The Pain Practitioner - The Lowdown on Back Pain

Integrative Pain Management for Optimal Patient Care

The Pain Practitioner December 2016

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Smoking and Back Pain: Adding Insult to Injury Collaborative Care of Spine Pain Autologous Stem Cell Therapy for Treatment of Chronic Low Back and Discogenic Pain Also in this issue: Epigenetics in Migraine

TW O SOURCES

OF PAIN

O NE SOURCE OF RELIEF

NUCYNTA® ER is the first and only FDA-approved long-acting opioid designed to control both nociceptive pain and the neuropathic pain associated with diabetic peripheral neuropathy (DPN).

NUCYNTA® ER is an opioid agonist indicated for the management of: • pain severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with DPN in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Not an actual patient.

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

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

TIME TO DUAL

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

COVERED FOR

94%

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

• Administer NUCYNTA® ER ~q12h3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Please see additional Important Safety Information, including BOXED WARNING, and Brief Summary on the following pages. © June 2016, 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: • pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

When discontinuing NUCYNTA® ER, gradually taper the dose.

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

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

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

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

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

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

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

Psychiatric disorders: hallucination, suicidal ideation, panic attack.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Withdrawal symptoms can occur in breast-feeding infants when maternal administration of

NUCYNTA® ER is stopped.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Rx Only

© 2016 Depomed, Inc., Newark, CA 94560 USA NUCYNTA® ER is a registered trademark of Depomed, Inc. All rights reserved. APL-NUCX-0041 Rev.3

Academy of Integrative Pain Management

www.aapainmanage.org

The Pain Practitioner

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 George D. Comerci, Jr, MD, FACP John Garzione, DPT Christian D. González, MD Michael Kurisu, DO, ABIHM Joseph Matthews, DDS, MSc Liaison to the Board Maggie Buckley

DECEMBER 2016

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

10 NOTES FROM THE FIELD Is Pain Really a 5th Vital Sign?

And Should It Be?

By Bob Twillman, PhD, FAPM, Executive Director PAGE 13

12 ADVOCACY AIPM’s State Pain Policy Advocacy Network: Fighting for You and Your Patients

By Amy Goldstein, MSW, Director of the State Pain Policy Advocacy Network

ACADEMY STAFF Executive Director Robert Twillman, PhD, FAPM Director of Professional Development Debra Nelson-Hogan Director of the State Pain Policy Advocacy Network (SPPAN) Amy Goldstein, MSW Assistant Director of Education Cathleen Coneghen SPPAN Assistant Director for Legislative and Regulatory Affairs Katie Duensing, JD Member Services Manager Whitney O’Donnell 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 Peter McKinley, Pak Creative Copy Editor Rosemary Hope

The Pain Practitioner is published by the Academy of Integrative Pain Management, 975 Morning Star Drive, Ste., A, Sonora, CA 95370, P: 209-533-9744, F: 209533-9750, Email: aapm@aapainmanage.org, website: www. aapainmanage.org. Copyright 2007 American Academy of Pain Management.

All rights reserved.

Send correspondance to: Debra Nelson-Hogan at dhogan@aapainmanage.org.

For advertising opportunities, media kits, and prices, contact: Sheila Miller at 209-533-9744, or smiller@aapainmanage.org The Pain Practitioner is published by the Academy of Integrative 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 Academy of Integrative 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 expressed or implied, of a product or service.

11 MEMBERSHIP One of AIPM’s Most Valuable Membership Benefits: Our Online Pain Care Learning Center

13 ANNUAL MEETING/EDUCATION Ask the Expert, 2016 Annual Meeting Online Courses, and Call for Speakers PAGE 22

16 RESEARCH Research Recap 22 Smoking and Back Pain: Adding Insult to Injury

By Brian F. White, DO, FAAPMR 24 Collaborative Care of Spine Pain

By W. Evan Rivers, DO

PAGE 26

26 Autologous Stem Cell Therapy: A Naturopathic Approach to the Treatment of Chronic Low Back and Discogenic Pain

By Harry Adelson, ND 32 Emerging Role of Epigenetics in Understanding Migraine

By Roger K. Cady, MD, and Paul L. Durham, PhD

PAGE 32

And More, on the Web...

NOW AVAILABLE ONLINE! Advanced Credentialed Pain Practitioner

Curriculum Review Course Consisting of 15 courses, this 14-hour CME activity can now be taken anytime, anywhere through our online Pain Care Learning Center. https://goo.gl/vnAXvt EXPECTATION MANAGEMENT The Most Challenging Issue in Pain Management How Christina Lewis, RN-BC, Civil Servant DOD Nurse Case Manager at Tripler Army Medical Center, approaches care for chronic pain patients who just want their pain “cured.”

https://goo.gl/G5qg2Fj

2017 ANNUAL MEETING Super Early Bird Rates

Take advantage of our lowest rates all year for our 28th Annual Meeting taking place in San Diego, California, October 19-22, 2017! http://aipm28.eventbrite.com STAY UPDATED Get Our Free Digital Publications in Your In-Box

Sign up to receive our bi-weekly e-newsletter—packed with research about integrative pain management—and the digital edition of our print magazine, The Pain Practitioner, which features bonus pain management content. http:// goo.gl/aQXf7p

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 Academy of Integrative Pain Management, 975 Morning Star Drive, Ste. A, Sonora, CA 95370

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.

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TH E PAIN PRACTITION ER

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NOTES FROM THE FIELD

Is Pain Really a 5th Vital Sign? And Should It Be?

By Bob Twillman, PhD, FAPM, Executive Director

Recently, there has been much discussion about “Pain as the 5th Vital Sign,” with critics contending that a) it is not; and b) its enshrinement as such in the late 1990s and early 2000s is largely responsible for our current problem with prescription opioid abuse. Several organizations, including the American Medical Association and the American Academy of Family Physicians, have passed resolutions decrying this concept and demanding that it be eliminated.

I think these critics are missing the mark—that it’s not required pain assessment that is to blame, but how we implemented that, and how we treat pain when we find it.

A BRIEF HISTORY OF PAIN AS THE 5TH VITAL SIGN “Pain as the 5th Vital Sign” was a Veterans Administration initiative born in the late 1990s, but it quickly became confounded with pain assessment and treatment standards introduced by The Joint Commission (JC) in 2001, causing the JC to now bear the brunt of the blame for the role of this slogan in causing our opioid abuse public health crisis. Critics contend that no subjective experience, such as pain, can properly be considered a vital sign, and further, that a high level of reported pain does not imply the same threat to a patient’s life that is implied by temperature, blood pressure, and pulse and respiration rates that are too high (or too low!).

In this, they are correct. However, this line of argument assumes that “Pain as the 5th Vital Sign” was meant to be taken literally. My perception has always been that it was more symbolic than literal— that it was meant remind us to assess a patient’s pain when assessing the four vital signs. More to the point, I don’t think the real problem is with the idea that we need to consistently ask patients about their pain. I think the real problem is with how health care institutions implemented the JC standards.

JOINT COMMISSION PAIN STANDARDS The JC pain standards say that health care institutions must a) assess patients’ pain experiences; b) document the results of those assessments; c) provide for treatment of pain, either in the institution or

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elsewhere; d) re-assess pain after an intervention, and document that re-assessment; and e) teach their professional staff members about how to assess and treat pain.

In implementing these standards, most facilities adopted a 0-10 pain intensity scale as their principal (and often, only) means of assessing pain, and wrote aggressive policies that often equated pain treatment with opioid prescribing. In practice, it’s as if they said, “We’re going to ask how much pain you have, on a 0-10 scale, and give you opioids until that rating is 4 or less.”

That is NOT what the standards say should be done, and such gross oversimplification was bound to produce problems. The fault is with our implementation of the standards, not the standards themselves.

at risk of a compartment syndrome because the bandages were too tight.

The problem here was a failure to provide the right treatment in response to the assessment results—assessment results, I might add, that were likely incomplete.

Prescribing more opioids was the incorrect response to the patient’s report of pain, and the patient could have suffered great harm as a result. But that doesn’t mean the pain assessment should be eliminated. To do that would be akin to saying we should stop taking patients’ temperatures and throw away our thermometers because we overprescribe antibiotics to patients with fevers. In this case, the right response would be to improve education about how to do a complete assessment and how to consider non-medication responses that could resolve the problem.

NOT ASKING ABOUT PAIN DOESN’T MAKE IT GO AWAY The implicit assumption that not routinely asking patients about pain would decrease opioid prescribing may or may not be correct. But it misses the point. Pain is malignant, decreasing quality of life, and failure to treat it makes quality of life even worse. The task we need to accomplish is providing a comprehensive set of pain treatments that effectively manages it; that is, we need to be changing the way we respond to reports of pain, not the fact that we solicit those reports. It’s not asking the questions that gets us in trouble, it’s how we respond to those questions, and if we stop asking the questions, we risk creating big problems of another kind. ❏ As an example, I recently read a blog post in which an orthopedic surgeon called for elimination of routine pain assessment because it results in overprescribing of opioids. As an example, he wrote about a patient recovering from ankle surgery who had increased pain several hours postsurgery. When the nurse called to report this (he was on call, not the attending surgeon for the patient), he refused to order more opioids, and instructed her to check to see if the bandages were too tight. After she hung up from talking to him, she contacted a hospitalist who ordered more opioids. When the attending surgeon saw the patient the next morning, he discovered that the patient was

| T HE PA I N P R AC TI TI O NE R | D E C E M B E R 2 0 1 6

Bob Twillman, PhD, is the executive director for the Academy of Integrative Pain Management. 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.

MEMBERSHIP

One of AIPM’s Most Valuable Membership Benefits: Our Online Pain Care Learning Center We often hear from our members that accessing free and low-cost CME in our online Pain Care Learning Center is one of the best reasons to be an AIPM member.

