PAINWeek Journal Vol. 4, Q2

vol. 4 q 2 2016

BIOFEEDBACK AND CHRONIC PAIN P.20 NEW TRENDS IN INTERVENTIONAL PAIN CONTROL P.30 TONGUE-TIED ON SUBLINGUAL ROUTE OF MORPHINE: A SUMMARY OF STUDIES P.40 CHRONIC NERVE COMPRESSION: WHY ARE WE EXCISING NERVES?P.50

TW O SOURCES

OF PAIN

O NE SOURCE OF RELIEF

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

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

Not an actual patient.

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

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

TIME TO DUAL

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

COVERED FOR

94%

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

• Administer NUCYNTA® ER ~q12h3

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use NUCYNTA® ER safely and effectively.

See full Prescribing Information for NUCYNTA® ER. INDICATIONS AND USAGE NUCYNTA® ER is indicated for the management of: • pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

When discontinuing NUCYNTA® ER, gradually taper the dose.

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

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

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

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

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

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

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

Psychiatric disorders: hallucination, suicidal ideation, panic attack.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Rx Only

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

EXECUTIVE EDITOR KEVIN

L. ZACHAROFF MD, FACPE, FACIP, FAAP

PUBLISHER PAINWeek, 6

Erie Street, Montclair, NJ 07042

ART DIRECTOR DARRYL

FOSSA

EDITORIAL DIRECTOR DEBRA EDITOR HOLLY

WEINER

CASTER

Charles E. Argoff MD, CPE Professor of Neurology Albany Medical College Department of Neurology Director Comprehensive Pain Center Albany Medical Center Department of Neurology Albany, NY

EDITORIAL BOARD

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

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

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

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

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

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

Mary Lynn McPherson PharmD, BCPS, CPE, FASPE Professor and Vice Chair University of Maryland School of Pharmacy Department of Pharmacy Practice and Science Hospice Consultant Pharmacist Baltimore, MD

Jennifer Bolen JD Founder Legal Side of Pain Knoxville, TN

Srinivas Nalamachu MD Clinical Assistant Professor Kansas University Medical Center Department of Rehabilitation Medicine Kansas City, KS President and Medical Director International Clinical Research Institute Overland Park, KS

Paul J. Christo MD, MBA Associate Professor Johns Hopkins University School of Medicine Department of Anesthesiology and Critical Care Medicine Baltimore, MD Michael R. Clark MD, MPH, MBA Vice Chair, Clinical Affairs Johns Hopkins University School of Medicine Department of Psychiatry and Behavioral Sciences Director, Pain Treatment Programs Johns Hopkins Medical Institutions Department of Psychiatry and Behavioral Sciences Baltimore, MD Geralyn Datz PhD Affiliate University of Southern Mississippi Department of Psychology Clinical Director Southern Behavioral Medicine Associates Hattiesburg, MS

Bruce D. Nicholson MD Clinical Associate Professor Department of Anesthesia Penn State College of Medicine Hershey Medical Center Hershey, PA Director of Pain Specialists Lehigh Valley Health Network Department of Anesthesiology Allentown, PA Marco Pappagallo MD Director of Medical Intelligence Grünenthal USA Bedminster, NJ Director Pain Management & Medical Mentoring New Medical Home for Chronic Pain New York, NY

Joseph V. Pergolizzi MD Adjunct Assistant Professor Johns Hopkins University School of Medicine Department of Medicine Baltimore, MD Senior Partner Naples Anesthesia and Pain Medicine Naples, FL Robert W. Rothrock PA -C, MPA University of Pennsylvania Department of Anesthesiology and Critical Care Pain Medicine Division Philadelphia, PA Michael E. Schatman PhD, CPE, DASPE Executive Director Foundation for Ethics in Pain Care Bellevue, WA Sanford M. Silverman MD, PA CEO and Medical Director Comprehensive Pain Medicine Pompano Beach, FL Thomas B. Strouse MD Medical Director Stewart and Lynda Resnick Neuropsychiatric Hospital at UCLA Los Angeles, CA

Copyright © 2016, PAINWeek.

The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff.

PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises.

All rights are reserved by PAINWeek to accept, reject, or modify any advertisement submitted for publication. It is the policy of PAINWeek to not endorse products.

Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

8 | PWJ | www.painweek.org

Q4 | 2016

The national conference on pain for frontline practitioners.

Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 36.0 AMA PRA Category 1 Credit(s) TM. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing, and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME /CE accreditation details, visit our website at www.painweek.org.

CONTENTS / PWJ / Q2 / 2016 14 | EXECUTIVE EDITOR’S LETTER by kevin l. Zacharoff

FEATURES

20 | COMPLEMENTARY&ALTERNATIVE

BIOFEEDBACK AND CHRONIC PAIN

by anthony Whitney

30 | INTERVENTIONAL PAIN MANAGEMENT NEW TRENDS IN INTERVENTIONAL PAIN CONTROL

50 | PODIATRIC PAIN SYNDROMES

CHRONIC NERVE COMPRESSION: why are we excising nerves? by andrew Rader

SHORT CUTS

52 | CLINICAL PEARLS by doug Gourlay

58 | ONE-MINUTE CLINICIAN

with matthew Foster , michael Bottros , kevin Barnard ,

jennifer Bolen , steven Ziegler , hal Blatman

by hans c. Hansen

59 | PAIN BY NUMBERS

40 | PHARMACOTHERAPY

60 | OP-ED: THE SCIENCE OF PREDICTION:

TONGUE-TIED ON SUBLINGUAL ROUTE OF MORPHINE: a summary of studies by cara m.

Brock/rabia Atayee

10 | PWJ | www.painweek.org

opioid risk assessment, the CDC, and college hoops by ted w. Jones

66 | PUNDIT PROFILE with joseph v. Pergolizzi

Q2 | 2016

Get things moving with reliable and rapid relief.

RELISTOR helps provide chronic non-cancer pain patients relief from opioid-induced constipation— without compromising analgesia.1,2 • 6 out of 10 RELISTOR® (methylnaltrexone bromide) patients (n=150) had at least 3 Spontaneous Bowel Movements (SBMs) per week (P<0.001)1,2 • One-third of patients taking RELISTOR (n=150) experienced an SBM within 4 hours of their first dose (P<0.001)1 IndIcatIons RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.

conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.

If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician.

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

discontinue the drug, taking into account the importance of the drug to the mother.

In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.

In clinical studies in adult patients with opioid-induced constipation and advanced illness, the most common adverse reactions (≥ 5%) were abdominal pain, flatulence, nausea, dizziness, and diarrhea.

Please see Brief Summary of full Prescribing Information for RELISTOR on the adjacent page. references 1. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562.

2. RELISTOR® (methylnaltrexone bromide) Prescribing Information, Salix Pharmaceuticals, Inc.

Product under license from Manufactured for: Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024 RELISTOR is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.

All other product/brand names are trademarks of their respective owners. ©2015 Valeant Pharmaceuticals North America LLC. All rights reserved.

Printed in USA. REL-US-0152 v.1 www.salix.com

The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

Limitation of use: Use of RELISTOR beyond four months has not been studied in the advanced illness population.

CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.

Severe or Persistent Diarrhea If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider.

Opioid Withdrawal Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients.

ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia.

This study (Study 1) included a 4-week, double-blind, placebo controlled period in which adult patients were randomized to receive RELISTOR 12 mg once daily (150 patients) or placebo (162 patients).

After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily.

Adverse reactions in adult patients with opioid-induced constipation and chronic non-cancer pain receiving RELISTOR are shown in the following table. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

Adverse Reactions* in 4-Week Double-Blind, PlaceboControlled Period of Clinical Study of RELISTOR in Adult Patients with Opioid-Induced Constipation and Chronic Non-Cancer Pain RELISTOR Placebo 12 mg once daily n = 162 n = 150 Abdominal Pain 21% 6% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% < 1% Chills 1% 0% * Adverse reactions occurring in ≥ 1 % of patients receiving RELISTOR 12 mg once daily and at an incidence greater than placebo.

During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature Adverse Reaction

change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR 12 mg every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 1) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%).

The safety of RELISTOR was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 2).

Patients were allowed to administer RELISTOR 12 mg less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 1. Additionally, in Study 2, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR. Opioid-Induced Constipation in Adult Patients with Advanced Illness The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in adult patients with opioid-induced constipation and advanced illness receiving palliative care: Study 3 included a single dose, double blind, placebo-controlled period, whereas Study 4 included a 14-day multiple dose, double-blind, placebo-controlled period.

The most common (≥5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR are shown in the following table.

Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness* Adverse RELISTOR Placebo Reaction n = 165 n = 123 Abdominal Pain 29% 10% Flatulence 13% 6% Nausea 12% 5% Dizziness 7% 2% Diarrhea 6% 2% * Adverse reactions occurring in ≥ 5 % of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo.

The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1%) and placebo (2%).

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

Gastrointestinal Perforation, cramping, vomiting General Disorders and Administrative Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported.

DRUG INTERACTIONS Other Opioid Antagonists Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day.

RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether RELISTOR is present in human milk.

However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of RELISTOR have not been established in pediatric patients.

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions,

tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals.

Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs.

Geriatric Use In the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended.

Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault).

Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment.

OVERDOSAGE A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate.

If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration Advise all patients to: • Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).

• Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use. • Be within close proximity to toilet facilities once RELISTOR is administered.

• Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued.

Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to: • Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days.

• Inject one dose every day.

• Inform their healthcare provider if their opioid regimen is changed, to avoid adverse reactions, such as diarrhea.

Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to: • Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

Gastrointestinal Perforation Advise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain.

Severe or Persistent Diarrhea Advise patients to discontinue RELISTOR if they experience severe or persistent diarrhea.

Opioid Withdrawal Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning.

Pregnancy Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.

Nursing Advise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024.

Manufactured for: Under License from:

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591

REL-RALAB56-102014

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Live conference

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e credits

6.0–12.0 C /CM

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CHiCAGO IL May 21 TAMPA FL * May 21–22 DALLAS TX June 4 NASHViLL TN * June 4–5 COLUMBUS OH June 11 N W ORL ANS LA * June 25–26 PiTTSBURGH PA June 25

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This activity is provided by Global Education Group for 6.0–12.0 AMA PRA Category 1 Credits™. *2 day meeting = 12.0 AMA PRA Category 1 Credits™.

This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard.

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HOUSTON TX * June 11–12 S ATTL WA October 8 MASHANTUCK T CT October 15 BALTiMOR MD * October 15–16 SHORT HiLLS NJ November 12–13 HONOLULU HI December 3

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KEVIN L.

ZACHAROFF MD, FACPE , FACIP, FAAP

S o much has happened this year regarding the abuse and misuse of opioid analgesics and their safe use in the management of chronic noncancer pain. It is hard to imagine how this could distract us from the fact that managing chronic noncancer pain in virtually all cases involves so much more than just a single prescription medication or treatment modality. As the annual PAINWeek National Conference rapidly approaches—September 6–10 in Las Vegas—there is no better time for us to think about exactly this point. With all of the focus on the nation’s “opioid epidemic,” we need to pause and reflect on how important education is regarding chronic pain, safe and appropriate treatment, and treatment alternatives. This issue of PWJ stays true to that mindset by providing us with articles about a variety of different pain-related topics.

Our first article by Drs. Cara Brock and Rabia Atayee sheds light on the fact that in the palliative care setting, we may need to think “outside the box” of traditional paradigms related to route of administration for common analgesic therapy in order to provide compassionate and effective treatment. The authors discuss the fact that in many cases, hospice pain treatment kits contain morphine intended for sublingual administration despite the fact that little or no scientific evidence exists to show that sublingual morphine is effective. This article makes a very good case for further research about the sublingual route for orally-administered analgesics in patients who have lost the capacity to swallow. I think you will find it quite thought-provoking and something important to consider for future research.

Walked on your feet lately? I think most, if not all, of us have had some kind of foot-related pain, and we probably don’t devote enough time and education to common painful foot disorders. In his article, Dr. Andrew Rader gives us some important perspectives about one such condition, Morton’s neuroma. Interestingly, the author discusses how this condition has been often treated by excision of the “neuroma,” when in actuality, evaluation and treatment should be more directed towards treating a compression neuropathy as opposed to a true neuroma. New information about an old condition always sets the stage for learning, and this could be your foot someday.

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It is quite difficult to find someone in the current pain environment who does not endorse the use of multidisciplinary approaches in a coordinated effort to manage and treat people with chronic pain.

Anthony Whitney, a licensed mental health counselor, provides us with an in-depth look at biofeedback as one of those multidisciplinary modalities, and also recalibrates common misconceptions about its definition and role in both pain management and an overall improved quality of life. We all know that empowering patients can be a key component of motivation, and ultimately a determinant of pain treatment outcomes. I hope you enjoy this article and take away some aspect of it that can positively impact your patients.

In the true spirit of opioid-sparing pain treatment, Dr. Hans Hansen successfully makes the case that while we may often take them for granted, interventional pain treatments have their place in chronic pain management—maybe now more than ever. The article points out that these techniques may, in some cases, negate the need for other pharmacologic treatments, and in other cases, the amount or duration of need for prescription pain medications can be significantly reduced. Unfortunately, as many of us have seen in today’s healthcare environment, reimbursement for performing these highly technical procedures has diminished or been denied entirely— which may be counter-intuitive considering that opioid analgesics are far too often the “go to” treatments. Additionally, the point is made that these approaches are best performed by clinicians with appropriate expertise and training, which may not always be the case.

Lastly, new techniques on the horizon are described. This article is informative and important in today’s pain treatment atmosphere.

Finally, this issue’s Pundit Profile focuses on my good friend and colleague, Dr. Joseph Pergolizzi. In my opinion, you would be hardpressed to find a more dedicated, caring, and multitalented pain management physician. All too often we don’t know much about the person behind the expertise—what drives them and keeps them going. Have a look at what makes Joseph both human and driven.

There is so much in this issue of value from a variety of different perspectives. It’s a great springboard to give you an idea about what the national meeting agenda will look like along with all the usual pain related topics. Have a great summer, and consider coming to the 10th annual PAINWeek meeting! I will be there; find me and come say hello and maybe even offer some suggestions for the next issue of PWJ .

— KEVIN L. ZACHAROFF

Kevin L. Zacharoff, MD, FACIP, FACPE, FAAP, is Pain Educator and Consultant and Faculty, Clinical Instructor at SUNY Stony Brook School of Medicine, Department of Preventive Medicine, in Stony Brook, New York.

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Rabia S. Atayee PharmD, BCPS

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Hans Hansen MD

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Ted W. Jones PhD

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Andrew Rader DPM, FAENS

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Anthony Whitney MS, LMHC, BCB

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Rabia Atayee is Associate Professor of Clinical Pharmacy and Palliative Care Specialist at the University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, in La Jolla, California, and President-elect of the Society of Palliative Care Pharmacists, where she is Associate Dean of Admissions and Outreach. Dr. Atayee coauthored her article with Cara M. Brock, PharmD, CGP, Assistant Professor of Clinical Sciences and Director of Professional Labs at Roosevelt University College of Pharmacy and Secretary of the Society of Palliative Care Pharmacists. Drs. Ayatee and Brock are both founding members of the Society of Palliative Care Pharmacists.

Hans Hansen was the President of the American Society of Interventional Pain Physicians (ASIPP) from 2013 to 2014; is on the Board of Directors of DABPM, AAPM, ASAM (addiction), FIPP; and is an editor of Pain Physician. He is a practicing physician, operating a number of pain management clinics in North Carolina.

Ted Jones is a psychologist with Pain Consultants of East Tennessee, an APS Clinical Center of Excellence. He is Past President of the Tennessee Pain Society. In addition to his full-time clinical work, he has published a number of research articles on opioid risk assessment.

Andrew Rader is the Founder of Indiana Foot and Ankle, and Medical Director of the Memorial Hospital Wound Care Center in Jasper, Indiana. He is Director of Research at the Lower Extremity Research Institute, also in Jasper.

Anthony Whitney is a Certified Biofeedback Specialist and Licensed Mental Health Counselor practicing in the Structured Intensive Multidisciplinary Pain Program and Outpatient Psychology department at St. Luke’s Rehabilitation Institute in Spokane, Washington. Anthony has specialized in the treatment of chronic pain and rehabilitation psychology services over the past 15 years and completed numerous national and regional presentations to increase awareness/ knowledge about the benefits of incorporating biofeedback and psychology services into the treatment of chronic pain.

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By Anthony

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Biofeedback is a process that enables an individual to learn how to change physiological activity for the purposes of improving health and performance. Precise instruments measure physiological activity such as brainwaves, heart function, breathing, muscle activity, and skin temperature. These instruments rapidly and accurately “feed back” information to the user. The presentation of this information—often in conjunction with changes in thinking, emotions, and behavior— supports desired physiological changes. Over time, these changes can endure without continued use of an instrument.1 This standardized definition of biofeedback was approved in 2008 by the Association for Applied Psychophysiology & Biofeedback ( AAPB), Biofeedback Certification International Alliance (BCIA ), and International Society for Neurofeedback and Research (ISNR ).

