PAINWeek Journal Vol. 4, Q4 by PAINWeek

vol. 4 q 4 2016

THE GENTLE ART OF SAYING NO: HOW TO ESTABLISH APPROPRIATE BOUNDARIES WITH PAIN PATIENTS P.18 THE ROLE OF SPECIAL K IN PAIN MANAGEMENT P. 26 THE ROLE OF THE ADVANCED PRACTICE PROVIDER IN THE ACUTE CARE SETTING P.3 6 STATE OF THE ART: PROLOTHERAPY REGENERATIVE MEDICINE P.44

TW O SOURCES

OF PAIN

O NE SOURCE OF RELIEF

NUCYNTA® ER is the first and only FDA-approved long-acting opioid designed to control both nociceptive pain and the neuropathic pain associated with diabetic peripheral neuropathy (DPN). NUCYNTA® ER is an opioid agonist indicated for the management of: • pain severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with DPN in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Not an actual patient.

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

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

TIME TO DUAL

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

COVERED FOR

94%

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

• Administer NUCYNTA® ER ~q12h3

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

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning. • NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3) • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) CONTRAINDICATIONS: Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (e.g., anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product; concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days. *Please see full Prescribing Information for DOSAGE AND ADMINISTRATION. †Some restrictions and limitations apply. See full terms and conditions available at NUCYNTA.com. Available to commercially insured and cash-paying patients only. Patients covered by Medicare, Medicaid, or any other federally funded benefit program are excluded. Patients must be 18 years of age or older. This promotion cannot be combined with any other programs, offers, or discounts. Depomed reserves the right to rescind, revoke, or amend this offer without further notice. ‡Data on file. Depomed, Inc. formulary data are sourced from MMIT. Transaction data are sourced from SHA Health. Data are current as of July, 2015. References: 1. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase Ill study. Expert Opin Pharmocother. 2010;11(11):17871804. 2. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151-162. 3. NUCYNTA® ER [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.

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

Use in Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients in the lower range of recommended doses. Closely monitor these patients, particularly when initiating and titrating NUCYNTA® ER and when given concomitantly with other drugs that depress respiration. Use in Patients With Chronic Pulmonary Disease: Patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, should be monitored for respiratory depression particularly when initiating therapy and titrating with NUCYNTA® ER. Consider the use of alternative nonopioid analgesics in these patients. Hypotensive Effect: May cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor for signs of hypotension during dose initiation or titration. Avoid use in patients with circulatory shock; may cause vasodilation that can further reduce cardiac output and blood pressure. Use in Patients With Head Injury or Increased Intracranial Pressure: Monitor patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Seizures: May aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures. Monitor patients with a history of seizure disorders for worsened seizure control during therapy. Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported with the concurrent use of NUCYNTA® ER and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system, and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,

tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. If concomitant treatment with SSRIs, SNRIs, TCAs, or triptans is clinically warranted, careful observation of the patient is advised, particularly when initiating or titrating the dose. Use in Patients With Gastrointestinal (GI) Conditions: Contraindicated in patients with Gl obstruction including paralytic ileus; may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Avoidance of Withdrawal: Withdrawal symptoms (e.g., anxiety, sweating, insomnia, restlessness, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection) may occur: • After abrupt discontinuation or a significant dose reduction of NUCYNTA® ER in physically dependent patients. When discontinuing NUCYNTA® ER, gradually taper the dose. • If mixed agonist/antagonist (e.g., butorphanol, nalbuphine, pentazocine) and partial agonist (e.g., buprenorphine) analgesics are used in patients who have received or are receiving NUCYNTA® ER. Avoid use with mixed agonists/ antagonists and partial agonists. • If opioid antagonists (e.g., naloxone, nalmefene) are administered in physically dependent patients. Administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. Driving and Operating Heavy Machinery: May impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA® ER and know how they will react to the medication. Hepatic Impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh Score 10 to 15). In patients with moderate hepatic impairment (Child-Pugh Score 7-9), initiate treatment with NUCYNTA® ER 50 mg no more than once every 24 hours, with a maximum dose of 100 mg per day. Monitor for respiratory and CNS depression when initiating and titrating NUCYNTA® ER. Renal Impairment: Use in patients with severe renal impairment (CLCR <30 mL/min) is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