Launched in January 2016, the Center now features more than 40 online courses including a basic core of continuing education accredited programs from leaders in the pain management field, many of whom have been speakers at our Annual Meetings and authors of articles in our magazine, The Pain Practitioner.

Our courses cover a variety of subjects including: • Overviews of pain conditions such as headache, back pain, complex regional pain syndrome, and myofascial pain as well as integrative therapies for managing these conditions.

• Thought-provoking discourses on ethical issues, such as the value of the patient-clinician relationship, perspectives on addiction, and the role of lifestyle on the management of chronic pain.

• Trending research topics, such as obesity and migraine, or studies on disparities of care, pharmacogenetics testing for the treatment of pain, and the role of the microbiome in pain management.

• Programs on non-pharmacologic and non-interventional approaches to pain management, with an emphasis on wellness.

In addition to CME credits for physicians and APA credits for psychologists, we also accredit many of the courses for pharmacists and nurses. Other disciplines can earn credit by submitting the documentation of attendance credit to their state boards.

SPECIALTY PROGRAMS Along with our robust catalog of educational activities, we also offer specialty programs at a discounted rate for our members such as: • The Curriculum Review Course, a 14-hour program designed as a study aid for those enrolled in the Advanced Certificate Program. This online course supplements the serious self-study required to pass the exam and it serves as a good foundation of pain management.

• The 2016 Annual Meeting content, available free as part of the registration fee for attendees (or $875 for members who did not attend, and $1,050 for nonmembers). Individual sessions are also available for those who do not want all of the content from the entire meeting, at only $40 for AIPM members and for $45 for non-members.

• Two outstanding programs on complex regional pain syndrome (CRPS) at no charge to any clinician. Our partner, the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA), helped us craft these programs presented by Philip Getson, DO. “A Comprehensive Overview of Complex Regional Pain Syndrome” and “An In-depth Look at CRPS: From Diagnosis to Treatment as Illustrated by Case Histories” give excellent education on this difficult-to-treat pain condition.

T MOS LAR U POP

The Most Popular Courses in AIPM’s Pain Care Learning Center:

• Who is at Risk for Opioid Addiction: How do I know?, Daniel Duhigg, DO • The Future of Pain Management: The Role of Self-Care and Integrative Collaboration, Wayne Jonas, MD • Is it Myofascial Pain, Fibromyalgia, Migraine, or Chronic Widespread Pain: A Differential Diagnosis, Joanna G. Katzman, MD, MPH

CONTRIBUTORS

Donations support the vital work of the Academy’s policy and advocacy efforts. We would like to thank the following contributor: Julian M. Aviles, MD Donations may be tax deductible as an ordinary business expense. If you would like to donate in support of our policy and advocacy please contact the Academy at 209-533-9744 or aapainmanage.org.

• Opioid-induced Hyperalgesia, Jeff Gudin, MD

NEWLY CREDENTIALED MEMBERS

• Post-traumatic Headache: Knowledge Update, Nathan D. Zasler, MD, and Sara Etheredge, PT, DPT

Advanced Diplomate Academy of Integrative Pain Management (ADAIPM) W. Clay Jackson, MD Philip R. Matthews, DO Michael Saenger, MD Jeffrey David Spence, MD Angela Stroe, DO, MD, LaC Alan Tran, MD Michael Wansbrough, MD Sami Fehmi Yasin, MD Patricia Bruckenthal, PhD, APRN-BC, ANP, FAAN

• Trusting Your Patients: Objectivity and Subjectivity in Health and Health Care, Peter Moskovitz, MD • The Pain in the Brain Is Primarily Migraine, Duran Michael Ready, MD • Myofascial Pain: A Manual Medicine Approach to Diagnosis and Treatment, Lucy Whyte Ferguson, DC, and Ben Daitz, MD • Comprehensive Pain Management Incorporating Complementary and Integrative Medicine: The Military Medicine Experience, Eric Schoomaker, MD, PhD, FACP, Lieutenant General, U.S. Army (Ret)

Advanced Fellow Academy of Integrative Pain Management Robert L. DeLillo, CRNA, NSPM-C, APRN, AFAAPM Peter J. Pollacheck, APN, CRNA

• Lumbar Region Pain: Common Sources, Prevalence, Evaluation, and Interventional Treatments, Brian F. White, DO, FAAPMR

Diplomate Academy of Integrative Pain Management Amy L. Bryer, DDS, FAGD Kashif M. Irfan, MD Gloria B. Maczuga-Stern, DMD

• Chronic Pelvic Pain: A Pain Generator Oriented Approach to Therapy, Robert Moldwin, MD • Microglia and Central Sensitization Syndrome: A New Paradigm for Understanding and Treating Chronic Pain and Depression, Gary E. Kaplan, DO, DABFP, DABPM, FAAMA

Dues are $250 per year.

Most of our education is FREE to our members and is top notch!

The education you need, when you want it.

See these and 40+ more courses at education.aapainmanage.org

IN MEMORY We honor the memory of the following deceased members: J. Jerry Rodos, DO, DSC Leonard E. Geffert, DPM

New courses are added to our Pain Care Learning Center regularly! Be sure to check the course catalog frequently at https://education.aapainmanage.org/ Why pay more for CME if you don’t have to? Become an AIPM member today at http://www.aapainmanage.org/join

TH E PAIN PRACTITION ER

| VOLUME 26, NUMBER 6 |

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ADVOCACY

AIPM’s State Pain Policy Advocacy Network: Fighting for You and Your Patients

By Amy Goldstein, MSW, Director of the State Pain Policy Advocacy Network

WHAT YOU’RE TELLING US

WHAT WE’RE DOING

During October 2016, SPPAN’s annual survey to our AIPM members gave us a glimpse of how you are using (or not!)

SPPAN’s resources and what policy issues you care most about. Of significant interest to us here in the policy and advocacy department is this: According to those AIPM members who responded, more than half of you were unaware that SPPAN produces unique written analyses for all high priority painrelated bills—and 40% of you say you haven’t received any policy email updates from SPPAN. We clearly need to do a much better job of getting relevant information in front of you more often— we don’t want SPPAN to be a best kept secret!

Also, the survey respondents ranked the following five policy priorities as most important:

In the past, we were able to take advantage of the autumn “down” time with most state legislatures adjourned and activity relatively halted. In late 2016, we are still watching legislatures that are considering pain-related legislation, and continuing to submit extensive comments to positively influence your ability to provide optimal pain care.

On that note, I’d like to highlight an integral member of our policy team, Katie Duensing, JD, Assistant Director for Legislative and Regulatory Affairs. Ms. Duensing is working hard every day for you.

And to that extent, she was even highlighted by a company that tracks bills and regulations for hundreds of organizations, as a standout policy director. Ms. Duensing is able to effectively track thousands of bills and regulations that pertain to pain care, as well as draft dozens of letters that are causing leading policymakers to make substantive changes to legislation and regulations, in order to improve your ability to deliver integrative pain care. AIPM is the only pain management organization that supports such a Herculean effort, and the only pain management organization fighting for good policy at every level of government.

Further, in addition to reacting to the massive wave of pain-related bills pouring in over the past four years, SPPAN is proud to be working proactively on developing model language to address one of our highest priorities—ensuring access to, and reimbursement for, non-pharmacological treatments for pain. Easy, you might say? Not a chance. This complex issue involves a number of stakeholders with skin in the game, and navigating potential pitfalls and “bill-killing” provisions is like walking a minefield. Fortunately, thanks to the interest and engagement of SPPAN’s members, we are able to discuss and address these challenges. Stay tuned to hear about plans for introducing bills with provisions that improve and protect optimal pain care. Currently, we are working with advocates in Florida and Minnesota, and discussing the feasibility of similar efforts in several other states.

➊ Advocating for balanced pain care education (not just prescribing education)

➋ Ensuring access to, and adequate insurance coverage for, integrative pain care

➌ Advocating for increased transparency and reduced barriers to care resulting from insurance coverage and pharmacy benefit management (e.g., prior authorization, step therapy, specialty tier, etc.)

➍ Assisting in developing state guidelines/rules for controlled substance prescribing/dispensing

➎ Advocating to advance parts of CARA (Comprehensive Addiction and Recovery Act) that are relevant to improving pain care (e.g., interagency task force, public awareness, partial fills, research, and synergy with VA/DOD programs)

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| T HE PA I N P R AC TI TI O NE R | D E C E M B E R 2 0 1 6

Look for our 2017 Policy and Advocacy Priorities coming to your inbox soon.

This annual roadmap will describe further details about our plans for action in the coming year.

HOW CAN YOU HELP RIGHT NOW? In addition to the “typical” asks, such as building stronger relationships with your local lawmakers so they are educated about our issues, we’d also like to hear from you about your challenges—and successes—in getting reimbursed when providing integrative pain care. We plan to compile information from our members so that we can more effectively share your stories with policymakers. We hear every day about reimbursement challenges, but policymakers need to hear more specifics.

What therapies are typically reimbursed?

Which ones are not? What coding are you using? How do the insurance providers vary in their reimbursement policies? Do you change the way you recommend/ provide care based on what is covered? Is there a difference in reimbursement based on your patients’ diagnoses? What reasons are insurers giving when your claims are denied?

We thank you in advance for your willingness to share any of this information with us. We are working hard every day to protect your ability to provide optimal pain care, and we will be even stronger with more information from you.

I look forward to hearing from you!

Contact me at Amy Goldstein, SPPAN Director, agoldstein@aapainmanage.org, or 209-288-2209.

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 personcentered pain policies. Bringing her demonstrated success in the policy and advocacy arena, 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.

ANNUAL MEETING / EDUCATION

Ask the Expert

What Three Things Do Clinicians Need to Know about Complex Regional Pain Syndrome (CRPS)?

A Discussion with Philip Getson, DO

It is underdiagnosed. Estimates of the number of people diagnosed with CRPS range from 250,000 to 2 million, and it is estimated that at least 50,000 new cases are diagnosed every year.