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Coping with and treating chronic pain is often a difficult and overwhelming process for all parties involved. People with chronic pain may experience a downward spiral as their body reacts to stress and pain in ways that exacerbate their condition. Incorporating biofeedback into the treatment of chronic pain can empower patients to stop this spiral by helping them better recognize, understand, and control their physical, mental, and emotional responses. Biofeedback is not a quick fix, but rather an investment in living with better health. abstract:

n a world where ever-advancing technology is providing awe inspir-

ing improvements in medical treatment—vast amounts of information/resources available in the palm of our hand with just the touch of a smart phone app; the ability to communicate face-to-face with practitioners/experts while thousands of miles apart; activity/health monitors that track activity, heart rate, sleep, and other behavioral patterns—it is shocking that so many people have little to no accurate body awareness or perception that the body is affected by our thoughts, feelings, and/or actions. The American Psychology Association’s “Stress in America” 2014 survey identified that 77% of people regularly experience stress symptoms, 48% feel they are more stressed now than they were 5 years ago, and 1 out of 4 Americans (76.2 million) suffer from pain that lasts longer than 24 hours. But despite improving awareness and knowledge of the lifestyle/behavioral changes necessary to reduce stress and ultimately prevent health problems, many individuals continue to not make such changes. A third of them do not even address stress related issues with their healthcare provider.² The increasingly fast-paced, productivity-driven culture CHRONiC PAiN: in which we all are attempting to function becomes even Mind, Body, and Well-Being more overwhelming and devastating when chronic pain is added to the negative wear and tear of daily stress levels. Chronic pain has the amazing ability to exacerbate weakRecognizing and changing behaviors that cause and/or nesses in the body, mind, and just about everywhere else. contribute to stressors is essential to management of the Chronic pain also causes many of the body’s natural negative impact stress and chronic pain can have on health defenses and protective behavioral responses (eg, the fight and well-being. Research further supports that lifestyle, or flight response) to work against themselves and concognitive and behavioral changes, participation in therapy, tribute to the negative effects caused by the chronic pain. and, in some situations, use of medication can improve As hard as it is to treat and manage the known negative chronic stress.3 However, actually making behavioral effects of chronic pain, it is my opinion that the negative changes can be challenging and even overwhelming for impact of the unknown is what makes attempting to work some. Biofeedback treatment and/or mental health coun- with chronic pain so overwhelming for the patient, provider, seling can provide the additional support and guidance and all others involved. As HP Lovecraft stated in his book to identify needed behavioral changes, enhance self-care Supernatural Horror in Literature, “The oldest and strongest skills, and overcome the barriers interfering with living a emotion of mankind is fear, and the oldest and strongest happier and healthier life. kind of fear is fear of the unknown.”4 Q2 | 2016

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COMPLEMENTARY&ALTERNATIVE

...AS MANY AS 85% TO 95% OF THe PATieNTS ReFeRReD TO Me FOR BiOFeeDBACK TReATMeNT ACTUALLY HAVe LiTTLe TO NO iDeA WHAT BiOFeeDBACK iS OR eNTAiLS.

Yes, biofeedback can help patients improve how they treatment, the response is usually “sure” or some other fairly manage chronic pain by guiding them in learning and noncommittal acknowledgement of understanding. However, more effectively using nonpharmacologic chronic pain/ with further inquiry, as many as 85% to 95% of the patients stress management techniques, but another significant referred to me for biofeedback treatment actually have little benefit of biofeedback is its ability to help reduce aspects to no idea what biofeedback is or entails. While the word of the unknown that so often intertwine within the expe- “biofeedback” wasn’t coined until 1969, the roots of biofeedrience of chronic pain.5 For example, while a patient may back and self-regulation are much older.9 Yogis have been already know that breathing from the diaphragm is ben- consciously controlling their autonomic nervous system— eficial, biofeedback can document just how effectively or slowing down their heart rate, increasing body temperature, ineffectively the patient is breathing. The patient can then decreasing oxygen consumption—for thousands of years. use the feedback, along with increased understanding and This act of self-regulation of the autonomic nervous system reduced unknown, to mindfully adjust/enhance the thera- was not believed to be possible in the West even as late as the peutic benefits of engaging in diaphragm breathing.

1950s. In the 1930s, Edmund Jacobson developed progressive relaxation techniques and Johann Schultz developed autoBecoming more aware of how the body is functioning is genic training. Both of these are self-regulatory techniques only part of the process. Patients must also learn how to and served as the basis in the research and discovery of biotruly relax their mind, body, and emotional state by facil- feedback.9 The clinical application of biofeedback emerged in itating the relaxation response. The relaxation response is the 1960s with the convergent work from 3 key researchers defined as “an integrated hypothalamic reaction in which who are thought to be the “fathers” of biofeedback—Neal a human being or animal experiences safety and a sense Miller, John Basmajian, and Joe Kamiya.9 of nurturing; resulting in decreased sympathetic nervous system activity that, physiologically and psychologically, is almost a mirror image of fight or flight response; it can TH ROL OF BiOF DBACK: be self-induced through the use of techniques associated How It Works with transcendental meditation, yoga, and biofeedback.” 6 Despite understanding that physical problems create mental Biofeedback can be integrated into treatment in a manner stress and mental stress creates physical problems, many that provides both the patient and the provider access patients still struggle to address the negative effect that into the patient’s body and/or mind. Gaining the ability physical and mental stresses have on their health and quality to monitor real time changes in the body including, but of life.7 Psychological factors, including mood, beliefs about not limited to, muscle tension regulation, brain waves, pain, and coping style have been shown to play an important heart rate variability coherence, and circulation patterns role in an individual’s ability to adjust to chronic pain.8 empowers the patient to make immediate adjustments and progressive changes over time. The practitioner can gain information about the body’s functional state, stress levels, TH HiSTORY OF BiOF DBACK ability to facilitate the relaxation response, assess asymmetry, and identify potential abnormalities and conscious/ Within my clinical experience I have observed an increase subconscious changes needed to improve functioning, in the use and appearance of the term “biofeedback.” When increase auto-regulation, facilitate homeostasis, and much I casually inquire if individuals are aware of biofeedback more. These all allow the patient to improve quality of life,

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decrease the unknown, strengthen internal locus of control, develop self-sufficient coping skills, and learn nonpharmacologic chronic pain/stress management techniques. Armed with better life awareness and control, patients can more easily recognize and change functional patterns to prevent or mitigate chronic pain.7 (See Table.)

To identify the appropriate biofeedback modality for a particular patient, the therapist considers the patient’s symptoms, emotional regulation, cognitive functioning, and past experiences and traumas. Biofeedback modalities may be used alone or in combination and are usually determined by the type of symptoms and the individuals preferred learning style.

AN ANALOGY

Continuing with this analogy, imagine you are provided with a device to connect to the lawn mower that produces sounds to help you identify areas of the yard in which the grass has been cut and other sounds to help you locate and track the edge of uncut grass while mowing. The addition of this device would make mowing easier and the outcomes better despite remaining blindfolded. Similar to the device in the analogy, biofeedback can be used to help make positive changes even when the chronic pain is unable to be changed.

For example, surface electromyography—or sEMG — biofeedback, which is used to get feedback about muscle tension patterns, works by translating muscle tension into a tone or beep that varies in pitch based on the intensity of the tension. The patient can then use the pitch changes and feedback provided by the therapist to identify muscle tension and to increase or decrease the tension levels as needed to make positive and adaptive improvements. Visual markers or tactile aids can also be used to further enhance the patient’s mind-body awareness and quality of changes.

Imagine it’s time to mow your lawn, but you are suddenly forced to do it blindfolded. Even with knowledge about your yard gained from having mowed 1 or 2 times a week for years, you can imagine how unacceptable the results would be and how quickly the process would become overwhelm- BiOF DBACK MODALiTi S ing and upsetting. You might be able to improve the process by getting support from someone you trust who could pro- Various biofeedback devices and sensors are used to measure vide verbal instructions and warnings of upcoming barriers. activity and change in the area of focus. The data are then Now imagine being told that it is unclear when, or if, you reviewed and interpreted by the therapist and/or specifically will be able to mow and care for your yard without being designed software to transform it into information that can blindfolded and that you’re going to have to “Just learn to be provided back to the patient in a meaningful manner. live with it.” This situation can serve as an analogy, with the blindfold representing some of the problems and limitations Scalp sensors can detect brainwave activity through elecchronic pain causes in a patient’s life, the daunting struggle troencephalography ( EEG). EEG biofeedback is often involved when attempting to overcome or adapt to them, incorporated into the treatment of headaches, alcoholism, and the hopeless and helpless feelings that the patients I epilepsy, attention deficit disorder, and a host of other diswork with describe when someone in their treatment team orders. Bands/straps placed around the patient’s abdomen tells them “You just need to accept that you have chronic and chest are used to detect changes in respiratory rate and pain and have to learn to live with it.” are often used to help with managing anxiety, hypertension,

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Table. Biofeedback Modalities, Descriptions, and Uses Modality

Description

Used to Treat*

Brainwave

Brainwave biofeedback uses scalp sensors to monitor the brain’s electrical activity using an electroencephalograph (EEG)

»»ADHD »»Alcoholism/substance abuse »» Epilepsy »» Headache »»Traumatic brain injury

Breathing

Respiratory biofeedback uses bands placed around the abdomen and chest to monitor breathing pattern and respiration rate

»»Anxiety »»Asthma »» Chronic obstructive pulmonary disease »» High blood pressure

Heart Rate

Heart rate biofeedback uses finger or earlobe sensors with a photoplethysmograph or sensors placed on the chest and lower torso (or on the wrists) using an electrocardiograph to measure both heart rate and heart rate variability

»»Asthma »» Depression »» High blood pressure »» Unexplained abdominal pain

Muscle

Muscle biofeedback uses sensors placed over skeletal muscles with an electromyography (EMG) to monitor the electrical activity that causes skeletal muscle contraction

»»Anxiety »»Asthma »» Cerebral palsy »» Fecal and urinary incontinence »» Headache »» High blood pressure »» Pain involving the lower back, pelvic muscles, and temporomandibular joint »» Paralysis and muscle weakness due to peripheral nerve injury and stroke

Sweat Gland

Sweat gland biofeedback uses sensors placed around the fingers or on the palm and wrist with an electrodermograph (EDG) to monitor changes in skin moisture produced by sweating

»» Excessive sweating »» High blood pressure

Temperature

Temperature biofeedback uses sensors placed on the hands or feet with a feedback thermometer to measure blood flow to the skin

»» Headache »» High blood pressure »» Raynaud’s disease »» Swelling

*Biofeedback is also beneficial for teaching optimal performance and when treating pelvic muscle dysfunction (eg, fecal and urinary incontinence, pelvic pain); a discussion of these disorders is beyond the scope of this article. Source: Reprinted, with permission, from Overview of biofeedback. Biofeedback Certification International Alliance website. Available at: www.bcia.org/i4a/pages/index.cfm?pageid=3524.

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THe ReLAXATiON ReSPONSe WiTHiN BiOFeeDBACK iNVOLVeS A MeNTALLY ACTiVe PROCeSS THAT eNHANCeS MiND-BODY AWAReNeSS, iNCReASeS ViGiLANCe, AND iS A SKiLL THAT iS LeARNeD.

unexplained abdominal pain, and other disorders, while earlobe and finger photoplethysmograph sensors, in conjunction with electrocardiograph sensors on the chest and lower torso, are primarily used in the treatment of asthma, depression, hypertension, and pain management.

Surface electromyography sensors are placed on the skin above specific muscles to monitor the electrical activity that causes skeletal muscle contraction. Muscle biofeedback is used for managing muscle generated pain, anxiety, cerebral palsy, incontinence, and other disorders.

MYTHS: Biofeedback & Relaxation Biofeedback is harmful. Just as a scale doesn’t change a person’s weight, biofeedback and the biofeedback instruments do not change or affect the body. They only collect and measure information. Change remains the patient’s responsibility, but biofeedback can greatly accelerate the learning process. Initially engaging in biofeedback therapy may feel overwhelming, but with support and encouragement it becomes empowering.10 The patient learns to recognize and change physical responses, like tense muscles, shallow breathing, or cold hands, creating the shift needed to begin to disrupt the chronic pain cycle and learn to not be or become a victim of chronic pain.7

The creative use of objects also has a place in the therapist’s armamentarium: for example, placing a cell phone, book, or hand on the patient’s abdomen to increase awareness of diaphragm/belly movement when learning how to engage in diaphragm breathing; or positioning reference “Maybe relaxation is important, but I don’t have time to points, such as dot-shaped stickers or the therapist’s hands, sit and do nothing.” In a culture where sleep is thought of on the shoulders or other areas of the patient’s body while as something that gets in the way of productivity, it is not the patient views themselves in a mirror or video moni- surprising that the idea of relaxation is thought of as being tor to enhance awareness of asymmetry, body mechanics, lazy, doing nothing, and/or not important. The relaxation posture, etc. response within biofeedback involves a mentally active process that enhances mind-body awareness, increases In addition to the biofeedback equipment that measures and vigilance, and is a skill that is learned. With training and presents information, a qualified biofeedback provider/ther- consistent practice the relaxation response becomes more apist, often in conjunction with patient changes in thinking, profound as well as powerful. I inform my patients that emotions, and behavior supports the patient in learning how the basic goal of the relaxation response is to learn to be to facilitate desired physiological changes, independence, physically relaxed and mentally alert. and self-empowerment. Over time, if the patient continues to incorporate and practice the skills/tools they have developed into aspects of their daily life, the changes and The most common misconceptions of relaxation: improvements can endure and strengthen without continued use of biofeedback instruments or the support provided Relaxation is like being deeply asleep—True relaxby the therapist. ation, which involves relaxation at a mental, physical, and Q2 | 2016

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COMPLEMENTARY&ALTERNATIVE

emotional state, facilitates vigilance and enhances performance (eg, driving, golfing, and being “in the Zone”).

the specialist follow up with the patient after making the referral can greatly reduce resistance, create an opportunity to provide additional information about biofeedback, allow All relaxation techniques produce the same results— patient concerns/questions to be addressed to reduce the Each person is unique, and the type of responses will differ unknown, and increase the potential for successful treatbased on the individual and the type of relaxation tech- ment follow through. niques used. There is no generic relaxed state, which is one of the reasons developing individualized treatment plans There is considerable evidence that supports the use of bioand goals are critical to maximize positive benefits. feedback as a nonpharmacologic therapy for chronic pain.

Patients with low back pain, chronic migraines, musculoskelYou must make yourself relax—Life is hard, and in gen- etal pain, and other pain conditions experience significant eral the rule is “The harder you work the better the results.” reductions in pain intensity and frequency while engaging To achieve the relaxation response, it is where the effort is in biofeedback training.12-16 invested that is important. Using high effort to force the body and/or mind to relax will actually increase stress and When providing treatment it is important to let patients tension levels. The relaxation response requires a balance know that there is no “magic” treatment, medication, or surbetween being passive and vigilant (passive vigilance) to facil- gery for chronic pain. Believing that there is such a single itate true relaxation. Where effort or hard work is needed is treatment can lead to decreased confidence, understanding, in continuing the motivation and effort required on a daily and motivation, as well as feelings of hopelessness, deteribasis to maintain and strengthen the daily facilitation of the orating emotional well-being, and an overall decrease of a relaxation response. It is similar to the effort required to patient’s internal locus of control.5 In addition, research maintain your daily teeth brushing routine to prevent cavities shows that “how well patients manage chronic pain depends and improve oral health throughout your lifetime. more on what they do for themselves rather than what is done to them; most of the ‘work/change’ of chronic pain Relaxation requires an empty mind—With a quick inter- management is done by the patient.”17 net search you can find countless intellectual (and many far from intellectual) battles about whether or not the mind can Based on my experience specializing in the treatment of become empty or still. This article is not the place to have chronic pain, I recommend providers consider referring for such a debate. Engaging in biofeedback and facilitating the biofeedback and/or psychological therapy when the patient: relaxation response is all about identifying and experiencing our thoughts, feelings, and sensations. The goal is not to ● Has consistently high pain complaints get rid of them, but rather to develop the skills to observe and learn without judging and to gain the ability to effort- ● Has pain that worsens despite treatment lessly return our focus back to breathing, relaxation, or to the identified focus of the technique/exercise that is being ● Reports intensive somatic complaints and/or fixations engaged in.11 ● Discontinues physical therapy because it causes too much pain TH ART OF R F RRiNG ● Exhibits signs of substance abuse, including misuse Patients may be resistant to the recommendation of bioof medication feedback as it falls into the psychology and/or alternative category of healthcare. The most common responses I hear ● Progressively reduces activity from patients when assessing their understanding or interpretation of being referred for biofeedback and/or psycho- ● Has poor emotional regulation logical pain management are: “My doctor thinks it’s all in my head.” “They don’t know what to do with me.” “They ● Demonstrates exaggerated or inconsistent think I’m crazy.” pain behaviors

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When experiencing referral resistance from a patient it is ● Has a history of “shopping” for doctors or medication beneficial to be mindful that the resistance is usually triggered and/or driven by a lack of understanding and the ● Has a history of trauma or abuse unknown. Most biofeedback practitioners and therapists have extensive experience managing patient resistance and ● Would benefit from an interdisciplinary are excellent resources for providers. Either directing the treatment team patient to the biofeedback specialist or arranging to have

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Additional information can be reviewed at www.bcia.org, from the Biofeedback Certification International Alliance), and www.aapb.org, from the Association for Applied Psychophysiology and Biofeedback. It is strongly recommended that the provider have BCIA certification: it ensures that the provider has complete biofeedback training, participates in ongoing continuing education, and has experience.

12. van Santen M, Bolwijn P, Verstappen F, et al. A randomized clinical trial comparing fitness and biofeedback training versus basic treatment in patients with fibromyalgia. J Rheumatol. 2002;29:575–581.

CONCLUSiON

15. Large RG, Lamb AM . Electromyographic (EMG) feedback in chronic musculoskeletal pain: a controlled trial. Pain. 1983;17:167–177.