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

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use NUCYNTA® ER safely and effectively. See full Prescribing Information for NUCYNTA® ER. INDICATIONS AND USAGE NUCYNTA® ER is indicated for the management of: • pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Usage • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA® ER for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • NUCYNTA® ER is not indicated as an as-needed (prn) analgesic. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning. • NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3) • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) CONTRAINDICATIONS Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (e.g., anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product; concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days. WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse: NUCYNTA® ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA® ER exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as NUCYNTA® ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA® ER and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA® ER, and monitor all patients receiving NUCYNTA® ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression).The potential for these risks should not, however, prevent the prescribing of NUCYNTA® ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as NUCYNTA® ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA® ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of NUCYNTA® ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death. Opioid agonists such as NUCYNTA® ER are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA® ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA® ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with NUCYNTA® ER and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA® ER are essential. Overestimating the NUCYNTA® ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA® ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Neonatal Opioid Withdrawal Syndrome: Prolonged use of NUCYNTA® ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Interactions with Central Nervous System Depressants: Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA® ER therapy. The co-ingestion of alcohol with NUCYNTA® ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin NUCYNTA® ER is made, start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant. Use in Elderly, Cachectic, and Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, closely monitor such patients, particularly when initiating and titrating NUCYNTA® ER and when NUCYNTA® ER is given concomitantly with other drugs that depress respiration. Use in Patients with Chronic Pulmonary Disease: Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with NUCYNTA® ER, as in these patients, even usual therapeutic doses of NUCYNTA® ER may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible. Hypotensive Effect: NUCYNTA® ER may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of NUCYNTA® ER. In patients with circulatory shock, NUCYNTA® ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA® ER in patients with circulatory shock. Use in Patients with Head Injury or Increased Intracranial Pressure: Monitor patients taking NUCYNTA® ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA® ER. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with ahead injury. Avoid the use of NUCYNTA® ER in patients with impaired consciousness or coma. Seizures: NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA® ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA® ER therapy. Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. Use in Patients with Gastrointestinal Conditions: NUCYNTA® ER is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Avoidance of Withdrawal: Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA® ER. In these patients, mixed agonists/antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing NUCYNTA® ER, gradually taper the dose. Driving and Operating Heavy Machinery: NUCYNTA® ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA® ER and know how they will react to the medication. Hepatic Impairment: A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA® ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA® ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA® ER. Renal Impairment: Use of NUCYNTA® ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interaction with Other CNS Depressants [see Warnings and Precautions (5.4)] • Hypotensive Effects [see Warnings and Precautions (5.7)] • Gastrointestinal Effects [see Warnings and Precautions (5.11)] • Seizures [see Warnings and Precautions (5.9)] • Serotonin Syndrome [see Warnings and Precautions (5.10)] Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The most common adverse reactions (reported by ≥10% in any NUCYNTA® ER dose group) were: nausea, constipation, dizziness, headache, and somnolence. The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA® ER dose group for NUCYNTA® ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively. Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The most commonly reported ADRs (incidence ≥ 10% in NUCYNTA® ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache. Postmarketing Experience: The following adverse reactions, not above, have been identified during post approval use of tapentadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Psychiatric disorders: hallucination, suicidal ideation, panic attack. Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA® ER. Advise patients how to recognize such reactions and when to seek medical attention. DRUG INTERACTIONS Alcohol: Concomitant use of alcohol with NUCYNTA® ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA® ER therapy. Monoamine Oxidase Inhibitors: NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events. CNS Depressants: The concomitant use of NUCYNTA® ER with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and NUCYNTA® ER for signs of respiratory depression, sedation and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced. Serotonergic Drugs: There have been post-marketing reports of serotonin syndrome with the concomitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when NUCYNTA® ER is coadministered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® ER with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Muscle Relaxants: Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than otherwise expected. Mixed Agonist/Antagonist Opioid Analgesics: Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonists (e.g., buprenorphine) may reduce the analgesic effect of NUCYNTA® ER or precipitate withdrawal symptoms. Avoid the use of mixed agonist/ antagonist analgesics in patients receiving NUCYNTA® ER. Anticholinergics: The use of NUCYNTA® ER with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. USE IN SPECIFIC POPULATIONS Pregnancy Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly. Teratogenic Effects - Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. NUCYNTA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Nursing Mothers: There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded. Because of the potential for adverse reactions in nursing infants from NUCYNTA® ER, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of

NUCYNTA® ER is stopped. Pediatric Use: The safety and efficacy of NUCYNTA® ER in pediatric patients less than 18 years of age have not been established. Geriatric Use: Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA® ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients. In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses. Renal Impairment: The safety and effectiveness of NUCYNTA® ER have not been established in patients with severe renal impairment (CLCR <30 mL/min). Use of NUCYNTA® ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known. Hepatic Impairment: Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The dose of NUCYNTA® ER should be reduced in patients with moderate hepatic impairment (Child-Pugh Score 7 to 9). Use of NUCYNTA® ER is not recommended in severe hepatic impairment (Child-Pugh Score 10 to 15). DRUG ABUSE AND DEPENDENCE Controlled Substance: NUCYNTA® ER contains tapentadol, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA® ER can be abused and is subject to misuse, addiction, and criminal diversion. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse and misuse. Abuse: All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. NUCYNTA® ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. NUCYNTA® ER should not be abruptly discontinued. If NUCYNTA® ER is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. OVERDOSAGE Clinical Presentation: Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. Treatment of Overdose: In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. Rx Only