CRPS is often misdiagnosed. People with CRPS are often misdiagnosed with fibromyalgia because the diagnoses for both overlap. Proper diagnosis of CRPS is more than just identifying the constellation of symptoms. Differential diagnoses include diabetic neuropathies, CNS manifestations of neoplasm, spinal cord injury, radiculopathy, and plexopathy. Psychological overlays often lead the clinician to believe that the problem is due to hysterical conversion reactions or symptom magnification in the case of underlying medical legalities.

CRPS is not taught well in medical school and too often it is not included in professional meetings.

How do we expect clinicians to understand a condition that is not taught? If you donâ&#x20AC;&#x2122;t understand how to diagnose or treat CRPS, find someone who does. There are plenty of us who have been treating this syndrome for years. Better yet, learn as much about it as you can.

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Learn about CRPS and earn free continuing education credit at the Pain Care Learning Center. For more information, go to https://education.aapainmanage.org/.

Philip Getson, DO, is a primary care physician in practice for 40 years and an assistant professor of medicine in neurology at Drexel University College of Medicine in Philadelphia, Pennsylvania. He is a member of the scientific advisory committee of the Reflex Sympathetic Dystrophy Association of America and one of their designated speakers. He has contributed to the national protocols for ketamine infusion therapy for complex regional pain syndrome (CRPS) and has lectured on the subject of CRPS nationally and internationally. He is a board-certified thermographer and immediate past vice president of the American Academy of Thermology.

TH E PAIN PRACTITION ER

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ANNUAL MEETING / EDUCATION

The Education You Need, When You Want It: The 2016 Annual Meeting Courses Are Now Available Online If you have not visited the Academy’s online Pain Care Learning Center (PCLC) lately, now is the time. Since its launch in January of this year, both Academy members and non-members have completed the available courses over 900 times and that number is growing daily.

Among the most popular online courses are the overview and in-depth look at the diagnosis and treatment of complex regional pain syndrome (CRPS) presented by Philip Getson, DO, and the discussion of which patients are at risk for opioid addiction by Daniel Duhigg, DO. However, there are educational programs available for all pain practitioners including sessions on myofascial pain, migraine, back pain, opioids, mindfulness, supplements, nutrition, and pelvic pain as well as the role of the microbiome in pain and pharmacogenetic testing to improve the treatment of pain.

In November, 34 programs from the 2016 annual meeting were launched and available free for all registered meeting attendees for one year. These programs can also be accessed for members at $40/credit and non-members at $45/ credit and a list of these can be found at http://blog.aapainmanage.org/2016annual-meeting-courses/. There is CME/ CE available for physicians, psychologists, nurses, and pharmacists and a certificate of attendance is available for all other pain practitioners upon completion of all courses.

We also offer bundles of courses on nutrition and opioids for a nominal fee for members and non-members. The nutrition bundle, Eating for Healing: The Evidence-based Nutrition, Supplements, and Lifestyle Choices for Pain Patients,

by Robert Bonakdar, MD; Nancy Cotter, MD, FAAPMR, FABIHM, FACN; Bryan White, PhD; and Victor S. Sierpina, MD, ABFM, ABIHM, includes several hours of education focusing on how nutrition, supplements, and lifestyle choices affect those with conditions such as headache, neuropathic pain, joint pain and IBS/IBD.

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The opioids bundle, Chronic Pain and Opioid Use: Best Practices in the Current Environment, by Paul Christo, MD; Brett Badgley Snodgrass, FNP-C, CPE, FACPP; Gary Reisfield, MD; and Jennifer Bolen, JD; provides an overview of the appropriate use of opioids and managing the patient’s risk for harm in the management of chronic pain. The tools for assessing, treating, and monitoring of opioids to reduce a patient’s risk for misuse, abuse, and addiction are discussed.

To access any of these courses, visit the PCLC at education.aapainmanage. org. If you have any questions, please contact Cathleen Coneghen, Assistant Director of Education, at 209-288-2212 or cconeghen@aapainmanage.org.

| T HE PA I N P R AC TI TI O NE R | D E C E M B E R 2 0 1 6

2016 Meeting Attendees Only: Access Your Free CME Now! Full meeting attendees can access the 2016 meeting sessions online—at no additional charge!

➊ View the list of courses at: http://blog.aapain manage.org/2016-annual-meeting-courses/.

➋ Click on the link of the course you want to take. ➌ Scroll to the bottom of the course page and click the “Add to Cart” button.

➍ Enter the Coupon Code that was emailed on November 14 and click “Apply to Order.”

➎ Click on the “Checkout” button and enter

your billing information (don’t worry— you won’t be charged).

➏ Scroll to the bottom of the page and click on “Review Order.”

➐ Click on “Submit Order.”

ANNUAL MEETING / EDUCATION

Call for Speakers!

A Meeting Like No Other A MEETING LIKE NO OTHER The Academy of Integrative Pain Management’s Annual Meeting in San Diego is going to be a meeting experience like no other in pain management, with practical, team-based presentations on the most commonly encountered and challenging painful conditions encountered in daily practice, delivered in unique, interactive instructional formats. In addition to learning how to practice integrative pain care, attendees will participate in practical problem-solving sessions with government agencies and policy makers who make patient access to care and multidisciplinary treatments possible.

PROGRAM GOALS • Acquisition of a rich, integrated knowledge base that can be recalled or retrieved, then applied in the context of treating a wide array of patients experiencing pain • Development of effective problem-solving skills and • Advocating for increased transparency and reduced barriers to care resulting from insurance coverage and pharmacy benefit management (e.g., prior authorization, step therapy, specialty tier, etc.)

MEETING CONTENT The program, built on the 2016 National Pain Strategy, will present the management of the most common pain conditions with an emphasis on team-based care. Our target audience is primary care providers and we include all appropriate disciplines and modalities in the delivery of evidence-based care.

We have identified key topics that must be covered and we are interested in how you would approach them. Each session must be supported by evidence and include elements to promote audience engagement (such as use of the ARS system, small group breakout sessions, directed Q&A). Most sessions have been allotted 50 minutes, but we can adjust the time if needed (e.g. two 25-minute sessions within one time slot).

SAVE THE DATE OCTOBER 19-22, 2017 SAN DIEGO, CALIFORNIA

CORE TOPICS • Successful Team Care for Back Pain • Breakthroughs from the Bench: The State of Research into: — Headache — Neuropathic Pain

— Fibromyalgia — Arthritis — Back Pain • Assessment, Diagnosis, Treatment, Effectiveness, and Team Approaches Content for: — Headache — Fibromyalgia — Neuropathic — Arthritis Pain — Back Pain • Interactive Case Study Sessions — Headache and Neuropathic Pain

— Fibromyalgia and Arthritis — Back Pain

• Successful Team Care and Integrative Pain Management. Present a successful case study—your experience, supported by evidence.

• Evidence Review of Back Pain Treatment • Regulatory, Reimbursement Realities Around Integrative Back Pain Treatments • Complex Cases in Low Back Pain • Breaking Down Barriers to the Proliferation of Safe, Sane, and Effective Integrative Pain Management in the US • Regulator Roundtable: What do the CDC, CMS, and other Regulatory Agencies Need to Know about Integrative Pain Management?

• Effective Communications between Patients and Providers • Keys to Patient Adherence • Personal Responsibility and Accountability • Patient Self-management

AIPM’s 28th Annual Meeting A Meeting Like No Other!

Join your colleagues at the ONLY pain management meeting dedicated to integrated pain management and team–based approaches to pain care.

• Practical, team-based presentations on the most commonly encountered and challenging painful conditions encountered in daily practice • Interactive case study discussions with experts and attendees • Experiential sessions on yoga, meditation, exercise, and more!

• Evidence-based, multidisciplinary approaches to pain management • Regulatory agency discussions • Keys to patient communication and self-management For more information and to register for the meeting, go to http://blog.aapainmanage.org/ aipm-annual-meetings/ or call 209-533-9744.

• Experiential Sessions, such as yoga, tai chi, gentle stretching, meditation

If you are interested in participating, please download the speaker proposal form at http://blog.aapainmanage.org/call-speakers-2017/and email it to Cathleen Coneghen, Assistant Director of Education, by February 1, 2017; cconeghen@aapainmanage.org, tel: 919.890.5215., fax: 919-706-5342.

DEADLINE: February 1, 2017

TH E PAIN PRACTITION ER

| VOLUME 26, NUMBER 6 |

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RESEARCH

Research Recap Every other week, Currents, the AIPMâ&#x20AC;&#x2122;s e-newsletter, publishes research and guidelines on issues related to chronic pain. You can subscribe to Currents and the digital issue of The Pain Practitioner from this link: http://blog.aapainmanage.org/notifications-the-painpractitioner/

Assessing the quality, efficacy, and effectiveness of the current evidence base of active self-care complementary and integrative medicine therapies for the management of chronic pain: a rapid evidence assessment of the literature.

Because chronic pain affects the whole person (body, mind, and spirit), patient-centered complementary and integrative medicine (CIM) therapies that acknowledge the patientsâ&#x20AC;&#x2122; roles in their own healing processes have the potential to provide more efficient and comprehensive chronic pain management. A systematic review of 146 randomized controlled trials was conducted to rigorously assess both the quality of the research on ACT-CIM modalities and the evidence for their efficacy and effectiveness in treating chronic pain symptoms. This article provides an introduction and background to the review, summarizes the methodological processes involved, details the initial results, and identifies strengths and weakness of the review. Specific results of the review as well as overall recommendations for moving this field of research forward are detailed.

Read more: http://www.ncbi.nlm.nih.gov/pubmed/24734865

Interrelations between pain and alcohol: an integrative review.

Pain and alcohol use are both highly prevalent in the general population, and pain-alcohol interrelations are of increasing empirical interest.

Previous research has identified associations between pain and alcohol dependence, and the current review provides novel contributions to this emerging domain by incorporating studies that have tested relations between pain and low-to-moderate alcohol consumption, and by identifying potential psychosocial mechanisms of action.

