (5).

But THC has also been demonstrated to have analgesic effects, as well as anti-emetic and appetite stimulant effects.

The two FDA-approved cannabinoid medications currently available in the United States are both THC-based medications, dronabinol (Marinol®) and nabilone (Cesamet®), with indications for treatment of chemotherapy-induced nausea and vomiting and for appetite stimulation in HIV-related cachexia. Both have been used off label for pain with some demonstrated success. A third cannabinoid medication widely used in Europe and Canada in pain treatment and expected to be approved for use in the US is nabiximols (Sativex®), a 50-50 mixture of THC and CBD. CBD has no euphorigenic effects and is being studied for a number of potential therapeutic effects including possible anxiolytic, anti-inflammatory and anticonvulsant effects, among others. Sixteen US states, many of which do not permit clinical use of herbal cannabis per se, have passed legislation specifically authorizing the use of CBD extracts that are low in THC. Ratios and cut offs vary by state.

There has been increasing societal demand for access to herbal cannabis over the past few years.

Research Limitations

Relatively little research has been done on the many other cannabinoids and potentially active chemicals in cannabis.

Cannabis growers in the US are experimenting with different strains with varying concentrations and ratios of different cannabinoids, but these experiments do not usually have the scientific rigor and the broad review required for FDA approval. In the absence of robust research, conclusions about THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

27

the resurgence of herbal cannabis

Table 1.

Recommendations for clinicians whose patients use cannabis • Be aware of and work within state regulations governing use of cannabis.

• Be aware of relevant federal laws and current policies on their interpretation.

• Advise patients considering or using cannabis on: —Potential cannabis benefits and risks —Cannabinoid medications and strains of cannabis (as possible, recognizing limited available information) —Routes of administration —Health risks of diversion and misuse; need for safe storage • Be guided in advising by available evidence, not marketing claims.

• Use a management paradigm similar to that for other controlled substances including: —Screen for risk of misuse and ongoing management to meet risk —Set goals both for symptom management and function —Regular follow-up to monitor responses —Consider written cannabis agreements —Consider urine drug screens —Advise on continuation or discontinuation of cannabis based on clinical outcomes of use —Refer patients who develop cannabis misuse for assessment and treatment as indicated.

—Adapted from (10)

the efficacy of different strains remain speculative. While some growers and dispensaries promote different strains for specific symptoms or disease states, scientific evidence is needed to support such claims.

Pharmaceutical development of cannabinoid medications has been relatively slow in the US due to complex licensing and approval requirements for cannabis research. Because cannabis is classified as a schedule I drug (“currently no accepted use and high potential for abuse”)(6), researchers must obtain a special schedule I research license from the US Drug Enforcement Administration (DEA) and then an investigational new drug number (IND) from the FDA. The study protocol must be approved At the Academy’s Annual Clinical Meeting by the National Institute on September 23, 2016 Drug Abuse (NIDA) and The Multidimensional Nature of Pain: by the US DEA as having Implications for Treatment and Recovery significant merit, and the A 1-hour keynote with regional DEA must review Seddon Savage, MD. the proposal and inspect the Sign up today!

For more information, go to study site. In addition, some meeting.aapainmanage.org/ registration/ states require protocol reviews by local review boards 28

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

or have other state-level requirements. Additional federal requirements were recently dropped, and the DEA and FDA are actively considering whether cannabis should be rescheduled in an effort to facilitate more research on cannabis and cannabinoids.

Another challenge to research has been that the US has a single federal cannabis grow facility at the University of Mississippi that contracts with NIDA to provide research grade cannabis that has been graded primarily on concentrations THC. In 2015, NIDA requested that new strains of cannabis be grown with varying concentrations of CBD and other cannabinoids in order to explore the therapeutic potential of other cannabinoids and combinations of cannabinoids.

Potential Benefits and Risks

Whether or not individual clinicians support the availability of cannabis for clinical purposes, increasing numbers of health care providers will find themselves working with patients who elect to use cannabis for management of pain and other symptoms. It is therefore important to understand potential benefits and risks of cannabis, routes for cannabis administration, and management strategies to minimize the risk of harm and to optimize outcomes.

In addition to demonstrated analgesic actions, antinausea effects, and appetite enhancement of cannabinoids medications and cannabis, some evidence suggests that herbal cannabis has a range of other clinical effects in some patients including improvement in spasticity in neurologic disorders, anti-convulsant properties, lowered intraocular pressure, antispasmodic actions on smooth muscle of the gastrointestinal system, and anxiolysis among them (7). Other studies suggest that patients who use cannabis or cannabinoids for pain treatment may reduce their use of opioids. However, further study is needed to define host factors, dosing, cannabinoid content and ratios, and other variables associated with such reported therapeutic effects.

Risks and side effects of cannabis have mostly been studied in the context of recreational use. It is possible that side effects may differ in clinical contexts because of patient variables such as age of onset of use, patterns of use, expectations, medication interactions, and co-morbidities.

Acute use of cannabis is often associated with cognitive and perceptual disturbances, reward (euphoria), sedation, and judgment and psychomotor impairments that can interfere with driving and other performance-based activities. At high doses psychosis can occur. Chronic use may result in impairment in social, work, intellectual, and academic function,

the resurgence of herbal cannabis

and may be associated with increased risk or earlier onset of psychotic illnesses including schizophrenia (8). Physical side effects include exacerbation of asthma and COPD when smoked, as well as tachycardia and orthostatic hypotension, which may create the risk of falls particularly in older patients. There is recent concern regarding a possible association of cannabis use with cardiovascular events including myocardial infarctions and peripheral and cerebral vascular events, although causative relationships are inconclusive (9).

Chronic cannabis use is associated with the evolution of physiologic dependence that may result in withdrawal syndrome on cessation which often includes sleep disturbance, anhedonia, anxiety, irritability, and other symptoms. Across the general population about 9% of recreational users develop addiction to marijuana (8), which is characterized by continued use despite recognition of adverse consequences due to use, with unsuccessful attempts to cut down or discontinue use.

tients to products of combustion that may aggravate COPD or asthma. Vaporization or “vaping”—heating cannabis until cannabinoids are vaporized and inhaled without combustion of the plant material—may be a safer alternative. Extracts and oils can also be used in this manner.

Oral consumption of marijuana is an alternative route of administration and assorted edible marijuana products are commercially available in some states. Their onset of action is slower, making titration of effects difficult and dosing less certain. Candies, baked goods, and other edibles can be mistaken for non-cannabis containing goodies; unintentional overuse and inadvertent consumption by children resulting in toxicity have been reported.

Cannabinoids are highly lipid soluble and may be effective transdermally in salves, creams, or patches, or transmucosally in tinctures. Commercial products are available, but human studies on these delivery systems are scant.

Routes of Administration

Clinical Management Considerations

Smoking is the most common route of marijuana administration and is associated with rapid onset of action facilitating titration for symptom control. However smoking exposes pa-

Little has been written on the clinical management of patients who use cannabis for pain or other symptoms. A working group of the American Pain Society recently published a Continued on page 54

Support your patients between visits ORIGINAL MCKENZIE® LUMBAR ROLLS & SUPPORTS CORRECT POSTURE WHILE SITTING OR SLEEPING

Self-treatment for back pain.

The Treat Your Own Back™ book demonstrates self-treatment techniques using the McKenzie Method®. The Original McKenzie® Lumbar Roll™ easily secures to office chairs, automobile seats and around the waist. Additional lumbar rolls are also available.

Self-treatment for neck pain.

The Treat Your Own Neck™ book teaches the causes of neck pain and provides exercises for relief. The Original McKenzie® Cervical Roll™ fits inside pillowcases to promote natural sleeping habits and alleviate pain.

Learn more and purchase online at OPTP.com 800.367.7393 | OPTP.COM

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

29

Help your patients for the week ahead

To learn more about 7-day, Schedule III Butrans, visit www.butrans.com.

WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse Butrans (buprenorphine) exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patientâ&#x20AC;&#x2122;s risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)].

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting

buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].

Accidental Exposure Accidental exposure to even one dose of Butrans, especially by children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome Prolonged use of Butrans 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)].

Butrans® (buprenorphine) Transdermal System CIII 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 risk of overdose and death with extended-release opioid formulations, reserve Butrans for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Butrans is not indicated as an as-needed (prn) analgesic.

CONTRAINDICATIONS • Butrans is contraindicated in patients with: significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (eg, anaphylaxis) to buprenorphine.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse • B utrans contains buprenorphine, a Schedule III controlled substance.

Butrans exposes users to the risks of opioid addiction, abuse, and misuse.

As modified-release products such as Butrans deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present.

Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Butrans, and monitor all patients during therapy for the development of these behaviors or conditions. Abuse or misuse of Butrans by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death.

Life-Threatening Respiratory Depression • Serious, life-threatening, or fatal respiratory depression has been reported with modified-release opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.

The risk of respiratory depression is greatest during the initiation of therapy or following a dose increase; therefore, closely monitor patients for respiratory depression. Proper dosing and titration of Butrans are essential. Overestimating the Butrans dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental exposure to Butrans, especially in children, can result

in respiratory depression and death due to an overdose of buprenorphine.

Neonatal Opioid Withdrawal Syndrome • Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome which may be life-threatening to the neonate if not recognized and treated, and requires management according to protocols developed by neonatology experts.

Interactions with Central Nervous System Depressants • Hypotension, profound sedation, coma, respiratory depression, or death may result if Butrans is used concomitantly with other CNS depressants, including alcohol or illicit drugs that can cause CNS depression. Start with Butrans 5 mcg/ hour patch, 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 and Patients with Chronic Pulmonary Disease • Closely monitor elderly, cachectic, and debilitated patients, and patients with chronic obstructive pulmonary disease because of the increased risk of lifethreatening respiratory depression.

Consider the use of alternative nonopioid analgesics in patients with chronic obstructive pulmonary disease if possible.

QTc Prolongation • Avoid in patients with Long QT Syndrome, family history of Long QT Syndrome, or those taking Class IA or Class III antiarrhythmic medications.

Hypotensive Effects • Butrans may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Monitor patients during dose initiation or titration.

Use in Patients with Head Injury or Increased Intracranial Pressure •M onitor patients taking Butrans who may be susceptible to the intracranial effects

Please read Brief Summary of Full Prescribing Information on the following pages, including Boxed Warning. ©2016 Purdue Pharma L.P.

Stamford, CT

06901-3431

MR-00366 03/16

of CO2 retention for signs of sedation and respiratory depression. Avoid the use of Butrans in patients with impaired consciousness or coma.

Application Site Skin Reactions • In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred.

Anaphylactic/Allergic Reactions • C ases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience.

Application of External Heat • Avoid exposing the Butrans application site and surrounding area to direct external heat sources. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death.

Use in Patients with Gastrointestinal Conditions • Avoid the use of Butrans in patients with paralytic ileus and other GI obstructions. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

ADVERSE REACTIONS • Most common adverse reactions (≥5%) reported by patients treated with Butrans in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

For more information, visit www.butrans.com.

for transdermal administration BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the Full Prescribing Information and Medication Guide.)

WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse BUTRANS® 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 BUTRANS, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)].

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of BUTRANS. Monitor for respiratory depression, especially during initiation of BUTRANS or following a dose increase. Misuse or abuse of BUTRANS by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].

Accidental Exposure Accidental exposure to even one dose of BUTRANS, especially by children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome Prolonged use of BUTRANS 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)].

4 CONTRAINDICATIONS BUTRANS is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus • Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.12) and Adverse Reactions (6)] 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse BUTRANS contains buprenorphine, a Schedule III controlled substance. As an opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse.

As modified-release products such as BUTRANS deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BUTRANS and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused [see Drug Abuse and Dependence (9)]. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing BUTRANS, and monitor all patients receiving BUTRANS 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 modified-release opioid formulations such as BUTRANS, but use in such patients necessitates intensive counseling about the risks and proper use of BUTRANS, along with intensive monitoring for signs of addiction, abuse, or misuse. Abuse or misuse of BUTRANS by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death [see Overdosage (10)]. Opioid agonists such as BUTRANS are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing BUTRANS. 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, lifethreatening, 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 [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 BUTRANS, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with BUTRANS and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of BUTRANS are essential [see Dosage and Administration (2)]. Overestimating the BUTRANS dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental exposure to BUTRANS, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of BUTRANS 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. 5.4 Interactions with Central Nervous System Depressants Hypotension,

profound sedation, coma, respiratory depression, and death may result if BUTRANS is used concomitantly with alcohol or other (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of BUTRANS 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 BUTRANS therapy is made, start with BUTRANS 5 mcg/hour patch, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)]. 5.5 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. Monitor such patients closely, particularly when initiating and titrating BUTRANS and when BUTRANS is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with BUTRANS, as in these patients, even usual therapeutic doses of BUTRANS may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 QTc Prolongation A positive-controlled study of the effects of BUTRANS on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a BUTRANS dose of 10 mcg/hour; however, a BUTRANS dose of 40 mcg/hour (given as two BUTRANS 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)]. Consider these observations in clinical decisions when prescribing BUTRANS to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia.

Avoid the use of BUTRANS in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide).

5.8 Hypotensive Effects BUTRANS 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 (7.2)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of BUTRANS. 5.9 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking BUTRANS 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 BUTRANS. BUTRANS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BUTRANS in patients with impaired consciousness or coma. 5.10 Hepatotoxicity Although not observed in BUTRANS chronic pain clinical trials, cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.

In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically and during treatment with BUTRANS. 5.11 Application Site Skin Reactions In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of BUTRANS treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy. 5.12 Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of BUTRANS. 5.13 Application of External Heat Advise patients and their caregivers to avoid exposing the BUTRANS application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds while wearing the system because an increase in absorption of buprenorphine may occur [see Clinical Pharmacology (12.3)]. Advise patients against exposure of the BUTRANS application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death. 5.14 Patients with Fever Monitor patients wearing BUTRANS systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the BUTRANS dose if signs of respiratory or central nervous system depression occur.