Chronic pain creates complex biopsychosocial sequelae, which combined with the vast amount of “unknown” often has a devastating impact on the individual as well as family and friends, thus early intervention is imperative. Given the complexity of treating chronic pain it is recommended that an interdisciplinary therapeutic team, including biofeedback as one of the disciplines, be developed for managing patients suffering with chronic pain.18 Compared with conventional medical treatments, an interdisciplinary team approach has been shown to be more effective in reducing medication use, emotional distress, healthcare utilization, and iatrogenic consequences.19 Interdisciplinary treatment is also more effective in getting people with chronic pain back to work and closing disability claims.20

16. Lacks P, Morin CM . Recent advances in the assessment and treatment of insomnia. J Consul Clin Psychol. 1992;60:586–594.

13. Newton-John TR , Spence SH, Schotte D. Cognitive behavioral therapy versus EMG biofeedback in the treatment of chronic low back pain.

Behav Res Ther.1995;33:691–697.

14. Mullally WJ, Hall K, Goldstein R. Efficacy of biofeedback in the treatment of migraine and tension type headaches. Pain Physician.

2009;12:1005–1011.

17. Jensen MP, Nielson WR , Kerns RD. Toward the development of a motivational model of pain self-management. J Pain. 2003;9:477–492.

18. Flor H, Fydrich T, Turk DC . Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain. 1992;49:221–230.

19. Turk DC , Okifuji A. Treatment of chronic pain patients: clinical outcomes, cost effectiveness, and cost-benefits of multidisciplinary pain centers. Crit Rev Phys Rehab Med. 1998;10:181–208.

20. Guzman J, Esmail R, Karjalainen K, et al. Multidisciplinary bio-psycho-social rehabilitation for chronic low back pain. Cochrane Database Syst Rev. 2002;(1):CD 000963.

References 1. Applied Psychophysiology & Biofeedback ( AAPB). 2016. Stress in America: paying with our health. Available at: www.aapb.org/i4a/ pages/index.cfm?page ID=1/.

2. The American Psychology Association’s ( APA ) Stress in America 2014 survey. Available at: www.apa.org/news/press/releases/stress/2014/ highlights.aspx.

3. OECD, Income inequality (indicator). 2016. Available at: data.oecd. org/inequality/income-inequality.htm.

4. Lovecraft HP. Supernatural Horror in Literature. New York, NY: Dover; 1973:11–106.

5. Turk DC , Okifuji A. Treatment of chronic pain patients: clinical outcomes, cost effectiveness, and cost-benefits of multidisciplinary pain centers. Crit Rev Phys Rehab Med. 1998;10:181–208.

6. Farlex Partner Medical Dictionary. Relaxation response. 2012. Available at: medical-dictionary.thefreedictionary.com/relaxation+response.

7. Greenhalgh J, Dickson R, Dundar Y. The effects of biofeedback for the treatment of essential hypertension: a systematic review. Health Technol Assess. 2009;13:1.

8. Chronic pain. The Health Psychology Network. 2016. Available at: healthpsychology.net.

9. Large RG, Lamb AM . Electromyographic (EMG) feedback in chronic musculoskeletal pain: a controlled trial. Pain. 1983;17:167–177.

10. Corrado P, Gottlieb H, Abdelhamid MH . The effect of biofeedback and relaxation training on anxiety and somatic complaints in chronic pain patients. Am J Pain Manag. 2003;13:133–139.

11. Yucha C, Montgomery D. Evidence Based Practice in Biofeedback and Neurofeedback. Wheat Ridge, CO: Association for Applied Psychophysiology and Biofeedback; 2008.

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By Han

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, D, DABPP

FIPP

By Han

we s a n i Pa d it n a t s r u nd e is a y a d o t e. n i l d e bl u rr u rs c c o n pai e t u nd c a A y l l a ic ch ron ai n p c i n ch ro ely. t u c a ns happe

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“Chronic

pain, when appropriately diagnosed, is manageable, but requires careful examination of the broad differential diagnosis. iPM is a powerful tool to help define this diagnosis and adds a minimally invasive treatment option.”

Interventional pain medicine (IPM) is a rapidly growing specialty that is devoted to treating those who suffer from pain. “Pain management” is generalized, whereas IPM is more specific in its mission as an integral component of a pain management plan and can sometimes offer a solution to avoid continuing escalation of prescription pain medications.

In many cases, interventional approaches can also assist in diagnosis of painful conditions.

Ultimately, in appropriate situations, IPM can assist restoration of function and quality of life for patients experiencing chronic painful conditions. abstract:

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e e

iNT RV NTiONAL

nterventional

pain medicine is defined as the practice of using “minimally invasive procedures for the diagnosis and management of chronic, persistent, or intractable pain.”1 The field of interventional pain management is enjoying the benefit of rapidly advancing technologies and new exciting therapeutic choices.

Unfortunately, as with other fields of medicine, the problems associated with reimbursement can be an ever present barrier to offering these cutting edge options to our patients. In many cases, it may seem easier and cheaper to write a prescription; the current opioid epidemic and the tragic loss of 17,000 souls a year to opioid related overdose seems to suggest otherwise.2 PAi N Pain as we understand it today is a blurred line. Acute pain Pain is a symptom, and not necessarily a disease itself, and occurs chronically and chronic pain happens acutely. Pain, with patients suffering from chronic pain, rarely is there addiction, and depression share similar neurophysiologic one pain generator. As with any chronic condition, a diag- characteristics and neurobiological pathways. Functional nosis is necessary for proper treatment. Often that diagnosis magnetic imaging (f MRI ) at the time of injury can identify is elusive with chronic pain states and often subjective in an individual who will develop chronic pain with a high level description. Chronic pain, when appropriately diagnosed, of confidence.3 This “chronification of pain” may potentially may be manageable, but requires careful examination of redefine “stale” thoughts about acute and chronic pain— the broader differential diagnosis. IPM can be a powerful old definitions of chronic pain just don’t fit in today’s world. tool to help define this differential and may additionally Additionally, pain is biopsychosocial phenomenon and often add a minimally invasive treatment option. This concept of reveals a spiritual component as well. It is incumbent upon advanced pain care through the interventional approaches practitioners to minimize risks and afford the best possible has the potential to maximize pain treatment outcomes and treatment outcomes. function, with minimal risks and can sometimes offer a solution to avoid continuing escalation of prescription pain IPM can be a strong component of a treatment solution medications. Diagnostic and therapeutic, the IPM model of with minimally invasive procedures including percutaneous risk vs reward is in the patient’s favor. precision needle placement which accurately exposes tissues

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www.painweek.org | PWJ | 33

at targeted areas to therapeutic agents and/or technologies. Surgery Center of Paducah, and CEO of ASIPP, has idenThese technologies might include ablation of targeted tified an important trend in pain medicine: “Steady decline nerves and surgical techniques, such as laser or endoscopic in reimbursements is limiting access to care.” discectomy, intrathecal infusion pumps, and spinal cord stimulators. IPM techniques and advance technologies are immensely valuable to diagnose and manage chronic per- TECHNOLOGY OPTiONS sistent or intractable pain.

With the explosive growth of opioid use, and the associated epidemic of misuse, abuse, and diversion, non-narcotic alternatives for pain control are in demand.11 Dr. Manchikanti $$$ notes that services and patients requiring interventional Interventional pain medicine is part of a value based health- pain management procedures are increasing, approachcare delivery system that starts with clinical effectiveness ing 12% annually. “We see no significant increase in the and cost utility, embracing research and evidence based number of epidural steroid injection visits per patient, but guidelines.4 Any control of cost is welcomed in today’s the number of patient visits is increasing.” Reimbursement healthcare environment, and IPM is poised to positively is declining in all areas of interventional pain management, impact the often debilitating disease of chronic pain and and the ambulatory surgical center setting saw an 8% to associated disability. Clinicians today are challenged to 36% decline from 2007 to 2009. The office setting has translate scientific advances into actual clinical value. IPM been affected as well. With the real problem of practice can be a leader in this forward thinking philosophy, having inflation on the rise, more stress and burden on the interalready demonstrated evidence and quality outcomes in var- ventionalist may further limit access to these potentially ious studies.2 beneficial procedures. This challenging reimbursement climate underscores the importance of the American MedWe are currently at the point where healthcare cost in the ical Association’s practice expense survey, which “is how private and public sector have intersected, and the govern- CMS calculates its physician payments,” according to Dr. ment role in providing reimbursement is rising.6 Medicare Manchikanti, and reflects true expenses for a physician’s expenditures continue to grow, far exceeding the growth services. With an almost 12% increase in US population of beneficiaries and is considered by many to be unsustain- who are over 65 years old, the number of patients seen by the able. Interventional procedures have rapidly expanded and interventionalist is expected to rise.12 The interventionalist contributed to this increase in cost. Interlaminar epidural is encouraged to participate in the survey to assure future injections, for example, rose 48% in one decade alone and viability of the specialty. transforaminal injections exploded by 806%. Facet blocks in the same time frame increased 228%, with neurolytic Improving the image of interventional pain management is procedures increasing approximately 800%. Sacroiliac joint essential for the specialty’s continued success and survival.13 injections also grew 308%. This is not to say that these pro- Some clinicians may have bad experiences with pain mancedures are not clinically indicated. The point is, awareness agement practices and physicians, and perhaps feel there is of IPM as an option is growing, and therefore utilization very little scientific basis for what an interventionalist does. is increasing. According to the SPORTS study,8 compared In fact, in many cases, these procedures do have rich data to surgery, regarding progressive disability, these interven- supporting their use to improve function and quality of life. tional procedures on a cost per year basis provide better As in any medical setting, success comes down to patient value. Further supporting a minimally invasive option is selection. “Patients should only be treated with interventhe fact that that the cost of surgery rarely calculates the tional treatments by a well-trained, qualified physician in time loss in productivity, restriction, and disability costs. an accredited setting.” Dr. Manchikanti points to Florida The risk/reward benefit of IPM may often be in favor of where 47% of facet joint blocks were performed by family the patient and payors.8,9 physicians, rather than by a specialist. Finally, due to the disturbing trend of burdensome regulatory requirements Unfortunately, interventional pain management approaches in interventional pain medicine, “Many centers are going are threatened from many fronts. Some practices are being out of business,” says Dr. Manchikanti, “because they can’t threatened to the point of extinction. The American Society control expenses.” of Interventional Pain Physicians (ASIPP) promoted a letter writing campaign and, through advocacy on Capitol Hill, restored some of the cuts on reimbursements, but more work EVOLViNG iNTERVENTiONAL PROCEDURES iN remains.10 As science advances, and valuable technologies PAiN MEDiCiNE — AN EXCiTiNG ERA are offered to patients, payor coverage may not always be With the application of advanced biomechanics and technolavailable for cutting-edge procedures to treat those suffer- ogies, the interventional pain physician has a list of options ing from chronic pain. Dr. Laxmaiah Manchikanti, medical for patients that are showing great promise. Dr. Frank director of the Pain Management Center and Ambulatory Falco, Clinical Assistant Professor at Temple University

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in Philadelphia, Pennsylvania, performs minimally invasive endoscopic spinal surgery, successfully avoiding the operating room in many cases. Endoscopic surgery is effective for herniated disc and spinal stenosis, and facet joint pain as well. This procedure can also isolate the medial branch nerve to ablate at the facet joint, with much more efficiency than the percutaneous approach that is commonly performed by a radiofrequency ( RF ) technique.

Indications for invasive endoscopic spinal surgery includes radicular pain from a herniated or bulging disc, extruded disc fragments, foraminal stenosis, hypertrophy of the facet joint, osteophyte ridging, and spondylolisthesis.14,15 EVERYTH i NG OLD i S NEW AGAi N —

CRYOANALGES i A

enhanced safety and reproducibility of cryoanalgesia creates a valuable alternative to either chemical or thermal RF neuroablation.

Cryoanalgesia is used on a number of different nerves, including the cluneal nerve, commonly associated with “pseudosciatica,” a cause of pain in the back and legs that mimics a herniated lumbar disc. Other neural targets include the occipital, intercostal, ilioinguinal, infrapatellar, and pudendal nerve. The procedure has also had success with the lateral femoral cutaneous nerve and nerves that develop a neuroma after amputation. It is an attractive option to treat trigeminal neuralgia, and safer than thermal options.16-18 COOLED RAD iOFREQUENCY

At the recent annual meeting of the ASIPP, Andrea Trescot, Chronic knee pain has been estimated at 16% of those over MD, of the Pain & Headache Center in Wasilla, Alaska, 45 years of age who suffer from osteoarthritis of the knee presented a compelling lecture to revisit an older technique, causing disability in 20% of these cases. Troubling percryoanalgesia, which freezes nerves for prolonged pain sistence of knee and hip pain after total knee and total hip relief. Cryoanalgesia, time tested and utilized since the early arthroplasty ranges from 5% to 40%. Almost 4% of these 1960s, is an effective alternative to other neuroablative tech- joints are subject to revision, at the staggering cost of $5 niques that use heat. Cryoanalgesia, and its lesion, results billion per year. in minimal to no neuroma formation after the procedure.

A compressed gas probe is advanced to the target nerve and, Knee innervation is attributed to a number of nerves, includas the gas expands by the Joule-Thomson effect, the tip ing the femoral, saphenous, tibial, common peroneal, and temperature drops to -70C. The resultant Wallerian degen- obturator nerves. Radiofrequency ablation of these nerves eration of the large myelinated nerves is rapidly observed. is an attractive option and minimally invasive. A specialized The greatest advantage of cryoanalgesia over a thermal or needle system is available that introduces controlled and surgical lesion is that eventually these nerves grow back, effective heat to tissues. Cooled RF is a new technology that restoring normal function with very rare residual adverse circulates water moderating the temperature close to the effects. The procedure can then be repeated, if needed. The active tip. Creating a larger volume lesion, without excessive heating, cooled RF generates a uniform heated zone up to 5 mm from the tip of the needle. The shape of the lesion is specialized and creates a larger volume of coverage than bipolar RF. Cooled RF has demonstrated significant relief with no adverse events observed.19,20

Cryoanalgesia, “time tested and

utilized since the early 1960s, is an effective alternative to other neuroablative techniques that use heat.”

Q2 | 2016

Another application that demonstrates the targeted approach to RF neural ablation is applying ablation prior to cement augmentation in malignant spine lesions. Radiofrequency ablation effectively relieves metastatic tumor pain that previously had limited treatment options. Reduced concerns over tumor extravasation and post radio therapy fracture is observed, suggesting increased function and patient satisfaction. Stabilizing the vertebrae with bone cement after the RF procedure further reduces pain and disability from spinal metastasis.21-23 WHAT’S NEW WiTH SPi NAL CORD STi MULATiON?

Spinal cord stimulation is a proven technology, with more than 40 years of clinical experience.24,25 SCS is thought to stimulate nerves by electrical neuromodulation, decreasing painful sensations. Traditionally, spinal cord stimulation is www.painweek.org | PWJ | 35

Spinal cord “ stimulation is

used in many settings, including chronic regional pain syndrome, failed back surgery syndrome, and neuropathy.

New uses are being discovered as the technology expands.”

which can alter stimulation at the dorsal columns. DRG stimulation allows the implanted system to produce less energy for the needed stimulation, and is battery sparing.26 Stimulation in the form of neuromodulation continues to evolve, with broad and growing pain applications, and is showing promise treating migraine headaches, occipital neuralgia, cluster headaches, and neuropathic limb pain, especially that associated with chronic regional pain syndrome.

SOLVi NG PROBLEMS

Researchers exploring evolving technologies for neural modulation have also been working on problems that have been inherently difficult for stimulators to avoid. For example, as a patient changes position, cerebral spinal fluid also moves within the spine. This can directly impact the stimulation obtained, with either too much energy in the supine position, or too little in the upright position. This may change the paresthesia amplitude or coverage, and patients find themselves trying to self-adjust to obtain adequate relief. Up to 70% of patients stated they became uncomfortable when stimulation parameters changed, particularly when recumbent. The patients found themselves decreasing the stimulation, leading to further problems of pain control overall. Adaptive technology such as implantable devices has solved much of this problem.27 Adaptive stimulation, according to David Schultz, MD, of Minnesota Advanced Pain Specialists, allows many patients to achieve satisfactory pain control and spinal cord stimulation in one position, and avoid uncomfortable paresthesia in another.

With the introduction of accelerometer technology, commonly used in cell phones, the patient can now experience applied to the dorsal columns of the spinal cord and often the full uninterrupted benefits of stimulation without creates a controlled paresthesia. This paresthesia made it concerns as to position. The accelerometer automatically difficult to target specific tissues, and at times was unpleas- changes the amplitude of the stimulation based on position, ant. Spinal cord stimulation is used in many conditions, improving pain relief and convenience to the patient, who including chronic regional pain syndrome, failed back no longer has to reach for the programmer based on anticsurgery syndrome, and neuropathy. New uses are being ipated variations in position. Although not available widely, discovered as the technology expands. The science of neuro- it is anticipated that more manufacturers will follow with modulation continues to evolve. Tim Deere, MD, an author- accelerometer technology.27-29 ity on interventional stimulation, says, “New approaches to reduce the unpleasant side effects of stimulation have High frequency stimulation, another new vision in stimopened this technology to those that would otherwise not ulation, blocks the peripheral nerve in 3 phases. Neurons be considered a good candidate.” fire before being blocked and, if the amplitude is not high enough, there can be asynchronous firing. If the amplitude Burst Stimulation is another form of neurostimulation that is high enough, a blocking phase results. High frequency delivers pulses of energy to a patient’s spinal cord. This stimulation does not cause a conduction blockage and blunts “burst stimulation” shows promise in development, and it is the wide dynamic range neuron similarly to conventional associated with little to no paresthesia.26 stimulation. Spinal cord stimulation in high frequency (over 10,000 Hz) results in greater reduction of neuropathic New evolving forms of stimulation target the dorsal root hypersensitivity. With high frequency stimulation, patients ganglion (DRG). The stimulator electrode is placed over the who fail conventional spinal cord stimulators, or perceive DRG at the assumed site of pathology. An advantage of DRG spinal cord stimulation as uncomfortable, report signifistimulation is there is little paresthesia. DRG stimulation is cantly reduced back and leg pain vs no stimulation and conpredictable in nature, and unaffected by cerebral spinal fluid, ventional stimulation. Studies suggest that sleep improves,

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and patient satisfaction is high. This technology may be an important advance in spinal cord stimulation therapy, and comparative studies are in progress.26,30

are multipotent, powerful, are found in most tissues, and have been studied for decades. There are over 18,000 studies evaluating their use in various human and animal tissues.