Read more: http://www.ncbi.nlm.nih.gov/pubmed/25766100

Acceptance and commitment therapy in youth with neurofibromatosis type 1 (NF1) and chronic pain and their parents: A pilot study of feasibility and preliminary efficacy.

Acceptance and Commitment Therapy (ACT), an empirically supported method for addressing chronic pain, helps individuals re-focus on valued relationships and activities. This pilot study investigated the feasibility and preliminary efficacy of a brief ACT workshop in the NF1 population. Preliminary findings suggest that a brief ACT group intervention is feasible and may help adolescents and young adults (AYA) with NF1 and plexiform neurofibroma tumors (PNs) cope with their chronic pain, although larger randomized studies are needed to confirm treatment efficacy.

Read more: http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.37623/ab stract;jsessionid=40B09E67AFB35896348BA811A69B8641.f03t01

Structure of pain management facilities in Germany: Classification of pain treatment servicesâ&#x20AC;&#x201D;Consensus of the Joint Commission of the Professional Societies and Organizations for Quality in Pain Medicine.

A collaboration of medical and psychological pain professional associations, patients, and the Joint Commission of Professional Societies and Organizations for Quality in Pain Medicine has developed verifiable structural and process-related criteria for the classification of medical and psychological pain treatment facilities in Germany based on the established system of graded care and existing qualifications.

These criteria also call for a basic qualification in pain medicine. The recommendations offer verifiable criteria for quality in pain medicine and treatment.

Read more: http://www.ncbi.nlm.nih.gov/pubmed/27221745

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| T HE PA I N P R AC TI TI O NE R | D E C E M B E R 2 0 1 6

Mechanisms involved in the development of chemotherapy-induced neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition. Current research suggests genetic predispositions to this condition, which then may influence cellular responses to chemotherapy. Changes in ion channels and neurotransmission, as well as changes in intracellular signaling and structures have been implicated in CIPN. This review explores these issues and suggests considerations for future research.

Read more: https://www.ncbi.nlm.nih.gov/pubmed/26087973

The Senza SCS System, an implanted, rechargeable spinal cord stimulation system, was approved by the FDA for treatment of chronic pain of the trunk and/or limbs that is difficult to manage or intractable.

The main components of the Senza SCS System include an implanted signal generator that is connected to one or two implanted leads, and external doctor and patient controllers. It is used as an aid in the management of chronic intractable pain of the trunk and/or limbs. Patients with the system can only be exposed to magnetic resonance imaging (MRI) using special procedures outlined in the device labeling.

Read more: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm449963.htm

Integrating cannabis into clinical cancer care.

Cannabis may offer benefits for the cancer patient, especially in the management of symptoms, such as anorexia, chemotherapy-induced nausea and vomiting, pain, insomnia, and depression. Although cannabis might be less potent than other available antiemetics, it is the only agent that works for some patients, and it is the only antiemetic that also increases appetite. Besides symptom management, an increasing number of studies support a possible direct anticancer effect of cannabinoids through different mechanisms involving apoptosis, angiogenesis, and inhibition of metastasis. Despite an absence of clinical trials, abundant anecdotal reports that describe patients having remarkable responses to cannabis as an anticancer agent, especially when taken as a high-potency orally ingested concentrate, are circulating. Human studies should be conducted to address critical questions related to the foregoing effects.

Read more: http://www.ncbi.nlm.nih.gov/pubmed/27022315

Traditional Chinese medications for knee osteoarthritis pain: A meta-analysis of randomized controlled trials.

Traditional Chinese medication (TCM) has analgesic and antiinflammatory effects in patients with knee osteoarthritis (OA). A comprehensive literature search was conducted using three English and four Chinese biomedical databases from their inception through March 1, 2015.

It included randomized controlled trials of TCM for knee OA with intervention durations of at least two weeks. TCM showed a lower risk of adverse events than standard Western treatments. The evidence suggests that TCM is safe and effective for improving pain, function, and wellness in treatments of knee OA. However, there is inherent clinical heterogeneity (diverse TCM formulations, controls, and treatment regimens) among the included trials.

Read more: http://www.worldscientific.com/doi/abs/10.1142/ S0192415X16500373?url_ver=Z39.88-2003&rfr_ id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

Xtampza ER contains a proprietary oxycodone formulation that helps avoid increases in peak plasma concentrations and rapid drug release when manipulated1 Abuse of Xtampza ER by injection, by the nasal route of administration, and by the oral route is still possible Xtampza ER is the exclusive, extended-release oxycodone on UnitedHealthcare commercial insurance beginning January 1, 2017

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 accompanying brief summary of the full Prescribing Information.

Reference: 1. Xtampza ER [prescribing information]. Canton, MA: Collegium Pharmaceutical, Inc; 2016.

Xtampza ER is a registered trademark of Collegium Pharmaceutical, Inc. ©2016 Collegium Pharmaceutical, Inc. All rights reserved. PP-XT-US-0307

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

THE LOWDOWN ON BACK PAIN

This issue of The Pain Practitioner features

Low back pain, the leading cause of disability worldwide.

Although most episodes are acute and resolve on their own within a short time, chronic pain conditions comprise a significant percentage of cases.

A

n emerging approach to the treatment of chronic low back pain is the use of concentrated/isolated autologous mesenchymal stem cells (MSCs) that are harvested from a patientâ&#x20AC;&#x2122;s own bone marrow and adipose tissue and reinjected into affected structures and tissue beds. Here, Harry Adelson, ND, presents preliminary results his groupâ&#x20AC;&#x2122;s clinical experience in this new and rapidly growing field. Based on their experience, injection of MSCs for low back and discogenic pain appears to be safe and effective.

In this issue, W. Evan Rivers, DO, discusses a successful collaborative care model for the management of spine pain syndromes. At the Spine Clinic at the University of New Mexico (UNM), a diverse panel of clinicians offers their individual strengths to improve the quality of service to their patients.

The fundamental goal of this collaborative structure is to improve access to high-quality spine care that is appropriate to the needs of the patient. Recognizing that the needs of patients may change over time and that different professionals may be necessary to address these needs, this group works together to minimize subsequent disability and dysfunction in the management of acute spine trauma and chronic spine pain and the correction of spinal deformities.

Also featured is compelling research on the impact of smoking on back pain discussed by Brian F. White, DO. As an interventionalist, Dr. White primarily focuses on procedures, but notes it is most often other factors that ultimately generate a successful outcome for the patient. Aside from the obvious factors including core strengthening, what may be among the most important is smoking cessation.

Smoking is the root cause of many musculoskeletal disorders. Smoking causes changes in pain processing and can induce structural changes in other systems that will predispose patients to painful musculoskeletal conditions. Epidemiologically, smokers have more pain, increased pain frequency, an increased number of pain sites, increased low back pain, and most importantly, an increased incidence of disabling back pain. Pathophysiologically, smokers have increased disc degeneration, impaired healing, and an increased risk for injury, as well as impaired pain pathways. Thus, smokers are more likely to get hurt and take longer to heal. The bottom line is that in order to maximize the effectiveness of pain management programs, patients need to stop engaging in behavior that makes the problem worse.

TH E PAIN PRACTITION ER

| VOLUME 26, NUMBER 6 |

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SMOKING AND BACK PAIN

Smoking and Back Pain: Adding Insult to Injury

By Brian F. White, DO, FAAPMR

Whether surgical or nonsurgical, interventionalists often focus predominantly on the challenges and technical aspects of the various procedures we perform. Unfortunately, no matter how technically proficient we are, it is most often other factors that ultimately generate a successful outcome for the patient. The things that matter in back pain include improving the stability of the lumbar spine, decreasing stress or force on the spine, improving healing, and improving patient coping mechanisms and managing expectations. Developing core strength and pelvic floor engagement, daily stretching of hamstrings and hip flexors, using appropriate body mechanics and ergonomics, managing depression and anxiety, and setting realistic expectations are undeniably important components of back pain management. But what may be the most important factors, with far-reaching effects, are smoking cessation and obtaining, and maintaining, an appropriate body weight. This article will focus on research describing the impact of smoking on back pain. The relationship between obesity and back pain will be covered in a subsequent issue.

Of all modifiable behaviors, smoking remains the largest cause of preventable death in the world (1). Aside from the obvious medical conditions associated with smoking, such as lung cancer, chronic bronchitis, and coronary heart disease, smoking is also the root cause of many musculoskeletal disorders (2). Smoking alters the processing of pain and its perception so that smokers perceive increased pain. Experimental studies indicate that nicotine has analgesic properties with initial use, but epidemiological evidence shows that smoking is a risk factor for chronic pain. Prolonged exposure to nicotine induces acetylcholine receptor desensitization and tolerance to nicotine-induced antinociception. In addition, when smoking is stopped, withdrawal from nicotine is associated with hyperalgesia, and these changes in the central nervous system persist long after patients stop smoking. In a survey of British adults, smokers and former smokers were found to have a higher lifetime risk for musculoskeletal pain (3). A Norwegian study of adults with musculoskeletal pain noted that smokers reported more intense pain than nonsmokers, even after other possible contributing and confounding factors were adjusted (4).

In addition to changes in pain processing, smoking can induce structural changes in other systems that will predispose patients to painful musculoskeletal conditions. Smoking may accelerate degenerative processes and make the body more vulnerable to injury (2). Smoking also increases the risk for lumbar disc disease and impairs bone and wound healing.

One of the underlying mechanisms for these changes involves impairments in oxygen delivery to tissues due to increases in sympathetic outflow and carboxyhemoglobin levels.

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A survey of German adults showed that current and former opioid users are more likely to use prescription analgesics than those who have never smoked (5). Another study showed that despite having higher pain scores and requiring more hydrocodone for relief, smokers had lower serum hydrocodone levels than nonsmokers (6), which suggests that smoking upregulates the metabolic pathway for morphine (2).