5.15 Use in Patients with Gastrointestinal Conditions BUTRANS is contraindicated in patients with paralytic ileus. Avoid the use of BUTRANS in patients with other GI obstruction. The buprenorphine in BUTRANS may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.16 Use in Patients with Convulsive or Seizure Disorders The buprenorphine in BUTRANS 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 BUTRANS therapy. 5.17 Driving and Operating Machinery BUTRANS may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of BUTRANS and know how they will react to the medication. 5.18 Use in Addiction Treatment BUTRANS has not been studied and is not approved for use in the management of addictive disorders. 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)] • QTc Prolongation [see Warnings and Precautions (5.7)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Hypotensive Effects [see Warnings and Precautions (5.8)] • Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)] • Application Site Skin Reactions [see Warnings and Precautions (5.11)] • Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.12)] • Gastrointestinal Effects [see Warnings and Precautions (5.15)] • Seizures [see Warnings and Precautions (5.16)] 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. A total of 5,415 patients were treated with BUTRANS in controlled and open-label chronic pain clinical trials. Nine hundred twenty-four subjects were treated for approximately six months and 183 subjects were treated for approximately one year. The clinical trial population consisted of patients with persistent moderate to severe pain. The most common serious adverse drug reactions (all <0.1%) occurring during clinical trials with BUTRANS were: chest pain, abdominal pain, vomiting, dehydration, and hypertension/blood pressure increased. The most common adverse events (≥2%) leading to discontinuation were: nausea, dizziness, vomiting, headache, and somnolence. The most common adverse reactions (≥5%) reported by patients in clinical trials comparing BUTRANS 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing BUTRANS 20 mcg/hour to BUTRANS 5 mcg/hour are shown in Table 3 below: Table 2: Adverse Reactions Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve Patients Open-Label Double-Blind Titration Period Treatment Period BUTRANS BUTRANS Placebo MedDRA (N = 1024) (N = 256) (N = 283) Preferred Term Nausea 23% 13% 10% Dizziness 10% 4% 1% Headache 9% 5% 5% Application site 8% 4% 7% pruritus Somnolence 8% 2% 2% Vomiting 7% 4% 1% Constipation 6% 4% 1% Table 3: Adverse Reactions Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients Open-Label Double-Blind Titration Period Treatment Period BUTRANS BUTRANS 20 BUTRANS 5 MedDRA (N = 1160) (N = 219) (N = 221) Preferred Term Nausea 14% 11% 6% Application site 9% 13% 5% pruritus Headache 9% 8% 3% Somnolence 6% 4% 2% Dizziness 5% 4% 2% Constipation 4% 6% 3% Application site 3% 10% 5% erythema Application 3% 8% 6% site rash Application 2% 6% 2% site irritation The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials.

Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/ Active-Controlled Clinical Trials with Incidence ≥2% MedDRA Preferred Term BUTRANS (N = 392) Placebo (N = 261) Nausea Application site pruritus Dizziness Headache Somnolence Constipation Vomiting Application site erythema Application site rash Dry mouth Fatigue Hyperhidrosis Peripheral edema Pruritus Stomach discomfort

21% 15% 15% 14% 13% 13% 9% 7% 6% 6% 5% 4% 3% 3% 2%

6% 12% 7% 9% 4% 5% 1% 2% 6% 2% 1% 1% 1% 0% 0%

The adverse reactions seen in controlled and open-label studies are presented below in the following manner: most common (≥5%), common (≥1% to <5%), and less common (<1%). The most common adverse reactions (≥5%) reported by patients treated with BUTRANS in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash. The common (≥1% to <5%) adverse reactions reported by patients treated with BUTRANS in the clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were: Gastrointestinal disorders: diarrhea, dyspepsia, and upper abdominal pain General disorders and administration site conditions: fatigue, peripheral edema, application

site irritation, pain, pyrexia, chest pain, and asthenia Infections and infestations: urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis Injury, poisoning and procedural complications: fall Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain in extremity, muscle spasms, musculoskeletal pain, joint swelling, neck pain, and myalgia Nervous system disorders: hypoesthesia, tremor, migraine, and paresthesia Psychiatric disorders: insomnia, anxiety, and depression Respiratory, thoracic and mediastinal disorders: dyspnea, pharyngolaryngeal pain, and cough Skin and subcutaneous tissue disorders: pruritus, hyperhidrosis, rash, and generalized pruritus Vascular disorders: hypertension Other less common adverse reactions, including those known to occur with opioid treatment, that were seen in <1% of the patients in the BUTRANS trials include the following in alphabetical order: Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing.

7 DRUG INTERACTIONS 7.1 Benzodiazepines There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Closely monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician. 7.2 CNS Depressants The concomitant use of BUTRANS 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 BUTRANS 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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. 7.3 Drugs Affecting Cytochrome P450 Isoenzymes Inhibitors of CYP3A4 and 2D6 Because the CYP3A4 isoenzyme plays a major role in the metabolism of buprenorphine, drugs that inhibit CYP3A4 activity may cause decreased clearance of buprenorphine which could lead to an increase in buprenorphine plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If co-administration with BUTRANS is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. Inducers of CYP3A4 CYP450 3A4 inducers may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to buprenorphine. After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. If co-administration or discontinuation of a CYP3A4 inducer with BUTRANS is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. 7.4 Muscle Relaxants Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Monitor patients receiving muscle relaxants and BUTRANS for signs of respiratory depression that may be greater than otherwise expected. 7.5 Anticholinergics Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concurrently with anticholinergic drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 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 [see Warnings and Precautions (5.3)]. Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. BUTRANS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one BUTRANS 20 mcg/hour, the maximum recommended human dose (MRHD).

Studies in rats and rabbits demonstrated no evidence of teratogenicity following BUTRANS or subcutaneous (SC) administration of buprenorphine during the period of major organogenesis. Rats were administered up to one BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, & 15) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6-17). Rabbits were administered four BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, 15, 18, & 19) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6-19). No teratogenicity was observed at any dose. AUC values for buprenorphine with BUTRANS application and SC injection were approximately 110 and 140 times, respectively, that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour. Non-Teratogenic Effects In a peri- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as BUTRANS or SC buprenorphine was associated with toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant

rats were administered 1/4 of one BUTRANS 5 mcg/hour every 3 days or received daily SC buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from gestation day 6 to lactation day 21 (weaning). Administration of BUTRANS or SC buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour. Maternal toxicity was also observed at the no observed adverse effect level (NOAEL) for offspring. 8.2 Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates. BUTRANS 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. 8.3 Nursing Mothers Buprenorphine is excreted in breast milk. The amount of buprenorphine received by the infant varies depending on the maternal plasma concentration, the amount of milk ingested by the infant, and the extent of first pass metabolism. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of buprenorphine is stopped. Because of the potential for adverse reactions in nursing infants from BUTRANS, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of BUTRANS in patients under 18 years of age has not been established. 8.5 Geriatric Use Of the total number of subjects in the clinical trials (5,415), BUTRANS was administered to 1,377 patients aged 65 years and older. Of those, 457 patients were 75 years of age and older. In the clinical program, the incidences of selected BUTRANS-related AEs were higher in older subjects. The incidences of application site AEs were slightly higher among subjects <65 years of age than those ≥65 years of age for both BUTRANS and placebo treatment groups.

In a single-dose study of healthy elderly and healthy young subjects treated with BUTRANS 10 mcg/hour, the pharmacokinetics were similar. In a separate dose-escalation safety study, the pharmacokinetics in the healthy elderly and hypertensive elderly subjects taking thiazide diuretics were similar to those in the healthy young adults. In the elderly groups evaluated, adverse event rates were similar to or lower than rates in healthy young adult subjects, except for constipation and urinary retention, which were more common in the elderly. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment In a study utilizing intravenous buprenorphine, peak plasma levels (Cmax) and exposure (AUC) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. BUTRANS has not been evaluated in patients with severe hepatic impairment. As BUTRANS is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance BUTRANS contains buprenorphine, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids.

BUTRANS can be abused and is subject to misuse, addiction and criminal diversion [see Warnings and Precautions (5.1)]. 9.2 Abuse 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. 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 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 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 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. 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. BUTRANS, 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 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 reduce abuse of opioid drugs. Risks Specific to the Abuse of BUTRANS BUTRANS is intended for transdermal use only. Abuse of BUTRANS poses a risk of overdose and death. This risk is increased with concurrent abuse of BUTRANS with alcohol and other substances including other opioids and benzodiazepines [see Warnings and Precautions (5.4) and Drug Interactions (7.2)]. Intentional compromise of the transdermal delivery system will result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by swallowing, snorting, or injecting buprenorphine extracted from the transdermal system. 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 dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. BUTRANS should not be abruptly discontinued [see Dosage and Administration (2.3)]. If BUTRANS is abruptly discontinued in a physicallydependent patient, an abstinence 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 BUTRANS is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, 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.

Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose.

The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used. Remove BUTRANS immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BUTRANS, carefully monitor the patient until spontaneous respiration is reliably re-established.

Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of BUTRANS, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10-24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal.

The severity of the withdrawal produced 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 with an opioid antagonist, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Addiction, Abuse, and Misuse Inform patients that the use of BUTRANS, even when taken as recommended, can result in addiction, abuse, and misuse, which could lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share BUTRANS with others and to take steps to protect BUTRANS from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting BUTRANS or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Exposure Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store BUTRANS securely and to dispose of unused BUTRANS by folding the patch in half and flushing it down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of BUTRANS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated [see Warnings and Precautions (5.3)].

Interaction with Alcohol and other CNS Depressants Inform patients that potentially serious additive effects may occur if BUTRANS is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions Instruct patients how to properly use BUTRANS, including the following: 1. To carefully follow instructions for the application, removal, and disposal of BUTRANS. Each week, apply BUTRANS to a different site based on the 8 described skin sites, with a minimum of 3 weeks between applications to a previously used site.

2. To apply BUTRANS to a hairless or nearly hairless skin site. If none are available, instruct patients to clip the hair at the site and not to shave the area.

Instruct patients not to apply to irritated skin. If the application site must be cleaned, use clear water only. Soaps, alcohol, oils, lotions, or abrasive devices should not be used. Allow the skin to dry before applying BUTRANS. Hypotension Inform patients that BUTRANS may cause orthostatic hypotension and syncope.

Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Driving or Operating Heavy Machinery Inform patients that BUTRANS may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in BUTRANS. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy Advise female patients that BUTRANS can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Disposal Instruct patients to refer to the Instructions for Use for proper disposal of BUTRANS. Patients can dispose of used or unused BUTRANS patches in the trash by sealing them in the Patch-Disposal Unit, following the instructions on the unit. Alternatively, instruct patients to dispose of used patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet. Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed.

Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product.

Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431 Manufactured by: LTS Lohmann Therapy Systems Corp., West Caldwell, NJ 07006 U.S. Patent Numbers 5681413; 5804215; 6264980; 6315854; 6344211; RE41408; RE41489; RE41571. © 2014, Purdue Pharma L.P. This brief summary is based on BUTRANS Prescribing Information 303385-0A, Revised 06/2014 (A)

Safe Use of NSAIDs

BY CHRISTINE RHODES, MS

Both acute and chronic poisoning with NSAIDs results in significant morbidity and mortality.

of NSAID-induced COX inhibition is decreased production of prostaglandins, which leads to decreased pain and inflammation. Prostaglandins are involved in maintaining GI mucosal integrity as well as regulating renal blood flow, and both acute and chronic toxicity often involves the GI and renal systems.

Both acute and chronic poisoning with NSAIDs results in significant morbidity and mortality. The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) has estimated that more than 100,000 hospitalizations and more than 16,000 deaths in the United States each year are due to NSAID-related complications with costs greater than $2 billion (1). On the flip side, various clinical and epidemiologic studies show that NSAIDs, including aspirin, may help Table. Common NSAIDs in Clinical Use. Generic name

Brand name(s)

celecoxib

Celebrex

diclofenac

Cambia, Cataflam, Dyloject, Flector, Pennsaid, Solaraze, Voltaren, Voltaren-XR, Zipsor, Zorvolex, Arthrotec (combination with misoprostol)

diflunisal

No brand name currently marketed

etodolac

No brand name currently marketed

fenoprofen

Nalfon

flurbiprofen

Ansaid

ibuprofen*

Advil, Caldolor, Children’s Advil, Children’s Elixsure IB, Children’s Motrin, Ibu-Tab, Ibuprohm, Motrin IB, Motrin Migraine Pain, Profen, Tab-Profen, Duexis (combination with famotidine), Reprexain (combination with hydrocodone), Vicoprofen (combination with hydrocodone)

indomethacin

Indocin, Tivorbex

ketoprofen

No brand name currently marketed

ketorolac

Sprix

mefenamic acid

Ponstel

meloxicam

Mobic

nabumetone

No brand name currently marketed

naproxen*

Aleve, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprosyn, Treximet (combination with sumatriptan), Vimovo (combination with esomeprazole)

oxaprozin

Daypro

piroxicam

Feldene

sulindac

Clinoril

tolmetin

No brand name currently marketed

*There are many over-the-counter (OTC) products that contain this medicine.

34

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

CRISTINA PEDRAZZINI / SCIENCE SOURCE

N

onsteroidal antiinflammatory drugs (NSAIDs) have been prescribed extensively throughout the world to treat pain and fever, and many clinicians prescribe NSAIDs for treatment of chronic conditions such as osteoarthritis and rheumatoid arthritis as well as acute musculoskeletal injuries. With over-the-counter (OTC) use included, more than 30 billion doses of NSAIDs are consumed annually in the United States alone. Most commonly ingested NSAIDs have few toxic effects, even when taken in significant quantities; however, as the consumption of both prescription and OTC NSAIDs increases every year, so do the numbers of overdoses and NSAID-related complications reported to poison control centers around the country. Additionally, adverse events related to drug interactions, or exposure to vulnerable patients with disease states that predispose patients to NSAID toxicity, are common and may result in significant morbidity and mortality.