Another interesting technology that is being introduced One advantage of stem cells is they are not a steroidal. in the world of spinal stimulation is an implantable elec- American chemists Edward Calvin Kendall and Philip trode that uses an external power source. Although this is Hench in the Mayo Clinic were the first doctors to discover not a new technology, this therapy applies RF energy to a cortisone, resulting in the 1950 Nobel Prize in medicine. conductive coil, and it is potentially cost effective. Other Dr. Hench was the first doctor to administer cortisone to advantages: it is MRI compatible and Bluetooth enabled. a patient with rheumatoid arthritis. In 1949 he was quoted: “As we have stated repeatedly, the use of these hormones should be considered an investigative procedure, not a treatREGENERATiVE MEDICi NE ment.” Others, such as Coombes, concluded that cortisone Regenerative medicine is a minimally invasive, nonsurgical injection is beneficial only as a short-term treatment for approach to restorative conditioning, according to Aaron such entities as tendinopathy, but may be worse than other Calodney, MD, Director of Clinical Research Precision treatments in the intermediate and long term. Coombes also Spine Care Texas Spine and Joint Hospital in Tyler, Texas. noted that among the patients with chronic unilateral lateral It is less aggressive than surgery and an important therapy epicondylalgia, the use of corticosteroids vs placebo resulted that is on the cusp of treatment options to major joints, soft in worse clinical outcomes after one year.30,31 tissue, and even intervertebral discs. “It’s still the wild west, though. We’re all in a learning phase with this treatment Mesenchymal stem cells are commonly referred to as adult option,” Dr. Calodney observes. Regenerative medicine uses autologous stem cells. These are cells that repair muscle, either tissue matrix retrieved from placental tissue, plasma bone, cartilage, and tendons. There is no risk of genetic rich protein, aspirate from bone marrow, or adipose cell that disease transmission or rejection, and, unlike embryonic is processed and injected to the target tissue. The concept of stem cells, they avoid political, ethical, and logistic clinical stimulating tissue to eventually regenerate is exciting, and problems. These cells are self-renewing and can be isolated potentially a game changer in soft tissue and joint therapy. from bone marrow, adipose tissue, synovium, periosteum, skeletal muscle, umbilical cord, and other tissues of mesoStem cell sources include embryonic, homologous, and dermal origin. They can differentiate into bone, cartilage, autologous in various alterations. Stem cell therapy can also muscle, and adipose tissues. It is not clear how these cells include placental derived tissue through a matrix. The FDA work; however, the secretion of cytokines involved with significantly restricts embryonic stem cells, which are cur- immunomodulation may promote proangiogenesis and cell rently not used in the United States. The placental derived proliferation. These cells also are important in differentistem cells have a very high concentration of factors that are ation of the undifferentiated nerve. Studies have promoted potentially beneficial from mesenchymal stem cells, and the use of stem cells, with symptom relief and a positive is available in the US. Mesenchymal stem cells are felt to effect on healing.32,33 be effective because of certain key factors in the regenerative cascade, including enhanced collagen growth factor, Platelet rich plasma ( PRP) is a plasma procurement of cytokine, and hyaluronic acid, stimulation, and ultimately centrifuged blood, producing a platelet rich content, and cell development. In the case of mesenchymal stem cells, is injected into various tissues. Results are promising in after resorption, collagens and fibrous proteins provide the reduction of pain, improved function, and resolution of structural scaffold for cell migration and attachment. This symptoms. Although further studies are necessary, PRP signals cytokines and recruits autologous stem cells to the is a promising treatment for a variety of conditions. PRP site. Growth factors induce cell growth and proliferation is associated with minimal adverse events, and the evolvacross the scaffold. This minimally invasive approach has ing understanding and application of stem cell therapy is a been shown to be effective in tendonitis, plantar fasciitis, dynamic and hopeful therapeutic option.30,31 ligamental tears, rotator cuff injury and tear, osteoarthritis, hip pain, and sacroiliac pain. Investigationally, stem cells are being considered for facet joint and interdiscal injection. CONCLUS iON Stem cells have also been known to promote wound heal- We live in an exciting period for interventional pain ing, particularly with venous stasis, Charcot ulcers, chronic medicine. Rapidly advancing technologies and treatment poorly healing wounds, and diabetic foot presentations. options are abundant, readily available to provide medicaHemopoetic stem cells, products such as red and white cells, tion-sparing approaches, and likely improve paint treatment help establish a blood supply to compromised tissues. Due to outcomes, function, and quality of life. The challenges stem cells’ inherent plasticity, they turn into other cell types, of making these treatments and technologies available such as mesenchymal stem cells. Mesenchymal stem cells in a cost-contained environment require careful patient Q2 | 2016

www.painweek.org | PWJ | 37

selection. Best practices apply the right technology to the right diagnosis. The skill of the clinician is a considerable variable, requiring standardized training, mentoring, and experience to ensure safety and quality outcomes. The field of IPM will continue to grow, may ultimately benefit our patients by potentially reducing suffering, and should be considered as an important part of the treatment paradigm of chronic pain.

17. Zakrzewska JM . Cryotherapy in the management of paroxysmal trigeminal neuralgia. J Neurol Neurosurg Psychiatry. 1987;50:485–487.

18. Campos NA , Chiles JH, Plunkett AR . Ultrasound-guided cryoablation of the genitofemoral nerve for chronic inguinal pain. Pain Physician.

2009;12(6):997–1000.

19. Kawaguchi M, Hashizume K, Iwata T, et al. Percutaneous radiofrequency lesioning of sensory branches of the obturator and femoral nerves for the treatment of hip joint pain. Reg Anesth Pain Med. 2001;26(6):576–581.

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1. Manchikanti L, Falco FJ, Singh V, et al. An update of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. Part I: Introduction and general considerations. Pain Physician.

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21. Stelzer W, Aiglesberger M, Stelzer D, et al. Use of radiofrequency lateral branch neurotomy for treatment of sacroiliac joint, mediated low back pain: a large case series. Pain Med. 2013;14(1):29–35.

2. Manchikanti L, Abdi S, Atluri S, et al, and the American Society of Interventional Pain Physicians. American Society of Interventional Pain Physicians ( ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2— Guidance. Pain Physician. 2012;15(suppl 3):S67–116.

3. Hashmi JA , Baliki MN, Baria AT, et al. Shape shifting: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain. 2013;136(Pt 9):2751–2768.

4. Gaskin DJ, Richard P. The economic costs of pain in the United States.

J Pain. 2012;13(8):715–724.

5. Manchikanti L, Falco FJ, Singh V, et al. Utilization of interventional techniques in managing chronic pain in the Medicare population: analysis of growth patterns from 2000–2011. Pain Physician. 2012;15(6):E969-E982.

6. Manchikanti L, Falco FJ, Boswell MV, et al. Facts, fallacies, and politics of comparative effectiveness research: Part 1— Basic Considerations. Pain Physician. 2010;13(1):E23-E54.

22. Ko KY, Hadi MA , Pasutharnchat K, et al. Cooled radiofrequency denervation for treatment of sacroiliac joint pain: two-year results from 20 cases. J Pain Res. 2013;6:505–511.

23. Malik K, Benzon HT, Walega D. Water-cooled radiofrequency: a neuroablative or neuromodulatory modality with broader applications?

Case Rep Anesthesiol. 2011;2011: 263101.

24. Georgy B, et al. Targeted radiofrequency ablation prior to cement augmentation of symptomatic malignant spine lesions: clinical evaluation.

2015 SIR Annual Meeting. Abstract 36.

25. Anchala PR , Irving WD, Hillen TJ, et al. Treatment of metastatic spinal lesions with a navigational bipolar radiofrequency ablation device: a multi-center retrospective study. Pain Physician. 2014;17(4):317–327.

26. North RB, Ewend MG, Lawton MT, et al. Spinal cord stimulation for chronic, intractable pain: superiority of “multi-channel” devices. Pain.

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7. Rajaee SS, Bae HW, Kanim LE, et al. Spinal fusion in the United States: analysis of trends from 1998 to 2008. Spine. 2012;37(1):67–76.

27. Penjabi MM , Takata K, Goel V, et al. Thoracic human vertebrae. Quantitative three-dimensional anatomy. Spine (Phila Pa 1976).

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8. Tosteson AN, Skinner JS, Tosteson TD, et al. The cost effectiveness of surgical versus nonoperative treatment for lumbar disc herniation over two years: evidence from the Spine Patient Outcomes Research Trial (SPORT ).

Spine (Phila Pa 1976). 2008;33:2208–2115.

28. Kalia V, Bizzell C, Obray R, et al. Spinal cord stimulation: the types of neuromodulation devices currently being used, and what radiologists need to know when evaluating their appearance on imaging. Curr Probl Diagn Radiol. 2010;39(5):227–233.

9. Tosteson AN, Lurie JD, Tosteson TD, et al. Surgical treatment of spinal stenosis with and without degenerative spondylolisthesis: cost-effectiveness after 2 years. Ann Intern Med. 2008;149(12):845–853.

29. MedTronic advanced pain therapy using neurostimulation for chronic pain. Clinical Summary. 2011;M221494A006.

10. Manchikanti L, Benyamin RM , Hansen H, et al. Reversal of epidural cuts in 2015 physician pay schedule: two steps forward, one step back.

Pain Physician. 2014;17(5):E565-E573.

11. Manchikanti L, Helm S 2nd, Fellows B, et al. Opioid epidemic in the United States. Pain Physician. 2012;15(3 suppl): ES 9- ES38.

12. Jasper GP, Francisco GM , Telfeian AE . et al. Transforaminal endoscopic discectomy with foraminoplasty for treatment of spondylisthesis.

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13. Becker’s ASC Review web site. Available at: www.beckersasc.com/ lists/150-pain-management-physicians-to-know.html.

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30. Coombes BK , Bisset L, Vicenzino B. Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomized controlled trials. Lancet.

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31. Coombes BK , Bisset L, Brooks P, et al. Effect of corticosteroid injection, physiotherapy, or both on clinical outcomes in patients with unilateral lateral epicondylalgia: a randomized controlled trail. JAMA .

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32. Faulk WP, Matthews R, Stevens PJ, et al. Human amnion as an adjunct in wound healing. Lancet. 1980;1(8179):1156–1158.

33. Mermet I, Pottier N, Sainthillier JM , et al. Use of amniotic membrane transplantation in the treatment of venous leg ulcers. Wound Repair Regen.

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

Kathryn Schopmeyer PT, DPT, CPE

A SUMMARY OF STUDIES By

Cara M. Brock PharmD, CGP Rabia S. Atayee PharmD, BCPS

e

PHARMACOTH RAPY

Despite published evidence showing a lack of sublingual absorption of morphine, its use continues in the palliative setting.â&#x20AC;?

Although the oral route is the most preferred route of administration of medications, when it is no longer viable, one option is sublingual administration of medications. In the palliative setting the use of sublingual morphine continues to be used in hospice emergency kits, despite no evidence of absorption by the oral mucosa. Numerous studies of the pharmacokinetics of morphine administered by the sublingual route have been published and none show evidence of sublingual absorption. Despite published evidence showing a lack of sublingual absorption of morphine, its use continues in the palliative setting.

Here we will provide a summary of the literature and the applicability of sublingual administration of opioids in the setting of pain and palliative care. abstract:

PHARMACOTHERAPY

e e

preferred route of administration of medications

SUMMARY OF EViD NC The sublingual route of administration of morphine solution is used before other alternate routes of administration are implemented in the palliative setting for those patients who lose the ability to swallow tablets. Patients at end-of-life are commonly treated for pain and dyspnea with an opioid contained in a hospice emergency kit provided at the start of hospice care. A review of literature regarding hospice emergency kits (comfort kits) reveals literature as recent as 2014 describing hospice comfort kits containing morphine sulfate with directions for sublingual administration.6 Table 1 summarizes the available literature regarding hospice comfort kit medications. Although Bishop et al did not collect data regarding the exact makeup of the kits, all respondents indicated their kits contained a medication for treating pain and one respondent indicated that a medication in their kit was to be used sublingually.7 One retrospective and one prospective study that examined the contents of hospice comfort kits provided to veterans both evaluated the use of hospice emergency kits that contained morphine concentrate solution with directions for sublingual use.8,9 In these studies both patients/caregivers and hospice nurses report using morphine from the comfort kit.8,9 A nationwide survey of electronic medical records of hospice patients revealed that morphine was prescribed to 84.4% of patients, although the route and dosage forms were not reported.6

is the oral route as it is fairly easy for patients, allows for flexibility in the outpatient and home setting, and is feasible in that most medications are available in oral formulations.

In the palliative care setting, the oral route may not always be the optimal route as some patients may not be able to A summary of pharmacokinetic studies involving sublingual swallow—some experience vomiting or their gastrointes- morphine is presented in Table 2. These studies aimed to tinal absorption is impaired.1 In these instances, clinicians evaluate the sublingual absorption of morphine and other are challenged to identify an alternative route of medication opioids. For the purposes of this discussion, the focus will administration. The sublingual route is a simple noninva- be on the sublingual absorption of morphine. Although sive alternative route, especially with analgesia. The oral the methods varied between studies, all results show the mucosa is a convenient site of administration for drugs due pharmacokinetic profile of sublingually administered morto the large amount of blood and lymphatic vessels that phine more closely resembles that of oral vs intravenously deliver absorbed drugs directly into the systemic circulation or intramuscularly administered morphine.1,10-13 Studies bypassing hepatic first-pass metabolism.2 When adminis- that reported bioavailability of sublingually administered tered orally, the bioavailability of morphine is reduced by morphine report bioavailability that more closely resembles two-thirds by first-pass hepatic metabolism. If morphine is oral administration than intravenous or intramuscular.1,11,12 absorbed in the oral cavity where first-pass metabolism is Authors of multiple studies conclude that the absorption of bypassed, the bioavailability should be much higher com- morphine administered via the sublingual route is due to pared to oral administration.3 In order for a drug to be a slow-swallow rather than sublingual absorption.11,12 One absorbed by the sublingual route it must be lipid soluble study also shows a delay to peak concentration as the mediand non-ionized at the physiological pH of the oral cavity.2,3 cation is slowly swallowed that may cause a delay to onset of An ideal drug for sublingual administration is at least mod- analgesia.11 These 5 published studies evaluating the absorperately lipid soluble and mostly unionized at the pH of the tion of sublingual morphine provide evidence to support the oral cavity.2 Morphine has both poor lipid solubility (par- conclusion that morphine is not effectively absorbed sublintition coefficient 0.00001) and high degree of ionization gually, but displays the plasma morphine concentrations over (90%) in the oral cavity.3 These characteristics preclude its time and bioavailability of orally administered morphine. absorption both sublingually and bucally.3 The advantages of sublingual route are that it allows for faster onset of action and avoids further hepatic metabolism via first pass effect.4,5 CLiNiCAL IMPLiCATiONS The disadvantages of sublingual route are lower medication Lipophilic opioids such as fentanyl and methadone are well bioavailability and in most cases the medication dribbles out studied, efficacious, and safe to administer sublingually in from the side of the mouth or patients swallow it.1,3 patients who are unable to swallow, but there is no data

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Table 1. Summary of Literature Regarding Use of Oral Morphine in Hospice Symptom Kits Primary Author

Study Design

n

Results

study of all 27 hospice agencies in New Hampshire. Agencies were asked to identify a respondent with management of clinical care responsibilities

21

»» All kits contain medication for treating pain (unspecified)

Year Bishop7 2009

● Telephone

»»1 kit contained a medication for treating pain to be used sublingually (unspecified)

collected: how kits are ordered, how soon they are available in patient homes, type of pharmacy supplying kits, and cost of kits, how often medications in kits are used, impact of medication use

● Data

Leigh9 2013

34

chart analysis of the Birmingham VA Medical Center Hospice Emergency Kit (HEK )

● Retrospective

collected: HEK medication utilization, symptoms treated, and safety/diversion concerns

● Data

● Questionnaire

»» Morphine concentrate 20 mg/mL sublingual 0.25–1 ml q2h as needed for pain or dyspnea included in HEK »» 36.8% documented use of morphine sulfate form hospice emergency kit in EMR

67–78

completed by hospice nurses

(response rate to individual questions varied)

collected: nurse opinions on home use, hazards, and benefits of HEK s in general, and specific questions regarding the VA HEK

● Data

»» 92.8% of hospice nurses surveyed report using morphine from the HEK »» 85.5% nurses reported commonly treating pain with HEK medications »» 85.5% nurses reported commonly treating shortness of breath with HEK medications

Bailey8 2014

longitudinal cohort study evaluating the use, effectiveness, side effects, and other impacts of hospice emergency kits (HEK ) on the care of veterans on home hospice

● Prospective

43

»» Morphine sulfate concentrate 20 mg/mL 0.25–1 ml SL q2h PRN included in HEK »» 44.2% of patients report pain as a severe or distressing symptom in the last 7 days of life

or caregivers were called weekly and surveyed regarding use of medications from the HEK including: when and how medications were used, perceptions on effectiveness and timeliness of symptom relief