EXECUTIVE EDITOR KEVIN

L. ZACHAROFF MD, FACPE, FACIP, FAAP

PUBLISHER PAINWeek, 6

Erie Street, Montclair, NJ 07042

ART DIRECTOR DARRYL

FOSSA

EDITORIAL DIRECTOR DEBRA EDITOR HOLLY

WEINER

CASTER

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

EDITORIAL BOARD

Steven D. Passik PhD Senior Medical Director Endo Pharmaceuticals Malvern, PA

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

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

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

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

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

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

Joseph V. Pergolizzi MD Adjunct Assistant Professor Johns Hopkins University School of Medicine Department of Medicine Baltimore, MD Senior Partner Naples Anesthesia and Pain Medicine Naples, FL

Jennifer Bolen JD Founder Legal Side of Pain Knoxville, TN

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

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

Bruce D. Nicholson MD Clinical Associate Professor Department of Anesthesia Penn State College of Medicine Hershey Medical Center Hershey, PA Director of Pain Specialists Lehigh Valley Health Network Department of Anesthesiology Allentown, PA

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

Marco Pappagallo MD Director of Medical Intelligence Grünenthal USA Bedminster, NJ Director Pain Management & Medical Mentoring New Medical Home for Chronic Pain New York, NY

Copyright © 2016, PAINWeek, a division of Tarsus Medical Group. The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff. PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises. All rights are reserved by PAINWeek to accept, reject, or modify any advertisement submitted for publication. It is the policy of PAINWeek to not endorse products. Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

8 | PWJ | www.painweek.org

Q4 | 2016

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

CONTENTS / PWJ / Q4 / 2016 12 | EXECUTIVE EDITOR’S LETTER by kevin l. Zacharoff

FEATURES

18 | BEHAVIORAL

THE GENTLE ART OF SAYING NO how to establish appropriate boundaries with pain patients by david Cosio

26 | PHARMACOTHERAPY

THE ROLE OF SPECIAL K IN PAIN MANAGEMENT by abigail Brooks / courtney Kominek

36 | ADVANCED PRACTICE PROVIDER

THE ROLE OF THE ADVANCED PRACTICE PROVIDER IN THE ACUTE CARE SETTING

44 | COMPLEMENTARY&ALTERNATIVE

state of the art PROLOTHERAPY REGENERATIVE MEDICINE by donna d. Alderman

SHORT CUTS

53 | CLINICAL PEARLS by doug Gourlay

54 | ONE-MINUTE CLINICIAN

with jennifer Bolen , matthew Foster , ted Jones ,

michael Weaver

55 | PAIN BY NUMBERS 56 | PUNDIT PROFILE with paul j. Christo

by theresa Mallick-Searle

10 | PWJ | www.painweek.org

Q4 | 2016

www.painweek.org

IN 2017 YOU CAN eXPeCT TO eXPeRieNCe 120+ HOURS OF COURSeS LiKe TH eSe:

KEVIN L.

ZACHAROFF MD, FACPE, FACIP, FAAP

S o much has happened this year in the world of chronic pain management. As usual, much attention and discussion has focused on safe and appropriate opioid prescribing. Indeed many debates were about that particular subject. It is therefore fitting to me that the spirit of this final PWJ issue of the year covers other important approaches to managing chronic pain.

research is needed, it’s important to know what options are available in certain refractory cases, and what the future hopefully holds for this patient population. I’m betting that ketamine in subanesthetic doses will be an important player in the future. As we near the doorstep of 2017, I’m sure we all need to think a bit more about the subject matter covered by Dr. David Cosio: the gentle art of saying “No.” As I have mentioned countless times in my lectures and articles, the patient-provider relationship is a critical piece of the healthcare puzzle, especially in the management of chronic pain. Dr. Cosio discusses the importance of the working alliance for all stakeholders and the responsibilities that everyone shares. Somehow in our culture, as I’m sure you all know, the prescription for medication has often become a sort of “trophy” for patients, with the prize being a prescription pain medication. In a highly illustrative manner, Dr. Cosio providers the reader with situations where the relationship is the key ingredient in a safe and effective pain treatment plan, not the medication. Theresa Mallick-Searle has written an article about two things we— and other pain related publications—probably don’t spend enough time featuring: acute pain and the role of advanced practice healthcare providers in its management. In true frontline practitioner fashion, Mallick-Searle presents a compassionate and cogent piece that focuses on just how important adequate management of acute pain is, especially in terms of the risk of developing chronic pain. I can personally guarantee this article is one of those keep-on-hand resources to help us think about the backstory to the undertreatment of pain, and its consequences. Lastly, but never least, is our Pundit Profile:Dr. Paul Christo. You will gain insight into some of the amazing things Dr. Christo has done to work towards the mission of “improving the lives of patients in pain through clinical care, education, and research.” No spoilers here— read the profile to see what remarkable clinicians like Dr. Christo do to contribute positively towards our profession and our patients.