More than 20 drugs fall under the category of NSAIDs (see Table). The major effect of all NSAIDs is to decrease the synthesis of prostaglandins by reversibly inhibiting cyclooxygenase (COX), the enzyme that catalyzes the formation of prostaglandins and thromboxanes from the precursor, arachidonic acid. In contrast, salicylates (e.g., aspirin), irreversibly bind to COX and inhibit production for the entire life of the cell, and acetaminophen inhibits COX centrally. The result

Thank you to our prevent cancer, although some investigators warn that the Corporate modest chemopreventive efficacy of NSAIDs is compounded by their significant toxicity that can be cumulative (2).

Council Members!

Cardiovascular Risk

SAFE USE OF NSAIDS

pain, shortness of breath or trouble breathing, sudden weakness or numbness in one part or side of the body, or sudden slurred speech. Clinicians should report adverse events involving NSAIDs to the FDA MedWatch program (5).

References

Numerous studies indicate that non-aspirin nonsteroidal 1. Singh G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. anti-inflammatory drugs cause an increased risk of serious Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther.

2000;7(2):115-121. cardiovascular thrombotic events, including myocardial 2. Tsioulias GJ, Go MF, Rigas B. NSAIDs and colorectal cancer control: promise infarction and stroke, either of which can be fatal. Estimates and challenges. Curr Pharmacol Rep. 2015 Oct 1;1(5):295-301.

3.

Food and Drug Administration. Silver Spring, MD. FDA Briefing Information for of increased risk range from 10% to 50% or more, dependthe February 10-11, 2014, Joint Meeting of the Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee. http://www.fda.gov/ ing on the drugs and the doses studied. This risk may occur downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Arthritisas early as the first weeks of treatment and may increase with AdvisoryCommittee/UCM383180.pdf. Accessed December 23, 2014.

4. Academy Coxib and traditional NSAID Trialistsâ&#x20AC;&#x2122; (CNT) Collaboration, Bhala N, Emberson J, American of Pain Management duration of use. The relative increase in serious thrombotic Merhi A, Abramson S, Arber N, et al. Vascular and upper gastrointestinal effects CORPORATE COUNCIL MEMBERSHIP of non-steroidal anti-inflammatory drugs: meta-analyses of events contributed by NSAID use appears to be similar in individual participant data from randomised trials. Lancet. or 2013;382:769-779. those with and without known cardiovascular disease or Contact risk Sheila Miller (smiller@aapainmanage.org) Jillian Manley (jmanley@aapainmanage.org) (209) 533-9744 5.

MedWatch: The FDA Safety Information and Adverse Event factors for cardiovascular disease. However, research shows to become a Corporate CouncilReporting MemberProgram. today!US Food and Drug Administration. http:// www.fda.gov/Safety/MedWatch/. Accessed May 19, 2016. that patients with known cardiovascular disease or risk factors have a higher absolute incidence of serious cardiovascular Christine Rhodes has an MS in nutrition and is a medical writer based in New York City. Besides servthrombotic events due to their increased baseline rate. ing as clinical editor of The Pain Practitioner, Cardiovascular adverse events can develop as early as the she is a Certified Holistic Health Coach, American Association of Drugless Practitioners. first week of treatment, and the risk increases throughout the patientâ&#x20AC;&#x2122;s treatment course, even in the absence of previous cardiovascular symptoms. The increased risk has been observed mostly at higher doses, so patients should be prescribed the lowest effective dose for the shortest duration possible.

The risk of heart attack and stroke with NSAIDs, either of which can lead to death, was first described in 2005 in the Boxed Warning and Warnings and Precautions sections of the prescription drug labels. Since then, the FDA has reviewed a variety of new safety information on prescription and OTC NSAIDs, including observational studies (3), a large combined analysis of clinical trials (4), and other scientific publications (3), and has required that manufacturers update their labeling to include the increased risk of cardiovascular events in all patients, and especially those on long-term or high-dose therapy or in patients with preexisting heart disease.

In addition, clinicians should avoid prescribing high-dose NSAIDs to patients with advanced age, those with chronic medical conditions such as diabetes, patients with active gastric ulcers, and those using other medications that may impair renal flow, such as ACE inhibitors. Alternative medications or modalities for pain relief may also be prescribed.

Patients should be advised to read the Medication Guide for prescription NSAIDs and the Drug Facts label for overthe-counter NSAIDs to avoid exceeding recommended doses.

Become a Corporate Council Member today!

Contact Sheila Miller at smiller@aapainmanage.org) Inform patients to seek medical attention immediately if they experience symptoms of heart attack or stroke such as chest

Thank you to our Corporate Council Members!

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

35

Is Group Acupuncture Effective for Chronic Pain?

BY BENJAMIN KLIGLER, MD, MPH

I

n the fall of 2014, the Patient-Centered Outcomes Research Institute (PCORI) funded a new study comparing the effectiveness of individual versus group acupuncture therapy for the treatment of chronic pain, specifically neck pain, back pain, and osteoarthritis. The Acupuncture Approaches to Decrease Disparities in Outcomes of Pain Treatment (AADDOPT-2) trial launched in March 2015. Led by Diane McKee, MD, and myself of the Albert Einstein College of Medicine department of family and social medicine, the project is a collaboration between Einstein, Montefiore Medical Center, Mount Sinai Beth Israel, and the Pacific College of Oriental Medicine. The study takes place in the setting of six Montefiore-affiliated community health centers in the Bronx, New York, a low-income urban area.

In an earlier trial funded by the National Center for

36

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

Complementary and Integrative Health (formerly NCCAM) at NIH, this same team found that individual acupuncture was both acceptable and effective in the ethnically diverse, medically underserved, and socioeconomically challenged population served by these health centers (1). In the earlier trial, 226 (46%) of 495 referred patients initiated acupuncture. Back pain was the most common referring diagnosis followed by osteoarthritis. Patients in that study were mostly Medicaid insured and often on disability insurance, had poor or fair overall health, and had high baseline levels of pain (mean BPI pain severity, 6.8; mean days with pain, 12.3 of 14 days). The average number of treatments was 8. Pain severity significantly improved from baseline, as did physical well-being (See Figure).

Overall, 30.3% of participants experienced a 30% or greater improvement in pain.

These results were consistent with a recent meta-analysis published in the Archives of Internal Medicine and JAMA finding acupuncture therapy to be “effective for the treatment of chronic pain (back and neck, osteoarthritis, chronic headache, and shoulder pain) and … therefore a reasonable referral option” for chronic pain (2,3). Our current “comparative effectiveness” study builds on those findings, testing whether group treatment is as effective as individual treatment in our patient population. Group or “community” acupuncture, in which several patients are treated simultaneously in a group setting by one acupuncturist, is a model that has gained popularity in the US in recent years, but its effectiveness has not been rigorously tested to date. A group model of care might allow acupuncture therapy to be delivered in a more cost-effective manner versus individual treatment.

The goal of the AADDOPT-2 trial is to recruit a total of 720 patients with chronic pain. Study participants are randomly assigned to either individual or group acupuncture therapy, delivered at their primary care site by licensed acupuncturists. The intervention includes channel palpa-

Overall, 30.3% of participants experienced a 30% or greater improvement in pain.

is group acupuncture effective for chronic pain?

Average Physical Function and Pain Severity Over Time in Patients Receiving Individual Acupuncture Treatment 36.00

Average SF12 Physical Functioning

Average BPI Pain Severity

7.00

6.50

6.00

5.50

5.00

35.00

34.00

33.00

32.00

31.00 -6

-4

-2

Baseline + 2

+4

+8

+ 12

+ 16

Baseline

+ 24

Weeks

A. Changes in brief pain inventory scores

tion, Tui na, Gua sha, and acupuncture needling as well as recommendations based in traditional East Asian medicine.

Subjects receive weekly treatment over the course of 12 weeks and are then followed for an additional 12 weeks to evaluate the impact of the treatment on their pain and quality of life. To date we have received more than 540 referrals from health center physicians—demonstrating again the demand for acupuncture services as we did in the first trial—and have enrolled and provided acupuncture therapy for 215 patients.

In addition to evaluating the impact of treatment on pain in our subjects, we are also conducting qualitative interviews with a subset of participants in each study arm to better understand the patients’ experience of acupuncture therapy and to capture information that might not come through easily in our quantitative measures. We are especially interested in how participants’ experience in the group setting resembles or differs from the experience At the Academy’s of those getting individual Annual Clinical Meeting treatment.

September 24, 2016 Lessons Learned: PCORI is an independent Group Acupuncture nonprofit, nongovernmental in Primary Care A 1-hour course with organization established by Melissa Diane McKee, MD, Congress in 2010 to specifiMS; Arya Nielsen, PhD. Sign up today! cally develop new strategies For more information, go to meeting.aapainmanage.org/ to answer the “real world” reregistration/ search questions most important to patients and clinicians.

Like all PCORI projects,

+ 12

+ 24

Weeks

B. Changes in physical functioning

the AADDOPT trial has a very active “stakeholder panel”—a group of advisors who helped design and help guide the course of the study to make sure it is immediately relevant to patient care and to outcomes that matter to patients. Our stakeholder panel includes patient partners, pain advocates and educators, primary care clinicians, insurance company representatives, and representatives of the national acupuncture community.

The panel meets regularly to help advise and provide input for the research team.

Given the mounting pressure to move away from opioids as the first-line treatment for chronic pain, studies examining the “real world” impact of novel treatments like group acupuncture therapy are desperately needed by clinicians and health care organizations across the country. The data that emerges from the AADDOPT-2 trial over the coming two years will hopefully provide new and important information on how to deliver acupuncture care—which is now clearly shown to be effective for these chronic pain conditions— to medically underserved populations.

References 1. McKee MD, Kligler B, Fletcher J, et al. Outcomes of acupuncture for chronic pain in urban primary care. J Am Board Fam Med. 2013;NovDec;26(6):692-700.

2. Vickers AJ, Cronin AM, Maschino AC, et al. Acupuncture for Chronic Pain: Individual Patient Data Meta-analysis. Arch Intern Med. 2012;Oct 22;172(19):1444-1453.

3. Vickers AJ, Linde K. Acupuncture for chronic pain.

JAMA. 2014;311(9) (March 5):955-956.

Benjamin Kligler, MD, MPH, is the vice chair and research director in the department of integrative medicine at Mount Sinai Beth Israel in New York, New York.

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

37

For patients who need consistent analgesia plus tolerability, now you can help them

Experience living on film A different way to transition from short-acting to long-acting opioid therapy BELBUCA™ is the first and only Schedule III long-acting opioid that uses novel buccal film technology to deliver buprenorphine for appropriate patients living with chronic pain1*

About BELBUCA™ *BELBUCA™ (buprenorphine) buccal film is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioid formulations, reserve BELBUCA™ for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• BELBUCA™ is not indicated as an as-needed (prn) analgesic.

IMPORTANT SAFETY INFORMATION about BELBUCA™ WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse BELBUCA™ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.

Assess each patient’s risk prior to prescribing BELBUCA™, and monitor 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 BELBUCA™. Monitor for respiratory depression, especially during initiation of BELBUCA™ or following a dose increase. Misuse or abuse of BELBUCA™ by chewing, swallowing, snorting, or injecting buprenorphine

CONTRAINDICATIONS BELBUCA™ is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (eg, anaphylaxis) to buprenorphine

extracted from the buccal film will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death.

Accidental Exposure Accidental exposure to even one dose of BELBUCA™, especially by children, can result in a fatal overdose of buprenorphine.

Neonatal Opioid Withdrawal Syndrome Prolonged use of BELBUCA™ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse • BELBUCA™ contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA™ exposes users to the risks of addiction, abuse, and misuse.

Reference: 1. BELBUCA™ (Prescribing Information). Malvern, PA: Endo Pharmaceuticals Inc; December 2015.

Find out how to transition appropriate patients onto long-acting BELBUCA™ at BELBUCAfilm.com

A different path forward • Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing BELBUCA™, and monitor all patients receiving BELBUCA™ for the development of these behaviors 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 (eg, 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 BELBUCA™, but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA™, along with intensive monitoring for signs of addiction, abuse, or misuse.

• Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA™ and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

• Abuse or misuse of BELBUCA™ by swallowing may cause choking, overdose, and death.

• Opioid agonists such as BELBUCA™ are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Strategies to reduce the risk include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.

• Contact a 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 buprenorphine, 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.

• While serious, life-threatening or fatal respiratory depression can occur at any time during the use of BELBUCA™, the risk is greatest during initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with BELBUCA™ and following dose increases.

• To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA™ are essential. Overestimating the dose of BELBUCA™ when converting patients from another opioid product may result in fatal overdose with the first dose.

• Accidental exposure to BELBUCA™, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine ADVERSE REACTIONS • The most common adverse reactions (≥5%) reported by patients treated with BELBUCA™ in the clinical trials were nausea, constipation, headache, vomiting, fatigue, dizziness, somnolence, diarrhea, dry mouth, and upper respiratory tract infection.

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

Please see additional Important Safety Information and full Prescribing Information at BELBUCA.com/physician.

Rx Only BELBUCA™ is trademark of Endo International plc or one of its affiliates. © 2016 Endo Pharmaceuticals Inc. All rights reserved. Malvern, PA 19355 BL-04375/March 2016 BELBUCA.com 1-800-462-ENDO (3636)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

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

WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse BELBUCA™ exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing BELBUCA™, and monitor 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 BELBUCA™. Monitor for respiratory depression, especially during initiation of BELBUCA™ or following a dose increase. Misuse or abuse of BELBUCA™ by chewing, swallowing, snorting, or injecting buprenorphine extracted from the buccal film will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death.