● Patients

»» 27.9% of patients reported treating pain within the last 7 days of life »» 4.7% of patients reported treating dyspnea in the last 7 days of life »» 30.2 % of patients/caregivers reported using morphine sulfate from the HEK

review for any patient who received care in an emergency department or hospital for uncontrolled symptoms

● EMR

43

»» No reported admissions for shortness of breath

19 with caregivers 1–3 months after death of the hospice patient to assess location of death, caregiver attitude regarding the HEK , and impact of the HEK on the patient and caregiver

»» 9.3% of caregivers reported feeling anxious or afraid about using HEK medications

cross-sectional study to characterize 4252 patients medications prescribed to hospice patients

»» Morphine prescribed to 84.4% of patients (3589)

data from the electronic medical records of a nation-wide hospice organization located in 11 states

»» Route and dosage form not collected

● Interviews

Sera6 2014

»» 7.7% of patients admitted for inpatient treatment of symptoms was for pain crisis

● Retrospective

● Includes

prescribed at any time during the study period were included in the study

● Medications

dosage formulations were considered to be the same drug; individual dosage forms were not reported

● Different

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www.painweek.org | PWJ | 43

PHARMACOTHERAPY

Table 2. Summary of Literature Regarding Absorption of Sublingual Morphine Primary Author Year Pannuti10 1982

Study Design

n

single dose of morphine 10 mg was administered by 8 patients with cancer pain the intramuscular, oral, rectal, and sublingual route

● A

morphine levels were drawn 3, 6, 9, 12, 15, 30, 45, 60, 75, 90, 105, 120, 180, 240, 360, 720, and 1440 minutes after administration

● Plasma

● Morphine

Results

»» Plasma levels of oral, rectal, and sublingually administered morphine rise slowly, reach a peak at 30 minutes, remain constant up to hour 3, then decrease in the 4th hour »» Compared to oral and rectal, sublingual morphine reaches peak concentration more quickly and shows a second peak at hour 3

plasma levels were measured

»» Authors conclude that sublingually administered morphine is initially absorbed in the oral mucosa, then later absorbed in the gastrointestinal tract McQuay13 1986

received 10 mg intravenous dose of morphine, heroin, or methadone on the first day of the study. Plasma morphine levels were drawn 1, 2, 5, 7.5, 10, 20, 30, 40, 60, 90, 105, 120, 150, 180, 240, 300, 360, 720, and 1440 minutes after administration

● Patients

5 patients requiring oral narcotic therapy

»» No significant advantage to the use of sublingual compared to oral morphine

10–35 healthy subjects in each test group

»» When compared to morphine—fentanyl, buprenorphine, and methadone were absorbed to a statistically significantly greater degree

a subsequent day patients were given 10 mg sublingual morphine (injection solution), heroin (two 5 mg tabs), or methadone (two 5 mg tabs).

The sublingual morphine was held under the tongue for 5 minutes, expectorated, and the mouth was rinsed with 50 mL tap water. Expectorate and rinse were analyzed to determine amount of morphine absorbed. Plasma morphine levels were drawn 30, 60, 90, 120, 240, 300, 360, 720, and 1440 minutes after administration

● On

Weinberg1 ● 1 ml of test solution placed under the tongue for 1988 10 minutes then expectorated, mouth rinsed with buffer solution and expectorated into the same tube. Subjects instructed not to swallow until after mouth was rinsed with buffer solution hydromorphone, methadone, heroin, levorphanol, buprenorphine, oxycodone, fentanyl, and naloxone were tested

● Morphine,

solution analyzed to determine the amount of drug expectorated by the subject to determine % of drug absorbed sublingually

● Expectorated

»» Oxycodone, heroin, levorphanol, hydromorphone, and naloxone absorption compared to morphine was not absorbed to a greater degree »» Sublingual drug absorption did not differ between strengths of opioid solution »» Fentanyl, methadone, and buprenorphine were well absorbed when the time of the experiment was shortened from 10 minutes to 2.5 minutes »» Sublingual bioavailability of morphine was 18%

7 healthy subjects »» Sublingual bioavailability of morphine was blood levels were drawn after sublingual 22.4% ± 9.2% (SD) (10 mg) and intramuscular (15 mg) doses of to compare plasma concentrations over time. Morphine plasma levels were drawn before and 5, 15, 30, 60, 120, 240, and 480 minutes after administration

● Morphine

44 | PWJ | www.painweek.org

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Table 2. Summary of Literature Regarding Absorption of Sublingual Morphine (cont.)

Primary Author Year Osborne11 1990

Study Design

n

Results

administered as an IV bolus (5 mg), oral tablet (11.7 mg), sublingual tablet (11.7 mg), buccal tablet (11.7 mg) and sustained release buccal tablet (14.2 mg)

10 healthy subjects

»» SL administration of morphine does not change the C max in healthy volunteers compared to oral administration

● Morphine

»» The Tmax of oral morphine was significantly less than that of sublingual

were made to reduce movement of the sublingual tablet, no other information provided regarding sublingual or buccal immediate release dosage forms

● Efforts

»» Oral bioavailability was 19.6% »» Sublingual bioavailability was 21.9% »» Authors conclude that sublingually administered morphine may attenuate and delay the onset of analgesia compared to oral administration

extended release tablets were kept in place for 2 hours, after which subjects were allowed to eat and drink but were instructed to avoid moving the tablet

● Buccal

morphine-3-glucuronide, and morphine-6glucuronide plasma levels were drawn 0, 5, 10, 15, 30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after administration. An additional sample was drawn at 24 hours for the extended release group

● Morphine,

Davis12 1993

mg morphine given orally, sublingually, or intramuscularly on different days

● 10

morphine levels were drawn prior to and at 5, 10, 15, 30, and 60 minutes, and 2, 4, and 6 hours after administration

● Plasma

● dose

intensity and pain relief assessed at each blood draw

● Pain

7 cancer patients with solid tumors

»» No difference in bioavailability in sublingual compared to oral administration of morphine.

1 patient had an unknown agent in the blood which interfered with assays

»» Oral bioavailability was 25% »» Sublingual bioavailability was 23% »» Results do not support sublingual absorption of morphine »» Authors conclude that much of the sublingual drug may be slowly swallowed and absorbed in the GI tract »» Pain and pain relief data not reported

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www.painweek.org | PWJ | 45

PHARMACOTHERAPY

to support the use of more hydrophilic opioids such as morphine, hydromorphone, or oxycodone sublingually.14 There are several commercially available sublingual formulations of fentanyl, but these are associated with several barriers including cost, lack of clear opioid dose conversion, and additional certification by prescriber and pharmacies in the REMS programs.15 Concentrated oral solution of methadone may be used sublingually by practitioners who are familiar with its unique pharmacology and dose considerations.16 The Expert Working Group of the Research Network of the European Association for Palliative Care recommends against the use of sublingual morphine due to the lack of evidence of efficacy and unpredictable absorption.17-19 Although there have been published reports of sublingual morphine use, there is no data to support the efficacy of this route of administration. Despite the evidence presented here, and the known pharmacokinetic properties of morphine, the practice of instructing the patient to administer morphine sublingually in the palliative setting continues. In the literature review within this paper there is no strong evidence that administering morphine sublingually is effective, but despite this data, morphine continues to be used sublingually in hospice patients. Bailey and colleagues showed that a very small percentage of the patients were admitted for pain crises when using morphine sublingually.8

CONCLUSiON Published studies comparing the efficacy of the sublingual route to oral or intravenous route are lacking and need to be conducted. Additionally, studies evaluating if a dose conversion is required when switching patient from oral to sublingual are needed. The current practice amongst palliative care practitioners is that the oral route is equivalent in dose to the sublingual route. Until these studies are conducted and published, palliative care practitioners who start their patients on sublingual morphine, hydromorphone, or oxycodone should monitor their patients carefully to assure 1) adequate time to onset of action, 2) use of highly concentrated solution of the opioid to decrease risk of dribbling out of the mouth due to high volume, 3) overall frequency of use and efficacy are appropriate. With close monitoring, if morphine or another hydrophilic opioid are ineffective then sublingual methadone or fentanyl or another route of administration should be considered for the hydrophilic opioids.

morphine administration. Review and new findings. Nurs Clin North Am. 1995;30(4):725–743.

4. Hagen NA , Moulin DE, Brasher PM , et al. A formal feasibility study of sublingual methadone for breakthrough cancer pain. Palliat Med. 2010;24(7):696–706.

5. Reisfield GM , Wilson GR . Rational use of sublingual opioids in palliative medicine. J Palliat Med. 2007;10(2):465–475.

6. Sera L, McPherson ML , Holmes HM . Commonly prescribed medications in a population of hospice patients. Am J Hospice Palliat Care.

2014;31(2):126–131.

7. Bishop MF, Stephens L, Goodrich M, et al. Medication kits for managing symptomatic emergencies in the home: a survey of common hospice practice. J Palliat Med. 2009;12(1):37–44.

8. Bailey FA , Williams BR , Goode PS, et al. Impact of a hospice emergency kit for veterans and their caregivers: a prospective cohort study. J Palliat Med. 2014;17(8):931–938.

9. Leigh AE, Burgio KL , Williams BR , et al. Hospice emergency kit for veterans: a pilot study. J Palliat Med. 2013;16(4):356–361.

10. Pannuti F, Rossi AP, Iafelice G, et al. Control of chronic pain in very advanced cancer patients with morphine hydrochloride administered by oral, rectal and sublingual route. Clinical report and preliminary results on morphine pharmacokinetics. Pharmacol Res Commun. 1982;14(4):369–380.

11. Osborne R, Joel S, Trew D, et al. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther. 1990;47(1):12–19.

12. Davis T, Miser AW, Loprinzi CL , et al. Comparative morphine pharmacokinetics following sublingual, intramuscular, and oral administration in patients with cancer. Hospice J. 1993;9(1):85–90.

13. McQuay HJ, Moore RA , Bullingham RE . Sublingual morphine, heroin, methadone, and buprenorphine: kinetics and effects. In: Foley KM , Inturrisi CE, eds. Advances in Pain Research and Therapy, Volume 8. New York, NY: Raven; 1986:407–412.

14. Kestenbaum MG, Vilches AO, Messersmith S, et al. Alternative routes to oral opioid administration in palliative care: a review and clinical summary. Pain Med. 2014;15(7):1129–1153.

15. Chang A, Roeland EJ, Atayee RS, et al. Transmucosal immediate-release fentanyl for breakthrough cancer pain: opportunities and challenges for use in palliative care. J Pain Palliat Care Pharmacother.

2015;29(3):247–260.

16. Simon SM , Schwartzberg LS . A review of rapid-onset opioids for breakthrough pain in patients with cancer. J Opioid Manage.

2014;10(3):207–215.

17. Morphine in cancer pain: modes of administration. Expert Working Group of the European Association for Palliative Care. BMJ .

1996;312(7034):823–826.

18. Hanks GW, Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer.

2001;84(5):587–593.

19. Ripamonti C, Bruera E. Rectal, buccal, and sublingual narcotics for the management of cancer pain. J Palliat Care. 1991;7(1):30–35.

References 1. Weinberg DS, Inturrisi CE, Reidenberg B, et al. Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther. 1988;44(3):335–342.

2. Coluzzi PH . Sublingual morphine: efficacy reviewed. J Pain Symptom Manage. 1998;16(3):184–192.

3. Robison JM , Wilkie DJ, Campbell B. Sublingual and oral

46 | PWJ | www.painweek.org

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The Science of Less

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

proven efficacy

rapid absorption

solumatrix fine particle technology™

low dose trusted molecule

low systemic exposure

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

Indication VIVLODEX is a nonsteroidal anti-inflammatory drug indicated for the management of osteoarthritis (OA) pain.

Important Safety Information Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

VIVLODEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Learn more about the Science of Less and low-dose SoluMatrix® NSAIDs at ScienceOfLess.com.

Please see brief summary of full Prescribing Information on adjacent pages.

VIV-0040

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNINGS: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

VIVLODEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms.

Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

INDICATIONS AND USAGE: VIVLODEX is indicated for management of osteoarthritis pain.

DOSAGE AND ADMINISTRATION: Dosage - Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg. In patients on hemodialysis, the maximum daily dosage is 5 mg. Non-Interchangeability with Other Formulations of Meloxicam - VIVLODEX capsules have not shown equivalent systemic exposure to other formulations of oral meloxicam. Therefore, VIVLODEX capsules are not interchangeable with other formulations of oral meloxicam even if the total milligram strength is the same. Do not substitute similar dose strengths of other meloxicam products.

CONTRAINDICATIONS: VIVLODEX is contraindicated in the following patients: known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product; history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients; and in the setting of coronary artery bypass graft (CABG) surgery.

WARNINGS AND PRECAUTIONS: Cardiovascular Thrombotic Events - Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.

Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery - Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG. Post-MI Patients - Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.

Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of VIVLODEX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If VIVLODEX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

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

treated patients compared to placebo-treated patients.

In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]). Avoid the use of VIVLODEX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If VIVLODEX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Renal Toxicity and Hyperkalemia - Renal Toxicity - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly.

Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of VIVLODEX in patients with advanced renal disease.

The renal effects of VIVLODEX may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating VIVLODEX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIVLODEX. Avoid the use of VIVLODEX in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If VIVLODEX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia - Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions - Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma. Seek emergency help if an anaphylactic reaction occurs. Exacerbation of Asthma Related to Aspirin Sensitivity - A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIVLODEX is contraindicated in patients with this form of aspirin sensitivity. When VIVLODEX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions - NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, StevensJohnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of VIVLODEX at the first appearance of skin rash or any other sign of hypersensitivity. VIVLODEX is contraindicated in patients with previous serious skin reactions to NSAIDs. Premature Closure of Fetal Ductus Arteriosus - Meloxicam may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VIVLODEX, in pregnant women starting at 30 weeks of gestation (third trimester). Hematologic Toxicity - Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with VIVLODEX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including VIVLODEX, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding. Masking of Inflammation and Fever - The pharmacological activity of VIVLODEX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring - Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms

or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically.

ADVERSE REACTIONS: Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Patients with Osteoarthritis Pain - Eight hundred sixty-eight (868) patients with osteoarthritis pain, ranging in age from 40 – 87 years, were enrolled in two Phase 3 clinical trials and received VIVLODEX 5 mg or 10 mg once daily. Fifty percent (50%) of patients were aged 61 years or older. Two hundred sixty-nine (269) patients received VIVLODEX 5 mg or 10 mg once daily in the 12-week, double-blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 1.

Table 1 Summary of Adverse Reactions (≥2%) – 12-Week Phase 3 Study in Patients With Osteoarthritis Pain Adverse Reactions

VIVLODEX 5 mg or 10 mg N=269

Placebo N=133

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

Table 2 Summary of Adverse Reactions (≥2%) – 52-Week Open-Label Study in Patients With Osteoarthritis Pain Adverse Reactions

VIVLODEX 10 mg N=600

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

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

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

DRUG INTERACTIONS: See Table 3 for clinically significant drug interactions with meloxicam.

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

Clinical Impact:

• Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding.

The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.

• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Intervention:

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

Aspirin

Clinical Impact:

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

VIVLODEX is not a substitute for aspirin for cardiovascular prophylaxis.

Intervention:

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

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers

Clinical Impact:

• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).

• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

Intervention:

• During concomitant use of VIVLODEX and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.

• During concomitant use of VIVLODEX and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function.

Diuretics

Clinical Impact:

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

Intervention:

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

Digoxin

Clinical Impact:

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

Intervention:

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

Lithium

Clinical Impact:

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

Intervention:

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

Methotrexate

Clinical Impact:

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

Intervention:

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

Cyclosporine

Clinical Impact:

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

Intervention:

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

NSAIDs and Salicylates

Clinical Impact:

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

Intervention:

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

Pemetrexed

Clinical Impact:

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

Intervention:

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

USE IN SPECIFIC POPULATIONS: Pregnancy - Risk Summary: Use of NSAIDs, including VIVLODEX, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VIVLODEX, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of VIVLODEX in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss.

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

experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment - No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Because meloxicam is significantly metabolized in the liver; use VIVLODEX in patients with severe hepatic impairment only if the benefits are expected to outweigh the risks. If VIVLODEX is used in patients with severe hepatic impairment, monitor patients for signs of worsening liver function.

Renal Impairment - No dose adjustment is necessary in patients with mild to moderate renal impairment.

Patients with severe renal impairment have not been studied. The use of VIVLODEX in subjects with severe renal impairment is not recommended. In a previous study, the free Cmax plasma concentrations following a single dose of meloxicam were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction).

Therefore, the maximum VIVLODEX dosage in this population is 5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.

OVERDOSAGE: Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care.

Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare. There is limited experience with meloxicam overdose. In four reported cases of meloxicam overdose, patients took 6 to 11 times the highest available dose of meloxicam tablets (15 mg); all recovered. Cholestyramine is known to accelerate the clearance of meloxicam. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a previous clinical trial. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

Manufactured (under license from iCeutica Pty Ltd.) for and Distributed by:

One Kew Place 150 Rouse Boulevard Philadelphia, PA 19112 VIV PBS-1 Jan 2016 References: 1. Full Prescribing Information for VIVLODEX. Iroko Pharmaceuticals, LLC; 2015. 2. Full Prescribing Information for ZORVOLEX. Iroko Pharmaceuticals, LLC; 2014. 3. Full Prescribing Information for TIVORBEX. Iroko Pharmaceuticals, LLC; 2014. 4. US Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. http://www.accessdata.fda.gov/scripts/cder/ob/.

Accessed November 23, 2015. 5. Altman R, Hochberg M, Gibofsky A, Jaros M, Young C. Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week, phase 3 study. Curr Med Res Opin. 2015;31(12):2331-2343.