Smoking decreases bone mineral content and increases the incidence of fractures in a dose-dependent relationship (7). Smoking also delays fracture healing. In a study of patients with long bone fractures, smokers took 269 days to heal, while nonsmokers healed in 136 days (7).

Smoking has similar deleterious effects on healing of tendons and ligaments as well (8). Psychosocial factors and depression also contribute to the interaction between smoking and chronic pain (Figure).

SMOKING AND LOW BACK PAIN

Research has shown that smoking is associated with low back pain independent of other cofactors (7). The association between smoking and low back pain is likely due to nicotine-associated disc degeneration, in which the toxic activity of nicotine increases the degradation of collagen and disc matrix proteins. In addition, vascular damage and vasoconstriction results in a decreased supply of blood and oxygen to the discs. A Finnish meta-analysis of smoking and back pain showed that the association between current smoking and low back pain was strongest for adolescents, presumably because of the disc destruction that occurs (OR [odds ratio] = 1.82) (9). In this study, smoking was moderately associated with chronic low back pain (OR = 1.79) and strongly associated with disabling low back pain (OR = 2.14). Thus, not only are smoking and back pain associated, but those patients who seek medical care for management of disabling back pain that prevents them from working are more than twice as likely to be smokers.

A strong dose-response relationship between smoking and low back pain was also demonstrated in an Australian review of twin studies (OR = 3.0). Interestingly, in their investigation of risk factors for low back pain, these authors also found that genetics play a dose-response role, with genetic factors contributing more strongly to chronic and disabling back

Shi Y, et al. Smoking and Pain: Pathophysiology and Clinical Implications. Anesthesiology. 2010;113:977-92

SMOKING AND BACK PAIN pain than to acute pain (10). A Turkish study of risk factors for low back pain also found a strong association between smoking low back pain as well as an association between smoking and lower education, lower socioeconomic level, and labor-intensive occupations (11). However, no correlations were noted between low back pain and alcohol intake, age, or gender.

In a prospective database review of 5,333 patients undergoing care for painful spinal disorders, current smokers reported greater pain than nonsmokers and nonsmokers showed greater improvement in pain than smokers over the course of care (12). Those who quit smoking during their care reported greater improvement than those who continued to smoke, and the patients who did not quit smoking had no clinical meaningful improvements in their back pain despite engagement in a treatment program for low back pain.

References 1.

2.

3.

4.

5.

6.

7.

8.

THE COST OF SMOKING

According to a German study on health care costs and employee productivity, current and former smokers cost up to one-third more than nonsmokers (13). Total annual costs are higher for former smokers than for current smokers because the cohort of former smokers includes anyone who smoked for any length of time, whereas the cohort of current smokers may not have not been smoking for very long.

A large US employer study noted that smokers had higher rates of absenteeism and health care utilization than nonsmokers, costing as much as $1,383 more per year per smoker (14). Another study of men in Finland estimated that smokers were associated with an annual increase of 1,600 Euros in health care costs than nonsmokers but, on the other hand, were responsible for a marked decrease in pension costs due to increased mortality. However, when a monetary value for life years lost was taken into account, the beneficial net effect of non-smoking to society amounted to about 70,000 Euros per individual (15).

Epidemiologically, smokers have more pain, increased pain frequency, an increased number of pain sites, increased low back pain, and most importantly, an increased incidence of disabling back pain.

Pathophysiologically, smokers have increased disc degeneration, impaired healing, and an increased risk for injury, as well as impaired pain pathways. Thus, smokers are more likely to get hurt and take longer to heal. The bottom line in regard to smoking is that in order to maximize the effectiveness of pain management programs, patients need to stop engaging in behavior that makes the problem worse. ❏

9.

10.

11.

12.

13.

14.

15.

Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004;291(10):1238-1245.

Shi Y, Weingarten TN, Mantilla CB, Hooten WM, Warner DO. Smoking and pain: pathophysiology and clinical implications. Anesthesiology.

2010;113(4):977-992.

Palmer KT, Syddall H, Cooper C, Coggon D. Smoking and musculoskeletal disorders: findings from a British national survey. Ann Rheum Dis. 2003;62(1):33-36.

Eriksen WB, Brage S, Bruusgaard D. Does smoking aggravate musculoskeletal pain? Scand J Rheumatol. 1997;26(1):49-54.

John U, Alte D, Hanke M, Meyer C, Völzke H, Schumann A. Tobacco smoking in relation to analgesic drug use in a national adult population sample. Drug Alcohol Depend. 2006; 85:49-55.

Ackerman WE 3rd, Ahmad M: Effect of cigarette smoking on serum hydrocodone levels in chronic pain patients. J Ark Med Soc. 2007; 104:19–21.

Abate M, Vanni E, Pantelone A, Salini V. Cigarette smoking and musculoskeletal disorders. Muscles Ligaments Tendons J. 2013;3(2):63-69.

Duygulu F, Karaoğlu S, Zeybek ND, Kaymaz FF, Güneş T. The effect of subcutaneously injected nicotine on achilles tendon healing in rabbits. Knee Surg Sports Traumatol Arthrosc. 2006;14(8):756–761.

Shiri R, Karppinen J, Leino-Arjas P, Solovieva S, Viikari-Juntura E. The association between smoking and low back pain: a meta-analysis. Am J Med. 2010;123(1):87.e7-35.

Ferreira PH, Beckenkamp P, Maher CG, Hopper JL, Ferreira ML. Nature or nurture in low back pain? Results of a systematic review of studies based on twin samples. Eur J Pain. 2013;17(7):957-971.

Unde Ayvat P, Aydın ON, Oğurlu M. Risk factors associated with lower back pain in the Polyclinic of Algology. Agri. 2012;24(4):165-170.

Behrend C, Prasarn M, Coyne E, Horodyski M, Wright J, Rechtine GR. Smoking cessation related to improved patient-reported pain scores following spinal care. J Bone Joint Surg Am. 2012;94(23):2161-2166.

Wacker M, Holle R, Heinrich J, et al. The association of smoking status with healthcare utilisation, productivity loss and resulting costs: results from the population-based KORA F4 study. BMC Health Serv Res. 2013 Jul 17;13:278.

Sherman BW, Lynch WD. The relationship between smoking and health care, workers’ compensation, and productivity costs for a large employer. J Occup Environ Med. 2013 Aug;55(8):879-84.

Tiihonen J, Ronkainen K, Kangasharju A, Kauhanen J. The net effect of smoking on healthcare and welfare costs. A cohort study. BMJ Open. 2012 Dec 11;2(6)

Brian F. White, DO, FAAPMR, is an interventional physiatrist at Bassett Medical Center in Cooperstown NY, and is affiliated with Columbia Medical School. He holds three specialty board certifications including: physical medicine and rehabilitation, electrodiagnostic medicine, and sports medicine.

Dr. White has a strong interest in musculoskeletal injury and pain as well as in interventional spine care.

Documenting your pain management experience has been out of reach for so many prescribers. Until now.

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2. You have at least 5 years of clinical experience, with at least 30% of your time spent caring for people with pain.

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TH E PAIN PRACTITION ER

| VOLUME 26, NUMBER 6 |

23

COLLABORATIVE CARE OF SPINE PAIN

Collaborative Care of Spine Pain

By W. Evan Rivers, DO

The Spine Clinic at the University of New Mexico (UNM) has established a successful collaborative care model for the management of spine pain syndromes. A diverse panel of clinicians offers their individual strengths to improve the quality of service provided by the clinic. The team members include four surgeons in the department of neurosurgery who regularly perform spine operations and three additional spine surgeons in the department of orthopedics who have spine specialty training. Together, these surgeons play an active role in the management of acute spine trauma and chronic spine pain, and the correction of spinal deformities.

In addition to the surgeons, a physical medicine and rehabilitation physician, or physiatrist, coordinates non-operative care for chronic spine pain. Physiatry provides management of chronic spine pain syndromes, electrodiagnostic testing, diagnostic injections, and therapeutic interventions. Physical therapy is the mainstay of managing acute, subacute, and chronic spine conditions. Several therapists collaborate directly with physicians on the UNM spine team to be sure patients are learning the self-management tools that will best allow them to succeed as they pursue treatment.

The psychological status of patients has been recognized as a major predictive factor in their recovery from spine injury and spine surgery. Counselors and psychologists are available to help manage mood and social pressures in the context of spine care.

Physician assistants have become irreplaceable members of the team who provide non-operative care and help patients understand how they fit into the treatment pathways available for spine pain syndromes, while helping coordinate pre-operative and post-operative care for patients. Their practices have expanded the ability of the facility to process referrals and maintain throughput.

Nurses work closely with physicians to triage patients and provide important education to patients about their conditions. Nurses are often the first contact patients have with the clinic and may be the first to address distressing symptoms—trust is essential, and competent assessment is key.

Many of the clinicians who work in the Spine Clinic are also involved in the Pain Consultation and Treatment Center, a multidisciplinary team of individuals devoted to comprehensive treatment for chronic pain. These colleagues offer excellent resources to extend care to patients with complex psychosocial considerations that could otherwise limit their ability to respond to treatment for spine pain.

TEAM ACCESS TO SURGEON A great advantage of the collaborative care model is the ability to provide rapid triage to patients with known neurological morbidity, such as myelopathy. Surgeon input also becomes invaluable for patients who present with symptoms that seem urgent. Often non-surgeon clinicians are intimidated by the patient’s degree of pain or disability or the presence of potentially neurological symptoms. Brief discussions can reassure clinicians and patients that the reported problem has no known surgical treatment and must be addressed through conservative, non-surgical strategies. On the other hand, access to spine surgeons provides great confidence for the non-surgeon members of the team, knowing that a rapid escalation of care is possible if needed.

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| T HE PA I N P R AC TI TI O NE R | D E C E M B E R 2 0 1 6

One of the best examples of the value of surgical access is the case of a gentleman referred for neck pain. In the interim between referral and initial evaluation, he developed a non-painful myelopathy with rapidly progressive loss of dexterity in the upper limbs.