Accidental Exposure Accidental exposure to even one dose of BELBUCA™, especially by children, can result in a fatal overdose of buprenorphine.

Neonatal Opioid Withdrawal Syndrome Prolonged use of BELBUCA™ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

1 INDICATIONS AND USAGE BELBUCA™ is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with long-acting opioid formulations, reserve BELBUCA™ for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release options) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• BELBUCA™ is not indicated as an as-needed (prn) analgesic.

4 CONTRAINDICATIONS BELBUCA™ is contradicted in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)] • Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.12), and Adverse Reactions (6)] 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse BELBUCA™ contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA™ exposes users to the risks of addiction, abuse, and misuse.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing BELBUCA™ and monitor all patients receiving BELBUCA™ for the development of these behaviors 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 BELBUCA™, but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA™, along with intensive monitoring for signs of addiction, abuse, or misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed BELBUCA™. Addiction can occur at recommended dosages and if the drug is misused or abused [see Drug Abuse and Dependence (9)].

Abuse or misuse of BELBUCA™ by swallowing may cause choking, overdose, and death [see Overdosage (10)].

Opioid agonists such as buprenorphine are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing BELBUCA™. Strategies to reduce the risk include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [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 buprenorphine, 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 [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 BELBUCA™, the risk is greatest during initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with BELBUCA™ and following dose increases.

To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA™ are essential [see Dosage and Administration (2.3)]. Overestimating the dose of BELBUCA™ when converting patients from another opioid product may result in fatal overdose with the first dose.

Accidental exposure to BELBUCA™, especially in children, might result in respiratory depression and death due to an overdose of buprenorphine.

5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of BELBUCA™ 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, failure to gain weight; and there have been reports of convulsions, apnea, respiratory depression, and bradycardia. 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 [see Use in Specific Populations (8.1)].

5.4 Risks due to Interactions with Central Nervous System Depressants Hypotension, profound sedation, coma or respiratory depression may result if BELBUCA™ 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 BELBUCA™ 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 BELBUCA™ is made, start with a lower dosage of BELBUCA™, monitor patients for signs of sedation, respiratory depression, and hypotension, and consider using a lower dosage of the concomitant CNS depressant [see Drug Interactions (7)].

5.5 Risk of Life-Threatening Respiratory Depression 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. Monitor such patients closely, particularly when initiating and titrating BELBUCA™ and when BELBUCA™ is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].

5.6 Risk of Apnea in Patients with Chronic Pulmonary Disease The use of BELBUCA™ in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

BELBUCA™-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of BELBUCA™ [see Warnings and Precautions (5.2)]. Therefore, closely monitor these patients, especially when initiating and titrating BELBUCA™. Alternatively, consider the use of alternative non-opioid analgesics in these patients.

5.7 QTc Prolongation BELBUCA™ has been observed to prolong the QTc interval in some subjects participating in clinical trials. Consider these observations in clinical decisions when prescribing BELBUCA™ to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Periodic electrocardiographic (ECG) monitoring is recommended in these patients. Avoid the use of BELBUCA™ in patients with a history of Long QT Syndrome or an immediate family member with this condition or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.2)].

5.8 Severe Hypotension BELBUCA™ may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of BELBUCA™. In patients with circulatory shock, BELBUCA™ may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BELBUCA™ in patients with circulatory shock.

5.9 Risks of Use in Patients with Head Injury or Increased Intracranial Pressure In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BELBUCA™ may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with BELBUCA™.

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

5.10 Hepatotoxicity Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual formulations of buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse events reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically during treatment with BELBUCA™.

5.11 Risk of Overdose in Patients With Moderate to Severe Hepatic Impairment In a pharmacokinetic study in subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration (2.5), Use in Specific Populations (8.6)].

5.12 Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. BELBUCA™ is contraindicated in patients with a history of hypersensitivity to buprenorphine.

5.13 Risk of Use in Patients with Gastrointestinal Conditions BELBUCA™ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

BELBUCA™ may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.14 Increased Risk of Seizures in Patients with Seizure Disorders Buprenorphine may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during BELBUCA™ therapy.

5.15 Risks of Use in Cancer Patients with Oral Mucositis Cancer patients with oral mucositis may absorb buprenorphine more rapidly than intended and are likely to experience higher plasma levels of the opioid. For patients with known or suspected mucositis, a dose reduction is recommended. Monitor these patients carefully for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

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

6 ADVERSE REACTIONS The following serious adverse reactions described elsewhere in the labeling include: • 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 (5.4)] • QTc Prolongation [see Warnings and Precautions (5.7)] • Severe Hypotension [see Warnings and Precautions (5.8)] • Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.12)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13)] • Seizures [see Warnings and Precautions (5.14)] 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.

A total of 2,127 patients were treated with BELBUCA™ in controlled and open-label chronic pain trials. There were 504 patients treated for approximately six months and 253 patients treated for approximately one year. The clinical trial population consisted of patients with chronic moderate-to-severe pain.

The most common serious adverse drug reactions (all ≤ 0.2%) occurring during clinical trials with BELBUCA™ were: cellulitis, pneumonia, ileus, atrial fibrillation, coronary artery disease, cerebrovascular accident, syncope, transient ischemic attack, chest pain, non-cardiac chest pain, ankle fracture, cholecystitis, osteoarthritis, and dehydration.

The most common adverse events (≥ 2%) leading to discontinuation were nausea, vomiting, and liver function test abnormality.

The most common adverse events (≥ 5%) reported by opioid naïve, opioid experienced, and overall patients exposed to BELBUCA™ in clinical trials and compared against placebo are shown in Tables 2, 3 and 4: Table 2: Adverse Events Reported in ≥5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Naïve Patients Open-Label Titration Phase

Double-Blind Treatment Phase

BELBUCA™ (N=749)

BELBUCA™ (N=229)

Placebo (N=232)

Nausea

50%

10%

7%

Constipation

13%

4%

3%

Vomiting

8%

4%

<1%

MedDRA Preferred Term

Headache

8%

2%

3%

Dizziness

6%

2%

<1%

Somnolence

7%

1%

<1%

Fatigue

5%

0%

1%

Table 3: Adverse Events Reported in ≥5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Experienced Patients Open-Label Titration Phase BELBUCA (N=810)

BELBUCA (N=254)

Placebo (N=256)

17%

7%

7%

Constipation

8%

3%

1%

Vomiting

7%

5%

2%

Headache

7%

2%

3%

Dizziness

5%

2%

<1%

Somnolence

5%

1%

<1%

Drug Withdrawal Syndrome

0%

4%

10%

™

Table 4: Adverse Events Reported in ≥5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies Open-Label Titration Phase MedDRA Preferred Term

Double-Blind Treatment Phase

™

BELBUCA (N=1889)

BELBUCA (N=600) ™

Placebo (N=606)

If concomitant use is necessary, consider increasing the BELBUCA™ dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider BELBUCA™ dosage reduction and monitor for signs of respiratory depression.

Double-Blind Treatment Phase

Nausea

MedDRA Preferred Term

™

Intervention:

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact:

May reduce the analgesic effect of BELBUCA™ and/or precipitate withdrawal symptoms.

Intervention:

Avoid concomitant use.

Examples:

butorphanol, nalbuphine, pentazocine

Muscle Relaxants Clinical Impact:

Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients receiving muscle relaxants and BELBUCA™ for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BELBUCA™ and/or the muscle relaxant as necessary.

Diuretics Clinical Impact:

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

Intervention:

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

Nausea

33%

9%

8%

Anticholinergic Drugs

Constipation

11%

4%

2%

Clinical Impact:

The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Vomiting

7%

5%

2%

Intervention:

Headache

8%

4%

3%

Monitor patients for signs of urinary retention or reduced gastric motility when BELBUCA™ is used concomitantly with anticholinergic drugs.

Dizziness

6%

2%

<1%

Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)

Somnolence

6%

<1%

<1%

Clinical Impact:

Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.

Drug Withdrawal Syndrome

1%

2%

5%

Intervention:

None

The most common (≥ 5%), common (≥ 1% to < 5%), and least common (< 1%) adverse reactions reported by patients taking BELBUCA™ in the controlled and open-label clinical studies are presented below: Most common adverse reactions (≥ 5%): nausea, constipation, headache, vomiting, fatigue, dizziness, somnolence, diarrhea, dry mouth, and upper respiratory tract infection.

Common (≥ 1% to < 5%) adverse reactions (organized by MedDRA [Medical Dictionary for Regulatory Activities] System Organ Class): Blood and lymphatic system disorders: anemia Gastrointestinal disorders: abdominal pain General disorders and administration site conditions: peripheral edema, pyrexia, drug withdrawal syndrome Infections and infestations: urinary tract infection, nasopharyngitis, sinusitis, bronchitis, gastroenteritis Injury, poisoning, and procedural complications: contusion, fall Metabolism and nutrition disorders: decreased appetite Musculoskeletal and connective tissue disorders: muscle spasms, back pain Psychiatric disorders: anxiety, insomnia, depression Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, sinus congestion Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash Vascular disorders: hot flush, hypertension Least common (<1%) adverse reactions: Abdominal discomfort, acute sinusitis, dyspepsia, toothache, asthenia, chills, cellulitis, tooth abscess, excoriation, laceration, aspartate aminotransferase increased, blood pressure increased, blood testosterone decreased, electrocardiogram QT prolonged, liver function test abnormal, musculoskeletal pain, neck pain, hypoesthesia, lethargy, migraine, tremor, cough, dyspnea, nasal congestion, rhinorrhea 7 DRUG INTERACTIONS Table 5 includes clinically significant drug interactions with BELBUCA™.

Benzodiazepines Clinical Impact:

There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.

Intervention:

Closely monitor patients with concurrent use of BELBUCA™ and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BELBUCA™, and warn patients to use benzodiazepines concurrently with BELBUCA™ only as directed by their physician.

Central Nervous System (CNS) Depressants Clinical Impact:

Due to additive pharmacologic effects, the concomitant use of CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention:

Consider dose reduction of one or both drugs. Monitor patients for signs of respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.4)].

Examples:

Alcohol, anxiolytics, general anesthetics, hypnotics, neuroleptics, phenothiazines, sedatives, tranquilizers, other opioids.

Inhibitors of CYP3A4 Clinical Impact:

The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BELBUCA™ is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.

Intervention:

If concomitant use is necessary, consider dosage reduction of BELBUCA™ until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the BELBUCA™ dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

CYP3A4 Inducers Clinical Impact:

The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.

Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Clinical Impact:

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.

Intervention:

Patients who are on chronic BELBUCA™ treatment should have their dose monitored if NNRTIs are added to their treatment regimen.

Examples:

efavirenz, nevirapine, etravirine, delavirdine

Antiretrovirals: Protease inhibitors (PIs) Clinical Impact:

Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.

Intervention:

Monitor patients taking BELBUCA™ and atazanavir with and without ritonavir, and dose reduction of BELBUCA™ may be warranted.

Examples:

atazanavir, ritonavir

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of BELBUCA™ or buprenorphine in pregnant women. Limited published data on use of buprenorphine, the active ingredient in BELBUCA™, in pregnancy, have not shown an increased risk of major malformations. In animal reproduction studies, embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis via the oral route of administration at doses approximately 53 to 11 times the maximum recommended human dose (MRHD), respectively. In pre- and post-natal development studies in rats, dystocia was observed after treatment with buprenorphine via the IM route of administration at a dose approximately 27 times the MRHD, and increased neonatal death was observed after treatment via the oral, IM, and SC routes of administration at doses approximately 4, 3, and 0.5 times the MRHD, respectively. No teratogenic effects were observed in rats treated with buprenorphine via the oral, IM, and IV routes of administration during organogenesis at doses approximately 853, 27, and 4 times the MRHD, respectively, or in rabbits treated with buprenorphine via the oral, SC, and IV routes of administration at doses approximately 267, 53, and 9 times the MRHD, respectively. However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings were not clearly treatment-related [see Data].

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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, including poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, 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. BELBUCA™ is not recommended for use in women immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including BELBUCA™, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Data Animal Data Buprenorphine administration during organogenesis was not teratogenic in rats or rabbits after intramuscular (IM) or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 27 and 53 times, respectively, the maximum recommended human dose (MRHD) for buccal BELBUCA™ of 1.8 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 4 and 9 times, respectively, the MRHD), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 853 times the MRHD) and 25 mg/kg/day in rabbits (estimated exposure was approximately 267 times the MRHD). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 5 times the MRHD), but were not observed at oral doses up to 160 mg/kg/day (estimated exposure was approximately 853 times the MRHD. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 53 times the MRHD) or oral administration of 1 mg/kg/day or greater estimated exposure was approximately 11 times the MRHD) were not statistically significant.

In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater (estimated exposure was approximately 11 times the MRHD) and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure was approximately 2 times the MRHD).

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 27 times the MRHD). Fertility, peri- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 4 times the MRHD), after IM doses of 0.5 mg/kg/day and up (approximately 3 times the MRHD), and after SC doses of 0.1 mg/kg/day and up (approximately 0.5 times the MRHD). Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 427 times the MRHD).

8.2 Lactation Risk Summary Based on two studies in 13 lactating women being treated for opioid dependence and their breastfed infants, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants [see Data]. There are no data on the effects of BELBUCA™ on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with BELBUCA™.

Clinical Considerations Infants exposed to BELBUCA™ through breast milk should be monitored for excess sedation and respiratory depression.

Withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breast-feeding is stopped.

Data Based on limited data from a study of six lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose. The median concentrations of buprenorphine and norbuprenorphine in infant urine were 1.0 nmol/L and 2.3 nmol/L, respectively.

Based on limited data from a study of seven lactating women being treated for opioid dependence who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L, respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.