SoluMatrix® is a registered trademark of iCeutica Pty Ltd., and is licensed to Iroko.

SoluMatrix Fine Particle Technology™ is a trademark of iCeutica Inc., and the technology is licensed to Iroko for exclusive use in NSAIDs.

why are we excising nerves?

Most US citizens will log an amazing 75,000 miles on their feet over the first 50 years o f life.

Rader DPM, FAENS

by Andrew

PODiATRiC

abstract: Most US citizens will log an amazing 75,000 miles on their feet over the first 50 years of life, and abnormalities in gait, ill-fitting shoe gear, repetitive stress, and trauma can all result in foot pain. One common malady is neuralgia in the intermetatarsal region of the foot. This condition was first described by Civinini in 1835.1 In 1876 a US orthopedic surgeon, Thomas Morton, published a case series of 15 patients with forefoot pain.2 By 1958 the condition was termed “Morton’s neuroma.”3 The most common surgical treatment for this condition became excision of the socalled neuroma; however, eagerness to excise this sensory nerve has come under some rightful scrutiny. There are no data to account for the exact incidence of this condition, but it is known that females are 10 times more likely to develop it, with 50 being the mean age of presentation.4

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the tibial nerve branches into the medial and lateral plantar nerves. The common digital nerves are branches of the medial and lateral plantar nerves. These common digital nerves course through the intermetatarsal spaces plantar to the deep transverse intermetatarsal ligament and divide into proper digital nerve branches supplying sensation to the adjacent plantar toes. As the nerves pass to the toes they are bordered on 3 sides by the adjacent metatarsal heads and dorsally by the intermetatarsal ligament. This forms a tunnel and a potential site of compression and irritation.

HiSTOLOGY So what is a neuroma? A neuroma is a mass composed chiefly of nerve fibers and nerve cells that may be the result of trauma, malformation, infection, or an overgrowth of vasculature and axons. It is a hypertrophic phenomenon.

The histology from a Morton’s neuroma excision should be consistent with phenomenon if a true neuroma is present.

Q2 | 2016

the result of inflammation, infection, metabolic processes, loss of oxygen, or physical compression. The characteristic nodular changes seen in Morton’s patients are exactly the same as those seen in asymptomatic patients.6 Morton’s neuroma is a misnomer. No neuroma is present.

Instead, there is a localized nerve compression injury causing a neuralgia.

However, excision of these nerve branches—termed Morton’s neuromas—yields pathology findings such as inconsistent nodular thickening, perineural, epineural and endoneural fibrosis, axonal demyelination, and degenerative vascular changes consisting of fibroelastic thickening and interfascicular larger arteries with elastic reduplication and hyalinosis of intrafascicular arterioles.5 These pathology findings make no mention of the tangled nerve masses that one would expect to see in the case of a neuroma.

SUBJ CTiV COMPLAiNTS The onset of Morton’s neuralgia will likely be insidious without significant initiating trauma. Typical complaints will be of stabbing, cramping, burning, and aching pain that is exacerbated by tight fitting shoe gear and activity. Often patients will relate a rolled up sock feeling under the digital sulcus.

The toes adjacent to the site of compression may feel numb.

In an article titled “Histologic comparison of the third interdigital nerve in patients with Morton’s metatarsalgia and control patients,” Bourke et al examined these nerves. They found histologically identical findings in Morton’s patients and in control patients, with the exception of demyelination seen more in the Morton’s group. Demyelination is usually

Even with minimal axonal damage, the symptoms may not be as localized as one would expect. Experimental mild nerve compression injuries have revealed immune cells invading the nerve, related dorsal root ganglion, and spinal cord leading to hyperexcitability, raised sensitivity, and pain that may be widespread.7

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Morton’s neuroma is a misnomer.

No neuroma is present.

DiAGNOSTiC IMAGiNG Imaging studies used are typically X-rays, MRI, and diagnostic ultrasound. X-rays are used primarily to rule out other causes of intermetatarsal region pain such as arthritis and fractures.

In a meta-analysis of 12 studies of Morton’s neuroma, MRI and ultrasound imaging were reviewed. The MRI group consisted of 217 patients, with 241 in the ultrasound group.

Ultrasound sensitivity was found to be 90%, specificity 88%, positive likelihood ratio 2.77, and negative likelihood ratio 0.16. While MRI sensitivity was 93%, specificity 68%, positive likelihood ratio 1.89, negative likelihood ratio 0.19.8 But again, what are the studies identifying, since the pathology is not consistent with a neuroma?

findings include the absence of joint effusion or pain on range of motion. Fluctuant palpable masses may indicate bursa formation. Elimination of other neurologic findings, such as tarsal tunnel or soleal sling syndromes, is important.

Nerve conduction studies and quantitative sensory testing may help delineate equivocal findings.

Positive findings may include impaired sensation on the adjacent aspects of third and fourth toes and even a mild splaying of the toes with weight bearing. The most consistent finding, however, is a positive Mulder’s sign on physical exam. This maneuver is performed by laterally compressing the forefoot with one hand while pushing up into the affected intermetatarsal space with the thumb of the other hand. A positive Mulder’s sign while performing this maneuver is described as a palpable click with associated pain.11

Symeonidis et al state that with diagnostic ultrasound it is difficult to separate the lesion from mass-like mucoid degeneration in adjacent loose connective tissue. In 48 TR ATM NTS asymptomatic feet, 54% were found to have sonographic After careful examination to rule out ligament, tendon, findings consistent with nerve thickening opening the door joint, and bone injuries, biomechanical causes such as ankle to potential false positives.9 And Bencardino et al report the equinus, neoplasm, and more proximal sites of nerve irritapresence of a mass in up to 33% of asymptomatic subjects tion, again, such as tarsal tunnel syndrome and soleal sling with MRI examination.10 Again, this leads us back to the syndrome, it is reasonable to diagnose Morton’s neuralgia. study which showed that nodular changes in the nerve are Treatment options for this condition are largely anecdotal exactly the same in Morton’s patients as they are in asymp- and include shoe gear changes, anti-inflammatories, padtomatic patients.6 ding, orthoses, alcohol sclerosing injections, botulinum toxin A, radiofrequency ablation, osteotomies of adjacent metatarsals, nerve excision, and nerve decompression.

PHYSiCAL EXAMiNATiON FiNDiNGS A combination of negative and positive findings may lead Wider accommodative shoe gear is a common initial the examiner to suspect a Morton’s neuralgia. Negative step. Frequently shoes will have a narrow toe box further

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compressing the nerve between the metatarsal heads.

Changing shoe gear has been found to be temporarily effective in up to 41% of patients.12 Often patients will also be placed into over-the-counter or prescription foot orthoses to control abnormal foot motion.

Unfortunately, the evidence for long-term success is poor.

Kilmartin and Wallace found that using orthoses to control the pronatory and supinatory forces on the foot were ineffective in relieving pain from identified Morton’s neuralgia.13

any measurable changes in nerve or adjacent muscle histology with ethanol injection…raises questions about the efficacy of using ethanol injections in the treatment of Morton’s neuroma in human clinical practice.”21 Radiofrequency ablation has been reported on by Genon and Moore. Genon et al found just over 18% of patients had complete relief of symptoms,22 and Moore states that 83% had complete relief of symptoms at 1 month postprocedure.23 However, in both studies, local steroid injections were administered at the time of the procedure, so the confounding variable of this renders the studies difficult to evaluate.

Local steroid injections are also a common treatment. Multiple injections are common and the longest follow-up studies are about 4 years. Rasmussen et al reported on 51 patients with a mean follow up of 4 years. Resolution of symptoms Park et al retrospectively compared 46 patients receiving occurred in 53%, and 47% required surgical intervention. decompression via cutting of the deep transverse intermetaA combination of bupivacaine and betamethasone was used tarsal ligament and 40 patients receiving the same and addiand typically only administered a single injection.14 Green- tionally undergoing shortening osteotomy of the longest field et al reported on 65 patients with a mean follow up of adjacent metatarsal. The mean follow up was 26 months.

3 years 10 months. Resolution of symptoms occurred in The decompression only group reported 84% good/excel28% of patients and about 17% required surgery. A com- lent results. The decompression and osteotomy group had bination of betamethasone and lydocaine was used, with a 96% good/excellent results.24 mean number of injections approaching 4.15 So the success of local steroid injections is somewhat mixed.

Nerve excision with and without reimplantation still remains the mainstay of treatment for Morton’s neuralgia.

There is a single report of botulinum toxin A injections, an Excision of the compressed nerve will frequently lead to open label study of 17 patients. Initial visual analog scale ( VAS) true neuroma formation as a result of the surgery. Dorsal pain scores were 7. At 1 month postinjection they improved to and plantar approaches have been described. The expected about 5, and at 3 months about 4. Approximately 30% had no outcome is relief of pain with numbness and possible parchange in their VAS scores. No long-term follow up was done.16 esthesia on the plantar intermetatarsal space extending into the adjacent toes. The goal is to trade pain for numbness.

Alcohol sclerosing injection therapy has multiple reports and has gained significant traction with many foot and ankle spe- In some of the longest follow up studies, success has been cialists. The outcomes of these studies vary widely. Hughes limited. Pace reports that 71% still had restrictions in shoe reported on 101 patients receiving 4 injections with a 21 gear at 4.5 years postop.25 Dereymaeker also reports that month follow up. Eighty four percent were pain free at the 70% had restrictions in foot wear at over 3.5 years postop end of the study with a median VAS dropping from 8 to 0.17 and between 51% to 82% reported paresthesias long term.26 Pasquali had 508 patients receiving 3 injections with a 1 year follow up. Almost 75% reported satisfaction with the treat- Nerve decompression alone has become an increasingly ment and the mean VAS dropped from 8.7 to 3.6.18 Gurdezi popular approach. The intent is to preserve sensation had a 5 year follow up on 45 patients. Twenty-nine percent while relieving the painful neuralgia. In a review of 8 peer were symptom free, but over 35% required surgery to relieve reviewed studies, success rates were 80% to 95% with the symptoms. Short-term results were encouraging, but the longest follow up being 10 years. Between 4% and 9% did long-term results were poor.19 However, there are contrast- require subsequent neurectomy due to inadequate pain ing studies that report failure rates of 78% with the same relief.27-34 In the 10 year follow up, close to 5% still reported number of injections. Espinosa used 20% alcohol and .25% some residual pain,31 but in comparison, this would seem to bupivacaine. He states, “Alcohol sclerosing therapy is…not be a very low failure rate. an effective treatment in the nonoperative management of painful interdigital neuromas and has been abandoned in our clinic.”20 Mazoch et al looked at the rat model utilizing CONCLUSiON 4%, 20%, and 30% alcohol with .5% bupivacaine. Intraneural, “Morton’s neuroma” is actually a compression neuropathy of perineural, and intramuscular injections were performed. the common digital nerve in between the third and fourth Histologic evaluations were then performed. There was metatarsals and should more properly be termed Morton’s no evidence of alcohol-associated cell necrosis, apoptosis, neuralgia. Clinical examination is accurate at diagnosing or apparent inflammation observed in any rat specimens this pathology, and MRI or ultrasound may be useful in regardless of concentration. The conclusion: “The lack of ambiguous cases. Shoe gear changes may provide some Q2 | 2016

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relief, but orthoses are not likely to be a useful adjunct therapy. Local steroid injections and alcohol sclerosing injections may provide short-term relief but are unlikely to provide long-term success.

17. Hughes RJ, Ali K, Jones H, et al. Treatment of Morton’s neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases. AJR Am J Roentgenol. 2007;188:1535–1539.

Nerve excision may also give relief, but subsequent paresthesia and shoe gear limitations are common. Decompression of the nerve addresses the pathology while preserving nerve function. When deciding on the ultimate treatment for this condition, the practitioner is urged to consider: where else in the human body is a nerve compression syndrome treated with excision of the nerve with the subsequent expected loss of function?

19. Gurdezi S, White T, Ramesh P. Alcohol injection for Morton’s neuroma: a five-year follow-up. Foot Ankle Int. 2013;34(8):1064–1067.

18. Pasquali C, Vulcano E, Novario R, et al. Ultrasound-guided alcohol injection for Morton’s neuroma. Foot Ankle Int. 2015;36(1):55–59.

20. Espinosa N, Seybold J, Jankauskas L, et al. Alcohol sclerosing therapy is not an effective treatment for interdigital neuroma. Foot Ankle Int. 2011;32(6):576–580.

21. Mazoch M, Cheema G, Suva L, et al. Effects of alcohol injection in rat sciatic nerve as a model for Morton’s neuroma treatment. Foot Ankle Int. 2014;35(11):1187–1191.

References

22. Genon M, Chin T, Bedi H, et al. Radio-frequency ablation for the treatment of Morton’s neuroma. ANZ J Surg. 2010;80:583–585.

1. Civinini F. Su di gangliare rigonfiamento dell piñata del piede.

Mem Chir Arcipedale di Pistoia. 1835.

23. Moore J, Rosen R, Cohen J, et al. Radiofrequency thermoneurolysis for the treatment of Morton’s neuroma. J Foot Ankle Surg. 2012;51:20–22.

2. Morton TG. A peculiar and painful affection of the fourth metatarso-phalangeal articulation. Am J Med Sci. 1876;71:31–39.

24. Park E, Kim Y, Lee H, et al. “Metatarsal Shortening Osteotomy for Decompression of Morton’s Neuroma”. Foot Ankle Int. 2013;12:1654–1660.

3. Sandel RK . Morton’s neuroma of the second toe. J Am Podiatry Assoc.

1954;48(3):116–117.

25. Pace A, Scammell B, Dhar S. The outcome of Morton’s neurectomy in the treatment of metatarsalgia. Int Orthop. 2010;34:511–515.

4. Thompson CE, Gibson JN, Martin D. Interventions for the treatment of Morton’s neuroma. Cochrane Database Syst Rev. 2004;(3) CD 003118.

26. Dereymaeker G, Schroven I, Steenswerckx A, et al. Results of excision of the interdigital nerve in the treatment of Morton’s metatarsalgia. Acta Orthop Belg. 1996;62(1):22–25.

5. Vernadakis AJ, Koch H, Mackinnon SE . Management of neuromas.

Clin Plast Surg. 2003;30(2):247–268, vii.

6. Bourke G, Owen J, Machet D. Histologic comparison of the third interdigital nerve in patients with Morton’s metatarsalgia and control patients. Aust N Z J Surg. 1994;64(6) 421–424.

7. Schmid A, Coppieters M, Ruitenberg M, et al. Local and remote immune-mediated inflammation after mild peripheral nerve compression in rats. J Neuropathol Exp Neurol. 2013;72(7):662–680.

8. Xu Z, Duan X, Yu X, et. al. The accuracy of ultrasonography and magnetic resonance imaging for the diagnosis of Morton’s neuroma: a systematic review. Clin Radiol. 2015;70(4):351–358.

27. Gauthier G. Thomas Morton’s disease: a nerve entrapment syndrome.

A new surgical technique. Clin Orthop. 1979;142:90–92.

28. Dellon AL . Treatment of Morton’s neuroma as a nerve compression: the role for neurolysis. J Am Podiatr Med Assoc. 1992;82:399–402.

29. Diebold PF, Daum B, Dang-Vu V, et al. True epidermal neurolysis in Morton’s neuroma: a five year follow up. Orthopedics. 1996;19:397–400.

30. Okafor B, Shergill G, Angel J. Treatment of Morton’s neuroma by neurolysis. Foot Ankle Int. 1997;18:284–287.

31. Vito GR , Taralico LM . A modified technique for morton’s neuroma: decompression with relocation. J Am Podtr Med Assoc. 2003;93:190–194.

9. Symeonidis P, Iselin L, Simmons N, et. al. Prevalence of interdigital nerve enlargements in an asymptomatic population. Foot Ankle Int. 2012;33:543–547.

32. Vilas C, Florez B, Alfonso M. Neurectomy versus neurolysis for Morton’s neuroma. Foot Ankle Int. 2008;29:578–580.

10. Bencardino J, Rosenberg Z, Beltran J, et al. Morton’s neuroma: is it always symptomatic? Am J Roentgenol. 2000;175:649–653.

33. Shapiro SL . Endocopic decompression of the inter-metatarsal nerve for Morton’s neuroma. Foot Ankle Clin. 2004;9:397–407.

11. Mulder JD. The causative mechanism in Morton’s metatarsalgia.

J Bone Joint Surg. 1951;33-B:94–95.

34. Barrett SL , Rabat E, Buitrago M, et. al. Endoscopic decompression of the intermetatarsal nerve (EDIN) for the treatment of Morton’s entrapment: multicenter retrospective review. Open J Orthrop. 2012;2:19-24.

12. Saygi B, Yildirim Y, Saygi E, et al. Morton neuroma: comparative results of two conservative methods. Foot Ankle Int. 2005;26:556–559.

13. Kilmartin T, Wallace W. Effect of pronation and supination orthoses on Morton’s neuroma and lower extremity function. Foot Ankle Int. 1995;16:256–262.

14. Rasmussen MR , Kitaoka HB, Patzer GL . Nonoperative treatment of plantar interdigital neuroma with a single corticosteroid injection.

Clin Orthop Relat Res. 1996;326:188–193.

15. Greenfield J, Rea J Jr, Ilfeld FW. Morton’s interdigital neuroma: Indications for treatment by local injections versus surgery. Clin Orthop Relat Res. 1984;185:142–144.

16. Climent J, Mondejar-Gomez F, et. al. Treatment of Morton neuroma with botulinum toxin A: a pilot study. Clin Drug Investig. 2013;33(7):497–503.

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SHORT CUTS

By Doug Gourlay MD, MSc, FRCPC, FASAM

“But I’m not an addict, Doc. I’m a pain patient!”