He was no longer able to button his shirts by the time of his first visit with the physiatrist. A brief examination revealed brisk reflexes in the legs, gait dysfunction, and a positive Hoffman’s sign in both hands. A surgeon was available the same day, and the patient underwent decompression surgery within two weeks. A rapid and complete restoration of function followed the operation.

Another informative case is that of a mid-40-year-old woman with a history of profound depression and suicide attempts. At evaluation, she reported suicidality due to extreme radicular pain in the leg that persisted despite weeks of expectant waiting and medical trials of nerve membrane stabilizers, nonsteroidal antiinflammatory drugs, muscle relaxants, and opioids. Advanced imaging studies revealed L4-5 extrusion with involvement of the L5 nerve root, and examination revealed focal deficits in the cutaneous and muscle distribution of the L5 nerve root. The physiatrist recommended immediate surgical resection to mitigate the risk of self-harm and minimize exposure to medication that could have worsened the control of psychiatric conditions. Immediately after the operation, a complete relief of leg pain was reported that has been sustained over 18 months of follow-up. The resolution of pain was accompanied by a complete remission in suicidal ideation, as well as a dramatic reduction in anxiety and depression.

SURGEON ACCESS TO PHYSIATRY One of the great benefits of collaborative approaches to spine care is the ability to use diagnostic injections and perform a thorough functional assessment. Many individuals have multiple areas of degeneration among spinal structures, many of which may be the cause of neurological deficit or dysfunction. The cases of clear and focal surgical pathology are relatively few compared to the cases of potential surgical overreach and escalating surgical morbidity.

An excellent example of collaboration between surgery and physiatry occurred during the care of an active septuagenarian with radicular pain and neurogenic claudication. He was initially seen by a neurosurgeon who performed a conventional posterior decompression for L4-5 central canal stenosis. The patient did well for several months, but then had a progressively worsening radiculitis in an L4 nerve root distribution on the left, which was provoked with ambulation. He was referred to physical therapy and physiatry. Despite participation in physical therapy, his radicular pain progressed and his functional status declined. Imaging studies revealed multiple levels of degeneration. Following a left L4 selective nerve root block he had complete pain relief for one hour – but after the local anesthetic wore off, his radicular pain persisted. Based on the functional assessment from physical therapy and the response to diagnostic injection from physiatry, an L4-5 extreme lateral interbody fusion was performed.

Following this surgery, he had complete relief of radicular pain, but progressively worsening axial low back pain, and he was referred back to physiatry after physical therapy yielded no improvement. Diagnostic injections revealed that his back pain was completely responsive to anesthetic block of the L3-4 and L5-S1 facet joints, and a radiofre-

COLLABORATIVE CARE OF SPINE PAIN

quency denervation was performed. Complete relief of back pain was reported, and he returned to walking several miles each day in the countryside. This case represents a common constellation of anatomical problems among aging individuals. It also reveals how collaborative treatment of spine conditions can improve pain, activity, and physical function in a vulnerable population.

There are cases of potential surgical pathology in a complex spine without a clear anatomical syndrome where response to diagnostic injections is entirely inconsistent with the clinical presentation. In these cases, recommendations to withhold surgical treatment have been greatly valued. This practice minimizes exposure to treatments that may be harmful and are not likely to be helpful.

DEVELOPMENT OF AN ENDOSCOPIC SPINE PRACTICE We have recently begun practicing endoscopic spine surgery, which incorporates diagnostic injections, extremely minimally invasive spine operations, and approaches that can be unfamiliar to traditionally trained spine surgeons and interventional spine physicians alike.

The combination of professionals from different backgrounds in the clinic and in the operating room has been an extraordinary asset to the development of these surgical techniques. Instrument placement and surgical target selection has benefited from the input of these coordinating professionals. The application of these techniques in a collaborative environment has rapidly advanced the learning curve for surgeons and interventionalists.

CONCLUSION The fundamental goal of this collaborative structure is to improve access to high-quality spine care that is appropriate to the needs of the patient. This collaboration recognizes that the needs of patients may change over time and that different professionals may be necessary to address these needs. Minimizing subsequent disability and dysfunction can be achieved by applying the known efficacy of physical, surgical, interventional, medical, and psychological care. The future holds progressively better access to appropriate care, with better detection of targets of spine pain, and more informed decisions in application of treatment. ❏ W. Evan Rivers, DO, works in the depart-

ment of neurosurgery in the University of New Mexico. He trained in physical medicine and rehabilitation and pain medicine at the Rehabilitation Institute of Chicago and Northwestern Memorial Hospital. He is committed to providing the highest quality of care to patients with spine pain syndromes.

When Pain is More Complicated Turn to Sierra Tucson

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Sierra Tucson is accredited by The Joint Commission and licensed as both a special hospital and a behavioral health residential treatment center.

TH E PAIN PRACTITION ER

| VOLUME 26, NUMBER 6 |

25

AUTOLOGOUS STEM CELL THERAPY FOR BACK PAIN

Autologous Stem Cell Therapy: A Naturopathic Approach to the Treatment of Chronic Low Back and Discogenic Pain

By Harry Adelson, ND

SUMMARY Low back pain is the leading cause of disability worldwide (1). An emerging approach to the treatment of chronic low back pain is the use of concentrated/isolated autologous mesenchymal stem cells (MSCs) that are harvested from a patient’s own bone marrow and adipose tissue and reinjected into affected structures and tissue beds. The purpose of this retrospective survey was to evaluate patient-reported outcomes one year after treatment of low back and discogenic pain in patients injected with adipose-derived stromal vascuFigure 1. Injection of lumbar discs with adipose-derived stromal lar fraction suspended in bone marrow aspirate concentrate vascular fraction suspended in bone marrow aspirate concentrate.

(SVF/BMAC). Of the patients surveyed (N = 30), there were no adverse outcomes and one non-responder. The average conditions such as osteoarthritis (13,14), sports/traumatic injury (15), improvement reported was 77.5% from baseline. Based on this author’s low back and discogenic pain, neck pain with or without cervicogenic experience, injection of SVF/BMAC concentrate for low back pain apheadaches (16), and osteonecrosis (17). pears to be safe and produces consistently satisfactory results.

MSCs are found throughout the body in many tissue types, but they are particularly abundant and easily harvested from the medullary INTRODUCTION cavity of flat bones and adipose tissue. MSCs can be easily concenLow back pain causes more global disability than any other trated from aspirated bone marrow using simple centrifugation (18), condition (2). According to research, conservative treatment appears thereby rendering bone marrow aspirate concentrate (BMAC). With to be of limited benefit (3), the usefulness of lumbar epidural steroid a little more effort, MSCs can be isolated from lipoaspirated adipose injection has been called into question (4-6), and surgery for low back tissue through a multi-step process of incubation and enzymatic digespain carries tremendous risk (7). tion with collagenase, followed by centrifugation and filtration (19), Naturopathic physicians in the US and Canada have a rich history thus rendering adipose derived stromal vascular fraction (SVF). It is the of performing prolotherapy (8). The injection of autologous stem cells experience of this author that the injection of SVF/BMAC offers supefor the treatment of chronic musculoskeletal pain can be viewed as the rior outcomes to either BMAC alone or SVF suspended in platelet-rich natural evolution of prolotherapy (9), and its proposed mechanism plasma alone (20). of action, namely the regeneration of damaged or degenerated tissues through the triggering of the body’s own healing response, is perfectly METHODS aligned with the guiding principles of naturopathic medicine (10).

Regenerative Injection Therapy is based on the premise that MSCs have been called “patient-specific drug stores for injured chronic low back pain is rarely due to a single pain generator (21). tissues” because of their ability to secrete bioactive factors and signals at Desiccated discs can be a pain generator, but so can neovascularizavariable concentrations in response to local microenvironmental cues tion in paravertebral tissue beds (22) and within the epidural space (11). MSCs release a spectrum of antiinflammatory, immunomodula(23). Thus, over 15 years of private practice, I have developed a tory, and trophic factors that trigger the regeneration and healing of simple algorithm for treating chronic low back pain, outlined in connective tissues through activation of stem cells endogenous to the Table 1. site (11). Stem cell therapy is based on the premise that all musculoIn January 2016, we reviewed the charts of 112 patients treated skeletal structures contain populations of MSCs whose primary role is for low back pain (Categories I-III) between January 1 and August 31, to maintain the health of their microenvironment; degeneration and 2015. Patients who were between the ages of 18 and 85 at the time of pain occur when these populations either become depleted or lose treatment and who fit the following criteria were included in the study: their ability to function properly (12). Therefore, the goal of stem cell Patients had to have lumbar discogenic pain (determined by patient therapy is to repopulate degenerated structures and tissue beds with report of midline lumbar pain that was made worse by bending forward) a robust population of viable MSCs (12). The site-specific injection along with lumbar disc desiccation that was visible on MRI. They had to of autologous stem cells has shown promise in musculoskeletal pain have undergone a single Category III stem cell treatment (see Table 1).

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AUTOLOGOUS STEM CELL THERAPY FOR BACK PAIN Table 1. A Regenerative Injection Therapy Algorithm for the Treatment of Low Back Pain Category I: Non-specific low back pain

1.

2.

3.

Perifacet injection L2/3-L5/S1 bilateral Iliolumbar ligament injection bilateral Sacroiliac ligament injection bilateral

Category II: Radiculopathy/paresthesia

1.

2.

3.

4.

Transforaminal epidural at most affected level/side (bilateral if sides equal) Perifacet injection L2/3-L5/S1 bilateral Iliolumbar ligament injection bilateral Sacroiliac ligament injection bilateral

1.

2.