No adverse reactions were observed in the infants in these two studies.

8.4 Pediatric Use The safety and efficacy of BELBUCA™ have not been established in pediatric patients.

8.5 Geriatric Use Of the total number of patients that were treated with BELBUCA™ in controlled and open-label chronic pain trials (2,127), 340 patients were 65 years and older. Of those, 49 patients were aged 75 years and older. The incidences of selected BELBUCA™-related adverse effects were higher in older subjects.

No notable differences in pharmacokinetics were observed from population pharmacokinetic analysis in subjects aged 65 compared to younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between the elderly and younger patients. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment BELBUCA™ has not been evaluated in patients with severe hepatic impairment.

The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study.

Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

Given that increased buprenorphine plasma levels are associated with a greater risk of toxicity and overdose, a dosage reduction in patients with severe hepatic impairment (i.e., Child-Pugh C) is recommended [see Dosage and Administration (2.5)]. Monitor patients with severe hepatic impairment for signs and symptoms of overdose. A dosage reduction in patients with moderate hepatic impairment (Child-Pugh B) is not needed, however, monitor these patients for signs and symptoms of toxicity or overdose.

A dosage reduction in patients with mild hepatic impairment (Child-Pugh A) is not needed [see Dosage and Administration (2.5), Warnings and Precautions (5.11) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent patients and 6 patients with normal renal function following IV administration of 0.3 mg buprenorphine.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance BELBUCA™ contains buprenorphine hydrochloride, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. BELBUCA™ can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

9.2 Abuse All patients treated with opioids, including BELBUCA™, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carry the risk of addiction, even under appropriate medical use.

Prescription drug abuse is the intentional, non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care providers(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all persons with substance use disorders. In addition, abuse of opioids can occur in the absence of true addiction.

BELBUCA™, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.

Risks Specific to Abuse of BELBUCA™ BELBUCA™ is intended for buccal use only. Abuse of BELBUCA™ poses a risk of overdose and death. This risk is increased with concurrent abuse of BELBUCA™ with alcohol and other substances, including other opioids and benzodiazepines [see Warnings and Precautions (5.4), Drug Interactions (7)]. Intentional compromise of the buccal film might result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the buccal film in the absence of legitimate purpose, or by swallowing, snorting, or injecting buprenorphine extracted from the buccal film.

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 dose reduction of a drug.

Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

BELBUCA™ should not be abruptly discontinued [see Dosage and Administration (2.4)]. If BELBUCA™ is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, or diarrhea or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].

10 OVERDOSAGE Clinical Presentation Acute overdosage with BELBUCA™ is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, 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.

Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema, as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

Naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used.

Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BELBUCA™, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required for at least 24 hours because of the possibility of extended effects of buprenorphine.

In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced 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 with an opioid antagonist, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Addiction, Abuse, and Misuse Inform patients that the use of BELBUCA™, even when taken as recommended, can result in addiction, abuse, and misuse, which could lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share BELBUCA™ with others and to take steps to protect BELBUCA™ from theft or misuse.

Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting BELBUCA™ or when the dose is increased and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Exposure Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store BELBUCA™ securely and to dispose of unused BELBUCA™ by opening unused packages and flushing the film down the toilet.

Interaction with Alcohol and other CNS Depressants Inform patients that potentially serious additive effects may occur if BELBUCA™ is used with alcohol or other CNS depressants and not to use such drugs unless supervised by a health care provider [see Warnings and Precautions (5.4)].

Interaction with Benzodiazepines Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BELBUCA™, and warn patients to use benzodiazepines concurrently with BELBUCA™ only as directed by their physician [see Drug Interactions (7)].

Hypotension Inform patients that BELBUCA™ may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12)].

Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Warnings and Precautions (5.13)].

Driving or Operating Heavy Machinery Inform patients that BELBUCA™ may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.16)].

Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in BELBUCA™. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions (5.12)].

Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of BELBUCA™ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].

Embryofetal Toxicity Advise female patients that BELBUCA™ can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation Advise patients that breastfeeding is not recommended during treatment with BELBUCA™ [see Use in Specific Populations (8.2)].

Important Administration Instructions Instruct patients how to properly use BELBUCA™, including the following: 1. To carefully follow instructions for the application of BELBUCA™ and to avoid eating or drinking until it dissolves.

2. To apply BELBUCA™ once daily, or every twelve (12) hours at the same time or times each day.

3. To avoid applying BELBUCA™ to areas of the mouth with any open sores or lesions.

4. To not use BELBUCA™ if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way.

Disposal Instruct patients to dispose of BELBUCA™ as soon as it is no longer needed. To dispose of unused BELBUCA™ film, inform the patient to: 1. Remove all BELBUCA™ films from their foil packages.

2. Drop the BELBUCA™ films into toilet and flush.

3. Discard foil packaging in trash.

Instruct patients not to flush BELBUCA™ down the toilet in the foil packages or cartons [see Dosage and Administration (2.8)].

Healthcare professionals can telephone Endo Pharmaceuticals (1-800-462-3636) for information on this product.

Distributed by: Endo Pharmaceuticals Inc. Malvern, PA 19355 © 2016 Endo Pharmaceuticals Inc. All rights reserved.

This brief summary is based on BELBUCA™ Prescribing Information, Revised 12/2015.

BL-04375/March 2016

Xerostomia: The Sticky Problem of Dry Mouth

By Shauna S. Pit tman, PharmD

A

irina bg / Shutterstock

lthough clinicians are generally aware that many of the medications used to treat chronic pain can cause or contribute to dry mouth, research comparing different management approaches for simple dry mouth is limited. Reports place the overall incidence at 17% to 29%, and it is significantly more commonly noted in women (1). Because not every patient who experiences dry mouth reports this symptom to a health care provider, however, the actual prevalence of dry mouth is unknown. One can surmise from the explosion of dry mouth products available over-the-counter that this is a common problem faced by many.

Chronic dry mouth is more than just uncomfortable.

Saliva, in fact, is needed to taste, swallow, and digest food, discourage tooth decay, and prevent bacterial and fungal growth in the mouth (2). Insufficient saliva production can contribute to bad breath, dental caries, irritation of the mouth, tongue, and gums, and problems eating and speaking (3). Dry mouth can occur in patients with sleep apnea, depression, anxiety, and malnutrition, and be exacerbated in those who consume tobacco products, alcohol, or caffeinated beverages (2-5).

While a decrease in saliva can be caused by conditions that directly affect the salivary glands such as chemotherapy, radiation therapy to the head and neck, and Sjögren’s syndrome, in the majority of cases it is a side effect of medications (1-3).

Though individually numbering into the hundreds, the classes of medication that most commonly cause most cases of dry mouth are antidepressants, antihistamines, antispasmodics, skeletal muscle relaxants, and opioid analgesics, as well as other medications specifically used for anticholinergic effects in overactive bladder and Parkinson’s disease (1-3,6). The xerostomic effects of medications are additive, which may explain why elderly patients, typically those on a greater number of medications, report dry mouth frequently (6-8).

to strong teeth, good digestion, and a healthy mouth (1,2).

For these reasons, two of the mainstays of treatment are stimulating saliva flow locally and adding an artificial saliva substitute. In patients with at least partially functioning salivary glands, chewing sugarless gum or sucking a lozenge can be an easy and effective way to stimulate saliva secretion (1). Using a spray or gel saliva substitute is another effective strategy for managing symptoms. One newer delivery system is the oral adhesive disintegrating disc that may provide a longer duration of effect due to longer contact time (9).

Effective home hygiene is essential with chronic dry mouth, and several commercially available product lines include mouthwashes and toothpastes formulated for dry mouth. Of the variety of ingredients in each product, those with chlorhexidine or xylitol may be preferable to others to decrease the risk of dental caries (10). Though the saliva substitutes may contain some of the same enzymes as saliva, as well as lubricants, demulcents and/or polymers, there are no mucin-containing products approved in the US. Natural ingredients such as aloe, slippery elm, green tea, zinc, yohimbine, yerba santa, and essential oils appear in some products, but their effectiveness is largely unknown (1). Compara-

Treatment Options

Although saliva is approximately 99% water, other components are vital to the function and feeling of moisture (1).

Buffers, enzymes, proteins, and mucin in saliva are essential THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

43

Xerostomia: The Stick y Problem of Dry Mouth

Table. Patient Education for Xerostomia (Dry Mouth) (1,2,6,21) • Dry mouth increases risk of mouth, teeth, and gums problems.

Practice good dental hygiene at home, with consideration to fluoridecontaining products.

• Regular dental cleaning by a professional is essential. Ask your dentist for coupons and samples of products for dry mouth.

• Soak dentures in a 0.2% chlorhexidine or dilute bleach solution.

• Avoid sticky, sugary, or acidic candies that may promote tooth decay.

• Acidic drinks and salty or spicy foods can irritate a dry mouth.

• Dry mouth may be worsened by lifestyle choices such as consumption of tobacco, alcohol, or caffeinated products.

• Assure good hydration. Drink water or sugarless drinks and suck ice chips.

• Chew sugar-free gum or suck on sugar-free hard candy to stimulate saliva. Be aware that frequent gum use may worsen TMJ, and that sorbitol and xylitol (in sugar-free products) can cause gas and bloating if used in excess.

• Use a vaporizer at night, especially if you are a mouth breather.

• Use a spray or gel for dry mouth before sleep and keep at bedside for use during the night.

• Avoid alcohol in mouthwashes, which may worsen dryness or irritation.

• Avoid sodium lauryl sulfate in toothpaste (foaming ingredient) as it may cause irritation in chronic dry mouth.

• Cinnamon, citrus, and mint flavors may be irritating to some people.

Tell your providers about your symptoms. Ask your provider or pharmacist if your medication could worsen your symptoms.

tive studies between products are lacking, and several of the products studied are not available in the US, so it is difficult to render a professional recommendation of one product over another (11). Consumer preferences are highly variable, as noted on reviews posted on online retail sites. General trends can be noted, but even with the most popular products by sales volume, there is wide variability with response and tolerance of texture and taste.

If over-the-counter topical At the Academy’s Annual Clinical Meeting stimulants and saliva substiSeptember 24, 2016 Do’s and Don’ts: Safe tutes do not provide adequate Prescribing of OTC relief, detailed oral exam, with Analgesics and Protecting Your consideration for sialometric Patients from Drug Interactions testing should be performed, Two, 1-hour courses with to rule out other serious Shauna Pittman, PharmD. Sign up today! causes of xerostomia (1,2).

For more information, go to The prescription stimulants meeting.aapainmanage.org/ registration/ pilocarpine (Salagen®) and cevimeline (Evoxac®) are most commonly utilized in patients 44

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

with at least partially functioning glands, but side effects and thrice daily dosing are major drawbacks for use in uncomplicated dry mouth, and both carry warnings for narrow-angle glaucoma, and cardiac and pulmonary disease (1,3,12-14).

Prescription fluoride toothpaste formulated for dry mouth may also be considered for patients that do not have adequate results with over-the-counter options (2). A prescription oxygenated glycerol tri-ester spray (AquoralR) was shown to be more effective than some saliva substitutes, but if not covered by insurance the price is prohibitive to many (15). Future developments may come from ongoing research into gene therapy, immunologic agents, and electrical stimulation devices to treat salivary gland hypofunction (1,3,16).

Patient Management

Although there are simple, and even complex means of diagnosing dry mouth, noting a subjective response to the question “does your mouth usually feel dry” during assessment may be sufficient (3,17). With an affirmative response, providers should first take a detailed history of prescription and OTC medications and consider discontinuing any nonessential medications that may be contributory to reported dry mouth. Next, dose adjustment or substitution of xerostomic medications with a different drug class could eliminate or reduce the negative impact on quality of life (1,3,18-20). The goal of treatment is to manage symptoms while avoiding oral complications (1). Lifestyle modifications and patient counseling (Table) can empower patients to mitigate and manage the effects of drug-induced xerostomia (2). Pain providers may choose to request samples and coupons from product manufacturers as a service to their patients.

Available research indicates that the studied saliva substitutes were preferable to no treatment or to placebo, however, comparative studies between most of the US available overthe-counter products are lacking (11). Patient needs and preferences dictate that a variety of products, perhaps even from different manufacturers, may need to be combined to form an optimal regimen to combat xerostomia. With provider awareness, patient education, and perhaps multiple product trials, many patients with medication-induced xerostomia should find satisfactory symptomatic improvement.

Resources

Dry Mouth: US Dept of Health and Human Services, National Institutes of Health 8 page booklet/pdf NIH Publication 14-3174 August 2014, not copyrighted, available to print for patient use. http://www.nidcr.nih.gov/oralhealth/

XEROSTOMIA: THE STICK Y PROBLEM OF DRY MOUTH

Topics/DryMouth/Documents/DryMouth_082714_508C. pdf. Accessed May 17, 2016.

12.

13.

References: 1.

Miranda-Rius J, Brunet-Llobet L, Lohor-Soler E, Farré M. Salivary secretory disorders, inducing drugs, and clinical management. Int J Med Sci. 2015;12:811-824.

2. Plemons JM, Al-Hashimi I, Marek CL, American Dental Association Council on Scientific Affairs. Managing xerostomia and salivary gland hypofunction: a report of the ADA Council on Scientific Affairs. February 2015. http://www.ada.org/~/ media/ADA/Science%20and%20Research/Files/CSA_Managing_Xerostomia. pdf?la=en Accessed May 9, 2016.

3. Villa A, Connell CL, Abati S. Diagnosis and management of xerostomia and hyposalivation. Ther Clin Risk Manag. 2015;11;45-51.

4. Villa A, Polimeni A, Strohmenger L, Cicciù D, Gherlone E, Abati S. Dental patients’ self-reports of xerostomia and associated risk factors. J Am Dent Assoc.

2011;142:811-816.