Separate the motive from the behavior.

Rather than debate the label—addiction vs pain— agree that “Behavior X” is problematic.

As an example: “Why is the patient continuously running out of medications early?” is often not as important as the fact that this behavior is occurring.

Get an agreement that “running out early” is not acceptable.

Tighten boundaries with more frequent appointments while seeking more definitive help.

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Getting the Most from PDMPs Matthew Foster, PharmD

Best Practices in Prescribing Protocol

Kevin Barnard; Jennifer Bolen, JD;

Stephen Ziegler, PhD, JD

PDMPs are one of several important tools, such as opioid treatment agreements and urine drug testing, that the pain management community can use to benefit our patients on a daily basis.

PDMPs can be used to really see how our patients are getting prescriptions filled, and if they’re doing things that make you question what they’re doing with their medication therapy. The best way that physicians can use PDMPs is to incorporate them early into their daily activities. It’s not just the patients who they might view as high-risk: ALL patients need to be reviewed with the PDMP simply because that should be a part of how a practitioner evaluates that patient every visit. It’s important to have a full picture of what else is going on with that patient’s prescribing.

The PDMPs are providing us with important information regarding our patients, but they shouldn’t be used in isolation. It’s something to help elicit those conversations between patient and provider to know exactly what’s going on with each patient so that we can tailor their therapy.

It’s important to know who is getting their prescriptions filled and don’t need to be monitored closely; but perhaps more importantly to identify those patients that do have therapeutic issues so we can get them the help they need.

2 |

Have a conversation before prescribing opioids: “I’m considering prescribing these for you, but just keep in mind they can cause problems and you really don’t know whether they will or won’t unless you take them. But here are things that you should be aware of that could go wrong and if something is going wrong, I need to know about it as the prescriber.” Build the infrastructure for referral, understand what’s available in your community so you can readily refer someone at least to AA or an addiction specialist or somebody who is equipped to handle the situation.

Most state licensing boards specify that if you’re in a chronic opioid prescribing situation, you have to do a history and physical evaluation, write up a treatment plan, be sure there is informed consent, and a treatment agreement. If it’s a new patient, take some time. Get the old medical records. Do a PDMP check. Get that information and you’ll cut down on the potential for a hit and run where a patient is coming in just to get a prescription. It can also set the stage for a very good relationship where the physician can trust but verify the patient’s situation.

The foundation of the patient–provider relationship is one of mutual respect and trust. To help ensure that trust and to address any potential road bumps, it’s important to have that open dialogue so that a patient can feel comfortable about discussing sensitive matters and vice-versa.

And as a frontline provider, don’t be hesitant to seek out additional resources to help guide the process.

Better Anatomical Visualization With Ultrasound Michael Bottros, MD

Ultrasound is being used to help locate peripheral nerves, to help coordinate injections, and to even show some improved potential outcomes in safety when it comes to trying to help patients with chronic pain.

What’s nice about ultrasound is that it can show the surrounding tissue and vasculature, as well as the actual nerves themselves. Although CT and fluoroscopy are considered gold standards, and fluoroscopy is typically used in outpatient-based procedures, fluoroscopy is really only good at showing bone and bony structures and not necessarily the actual targets that you’re looking for. We think we know where that nerve should be, based on anatomical dissections and what we know of anatomy, but everyone’s a little different and ultrasound can actually show that. You can use ultrasound with a lot of different types of injections and therapies for patients with chronic pain. There are certain types of injections for which the evidence is lacking. For the typical epidural steroid injection, you can’t really see the spread of your local anesthetic, so it’s not been very well considered for use in these types of situations. There are other situations where it can be very useful, especially in the neck-type region, such as for cervical medial branch blocks or third occipital nerves or greater occipital nerves. There’s been very good evidence because the anatomy is favorable and it’s more of a superficial injection. Also in terms of sympathetic blocks, the stellate ganglion has been very well studied in ultrasound and you can avoid hitting vasculature, which you would normally have to do if you go through the classic approach using fluoroscopy. Typically, you have to go through the thyroid tissue, which is pretty vascularized. You can avoid that using ultrasound-guided techniques.

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4 |

Nutrition and Pain: Rules for Success Hal Blatman, MD, DAAPM , ABIHM

If your pain is worse there’s a reason for it and the most overlooked reason is food. If we’re eating inflammatory foods, that turns into pain.

The foods are very common, are highly addictive, and aren’t something that we want to quit eating. It’s really hard to convince somebody that the foods they love are so dangerous to their bodies. It’s not enough for a patient to say, “Well I’m going to change my diet, so I’ll eat less of this.” If there’s a speck of something that turns on your inflammatory system, you’re on for the next 4 weeks. You can’t minimize it. You need to not eat any of it and that’s a level of commitment that is difficult for people to maintain. So, what should we be coaching? First, foods are inflammatory—bread flour, sugar, potatoes, fruit juice, artificial sweeteners, and hydrogenated fat. Second, read the label on everything that goes into a meal. People need to know that there’s no high fructose corn syrup or wheat used as a thickener. Even vegetable soup stock has wheat in it as a thickener. Third, be careful of food contaminants during preparation. Was the cheese knife clean? Was the cutting board clean?

I tell my patients with pain to write down as specifically as they can everything they ate in the last 24 hours. The next time the pain occurs, do the same thing. And by the third or fourth time, you’re starting to identify what’s in common. I don’t think doctors are educated enough in this whole process to be able to speak to patients with enough conviction to get them to buy into it. But by repetition and by staying with it, patients can learn and find their way out of pain.

Q2 | 2016

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In 2010, medical claims from

1,750

12,165

young adults

were studied for associations between sleep problems and new or worsening chronic pain.

The subjects were followed for 3 years.

50%

of those with sleep problems at the outset of the study had them for the full duration.

38% of that cohort reported

chronic pain vs

14 %

of those without sleep problems.

The association was stronger in women than in men.1 In a study of neck pain, the CT scans of

182

patients were evaluated.

34%

were smokers, and this cohort had more cervical disk disease and resultant pain than nonsmokers.2

with 24 different chronic pain conditions were examined:

Chronic pain costs

32,000

$

per patient per year.

Chronic pain complaints resulted in a mean of

5.2 discrete imaging tests per patient.

ALMOST

39% were prescribed opioid medication.3 In a 6-month randomized trial conducted at 5 addiction research centers,

153

ex-prisoners received naltrexone for opioid addiction, and

155 received counseling or attended community treatment programs.

The naltrexone cohort reported significantly fewer relapses

(43% vs 64%) and longer median time between relapse

(10.5 weeks vs 5 weeks) compared to controls.

0% recorded overdose, compared to some in the control group, even at 18 months post-study.4

A study found that of

2,221 patients

who underwent bariatric surgery, average weight reduction was

28% compared to pre-procedure.

50%–70% reported clinically significant improvements in pain, physical function, and walking speed.

75%

of subjects with osteoarthritis before surgery reported reduced knee and hip pain, post-procedure.

These benefits prevailed for the entire 3 year span of the study.5

Vaginal hysterectomy

was associated with

50%

less postsurgical pain than abdominal hysterectomy.6

1. http://bit.ly/1XwNqWW 2. http://bit.ly/1ONbePu 3. http://bit.ly/20Gq40r 4. http://bit.ly/1WiFb1U 5. http://bit.ly/25h3UFn 6. http://bit.ly/1qLAlMB

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Opioid Risk Assessment, the CDC, and College Hoops

by ted w. Jones PHD

…predicting human behavior is very difficult and having better than a 50% predictive accuracy is about all we can ask for.

The Centers for Disease Control (CDC) recently released a report with recommendations about prescribing opioids for chronic pain.1 The guidelines have generated a good deal of discussion, particularly with their recommendations about morphine equivalent daily dose limits.

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However, one area of the report has gone largely unnoticed or not commented on, and it’s an important one: their recommendations, or perhaps better said their lack of recommendations, about opioid risk assessment. As many state laws and professional guidelines require opioid risk Q2 | 2016

assessment as part of the evaluation of chronic pain patients, patient. The CDC report of 2015 does not recommend this. this discrepancy is important. One could almost infer that Why the change? the CDC by their lack of endorsement is suggesting that opioid risk assessment be ended as a standard of care. I will The current CDC report drew heavily on 2 past reviews argue here that opioid risk assessment tools do help cli- of the literature in drawing its conclusions on many topics, nicians predict medication aberrant behavior and should including opioid risk assessment.3,4 These 2 past reviews of continue to be a necessary tool for all those involved in the literature, in the CDC’s mind, do not support the use the prescribing of opioid medications. Our knowledge base of opioid risk assessment. “Insufficient accuracy” is cited by does have some flaws but it is better than the limited credit the CDC.1 “Poor quality studies” was reported by Chou et al CDC gives it. More importantly, the overall science of pre- in 2015 and “evidence also remains limited” was reported dicting human behavior is inexact, even at the best of times. by Chou et al in 2014. A complete point by point analysis of Practitioners are much in the same position as the NCAA these findings is beyond the scope of this article, but a few basketball selection committee. We all use the data we have comments and criticisms can be made. at the time to make the best predictions we can, knowing that sometimes we will be wrong—but doing the best we Missed Some can and being right most of the time.

In the literature reviews on which the new CDC guidelines are based, it is noted that the authors did not consider all of Backtracking the literature available. The CDC report mentions only 4 The basic findings of the recent CDC report about opioid risk assessment tools by name— ORT, SOAP, SOAPP-R, risk assessment are summed up on page 28: and the Brief Risk Interview. In reality there are 10 opioid risk assessment tools that have been published in the Previous guidelines have recommended screenpeer-reviewed literature. Omitted were the Pain Medication ing or risk assessment tools to identify patients Questionnaire,5 the Diagnosis Intractability Risk Efficacy at higher risk for misuse or abuse of opioids. scale ( DIRE),6 the Prescription Drug Use Questionnaire However, the clinical evidence review found that Self-report (PDUQp),7 the Narcotic Risk Manager ( NRM ),8 currently available risk stratification tools (e.g., the Brief Risk Questionnaire ( BRQ),9 and the Screen for Opioid Risk Tool, Screener and Opioid Assessment Opioid-Associated Aberrant Behavior Risk (SOABR).10 To for Patients with Pain Version 1, SOAPP-R, and Brief only name 4 tools when there are more than double that Risk Interview) show insufficient accuracy for clasnumber leaves the casual reader thinking options are very sification of patients as at low or high risk for abuse limited, when in fact they are not. or misuse (KQ4). Clinicians should always exercise caution when considering or prescribing opioids for any patient with chronic pain outside of active cancer, palliative, and end-of-life care and should not overestimate the ability of these tools to rule out risks from long-term opioid therapy.

This finding makes an indirect reference to the joint guidelines put forth by the American Pain Society and American Academy of Pain Medicine in 2009.2 In that article, written by some of the same authors as the current CDC guidelines, the following was stated: Before initiating COT [continuous opioid therapy], clinicians should conduct a history, physical examination and appropriate testing, including an assessment of risk of substance abuse, misuse, or addiction…. Thorough risk assessment and stratification is appropriate in every case. This approach is justified by estimates of aberrant drug-related behaviors…

With little elaboration, the current CDC report backtracks on the use of opioid risk assessment. In 2009, opioid risk assessment was recommended “in every case” for every Q2 | 2016

Similarly, the CDC cites a total of 6 studies from which to draw information. By my count there are 26 studies that offer empirical data on opioid risk assessment tools—some are older, some more recent, and they vary in methodological rigor. It appears to me that there is more information to draw on about opioid risk assessment than the CDC report suggests.

Poor Quality?

Past reviews of risk assessment tools in the scientific literature used a specific rubric to rate the quality of studies that—in the CDC’s mind—render the conclusions less than persuasive. The CDC cites specific methodological problems: Methodological shortcomings in both studies included exclusion of patients who were not evaluated with all of the risk assessment instruments (in one study, nearly 300 of 347 patients were excluded for this reason, and in the other the proportion excluded was not reported) and use of a case-control design. In both studies, cases were based on opioid discontinuations due to abuse, without further specification. One study also evaluated aberrant behaviors, but this outcome was not clearly defined.1

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In 2009, opioid risk assessment was recommended ‘in every case’ for every patient. The CDC report of 2015 does not recommend this. Why the change?

Without any more knowledge of those older studies than What this complaint means is that in a good research design this, it would appear these studies’ findings are less than about prediction, the people whose judgment you are using helpful. One gets the impression that the literature has been to predict as an outcome measure should not be aware of reviewed in a rigorous fashion. However, there is more to the results of the original assessment so that they’re not this story. Above, the CDC finds that 2 past studies excluded influenced in a way that biases their decisions. In real world a large number of patients, thus invalidating the studies. research however, I hold that blinding is impossible. It is a However, the fact is that the patients omitted were ones standard of care now that clinicians use the results of an who were admitted to pain treatment but were never treated opioid risk assessment in planning and monitoring treatwith opioid medications. These patients received injections ment. Clinicians can not legally or ethically be blind to risk and/or adjuvant medications or no treatment at all, but were assessment data. Even if clinicians are aware of one tool’s prescribed no opioids. This means that it would have been results but are blind to others, the fact is that risk assessment inappropriate to include these patients in either study as tools are moderately correlated with each other.9 If a clinithey had no chance to show medication aberrant behav- cian is influenced by one tool, the decisions they make will ior. Opioid risk assessment is at its very heart about assess- affect clinical decisions in the same way as if the clinician ing patients in predicting their use of opioid medications. was aware of the other tool. To do a “clean” blinded study, Patients who receive nonopioid treatments do not need to one would have to treat patients with no regard to any risk be included in a study on opioid risk assessment. To have information. This is impossible to do in this day and time in included these patients would have biased the results and a real clinical setting. I maintain that we need to accept this invalidated the study. A more careful examination by past limitation and use the information we have, as imperfect as reviewers would have revealed the reason for these patient it is, rather than discount the research altogether. omissions. My fear is that a graduate student analyzed data with the use of a checklist and indicated “Yes, the study did Insufficient Accuracy not give all patients all of the risk tools” and thus the study The CDC summarizes its stand on risk assessment by saying was rated as poor quality without any thoughtful consider- that risk assessment tools have “insufficient accuracy.” That ation of the study design and purpose. This (what I would is, they say, not only are the validation studies on these call) sloppy analysis of these 2 studies has led the CDC to tools weak in design but that the tools give poor results. discount important and valid findings about several opioid Let us examine this a bit further. It is true that the ORT risk tools. and SOAPP-R have been shown to have poor predictive abilities in some settings.11-13 However, one study showed The CDC also complained in the quote above about a lack that the ORT has significantly better accuracy when the of clarity, about the outcome measures “not clearly defined” questions are verbally administered to patients, rather than in these studies. These studies used the clinical judgment when patients are simply handed a form to complete.14 Thus, of the clinician to end opioids as the prediction criterion. there are proven ways for clinicians to improve the predicThis outcome measure does indeed have some degree of tive abilities of the ORT. subjectivity. What exactly is a short pill count? One pill?

Two pills? Three? Does it matter if it is a prn medication vs a The SOAPP-R can also be improved in its accuracy. The long-acting opioid? This is a problem for all validation stud- original SOAPP showed good predictive abilities in a comies of opioid risk tools. I hold that this is an inevitable prob- parative study.11 This may be due to its use of a cutoff score lem in the applied research on opioid risk tools. There is no of 8. The SOAPP-R on the other hand has an official cutoff one universally accepted definition of medication aberrant score of 18 and appears to have poor sensitivity as a result. behavior, and clinically meaningful data will always have In the SOAPP-R manual, another cutoff score of 12 is sugsome degree of subjectivity. One could use “UDT positive gested to differentiate low from medium risk. There is no for illicit substances” as an outcome measure and it would be empirical data to support this alternate cutoff score. Howclear and objective, but not wholly clinically meaningful as ever, based on the results of SOAPP, it is quite likely that there are several other medication aberrant behaviors that the SOAPP-R use of this lower cutoff score improves its are important to predict. Patient behaviors and data need predictive accuracy. As this is an “unofficial” cutoff score, to be considered in their clinical context. What is termed there are no studies in the literature and probably won’t be. “inappropriate behavior” by patients will always involve some But this lower cutoff score, which is used by many clinicians degree of judgment. That said, a clinical decision to end opi- that I talk to, is likely giving better predictive results than oids due to some form of medication aberrant behavior is at the scientific literature gives the SOAPP-R credit for. least as valid a criterion as any, and the use of it as an outcome measure should not make a study “poor quality.”

How Accurate Can We Be? The CDC and its supporting literature reviews offer some Finally, one review of the literature cited by the CDC states predictive scores and concludes “insufficient accuracy.” Prethat there was “unclear blinding” in the studies reviewed.3 diction values cited by the CDC range anywhere from 25%

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Q2 | 2016

…a clinical decision to end opioids due to some form of medication aberrant behavior is at least as valid a criterion as any, and the use of it as an outcome measure should not make a study ‘poor quality.’ to 85%. Some tools show higher predictive accuracy than It is also worth noting that no one—not one of the millions others but the CDC report concludes “insufficient accuracy” of fans who fill out their own predictive brackets—has ever for all risk tools. The question then becomes what predic- predicted every game in the tournament correctly. tion values should we expect from these tools? What is an acceptable value, one that would lead the CDC to endorse What does this tell us? Through the use of a prediction proopioid risk assessment tool(s)? They don’t say and we are left cess that involves many, many hours and involves poring over to wonder this for ourselves. many, many statistics, the overall predictive accuracy for the NCAA men’s basketball selection committee ranges from In order to better understand what we can expect from our around 55% to 80% with an average of about 66%. They risk assessment tools, let us turn to other areas of prediction call the tournament “March Madness” for a reason. While at use in our society. We engage in all sorts of prediction on the whole the higher seeded teams usually win, upsets processes. College admission counselors engage in a predic- abound. Can we expect a higher rate of predictive accuracy tive enterprise every spring as they work to determine who from our opioid risk assessvment tools? Rather than saying will do well at their school if admitted. High school students our tools have “insufficient accuracy,” perhaps we should say vote on “Most Likely to Succeed.” Polls predict outcomes of that predicting human behavior is very difficult and having future votes. Prediction is most prominent in the world of better than a 50% predictive accuracy is about all we can ask sports. College sports teams go after 3 star, 4 star, and 5 star for. In my opinion opioid risk tools that have predictive accurecruits. The NFL draft is an elaborate exercise in trying to racy in the 55% to 80% range—and there are some tools predict who will be a successful player. Ratings, rankings, out there with these prediction rates—should be assessed as underdogs, and teams favored to win—these are all exer- having sufficient accuracy for use in clinical settings. cises in prediction. Las Vegas has a huge industry based on predictions and actual outcomes. One area in which we can The Bottom Line get some empirical data on prediction is the men’s NCAA basketball tournament.