Intradiscal injection at affected level(s) Transforaminal epidural at most affected level/side (if sides equal: bilateral, in case of no radiculopathy/paresthesia: unilateral at level of most affected disc) Perifacet injection L2/3-L5/S1 bilateral Iliolumbar ligament injection bilateral Sacroiliac ligament injection bilateral

Category III: Discogenic pain; determined by patient report of midline lumbar pain made worse bending forward accompanied by disc desiccation on MRI (decreased signal strength upon T2 weighting); with or without radiculopathy/paresthesia

3.

4.

5.

They had not undergone lumbar fusion or laminectomy prior to treatment (although those who had undergone microdiscectomy were included). Finally, they had experienced continuous pain for no less than one year prior to treatment.

Between February and August, 2016, I phoned all the patients who fit the above criteria and who were between 12 months and 16 months post-treatment to ask them two questions: 1) What percentage improvement have you experienced since your stem cell injection?, and 2) Overall, are you satisfied with the stem cell treatment?

Figure 2. Patient-reported improvement one year after treatment.

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0 1

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16 17

18 19

RESULTS Of the patients surveyed (N = 30), none had any adverse reactions.

One patient reported having experienced no benefit at all, but neither was he made worse by the treatment. Five patients reported 50% improvement. Four patients reported 100% improvement. The remaining 20 patients reported an average of 77.5% improvement (ranging between 50% and 100%). Overall, 29 out of 30 patients (96.7%) identified themselves as “satisfied” with their stem cell treatment.

20 21

22 23

24

25 26

27 28 29 30

31

DISCUSSION Based on our experience, injection of SVF/BMAC for low back and discogenic pain appears to be safe and produces consistently satisfactory results. Clearly, this simple survey does not claim to provide any hard evidence; it is intended as an empirical report of our clinical experience in this new and rapidly growing field. ❏ References are on page 37.

Harry Adelson, ND, opened Docere Clinics in Salt Lake City in 2002, and from day one his practice has been 100% regenerative injection therapies for the treatment of musculoskeletal pain conditions.

Since February of 2010, Dr. Adelson has performed more than 4,000 bone marrow and adiposederived adult stem cell procedures, placing him in the company of those most experienced in the world with use of autologous stem cells for the treatment of musculoskeletal pain conditions.

Dr. Adelson lives and practices in Park City, TH E PAIN PRACTITION ER

| VOLUME 26, NUMBER 6 |

27

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 • Butrans 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 • Monitor 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 • Cases 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)

EPIGENETICS IN MIGRAINE

Emerging Role of Epigenetics in Understanding Migraine

By Roger K. Cady, MD, and Paul L. Durham, PhD

ABSTRACT An individualâ&#x20AC;&#x2122;s susceptibility to migraine involves a complex interplay between genes (nature) and environment (nurture). The concept of a hyperexcitable nervous system that is implicated in the underlying pathophysiology of migraine is largely determined initially by oneâ&#x20AC;&#x2122;s genetic background.

Conversely, initiation of a migraine attack appears to be in response to environmental change. Well indoctrinated into the lexicon of migraine is the concept of a migraine threshold, a physiological set point where genetics and the environment interact to create the perfect storm of molecular events that trigger migraine. Epigenetics is the study of how genes can be activated or inactivated in response to environmental influences and lifestyle choices without changing the DNA sequence. Based on recent epigenetic findings we propose a model for understanding migraine that may help explain risk factors, disease progression, headache phenotypes, drug response, and the critical contribution of lifestyle, medication, and stress on migraine pathology.

INTRODUCTION The pathophysiological basis of episodic and chronic migraine is built around the concept of a hyperexcitable brain. This model presupposes that a person inherits genes that may lead to the development of a hypervigilant nervous system characterized by an enduring potential to generate recurrent attacks of migraine. The migraine attacks are hypothesized to occur when this hyperexcitable nervous system is exposed to migraine triggers (1). We propose that changes in the environment or lifestyle, such as sleep disruptions and stress/anxiety, act as risk factors to promote and sustain this hypervigilant phenotype associated with migraine pathology. In this sensitized state, individuals are 32

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EPIGENETICS IN MIGRAINE

more susceptible to sensory stimuli often reported as migraine triggers, including bright or changing light patterns, strong odors, certain foods, and loud or irregular sounds. However, it is not usually a single trigger, but rather the presence of multiple risk factors that better predicts attacks of migraine (2). We propose that changes in gene expression occur in response to risk factors associated with migraine. This hypothesis is built on an emerging science called epigenetics, the study of how genes can be activated or inactivated in response to environmental influences and lifestyle choices without changing the DNA sequence. This may provide a rationale for the development of a hyperexcitable nervous system in migraineurs and help explain the underlying pathology of episodic and chronic migraine.

The genes inherited from our parents likely predispose us not to a single disease, but to the potential of developing many different diseases throughout a lifetime. However, what may ultimately determine which diseases manifest in our lifetime is not simply a result of genetic mutations and polymorphisms, but how the expression of our genes can be altered in response to interactions with our environment and lifestyle choices. Accumulating evidence supports a dominant role for epigenetics in determining when and even if an individual will develop disease-specific pathology (3,4). Thus, epigenetic mechanisms may serve as a template for both the development and possible reversal of a disease process. An important role of epigenetics in primary headaches has been proposed within the context of an adaptive behavioral model that functions to restore homeostasis (5). The focus of this review will be on understanding how environmental factors and lifestyle influence expression of our genes via epigenetic mechanisms to promote or inhibit migraine progression. It is our intent that this information will be useful to clinicians and ultimately lead to better management of migraine patients.

EPIGENETIC REGULATION OF GENE EXPRESSION In contrast to mutations in genetic alleles, epigenetic mechanisms do not involve alterations of the primary DNA sequence, yet constitute a self-propagating mechanism to store information as cellular memories from previous experienced stimuli (6).

Importantly, epigenetic modifications are dynamic and thus allow an organism to adapt to changes in the environment that impact our longevity, health, and well-being (7,8). Although the risks of developing chronic diseases are attributed to both genetic and environmental factors, 70% to 90% of disease risks may be attributable to differences in environments (7).

Epigenetic changes, which can selectively activate or inactivate specific genes, are mediated at the chromatin level via chemical modifications of our DNA and associated histone proteins in response to environmental interactions (3, 9,10). Two important epigenetic mechanisms reported to regulate gene expression in human cells involve methylation of DNA and deacetylation of histone proteins. DNA methylation is characterized by the addi-

tion of a methyl group (-CH3) on the cytosine nucleotide within CpG regions of the promoter, which functions as a molecular on/ off switch to modulate gene expression. These promotor regions are present in approximately 40%-50% of human genes. DNA methylation, which is performed by enzymes known as DNA methyltransferases, produces stable epigenetic configurations that can be maintained throughout life. In general, hypermethylation of DNA in the promoter region of genes results in gene silencing, and, conversely, promoter hypomethylation is characteristic of gene activation.

DNA methylation is a dynamic process that facilitates a response to changes in environmental factors such as diet, physical or psychosocial stress, and trauma, especially when they occur during critical periods of development or with aging (11-13).

A study with monozygotic twins showed that while patterns of DNA methylation were similar in young twins, the patterns were quite distinct in older twins (14). Similarly, studies in patients with Alzheimerâ&#x20AC;&#x2122;s disease (15), inflammatory periodontal disease (16), and autoimmune disease (17) provide evidence of the importance of different DNA methylation patterns in determining disease severity. These findings suggest that environmental and lifestyle factors for each individual may promote epigenetic events that influence the onset and progression of many diseases.

Histone modifications function as a molecular rheostat to regulate how tightly or loosely DNA is packaged within the nucleus.

They also control the accessibility and binding of proteins known as transcription factors to the DNA promoter sequence of genes.

Modification of histone tails including acetylation, phosphorylation, and/or methylation is mediated by enzymes that selectively add or remove these functional groups (18). A much-studied modification is the removal of the acetyl group (deacetylation) by histone deacetylases (HDACs), which results in tighter compaction of the chromatin, thereby preventing transcription and consequently inhibiting gene expression.

MIGRAINE AND THE ROLE OF NEURONAL SENSITIZATION Individuals with migraine are thought to have a hyperexcitable nervous system that likely involves changes in genes that code for ion channels, receptors, gap junction proteins, and signaling molecules, all of which regulate neuronal excitability. Were these individuals born with this genetic predisposition? Or, did it develop over time because environmental risk factors caused modification of genes that at the molecular level increased the vigilance or excitability of their nervous system to the degree that it became maladaptive? As an example, a child enduring trauma may be protected biologically by expression of genes that increase environmental vigilance in an effort to find greater security.

However, even when the threat resolves, those genes may continue to be expressed, thus maintaining the nervous system in a state of heighted awareness and neuronal hyperexcitability. As future environmental threats are encountered, this vigilant state may TH E PAIN PRACTITION ER

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EPIGENETICS IN MIGRAINE increase the risk of more frequent and severe attacks of migraine.

In support of this notion, childhood maltreatment and especially emotional abuse increase the likelihood of developing migraine via epigenetic changes mediated by DNA methylation (19).

RISK FACTOR: PSYCHOLOGICAL STRESS Stress is the most common environmental risk factor implicated in the underlying pathology of episodic and chronic migraine.

Whether the threat is imaginary or real, external stress greatly affects our physiological and psychological well-being and influences the maintenance of homeostasis. Elevated levels of stress result in increased CNS-induced changes in arousal state, vigilance, cognition, attentiveness, and even aggression. Environmental factors such as stress seem to influence disease onset, promote progression, and maintain the clinical phenotype associated with many neurological diseases (20). In support of this notion, epigenetic modifications are reported to occur that mediate long-term as well as rapid, dynamic changes in gene expression during periods of stress (21).