5. Bergdahl M, Bergdahl J. Low unstimulated salivary flow and subjective oral dryness: association with medication, anxiety, depression, and stress. J Dent Res. 2000;79:1652-1658.

6. Scully C. Drug effects on salivary glands: dry mouth. Oral Dis. 2003;9,165-176.

7. Villa A, Abati S. Risk factors and symptoms associated with xerostomia: a crosssectonal study. Aust Dent J. 2011;56:290-295.

8. Singh ML, Papas A. Oral implications of polypharmacy in the elderly. Dent Clin North Am. 2014;58:783-796.

9. Kerr AR, Corby PM, Shah SS, Epler M, Fisch GS, Norman RG. Use of a mucoadhesive disk for relief of dry mouth: a randomized, double-masked, controlled crossover study. J Am Dent Assoc. 2010;141(10):1250-1256.

10. Rethman MP, Beltran-Aguilar ED, Billings RJ et al. Non-fluoride caries preventive agents: full report of a systematic review and evidence-based recommendations. Report of the Council on Scientific Affairs. May 24, 2011. Chicago, IL: ADA Center for Evidence-Based Dentistry. http://ebd.ada.org/~/media/EBD/Files/clinical_recommendations_non_fluoride_caries_preve.ashx. Accessed May 9, 2016.

11. Furness S, Worthington HV, Bryan G, Birchenough S, McMillan R. Interventions

14.

15.

16.

17.

18.

19.

for the management of dry mouth: topical therapies. Cochrane Database Syst Rev. 2011;(12):CD008934.

Ramos-Casals M, Tzioufas AG, Stone JH, Sisó A, Bosch X. Treatment of primary Sjögren syndrome: a systematic review. JAMA. 2010;304:452-460.

Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multi-center trial. P92-01 Study Group. Arch Intern Med. 1999;159:174-181.

Fife RS, Chase WF, Dore RK, et al. Cevimeline for the treatment of xerostomia in patients with Sjogren syndrome: a randomized trial. Arch Intern Med. 2002;162:1293-1300.

Mouly SJ, Orler JB, Tillet Y, et al. Efficacy of a new oral lubricant solution in the management of psychotropic drug-induced xerostomia: a randomized controlled trial. J Clin Psychopharmacol. 2007; 27:437-443.

Strietzel FP, Lafaurie GI, Mendoza GR, et al. Efficacy and safety of an intraoral electrostimulation device for xerostomia relief: a multicenter, randomized trial.

Arthritis Rheum. 2011;63:180-190. van der Putten GJ, Brand HS, Schols JM, de Baat C. The diagnostic suitability of a xerostomia questionnaire and the association between xerostomia, hyposalivation, and medication use in a group of nursing home residents. Clin Oral Investig.

2011;15:185-192.

Sreebny LM, Valdini A. Xerostomia. A neglected symptom. Arch Intern Med. 1987;147:1333-1337.

Azodo CC, Ezeja EB, Omoaregba JO, James BO. Oral health of psychiatric patients: the nurse’s perspective. Int J Dent Hyg. 2012;10:245-249.

20. Trindade E, Menon D, Topfer LA, Coloma C. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ. 1998;159:1245-1252.

21. Visvanathan V, Nix P. Managing the patient presenting with xerostomia:a review. Int J Clin Pract. 2010;64:407.

Shauna S. Pittman, PharmD, clinical pharmacy specialist, Pain Management, Contractor, Caduceus Heathcare

FIND YOUR STATE’S POLICY PAGE ON SPPAN’S WEBSITE

sppan.aapainmanage.org

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

45

On Gratitude: A Conversation with Robert Emmons

BY BRUCE F. SINGER, PSYD

R

obert A. Emmons, PhD, is a professor of psychology at the University of California, Davis, where he has taught since 1988. He is the author of nearly 200 original peer-reviewed journal publications and book chapters and has written or edited six books, including The Psychology of Ultimate Concerns (Guilford Press), The Psychology of Gratitude (Oxford University Press), and the forthcoming The Little Book of Gratitude (Hachette). A leader in the positive psychology movement, Dr. Emmons is the founding editor and editorin-chief of The Journal of Positive Psychology. His research focuses on the psychology of gratitude and thankfulness in both adults and youth and also includes the psychology and spirituality of joy and grace as they relate to human flourishing.

Research has shown that the practice of gratitude yields numerous benefits, including (1): • A 23% lower level of cortisol.

• A 7% reduction in biomarkers of inflammation in patients with congestive heart failure.

• A reduction in dietary fat intake of as much as 25% when people are keeping a gratitude journal.

• A deceleration of the effects of neurodegeneration (as measured by a 9% increase in verbal fluency) that occurs with increasing age.

• A 16% reduction in diastolic blood pressure and a 10% reduction in systolic blood pressure.

• A 10% improvement in sleep quality in patients with chronic pain, 76% of whom had insomnia, as well as a 19% reduction in depression levels.

As a pain and addiction psychologist, I have written about utilizing gratitude with chronic pain patients (2) and have introduced therapy groups on gratefulness into biopsychosocial treatment programs for chronic pain syndromes. Individuals are encouraged to maintain gratefulness logs and explore websites such as gratefulness.org where essays, poems, and activities that focus on cultivating gratitude are plentiful. So, for me, it was a personal pleasure and an honor to reach out to Dr. Emmons to

46

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

understand his thoughts on what I consider a profoundly significant component of mental and spiritual health.

BFS: I’ve been trying to come up with my earliest

memory of experiencing gratitude and I have to admit that it hasn’t been easy. I recall times as a young boy when I complained about a dinner my mother had made, and how she would tell me that I should be happy to have food as “there are thousands of children in India who are starving.” I’m not sure that was the best exposure to principles of gratefulness but it did lead me, eventually, to appreciate the life I was born into. Do you recall your first experience with gratitude?

RAE: I cannot. But I’m sure it was not when I was young. Gratitude does not come easily or naturally to young

Robert Emmons, author and a leader in the positive psychology movement. His research focuses on the psychology of gratitude and thankfulness. He suggests that people with chronic pain can practice gratitude by reflecting on specific kindnesses they have received.

On Gr atitude: A Conversation with Robert Emmons

Flow of Gifts Meditation In this activity you will focus for a moment on the benefits or “gifts” that you have received in your life. These gifts could be simple everyday pleasures, people in your life, personal strengths or talents that you possess, moments of natural beauty, or gestures of kindness you’ve received from others.

We might not usually think about these things as gifts but that is how I want you to think about them.

Slowly repeat the word “gift” or a phrase such as “I am gifted” or “I have been gifted” several times.

Now, in addition to thinking about these gifts, try to really experience them. “All goods look better when they look like gifts,” wrote the British author G.K. Chesterton. Consider the effort or thoughtfulness of the giver. Ponder how little you’ve done to earn or merit the gift, yet here it is anyway. Enrich the gift by

savoring it, relishing it, delighting in it, thinking about what your life would be like without it. Instead of taking it for granted, take it as granted. As you proceed through this step, try to bring to mind surprising or unexpected gifts that you have received.

We are not simply the final destination in the flow of these gifts.

Rather, we find ourselves midstream. Good things flow to us from our givers (other people, God, the universe) but also flow from us to others. We are simultaneously receivers and givers. In some spiritual traditions the term “favor” is used.

You may find it useful to think about how you have received favor today, and how you can pass along that favor to others. You may find it useful to visualize a stream of water, a stream of remarkable clarity, with no beginning and no ending, flow-

children. When I was an early adolescent, I enjoyed riding my bike around Newtown and admiring fall foliage. I believe that my gratitude was mostly nature-related. I felt awe and wonder at nature, tinged with a cosmic gratitude.

BFS: I discovered your work on gratitude through my own clinical work as a pain psychologist, but I wonder what led you to want to research the effects of gratefulness on chronic pain?

RAE: I had the opportunity to partner with colleagues in the department of physical medicine and rehabilitation here at the UC Davis Medical Center. They had a federal research and training grant to help people with neuromuscular disorders. It seemed to me that since gratitude led to wholeness and wellness and happiness that its healing power could extend to people with chronic pain.

BFS: What have you discovered from your research on gratefulness and chronic pain that surprised you?

RAE: Actually, we did not find that our gratitude intervention helped reduce pain all that much, nor lessen pain’s influence on daily activities. That surprised me, but it helped establish that there are boundary conditions on the healing power of gratitude. Although it is often associated with better

ing into you, and then on from you.

As a channel of gifts and favor, ask yourself, “How can I pass along this goodness to those in need?

How can I share these gifts with others?” Commit to not hoarding these gifts. In what way can you give back for the many ways you have been gifted? What are some concrete ways that you can honor the giver? Can you “pay it forward”? Who can you tell about this gift you received? Let your gratitude overflow into blessing, filling those around you.

Excerpted from Robert Emmons’ new book, Little Book of Gratitude, which will be out this summer (3).

outcomes, it is not a panacea or a miracle drug. I think it is really hard to conjure up thankfulness when you have chronic pain. For many of our participants, a good and grateful day was when their pain was 5 instead of 10 on the pain meter.

BFS: How do you define gratitude now? Has this definition evolved over time for you because of your work in this area?

RAE: Not really. Gratitude is still an affirmation of the goodness in one’s life and the recognition that the sources of this goodness lie at least partially outside the self. It’s very much a form of awareness, a way of seeing.

BFS: What practical suggestions might you have for an individual with chronic pain to practice gratefulness as a pain management tool?

RAE: I would say it is best to stay very specific and focused on others, such as people doing things for them that they cannot do for themselves. What specific kindnesses, gifts, favors, did they receive? What pleasant things happened that were surprising or unexpected? And why did those things happen? This sort of reflection can be useful.

BFS: How would you imagine gratefulness could be integrated into current pain management practices?

RAE: I think it can be part of a meditation, just as mindTHE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

47

On Gr atitude: A Conversation with Robert Emmons

fulness is. I heard someone say that gratefulness is the new mindfulness. I like this “flow of gifts” meditation (see box).

BFS: Are there any emerging literature or recent research findings you might want to share?

RAE: With respect to chronic pain, the biggest impact could be that gratitude is effective in reducing the length of depression episodes as well as their future recurrence. As you well know, depression co-occurs with chronic pain. Gratitude interventions are promising treatments for mental illnesses, especially mood disorders. Promotion of gratitude has even been associated with reductions of hopelessness, suicidal ideation, and suicidal attempts independently of depression (4,5).

BFS: In my work with mindfulness I focus on compassion: both toward myself and to others. It seems to me that in practicing compassion I experience the giving and receiving of gratefulness. Have you thought much about the nexus between compassion and gratefulness and whether compassion is a component of gratitude or vice versa?

RAE: Well, we could think of them both as prosocial, in that they are often associated with behavior that is designed to make life better for oneself and for others. They both

NEW, ONLINE...

FREE TO MEMBERS!

lead to happiness. In other respects, they are very different.

Gratitude is a celebration of the good, whether in one’s life or in others, as when good fortune befalls a loved one. Compassion is feeling sorrow and pity for the bad fortunes of others.

BFS: As a follow-up, the Vietnamese Buddhist monk, Thich Nhat Hanh, sees compassion as a means for social activism and change. Some say that gratefulness promotes a certain passivity in this regard as in “Be grateful for what you have.” What might be your thoughts on this?

RAE: That’s interesting, I often think about it the other way around. Compassion can be more passive (especially if one perceives efforts to help will be ineffective), and gratitude is motivating. I could feel bad about another person’s suffering, without committing to getting personally involved.

On the other hand, gratitude causes us to want to give back the goodness we have received; in fact, reciprocity or paying forward the kindness is the action tendency associated with gratitude as an emotion. There is research linking gratitude to life purpose and increased goal striving, to helping and generosity, and of course to philanthropy (6,7).

BFS: Do you think we are taught gratefulness or is it in-

ACCREDITED EDUCATION. ANYTIME YOU WANT. WHENEVER YOU WANT. The Academy’s new online learning management center provides on-going education for those caring for people with chronic pain. All programs are accredited for continuing education and include: • Audiovisual presentations from leading experts in the field of pain management.

• Written educational activities that are theoretical and practical.

• New programs added every month.

• The ability to print your accreditation certificate and access your continuing education history at any time.

GO TO EDUCATION.AAPAINMANAGE.ORG TO GET STARTED TODAY!

48

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

ON GR ATITUDE: A CONVERSATION WITH ROBERT EMMONS

herent in our DNA? I’ve worked with patients who have said they have nothing to be grateful for. What would you say to someone who dismisses the qualities of gratefulness?

RAE: I would ask them to make a list of people in their lives whom they have depended upon in the past or in the present. I would ask them to what degree they believe they could exist apart from the care and nurturance they have received, and are continuing to receive. I would ask them to contemplate all the people and institutions that make their lives possible, keep them safe, and provide them with opportunities. If they are honest this list will be virtually endless.

BFS: I appreciate the time you’ve taken to have At the Academy’s Annual Clinical Meeting this conversation. One last September 24, 2016 GUIDED IMAGERY FOR PAIN question that I am sure anyTwo, 30-minute courses with one reading this would want Bruce Singer, PsyD. to ask: What are you grateful Sign up today!

For more information, go to for in your life? meeting.aapainmanage.org/ registration/ RAE: This sounds trite but most of all I am grateful for the opportunity to spread

the word that gratitude heals, energizes, and changes lives.

The more I study gratitude, the more I realize that you cannot overplay its hand. That people are open to this message is extremely gratifying.

References 1.

2.

3.

4.

5.

Gratitude is Good Medicine. UC Davis Medical Center. https://www.ucdmc.ucdavis.edu/medicalcenter/features/2015-2016/11/20151125_gratitude.html. Posted November 25, 2015. Accessed April 25, 2016.

Singer BF. Grateful In Spite of Pain. A Network for Grateful Living. http:// www.gratefulness.org/grateful_living/grateful-in-spite-of-pain/. Accessed April 25, 2016.