1. There is more information, and there are more studies about opioid risk assessment than the CDC In the NCAA basketball tournament, 64 teams are divided referenced in its review. into 4 groups of 16 (let’s ignore “play-in games” for our purposes here). Each group of 16 teams are ranked 1 to 2. The studies that have been done are of higher qual16. These rankings, or “seeds,” indicate which teams are ity than the CDC and its reviewers suggest. favored to win. To determine seeds there is a group of 10 knowledgeable and unbiased individuals (the selection 3. The studies that have been done are using the best committee) who spend hours and hours individually and available methods. Randomized, blinded studies together poring over many, many statistics drawn from with matched control groups and clear and exact many, many sources. They vote and revote to finally come outcome measures are simply not possible to do in to a consensus about how each group of 16 should be seeded. the current practice environment. We need to use the What is nice about this predictive process for our purposes information available and not discount what is that, unlike professional sports, these tournament games we have. are all played on neutral courts so the seeding does not bias or favor the higher seeds over the lower seeds. Once the 4. Some of the “poor” opioid risk tools we now use tournament is over, the actual accuracy of this intensive can be improved upon and are likely giving better assessment and prediction process can be determined. results to clinicians than the documented research would suggest.

If the NCAA selection committee predictions were accurate, at least 2 things would be true. First, the top 4 seeds in 5. Our society has a large number of predictive proeach group would be playing for the championship of that cesses that yield less than perfect results. If we use group—that is, all top 4 seeds would be in the “Sweet 16” the NCAA men’s basketball tournament seeding round of games. Secondly, all higher seeds would beat all process as an example—a process that uses many, lower seeds. So how well does the committee do in seeding many hours of time to produce predictions—we find teams? In 2016, 10 out of 16 made it to the Sweet 16, for a sucthat it is correct in its prediction only around 66% cessful prediction rate of 63%. In 2015, 9 out of 16 made it to of the time. To criticize opioid risk assessment tools the Sweet 16 (56%). In 2014, 10 out of 16 made it to the Sweet for having similar predictive results is quite unfair.

16 (63%). As to high vs low seed games, in 2016 higher seeds I do not think it is a failure of our risk tools to have beat the lower seeds 68% of the time (41 out of 60 games). In 55% to 80% accuracy; I think this is the best we can 2015, 80% of higher seeds won (48 out of 60 games). In 2014, expect when trying to predict future human behav67% of the higher seeds won their games (40 out of 60 games). ior that is influenced by a host of factors.

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We will have our patient upsets and surprises. We must work to have an assessment process in which the majority of our patients are successful.

6. I think the CDC has done the pain treatment field a disservice by not endorsing the use of opioid risk assessment tools. We need all the information we can get, and undercutting the use of these tools with a lukewarm or nonexistent endorsement is not helpful to clinicians or patients.

7. The CDC is correct when it recommends that clinicians use other data in addition to a risk assessment score to assign risk and make predictions. Clinicians should administer an opioid risk assessment tool and then also review urine drug testing data, prescription drug monitoring program data, and data from past medical records to make a final determination about risk and possible future medication aberrant behavior.

8. The CDC is also correct when it calls for more study on opioid risk assessment. In my mind there has been an unfortunate limited number of studies about current or any new opioid risk tools. It is vital that we make every effort to study our tools and determine in what clinical situations, what subgroups, what geographical areas, and in what cultures they work best. It is unlikely that there is one opioid risk tool that is best for all pain practices and all situations. Clinicians need to be informed consumers and understand the pros and cons of each available tool before selecting the tool that is best for their situation. We owe it to our patients to do all we can to decrease opioid addiction, abuse, misuse, and diversion of opioids through the consistent use of empirically supported opioid risk assessment tools.

5. Adams LL , Gatchel RJ, Robinson RC , et al. Development of a self-report screening instrument for assessing potential opioid medication misuse in chronic pain patients. J Pain Symp Manag. 2004;27(5):440–459.

6. Belgrade MJ, Schamber CD, Lindgren BR . The DIRE score: predicting outcomes of opioid prescribing for chronic pain. J Pain. 2006;7(9):671–681.

7. Compton PA , Wu SM , Schieffer B, et al. Introduction of a self-report version of the Prescription Drug Use Questionnaire and relationship to medication agreement non-compliance. J Pain Symptom Manage.

2008;36(4):383–395.

8. Gostine ML , Davis FN, Risko R. Risk Assessment in the Digital Age: Developing Meaningful Screening Tools for Opioid Prescribers. Pract Pain Manag. 2014;14(4):1–9.

9. Jones T, Lookatch S, Moore T. Validation of a new risk assessment tool: the Brief Risk Questionnaire. J Opioid Manage. 2015;11(2):171–183.

10. Ehrentraut JH, Kern KD, Long SA , et al. Opioid misuse behaviors in adolescents and young adults in a hematology/oncology setting. J Pediatr Psychol. 2014;39(10):1149–1160.

11. Moore TM , Jones T, Browder JH, et al. A comparison of common screening methods for predicting aberrant drug-related behavior among patients receiving opioids of chronic pain management. Pain Med. 2009;10(8):1426–1433.

12. Jones T, Moore TM , Levy J, et al. A comparison of various risk screening methods for patients receiving opioids for chronic pain management.

Clin J Pain. 2012;28(2):93–100.

13. Jones T, Schmidt M, Moore TM . Further validation of an opioid risk assessment tool: the Brief Risk Questionnaire. Ann Psychiatry Ment Health.

2014;3(3):1032–1038.

14. Jones T, Passik SD. A comparison of methods of administering the opioid risk tool. J Opioid Manag. 2011;7(5):347–352.

References 1. Dowell D, Haegerich TM , Chou R. CDC guideline for prescribing opioids for chronic pain— United States, 2016. MMWR Recomm Rep. 2016;65:1–49.

2. Chou R, Fanciullo GJ, Fine PG, et al Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain.

2009;10(2):113–130.

3. Chou R, Turner JA , Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162:276–286.

4. Chou R, Deyo R, Devine B, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. Evidence report/technology assessment no. 218. (Prepared by the Pacific Northwest Evidence-based Practice Center under contract no. 290–2012–00014-I). AHRQ publication no. 14-E005- EF. Rockville, MD: Agency for Healthcare Research and Quality; 2014.

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To access this free CE/CME Internet-based activity, visit:

www.PAINWeek.org/mixed-pain

Multimodal Approaches to t h e T r e atm e n t of M i x e d Pa i n

What Is New? An Internet-based slides and audio archive from PAINWeek® 2015 National Conference.

Program Chair Oscar de Leon-Casasola, MD Professor of Anesthesiology and Medicine Senior Vice-Chair for Clinical Affairs School of Medicine and Biomedical Sciences University at Buffalo Chief, Pain Medicine and Professor of Oncology Roswell Park Cancer Institute Buffalo, New York

Credits Available Physicians – maximum of 1.0 AMA PRA Category 1 Credit(s)™ Nurses – maximum of 1.0 contact hour Pharmacists – maximum of 1.0 contact hour (0.1 CEU)

This activity is neither sponsored by nor endorsed by PAINWeek®.

To access this free CE/CME Internet-based activity, visit:

www.PAINWeek.org/mixed-pain

Jointly provided by Postgraduate Institute for Medicine and Miller Medical Communications, LLC.

This activity is supported by an independent educational grant from Depomed, Inc.

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with

Joseph V. Pergolizzi MD

Joseph Pergolizzi is Adjunct Assistant Professor at Johns Hopkins University School of Medicine in Baltimore, Maryland, and Senior Partner and Director of Research at Naples Anesthesia and Pain Associates in Naples, Florida.

66 | PWJ | www.painweek.org

Q2 | 2016

“Many people think that pain is just a natural part of life.

I never saw pain as acceptable.”

What inspired you to become a healthcare provider?

I sought a career that would allow me to make a positive difference in the lives of as many people as possible. Despite the challenges facing physicians, in my opinion it is still—by far—the greatest career a man or woman could have. We are starting to make major breakthroughs in our understanding and treatment of pain, and I am very glad to be in medicine at this time in history. I cannot image a greater benefit to humanity than being able to control pain.

Why did you focus on addiction and pain management?

Pain is one of the last frontiers in modern medicine.

Even before I was a physician, I noticed that our society does not really take pain very seriously as a medical condition. Many people think that pain is just a natural part of life. I never saw pain as acceptable. I view pain as a physiological and psychological response to stimuli, and it is something that we can manage the better we can understand it.

Today, in my practice, I sometimes meet people who have been suffering moderate to severe life-altering pain syndromes without a diagnosis and without adequate pain treatment. Some of them almost cry when they find a physician who believes them and their story about pain.

Who were your mentors?

I have been blessed by having people care about my well-being my entire life and I have tried to be just as magnanimous with my pedagogical endeavors.

Q2 | 2016

My list of mentors begins with my Dad, then my father-in law. Others include: Ed Benz, Myron Weisfeldt, Cathy De Angelis, and Marty Auster from Hopkins; Young Kim from Georgetown and NIH; Phil Balistreri from Georgetown; Robert Raffa from Temple University; May Chin from George Washington; Armando Sardi from St. Agnes; Michael Bloomberg, Pedro Granadillo and Edmundo Muniz in business; Eugene Hollerand from St. Johns in Physical Chemistry.

I also consider myself to be mentored by my own religious faith in Christ. My faith is a key component in my life.

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

I would return to full-time academia to be a professor of medicine or pharmacy at a leading medical school. I enjoy teaching very much. I cannot imagine stepping away from healthcare! Pain is not taught as well as it could be in our medical schools.

Not all physicians graduating medical school today leave with the training or confidence to deal with moderate to severe pain.

What is your most marked characteristic?

High energy and the desire to engage people in advancing healthcare. I have great enthusiasm for the many medical breakthroughs we are seeing today. We are seeing a shift toward greater patient empowerment and changes in how healthcare resources are distributed. We know so much about genetics that personalized medicine seems around the corner. These are the things that make me glad to get up and go to work on Monday!

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PUNDIT PROFILE/JOSEPH PERGOLIZZI

“I think my goal in life has always been to have a legacy, to have a portion of my personality, my vision, and my work stretch forward to benefit others.”

What do you consider your greatest achievement?

My achievements are my foundations: my family, my clinical research organization (NEMA), my publications, my role at PAINWeek, and my Johns Hopkins affiliation. These are all things that reach into the future.

I think my goal in life has always been to have a legacy, to have a portion of my personality, my vision, and my work stretch forward to benefit others. I would like to think that generations from now, some of what I have done will matter. That’s why medicine is such a vital part of my life and why I care so deeply about solving the ancient problem of unrelieved pain.

What is your favorite language?

English with a few Italian words thrown in. Is Brooklynese a language?

If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be?

and of itself. I can tell you what I would not want to take: 2001: A Space Odyssey, any Stephen King novel, and any hip-hop music. Those things would disturb my space travel!

What would you like your legacy to be?

Like any father, I think my greatest legacy is my family. My children are my most important achievement, my greatest legacy, and my one true source of pride. I have three wonderful children who I know will make a positive and powerful impact on their generation.

Professionally, I would like my legacy to be a greater understanding of chronic pain and how to treat it.

Chronic pain is truly a silent epidemic. I want to be the voice of the chronic pain patient and the physician who is working with others to solve this terrible problem.

What is your motto?

Success is not final, failure is not fatal: it is the courage to continue that counts. (Winston Churchill)

I would take Stephen Hawking’s A Brief History of Time; Forest Gump and The Godfather Trilogy; and The Beatles White Album. These are things you can revisit over and over. If I could add a TV series, I would take The Wire.

(I’m probably overpacking!)

I think if I was in outer space for a prolonged period of time, the journey would be pretty entertaining in

68 | PWJ | www.painweek.org

Q2 | 2016

GRALISE® (gabapentin) tablets Rx Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use GRALISE safely and effectively. See full Prescribing Information for GRALISE. INDICATIONS AND USAGE • GRALISE is indicated for the management of postherpetic neuralgia.

• GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

DOSAGE AND ADMINISTRATION • GRALISE should be titrated to an 1800 mg dose taken orally, once-daily, with the evening meal.

GRALISE tablets should be swallowed whole. Do not crush, split, or chew the tablets. For recommended titration schedule, see DOSAGE AND ADMINISTRATION in full Prescribing Information.

• If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber).

• Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 mL/min or in patients on hemodialysis.

CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.

WARNINGS AND PRECAUTIONS GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

The safety and effectiveness of GRALISE in patients with epilepsy has not been studied.

Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Table 1: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in GRALISE) in the Pooled Analysis

Indication Epilepsy Psychiatric Other Total

Placebo Patients with Events Per 1000 Patients 1.0 5.7 1.0 2.4

Relative Risk: Risk Incidence of Difference: Events in Drug Additional Drug Patients Patients/Incidence Drug Patients with Events Per in Placebo with Events Per 1000 Patients Patients 1000 Patients 3.4 3.5 2.4 8.5 1.5 2.9 1.8 1.9 0.9 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed, are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that GRALISE contains gabapentin, which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber).

Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown.

In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and pre-existing tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions.

In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness.

Table 2: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group) Body System – Preferred Term Ear and Labyrinth Disorders Vertigo Gastrointestinal Disorders Diarrhea Dry mouth Constipation Dyspepsia General Disorders Peripheral edema Pain Infections and Infestations Nasopharyngitis Urinary tract infection Investigations Weight increased Musculoskeletal and Connective Tissue Disorders Pain in extremity Back pain Nervous System Disorders Dizziness Somnolence Headache Lethargy

GRALISE N = 359 %

Placebo N = 364 %

1.4

0.5

3.3 2.8 1.4 1.4

2.7 1.4 0.3 0.8

3.9 1.1

0.3 0.5

2.5 1.7

2.2 0.5

1.9

0.5

1.9 1.7

0.5 1.1

10.9 4.5 4.2 1.1

2.2 2.7 4.1 0.3

The following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis, viral herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection.

Postmarketing and Other Experience with Other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome.

Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain, and sweating.

DRUG INTERACTIONS In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day).

Hydrocodone Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of the interaction at other doses is not known.

Antacid (containing aluminum hydroxide and magnesium hydroxide) An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by approximately 20%, but by only 5% when gabapentin immediate release was taken 2 hours after the antacid. It is recommended that GRALISE be taken at least 2 hours following the antacid (containing aluminum hydroxide and magnesium hydroxide) administration.

Drug/Laboratory Test Interactions False positive readings were reported with the Ames-N-Multistix SG® dipstick test for urine protein when gabapentin was added to other antiepileptic drugs; therefore, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein.

USE IN SPECIFIC POPULATIONS Pregnancy Category C: GRALISE should be used during pregnancy or in women who are nursing only if the benefits clearly outweigh the risks. See full Prescribing Information for more information about use of GRALISE in pregnancy.

Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied.

Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age.

Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCl between 15 and 30 or in patients undergoing hemodialysis. [see Dosage and Administration in full Prescribing Information].

DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies.

OVERDOSAGE Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care.

Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

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

ONCE daily with EVENING MEAL

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

ONCE daily with

ONCE daily with

EVENING MEAL

EVENING MEAL

ONCE daily with

EVENING • Patients receiving GRALISE experienced significant pain reduction vs placebo beginning Week 1 and continuing MEAL throughout the 10-week study (P<0.05)2,3

•Average daily pain score reduction for GRALISE was -2.1 vs -1.6 with placebo (P=0.013)2 Study Design: Patients from 89 investigative sites participated in this randomized, double-blind, parallel design, placebo-controlled, multicenter clinical trial. The study period included a 1-week baseline period, followed by randomization and a 2-week titration to a once-daily dose of 1800 mg G-GR or matched placebo, followed by an 8-week maintenance-dose period, followed by a 1-week dose-tapering period. 452 patients were randomized, with 221 receiving 1800 mg of GRALISE and 231 receiving placebo.2 Primary endpoint: change in the baseline observation carried forward (BOCF) average daily pain score from the baseline week to Week 10 of the efficacy treatment period.2

Learn more today at www.Gralise.com INDICATIONS AND USAGE GRALISE is indicated for the management of postherpetic neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS The most common side effects were dizziness (10.9%) and somnolence (4.5%).

USE IN SPECIFIC POPULATIONS Reductions in GRALISE dose should be made in patients with age-related compromised renal function.

WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

For more information about GRALISE, please see Brief Summary on the following page.

References: 1. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012.

2. Sang CN, Sathyanarayana R, Sweeney M. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281-288.

3. Argoff CE, Chen C, Cowles VE. Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview. Expert Opin Drug Deliv. 2012;9:1147-1160.

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

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