Of particular relevance is the finding that stress-induced epigenetic changes can persist long after the stressor has ended and can lead to prolonged, stable functional changes in the brain. Thus, epigenetic mechanisms are likely promoting and maintaining the persistent, pathologic effects of stress. Stressful events, which are known to significantly alter the epigenome, can provide a potent stimulus that renders an individual more vulnerable to other risk factors implicated in a number of psychological and neurological diseases. Likewise, many psychological diseases involve a genetic predisposition, but disease progression can be positively or negative-

ly modified by environmental events that may leave an imprint on our genome (22). Interestingly, prenatal stress in humans has been shown to cause changes in methylation patterns of a number of genes within regions of the brain that are implicated in modulation of the stress response (23,24). Other environmental factors known to alter chromatin structure and gene expression are prenatal diet (25) and maternal care (26). Since epigenetic changes are strongly associated with synaptic plasticity and the ability to make behavioral adaptations to modulate the pathophysiological effects of chronic stress, understanding a patient’s previous and ongoing level of stress should be an important component of managing migraine.

RISK FACTOR: MEDICATION OVERUSE HEADACHE FROM OPIOIDS The chemical environment created by chronic medication use provides another potential mechanism of epigenetic influence on our genome (27,28). Chronic opioid exposure, for example, is associated with increased DNA methylation in chronic substance abusers (29). Results from a recent study provide a novel epigenetic mechanism for opioid-induced hyperalgesia involving inhibition of expression of genes associated with endogenous anti-nociceptive pathways (30). In this model, chronic opioid administration, which may lead to global methylation, is proposed to increase the clinical symptom of pain by altering the ability of the nervous system to regulate defensive behaviors at the cellular level. Findings from other studies support the notion of epigenetic regulation of the genes that modulate opioid receptor expression and pain sensitivity (31). More recently, demethylation of the

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EPIGENETICS IN MIGRAINE brain-derived neurotrophic factor (BDNF) gene promoter was implicated in the development of opioid-induced pain hypersensitivity (32). Further, studies of populations with medication overuse headache demonstrate that many patients withdrawing from opioids do not benefit and persist in a chronic headache pattern (33). Chronic opioid use can modify opioid receptor expression contributing to morphine intolerance and hyperalgesia, and should not be prescribed as first-line treatment for recurrent headache disorders (34,35).

RISK FACTOR: SLEEP DEPRIVATION Sleep for a migraine patient is essential for restoring homeostasis within the nervous system. Recent findings provide insight into the fundamental roles performed by epigenetic mechanisms in the regulation of genes associated with maintaining the circadian system and ultimately preventing sleep-wake disorders (36).

Changes in sleep patterns are frequently reported by migraine patients (37). In particular, sleep deprivation broadly affects gene expression in the brain and plays an important role in regulating neuronal excitability and reported pain levels (38). Interestingly, sleep deprivation has been shown to promote epigenetic changes to increase the need for restorative sleep (39).

In this study, the investigators concluded that acute sleep deprivation causes a reprogramming of the epigenetic landscape of the cerebral cortex, suggesting a novel molecular pathway by which sleep impacts brain function and health.

BENEFIT OF EXERCISE TO REDUCE STRESS There is a long list of modalities and environmental factors thought to be beneficial in the treatment of migraine. However, the underlying mechanisms by which positive factors influence epigenetic signatures are just beginning to be delineated. Several non-pharmacological treatment options are likely to facilitate a reduction in overall stress levels in the patient. These include breathing exercises, meditation, massage therapy, acupuncture, and physical exercise. For example, regular exercise has been shown to enhance cognition, provide protection against neurodegeneration, and reduce stress-induced anxiety (40-42). In particular, exercise results in distinct epigenetic modifications at the dentate gyrus that are

associated with reduced anxiety and improved stress-coping and cognition (43). Thus, regular exercise is likely to provide a non-pharmacological means to help manage chronic migraine by reducing stress and anxiety levels.

CLINICAL RELEVANCE AND FUTURE DIRECTIONS We are now entering an age of medicine when the severity and frequency of many diseases, and complex diseases in particular, may be manifested through dynamic epigenetic modulation of gene expression in response to changes in our environment, diet, and stress levels (20,44,45). We believe that epigenetic modifications mediated by known migraine risk factors help to explain the complex nature of migraine pathology, and this knowledge needs to be integrated into the management of individual patients with migraine.

The future of precision medicine should be based on a combination of information from genetic studies that identify genes that predispose us to a particular disease and the knowledge that epigenetic changes can significantly alter gene expression to minimize disease progression or possibly improve drug response. Further elucidation of the epigenetic changes associated with episodic and chronic migraine will likely lead to targeted therapies that can prevent or even reverse the expression of pro-inflammatory genes responsible for sustaining a hypervigilant nervous system. ❏ References are on page 37.

Roger K. Cady, MD, has been

Vice President of Neurology at Alder Biopharmaceuticals, Inc., in Bothell, Washington, since May 9, 2016. In addition, he founded and served as the Medical Director of the Headache Care Center, and was the founder of Clinvest and Primary Care Network. He also served as Medical Director for the Shealy Institute in Springfield, Missouri. Dr. Cady is well known for his pivotal contributions in the field of headache and migraine management. A Fellow of the American Headache Society, he also is a member of the Board of Directors for the National Headache Foundation (NHF).

CONVENTIONAL THINKING ABOUT THE NATURE OF CHRONIC PAIN AND DEPRESSION IS FLAWED According to Dr. Gary Kaplan, conventional thinking about the nature of chronic pain and depression is essentially flawed.

Although physicians continue to diagnose conditions like migraines, fibromyalgia, chronic fatigue, chronic back pain, depression, anxiety, and PTSD, a growing body of research shows that these are in fact symptoms of something else— a deep-rooted inflammation in the brain. This inflammation can affect the nervous system for months—even years— to devastating effect.

Paul L. Durham, PhD,

is Distinguished Professor of Cell Biology at Missouri State University in Springfield and Director of its Center for Biomedical and Life Sciences, a multidisciplinary laboratory that utilizes cellular/molecular, microbiological, biochemical, and chemical techniques.

TH E PAIN PRACTITION ER

TOTAL RECOVERY

by Dr. Gary Kaplan is available wherever books and e-books are sold.

Or visit: www.kaplanclinic.com

| VOLUME 26, NUMBER 6 |

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Academy of Integrative Pain Management CORPORATE COUNCIL MEMBERSHIP

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25. Burdge GC, Hoile SP, Lillycrop KA. Epigenetics: are there implications for personalised nutrition? Curr Opin Clin Nutr Metab Care. 2012;15(5):442-447.

26. Szyf M, Weaver IC, Champagne FA, Diorio J, Meaney MJ. Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat. Front Neuroendocrinol. 2005;26(3-4):139-162.

27. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71(22):1821-1828.

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30. Doehring A, Oertel BG, Sittl R, Lotsch J. Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain. Pain. 2013;154(1):15-23.

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Buchbinder R, Blyth FM, March LM, Brooks P, Woolf AD, Hoy DG. Placing the global burden of low back pain in context. Best Pract Res Clin Rheumatol. 2013;27(5): 575-589.

2. Hoy D, March L, Brooks P, et al. The global burden of low back pain: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis. 2014;73(6):968-974.

3. Bredow J, Bloess K, Oppermann J, Boese CK, Löhrer L, Eysel P. Conservative treatment of nonspecific, chronic low back pain: Evidence of the efficacy-a systematic literature review. Orthopade. 2016;45(7):573-578.

4. Radcliff K, Kepler C, Hilibrand A, et al. Epidural steroid injections are associated with less improvement in the treatment of lumbar spinal stenosis: a subgroup analysis of the Spine Patient Outcomes Research Trial. Spine (Phila Pa 1976). 2013;38(4):279-291.

5. Ghahreman A, Ferch R, Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Med. 2010;11(8):1149-1168.

6. Pinto RZ, Maher CG, Ferreira ML, et al. Epidural corticosteroid injections in the management of sciatica: a systematic review and meta-analysis. Ann Intern Med. 2012;157(12):865-877.

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9. DeChellis DM, Cortazzo MH. Regenerative medicine in the field of pain medicine: Prolotherapy, platelet-rich plasma therapy, and stem cell therapy—Theory and evidence.

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10. Pizzorno JE Jr, Murray MT. Textbook of Natural Medicine. 4th ed. New York, NY: Elsevier Health Sciences; 2012.

11. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: enviromentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.

12. Barry F, Murphy M. Mesenchymal stem cells in joint disease and repair. Nature Rev Rheumatol. 2013;9(10): 584-594.

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16. Adelson H. Bone Marrow and Adipose Derived Autologous Stem Cells for the Treatment of Chronic Musculoskeletal Pain. Presented at: 25th Annual Meeting of the American Academy of Pain Management; September 2014; Phoenix, AZ. 17. Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series. J Med Case Rep. 2011;5:296.

18. Hendrich C, Franz E, Waertel G, Krebs R, Jäger M. Safety of autologous bone marrow aspiration concentrate transplantation: initial experiences in 101 patients. Orthop Rev (Pavia). 2009;1(2):e32.

19. Michalek J, Moster R, Lukac L, et al. Autologous adipose tissue-derived stromal vascular fraction cells application in patients with osteoarthritis. Cell Transplant. 2015;Jan 20.

20. Adelson H. Autologous stem cell therapy: a naturopathic approach to the treatment of chronic musculoskeletal pain conditions, part II of II. Pain Practitioner. 2015;25(4):40-43.

21. Linetsky FS, Trescot AM, Wiederholz MH. Regenerative injection therapy. In: Sackheim KA, ed. Pain Management and Palliative Care. New York, NY: Springer; 2015:369-375.

22. Kalawy H, Stålnacke B-M, Fahlström M, Öhberg L, Linetsky F, Alfredson H. New objective findings after whiplash injuries: high blood flow in painful cervical soft tissue: an ultrasound pilot study. Scandinavian J Pain. 2013;4(4):173-179.

23. Cooper RG, Freemont AJ, Hoyland JA, et al. Herniated intervertebral disc-associated periradicular fibrosis and vascular abnormalities occur without inflammatory cell infiltration. Spine (Phila Pa 1976). 1995;20(5):591-598.

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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.

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