Emmons R. The Little Book of Gratitude. New York: Hachette; 2016.

Van Dusen JP, Tiamiyu MF, Kashdan TB, Elhai JD. Gratitude, depression and PTSD: Assessment of structural relationships. Psychiatry Res. 2015;230(3): 867-870.

Kleiman EM, Adams LM, Kashdan TB, Riskind JH. Gratitude and grit indirectly reduce risk of suicidal ideations by enhancing meaning in life: Evidence for a mediated moderation model. J Res Pers. 2013;47(5):539–546.

6. Emmons RA, Mishra A. Why gratitude enhances wellbeing: What we know, what we need to know. In Sheldon K, Kashdan T, Steger MF. (Eds.) Designing Positive Psychology: Taking Stock and Moving Forward. New York: Oxford University Press; 248–262.

7. Grant AM, Gino F. A little thanks goes a long way: Explaining why gratitude expressions motivate prosocial behavior. J Pers Soc Psychol. 2010;98(6):946–955.

Bruce F. Singer, PsyD, is a licensed psychologist who serves as Chief of Psychology for Crossroads Centre Antigua.

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

49

discussion

Co-prescribing of Naloxone in Conjunction with Opioid Therapy A Statement from the American Academy of Pain Management, as posted on the Academy’s website

The United States is in the midst of two extraordinarily challenging and persistent public health crises, which are equally puzzling and intertwined.

Chronic pain was noted by the Institute of Medicine in its 2011 report, Relieving Pain in America, to affect more than 100 million American adults, and to cost $560-$635 billion dollars per year, both of which exceed the respective combined totals for cancer, heart attack and stroke, and diabetes.

Later studies found that about 25 million American adults experience daily chronic pain, while the Institute of Medicine also noted that 10 million Americans are disabled by painful conditions, and chronic pain at least doubles the risk of completed suicide (1).

Prescription drug abuse has become even more widely known as a public health crisis. Data from the 2014 National Survey on Drug Use and Health show that 10.3 million Americans aged 12 and older used prescription pain relievers non-medically in the past year indicating significant exposure, while approximately 1.5 million meet DSM-IV criteria for opioid dependence (2). Cost estimates for this problem range from about $50 billion per year to $120 billion per year, depending on source and the types of costs included.

Perhaps most concerning, the US Centers for Disease Control and Prevention reports that, in 2014, 28,647 Americans died of overdoses involving licit and illicit opioids, with roughly 18,000 of those involving prescription opioid analgesics (3).

Risk Mitigation

The admonition primum non nocere (first, do no harm) is often cited as a primary tenet of medical practice. One aspect of meeting this standard involves prospectively identifying risks and taking steps to mitigate those risks by providing patients with counter-measures. A classic example of this is prescribing an epinephrine auto-injector to someone with an identified risk of anaphylaxis.

In the case of opioid therapy, the greatest risk is the potential for fatal respiratory depression resulting from opioid use. Prescribers and patients need to recognize that several parties are at risk in this regard, including the following: 50

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

• People with a prescription for opioids – Patients taking them exactly as directed – Patients taking them other than exactly as directed – Patients taking them with other central nervous system depressants, both prescription and non-prescription – Patients altering the route of administration • People without a prescription for opioids – Those who use medications prescribed for others, intentionally or unintentionally – Those who use illicit opioids A variety of interventions has been proposed to stem the tide of overdose deaths, the number of which continues to increase on a yearly basis. Among these proposed riskmitigating remedies is increasing the availability of opioid antagonists, principally naloxone, so that they are available for administration by non-health care providers who encounter someone experiencing clinically significant respiratory depression. The past few years have seen incredible activity in state and federal legislatures, with more than 250 bills expanding access to naloxone introduced in 46 states and the US Congress, in 2015 alone (4).

Studies in North Carolina by Project Lazarus (5), and in Massachusetts by a variety of health and law enforcement agencies (6), have demonstrated that increasing the availability of naloxone on a community-wide basis can result in a substantial number of overdose reversals. Consequently, many policy efforts have focused on making naloxone available in pharmacies without a prescription, to first responders of all types, and to people with pain and their caregivers when opioid analgesics are prescribed.

The purpose of this statement from the American Academy of Pain Management is to set out guiding principles for clinicians who prescribe opioid therapy for their patients.

Given the widespread concerns about the risks of long-term opioid therapy, it is prudent for prescribers to assess their patients receiving opioid therapy for factors that increase risk of clinically significant respiratory depression, and to provide appropriate education for those patients about those factors. Providing a prescription for naloxone or another opioid

Co -prescribing of Naloxone in Conjunction with Opioid Ther apy

antagonist may be part of the risk mitigation plan developed by the prescriber in conjunction with the patient (7). Following is a brief synopsis of significant risk factors, followed by a series of practice recommendations from the Academy.

Risk Factors for Opioid Overdose

A wide array of potential risk factors for opioid overdose has been identified. Clinicians are urged to carefully evaluate each patient before prescribing opioid therapy, and to repeat that evaluation periodically while the patient is receiving opioid therapy, as some of these risk factors may change over time. Risk factors identified in the scientific literature include the following (8,9): • Age 25-65 • Personal history of substance abuse (any substance, including other illicit or licit drugs, alcohol, marijuana, and tobacco) • Previous non-medical use of prescription opioids • History, current symptoms, or diagnosis of mental disorders • History of obtaining simultaneous prescriptions from multiple prescribers • High opioid dose • Opioid rotation • Type of opioid prescribed (e.g., methadone, extended release opioids) • Dosing regimen (around-the-clock use of extended release/long-acting opioids + as-needed short-acting opioids is higher risk) • Concomitant prescriptions for other central nervous system depressants (e.g., benzodiazepines, sleep medications, barbiturates, etc.)

• Diagnosis of chronic kidney or liver disease • Diagnosis of acute or chronic respiratory disease • Sleep apnea Recommendations for Prescribers

When prescribing opioid therapy for patients, prescribers should do the following (10): • Conduct a comprehensive assessment of overdose risk.

A comprehensive risk assessment should include not only risk factors (such as those listed above) for the identified patient receiving prescriptions for opioid therapy, but also others who may be in that patient’s social milieu. Children who might intentionally or unintentionally access the patient’s medications, family members with their own substance use disorders, and even visitors to the home, all might be at risk

of overdosing on opioids being prescribed to the patient, and thus might benefit from the presence of naloxone in the home.

• Discuss existing risk factors with the patient and any caregivers who may be present. Educating patients about risk factors is of paramount importance, as doing so may elicit more information from them about factors they had not previously discussed. Additionally, educated patients may recognize changes in their medical conditions that could transiently increase their overdose risk, and then take appropriate steps to mitigate that risk.

• Discuss the appropriate use of opioid analgesics with the patient and caregivers. Included in this discussion should be at least the following points: – Take your medication only as directed – Do not share your medication with others – Store your medication securely so that others can’t access it – Dispose of expired, unused, or unneeded medications in a safe and effective manner • After establishing that the patient understands the risk of overdose, offer the patient a prescription for an FDAapproved naloxone product. In all medical encounters, it is ultimately the patients, exercising their right of autonomy, who decide which risks are worth accepting in pursuit of anticipated benefits of a given treatment. In the case of overdose risk associated with opioid therapy, patients should understand the nature and magnitude of their risk and then be given the opportunity to exercise their autonomy in choosing whether or not they will fill a naloxone prescription.

By offering the prescription, prescribers are providing the opportunity for the patient to exercise that right. Prescribers are free to offer their own opinions regarding the necessity of filling the prescription, but unless they offer it to the patient, it cannot be filled.

At the Academy’s • Provide the patient with the Annual Clinical Meeting September 22, 2016

Best Practices for Opioid Prescribing in the Current Regulatory Environment A 6-hour course with Paul Christo, MD; Brett Badgley Snodgrass, FNP-C, CPE, FACPP; Gary Reisfield, MD; Jen Bolen, JD Sign up today!

For more information, go to meeting.aapainmanage.org/ registration/

THE PAIN PRACTITIONE R

necessary education about using naloxone, or ensure that this education can be obtained elsewhere, e.g., in the pharmacy when the prescription is filled. Presenting

a prescription without education is insufficient because patients and caregivers need to understand the proper use of naloxone and subsequent | VOLUME 26, NUMBER 3 |

51

Co -prescribing of Naloxone in Conjunction with Opioid Ther apy

steps to take, e.g., immediately calling 911 to transport the overdose victim to a hospital. Prescribers can provide this education themselves, either directly or through their staff, or they can work with pharmacies in their areas to ensure that those pharmacies are providing the proper education for patients and caregivers. Offering a prescription without offering necessary education is unacceptable.

The American Academy of Pain Management recognizes that this statement is more aggressive in its recommendations than those issued by other organizations. We recognize that research about the effective use of naloxone in community settings is in its infancy, and that subsequent findings may lead us to modify these recommendations. Until that research is available, however, we choose to advise prescribers to err on the side of caution, given that the consequences of not having naloxone available when it is needed can be the most dire imaginable. While we primarily considered patients receiving opioid therapy for chronic pain when drafting this statement, we also believe that patients receiving opioid therapy for acute pain may be at significant risk of overdose, and we encourage prescribers to consider offering naloxone prescriptions to every patient for whom an opioid prescription is provided.

This statement was posted on the Academy’s website Feb. 2, 2016.

This activity is supported by an educational grant provided by kaléo, Inc.

References 1. Institute of Medicine. Relieving Pain in America. Washington, D.C.: The National Academies Press; 2011.

2. Center for Behavioral Health Statistics and Quality. National Survey on Drug Use and Health (NSDUH): Summary of Methodological Studies, 1971-2014.

Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.

3. Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System, Mortality File. Number and Age-Adjusted Rates of Drug-poisoning Deaths Involving Opioid Analgesics and Heroin: United States, 2000–2014. Atlanta, GA: Centers for Disease Control and Prevention; 2015. Available at http://www.cdc.gov/nchs/data/health_policy/AADR_drug_ poisoning_involving_OA_Heroin_US_2000-2014.pdf.

4. The United States Department of Justice. Attorney General Holder Announces Plans for Federal Law Enforcement Personnel to Begin Carrying naloxone. Accessed April 19, 2016. https://www.justice.gov/opa/pr/attorney-general-holderannounces-plans-federal-law-enforcement-personnel-begin-carrying Published July 31, 2014. Accessed April 19, 2016.

5. Albert S, Brason FW, Sanford C, Dasgupta, Graham J, Lovette B. Project Lazarus: Community-based overdose prevention in rural North Carolina. Pain Med. 2011;12:S77-S85.

6. Massachusetts Department of Public Health. Opioid Overdose Education and Naloxone Distribution: MDPH Naloxone pilot project core competencies. http:// www.mass.gov/eohhs/docs/dph/substance-abuse/core-competencies-fornaloxone-pilot-participants.pdf Published 2011. Accessed April 19, 2016.

7. Green TC, Heimer, Grau LE. Distinguishing signs of opioid overdose and indication for naloxone: an evaluation of six overdose training and naloxone distribution programs in the United States. Addiction. 2008;103(6):979-989. doi:10.1111/j.1360-0443.2008.02182.x 8. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) National Practice Guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015;9(5):358-367.

9. Han B, Compton WM, Jones CM, Cai, R. Nonmedical prescription opioid use and use disorders among adults aged 18-64 years in the United States, 20032013. JAMA. 2015;314(14):1468-1478.

10. Substance Abuse and Mental Health Services Administration. SAMHSA Opioid Overdose Prevention Toolkit. HHS Publication No. (SMA) 14-4742. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.

Clinician Response to the Statement from the American Academy of Pain Management

by Jennifer Schneider MD; Bennet Davis MD; Amy Kennedy PharmD, and K athy Davis, ANP-C The faculty of the Weitzman Foundation Pain ECHO Program would like to comment on the February 2, 2016, The American Academy of Pain Management Statement on “Co-Prescribing of Naloxone in Conjunction with Opioid Therapy.”

The Pain ECHO program is an ongoing program for educating primary care practitioners on topics related to improving the evaluation and treatment of pain.

This letter does not represent the views of the Weitzman Foundation.

The AAPM is to be commended for attempting to address the increasing public health crisis of prescription drug abuse, and for considering the role of naloxone (now available in several formulations),

52

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

which can mitigate the risk of fatal respiratory depression. Unfortunately, this Statement paints all opioid prescribing with a broad brush, thereby contradicting its own stated approach of “primum non nocere” (“first do no harm”). It makes broad generalizations which are likely to strike fear in the hearts of prescribers, alleging risks that do not represent the reality of competent opioid prescribing.

Here are the relevant issues: Taking opioid analgesics as prescribed

The section on risk mitigation states that among the several parties at risk are patients who take their opioids exactly as

directed. If this were true, then it would be unsafe to prescribe any opioids for any patients! On the contrary, it is a goal of prescribers to have all their patients take drugs exactly as prescribed, because this is the safest way of taking them.

Extended-release opioids as a risk factor

The section on risk factors for opioid overdose includes extended-release (ER) opioids as a risk. We have been educating prescribers for years to prescribe ER opioids rather than large quantities of immediate-release (IR) formulations for round-the-clock use. The latter have a

Co -prescribing of Naloxone in Conjunction with Opioid Ther apy

higher likelihood of abuse and diversion (with a higher street value) and are more likely to be used to alleviate anxiety and attain euphoria than are the ER formulations, resulting in ever-escalating doses to alleviate that anxiety.

Universal availability of naloxone

As for the recommendation that prescribers should “consider offering naloxone prescriptions to every patient for whom an opioid prescription is provided,” this will provide naloxone to many more patients who will not need it, at a huge expense.

This is especially true because the AAPM recommends that even opioid prescriptions for acute pain should be accompanied by a naloxone prescription.

According to the Medical Letter dated Jan. 4, 2016, Narcan Nasal Spray costs $62.50 for a single nasal spray device.

Evzio (made by Kaleo) costs $375 for a single autoinjector. (An educational grant

by Kaleo funded the preparation of the AAPM’s Statement). A generic naloxone vial and syringe costs only $17.40, but provides the consumer with a syringe (which may be misused).

Our recommendations

All in all, we believe that these recommendations reflect a serious lack of nuance. Instead of taking an all-inclusive approach by handing every pain patient a naloxone prescription along with their opioid, prescribers need instead is to become more diligent about doing initial and ongoing risk assessments to determine whether the patient is a good candidate for chronic opioid treatment.

The initial risk assessment should include using the standardized Opioid Risk Tool (ORT) or other available risk assessment instrument; obtaining prior prescribers’ notes for review; if relevant, checking for prior misuse through arrest records available to the public through online access in most states; and checking the state pharmacy prescription drug monitoring program record. Prescribers also need to have a well developed and comprehensive written opioid agreement/ educational tool for all patients to read and sign before opioids are prescribed and thereafter annually. Finally, urine drug screens should be obtained when opioids are begun for chronic pain and at intervals thereafter, but not at every visit; unexpected urine drug screens are more likely to reveal unexpected opioids

or drugs of abuse, as well as diversion of the medications.

It is imperative that prescribers recognize that opioids are not the only modality for treating chronic pain. Patients most at risk for misuse are also often patients who need behavioral health assessment and treatment, as pain is likely to be more difficult to treat if psychosocial issues are present. As part of this assessment it is very useful to administer the Adverse Childhood Events (ACE) brief questionnaire, as a history of such events constitutes a significant risk factor for chronic pain and complicates its treatment. It is also crucial to assess the functional outcome of treating pain with opioids; successful treatment is treatment that improves the patient’s daily function as measured through functional outcomes instead of focusing on solely improving the pain score.

Thank you for allowing us to provide comments as we work toward our mutual goals of treating chronic pain effectively and reducing the prescription drug abuse epidemic.

Sincerely, Weitzman Foundation Pain ECHO Program Faculty, Middletown, CT

Academy Response to clinician’s comments

By Joanna K atzman, MD, MSPH, president, american academy of pain management Thank you very much for taking the time to comment on the Academy’s thoughtful and deliberate approach to addressing the dual epidemics of chronic pain and unintentional opioid overdose deaths in the United States. We certainly agree with your opinion that there are many risk factors to consider prior to initiating both long- and short-acting opioid analgesics for chronic non-cancer pain. These include appropriate screening for risk of misuse and urine toxicology screening, prior history of addiction, etc.

Unfortunately, risk factors for unintentional opioid overdose death are still not completely understood at this time.

The risk for overdose death can quickly change for an individual patient. For instance, a patient that first began opioid analgesics with apparent low risk one

year ago may have developed a medical illness that increases his/her risk for the respiratory depression and overdose death.

Most people in the United States who misuse prescription opioids receive their medications from a family member, friend, or one doctor. Many of these family member and friends are receiving their medications from one doctor as well (1).

The Substance Abuse and Mental Health Services Administration endorses naloxone coprescribing and the new Centers for Disease Control and Prevention Guideline recommendations state that naloxone has had enormous benefits for community use, but that we don’t yet know the impact for clinical care (2).

We do not believe that asking patients if they want a prescription to naloxone

in whatever format they choose implies they will misuse their medication, nor does it suggest incompetence among prescribers. We simply suggest that all available and appropriate precautions be offered if there is even the slightest risk of accidental overdose. Adequate protection simply makes good sense.

References 1. Substance Abuse and Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health: Mental Health Findings, NSDUH Series H-49, HHS Publication No. (SMA) 14-4887. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2014.

2. Larochelle MR, Liebschutz JM, Shang F, Ross-Degnan DR, Wharam JF. Opioid Prescribing After Nonfatal Overdose and Association With Repeated Overdose: A Cohort Study. Ann Intern Med. 2016; 164 (1): 1-9.

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

53

the resurgence of herbal cannabis

Continued from page 29

white paper suggesting a set of clinical considerations (10).

These were developed as consensus recommendations, based on scant available evidence, clinical experience of the authors in treating patients who use cannabis, and extrapolation from lessons learned in the use of other controlled substances such as opioids and benzodiazepines (See a revised and adapted version of these recommendations on page 28).

Whether herbal cannabis in clinical care is eventually replaced by cannabinoid medications as research sheds more light on the mechanisms of actions and interactions of cannabinoids remains to be seen. However, given current legalization efforts and investments in the cannabis industry, it seems likely that herbal cannabis will be legally available in some context going forward. It is important for clinicians to understand its clinical pharmacology and to be able to monitor and advise patients who elect to use cannabis in order to reduce the potential for harm and support favorable outcomes.

References 1. Marijuana Policy Project.2016. http://www.mpp.org. Accessed May 17, 2016.

2. Hayashi Y. Marijuana companies stuck doing business the old-fashioned way, in cash. The Wall Street Journal. March 31, 2016. http://www.wsj.com/

Home Pain Medication Lock Box

CALL $5 D FOR ISCO PATI UNT E COUP NT ONS

• Fold-down handle for easy storage

• Tamper-proof hinges

on the inside to prevent tampering

• Vented side walls for refrigerator use

• Easily removable divider

inside box to organize weekly pills

• Emergency breakable access panel on the bottom

• Pre-drilled holes

on the bottom to secure the box

Products to Safeguard Pain Medication at Home Multiple products starting at $19.99 LOCKMED products are available at Pharmacies nationwide, or Call to order at (888) 458-2746, or via www.LOCKMED.com

54

| T H E PA I N PRACTITION ER | J U N E / J U LY 2 0 1 6

3.

4.

5.

6.

7.

8.

9.

articles/marijuana-companies-stuck-doing-business-the-old-fashioned-way-incash-1459416605. Accessed May 17, 2016.

Wee H. Legal U.S. Pot Sales Soar to $5.4B in 2015: A Report. CNBC. 2/1/2016. http://www.cnbc.com/2016/02/01/legal-us-pot-sales-soar-in-2015.html. Accessed May 17, 2016.

How Much Money Can a Marijuana Grower Make. Marijuana Business News. com. http://www.marijuanabusinessnews.com/how_much_money_does_a_marijuana_grower_make.aspx. Accessed May 17, 2016.

ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in Cannabis Potency over the Last 2 Decades (1995-2014): Analysis of current data in the United States. Biol Psychiatry. 2016;79(7):613-619.

Drug Scheduling. Drug Enforcement Administration. http://www.dea.gov/druginfo/ds.shtml. Accessed May 17, 2016.

Belendiuk KA, Baldini LL, Bonn-Miller MO. Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders. Addict Sci Clin Pract. 2015; Apr 21;10:10.

Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marjuana use. N Engl J Med. 2014 Jun 5;370(23):2219-2227.

Jouanjus E, Lapeyre-Mestre M, Micallef J, et al. Cannabis Use: Signal of Increasing Risk of Serious Cardiovascular Disorders. J Am Heart Assoc. 2014 Apr 23;3(2):e000638 10. Savage SR, Romero-Sandoval A, Schatman M, et al, Cannabis in Pain Treatment: Clinical and Research Considerations. J Pain. 2016 Mar 4 Epub ahead of print.

Seddon Savage, MD, is medical director of the

Chronic Pain and Recovery Center at Silver Hill Hospital in Connecticut, is an associate professor of anesthesiology on the adjunct faculty of the Geisel School of Medicine at Dartmouth College, and works as an advisor to the Dartmouth-Hitchcock Substance Use & Behavioral Health Initiative.

The only multidisciplinary organization dedicated to advancing integrative pain care • Join more than 4,300 clinicians • Earn free-CME/CEU on our Pain Care Learning Center • Save on Annual Meeting registration • Gain access to the most up-to-date state and federal policies in pain management Choose the membership that’s right for you: General Membership Open to all clinicians and affiliates Student Membership Complimentary to all full-time students or residents Pain Management Facility Membership Open to hospitals, clinics, and other institutions offering interdisciplinary pain management To Join Phone (209) 533-9744 Online: www.aapainmanage.org/membership/

ADVERTISING DIRECTORY

To advertise Sheila Miller (209)533-9744, SMILLER@AAPAINMANAGE.ORG

1st Providers Choice IMS Pain Management Specific EMR www.1stproviderschoice.com 480-782-1116 PAGE C-4 AIS PainCare Intrathecal Pain Medication www.aispaincare.com 877-443-4006 PAGE 49 Bizmatics, Inc. PognoCIS www.prognocis.com/pain 877-693-6748 PAGE 45 Collegium Pharmaceutical, Inc. Xtampza ER www.collegiumpharma.com 781-232-0747 PAGES 21,22,23,24 Depomed Nucynta ER www.nucynta.com/ 866-458-6389 PAGES C-2,3,4,5,6,7 Depomed Gralise www.gralise.com 866-458-6389 PAGES 9,10 Doctors Supplement Store Patient Direct Service www.DoctorsSupplementStore.com 877-846-7122 PAGE 55 Endo Belbuca www.belbuca.com 1-800-462-ENDO (3636) PAGEs 38,39,40,41,42 LockMed Medical Product Company LOCKMED Home Medication Lock Box www.LOCKMED.com 888-458-2746 PAGE 54 Micro Format, Inc. Secure Prescription Paper www.RxPaper.com www.PrescriptionPaper.com 800-333-0549 PAGE 55 Neurogenx, Inc. NEUROGENX 4000PRO www.neurogenx.com 800-335-7624 PAGE 19 OPTP Pain education and therapy products www.optp.com 800.367-7393 PAGE 29 Practice Matrix 855-808-9090 PAGE 55 Purdue Pharma Butrans www.Butrans.com PAGE 30, 31, 32, 33 Silver Hill Hospital Chronic Pain & Recovery Center www.silverhillhospital.org 866-542-4455 PAGE 17 Transition Consultants Medical Practice Sales, Appraisal and Financing www.TransitionConsultants.com 800-416-2055 PAGE 55

BE/BC Pain Management Specialist Carilion Clinic, a physician-led integrated health system based in Roanoke, VA has an excellent employed opportunity for a BE/BC Pain Management Specialist to join our comprehensive interdisciplinary pain service, working directly with the Section(s) of Anesthesia, Physical Medicine and Rehabilitation, and Neurosciences to deliver full scope, team-oriented Pain Management Services for acute and chronic pain in a modern 703-bed academic/tertiary referral medical center with Level I Trauma Services. Applicants must be fellowship trained in Pain Management, and BC/BE in Anesthesiology, with proven leadership experience.

Candidates must be skilled with radiofrequency and interventional modalities including intrathecal delivery systems, spinal cord stimulators, and ESI. Carilion Clinic is the largest not-for-profit integrated health system serving nearly one million people in Western Virginia, with 7 hospitals, 220+ physician practice locations, and 24 GME programs. This network of 650+ multi-specialty physicians in over 60 specialties offers Carilion physicians faster access to patient information and history with a sophisticated, fully integrated electronic medical record system (EPIC) and excellent access to subspecialty consultation.

Roanoke is a metro area of over 300,000 located at the southern tip of Virginia’s spectacularly beautiful Shenandoah Valley, surrounded by the Blue Ridge Mountains and close to the 22,000 acre Smith Mountain Lake. The area offers sensational outdoor activities but also a surprising array of cultural activities from fine dining, to multiple musical venues and playhouses, to symphonies and ballets. Access to major air-travel hubs is remarkably easy through the Roanoke Airport. The weather features mild winters, an abundance of sun, and extended springs and autumns. The region features top-notch schools and Universities and has been coined “the best kept secret in the east.”

Equal Opportunity Employer: Minorities/Females/Protected Veterans/Individuals with Disabilities/Sexual Orientation/Gender Identity Please submit CV’s to: Amy Silcox, Physician Recruitment and Onboarding, 213 S. Jefferson Street Suite 1401. Roanoke, VA 24011 Office: 540-224-5187, Email: amsilcox@carilionclinic.org

The practice sales and appraisal company

CONSIDERING SELLING YOUR PRACTICE? WE HAVE MOTIVATED BUYERS SEEKING TO ACQUIRE PAIN MANAGEMENT PRACTICES NATIONWIDE.

CALL FOR A FREE CONSULTATION

(800) 416-2055

WWW.TRANSITIONCONSULTANTS.COM

The Best Patient You’ll Get Today, Is the One You Just Put On-Hold!

Educate, inform and promote treatment options to your patients easily with on-hold advertising.

• Only a onetime fee • Special offer, mention AAPM and buy now for only $599 (regular $799) • Free sample play!

Call Now! 855-808-9090

THE PAIN PRACTITIONE R

| VOLUME 26, NUMBER 3 |

55

NONPROFIT ORG US POSTAGE PAID BURL VT 05401 PERMIT #19

975 Morning Star Drive #A Sonora, CA 95370

Where Customer Service is Our #1 Focus

Pain Management and Physical Medicine - Fully Certified EHR

Fully Certified Pain Management Electronic Health Records & Practice Management Software n Save Valuable Documentation Time with Pain Specific Procedure & Injection Templates n E-Prescribing of ControlledSubstances (EPCS) Ready n Patients Current Medication Automatically download directly into your EMR n Drug Formularies & Insurance Formularies Included n ICD-10 Ready with Pain & Physical Medicine Crosswalk Included from ICD-9 n Cloud Based & Server Based Solutions, I-Pad, Android or Windows Tablet friendly n Head home right as you finish with your last patient with an Efficient Pain Specific EMR & Documentation Software n IMS has the capability to accommodate any Registry submission type for Meaningful Use. This includes HL7, HIE and exportation of several file types.

Call Today for a Free Demo!

Mention this ad for a AAPM Discount!

Call 480-782-1116 | www.1stProvidersChoice.com