Dr. Donna Alderman provides an in-depth and interesting look at prolotherapy and its potential utility for treating patients with common As we leave 2016 behind, and in the spirit of this particular issue of types of chronic pain related to musculoskeletal disorders and osteo- PWJ, let’s jointly make a commitment to heading towards the coming arthritis. There were two aspects of this article that I found highly year with one common goal—the patient. Safety, efficacy, responsicompelling. First and foremost, that approaches like prolotherapy, bility, compassion, and open minds regarding appropriate treatment along with other complementary and alternative treatments, are options are critical to achieving that commitment and goal. Have a likely going to become increasingly important for practitioners to happy and healthy New Year! consider when attempting to mitigate risks associated with other therapies. Secondly, and equally as important, is that therapies which — KEVIN L. ZACHAROFF help the body “heal itself” may indeed be keys to unlocking some of the challenges associated with chronic pain and its treatment. As an anesthesiologist, it gave me great pleasure to read the article by Drs. Abigail Brooks and Courtney Kominek about a medication very familiar to my specialty: ketamine, or “Special K.” The authors discuss its mechanism of action and potential role in helping to manage challenging and often intractable types of chronic pain, such as complex regional pain syndrome, cancer pain, and neuropathy. There are many sides to ketamine’s risks and benefits and although more

12 | PWJ | www.painweek.org

Kevin L. Zacharoff, MD, FACPE, FACIP, 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.

Q4 | 2016

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■ Donna D. Alderman DO

P.44

■ Abigail Brooks PHARMD, BCPS

P.26

■ David Cosio PHD

P.18

■ Theresa Mallick-Searle MS, RN-BC, ANP-BC

P.36

Donna Alderman is an expert in the field of musculoskeletal regenerative medicine. She is Board-Certified in prolotherapy and has been practicing this nonsurgical treatment for musculoskeletal pain since 1996. Dr. Alderman is Medical Director of the Hemwall Center for Orthopedic Regenerative Medicine, with two offices in California, and can be reached via her website www.prolotherapy.com.

Abigail Brooks is a Clinical Pharmacy Specialist in Pain Management, and Associate Director, PGY2 Pain & Palliative Care Pharmacy Residency Program at the West Palm Beach VA Medical Center in Florida. Dr. Brooks coauthored her article with Courtney Kominek, PharmD, BCPS, CPE, who is a Clinical Pharmacy Specialist in Pain Management at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

David Cosio is the psychologist in the Pain Clinic and the CARF-accredited, interdisciplinary pain program at the Jesse Brown VA Medical Center, in Chicago. He received his PhD from Ohio University, with a specialization in Health Psychology; completed a behavioral medicine internship at the University of Massachusetts-Amherst Mental Health Services; and a Primary Care/Specialty Clinic Post-doctoral Fellowship at the Edward Hines Jr. VA Hospital. Dr. Cosio has published several articles on health psychology, specifically in the area of patient pain education.

Theresa Mallick-Searle is an Adult Nurse Practitioner specializing in acute and chronic pain management at Stanford Health Care in the Department of Pain Medicine, Palo Alto, California. As part of her commitment to bringing awareness to the impact of unmanaged pain, she lectures nationally on topics surrounding both acute and chronic pain.

14 | PWJ | www.painweek.org

Q4 | 2016

“Meetings come to an end, but learning never stops. PWJ keeps you going all year long.”

— Michael R. Clark Md, mph, mba

ACCeSS PAiNWeeK 365 DAYS A YeAR PAINWeek® is an innovative single point of access designed specifically for frontline practitioners, recognized as a trusted resource for the latest pain management news, information, and education. →Visit www.painweek.org to access key opinion leader insights expressed via the following sections: ❶ Expert Opinion ❷ Key Topics ❸ One-Minute Clinician ❹ Pundit Profile ❺ PWJ—PAINWeek Journal

The gentle art of saying

How to establish appropriate boundaries with pain patients Cosio PHD

ByÂ DavidÂ

B HAViORAL

Boundaries are simply rules or limits that individuals create to identify reasonable, safe, and permissible ways for others to behave around them, and to determine how they’ll respond when someone oversteps these boundaries.1 It is apparent that pain management, in particular, requires appropriate boundary setting—by the practitioner, for the patient. This is crucial regardless of the treatment plan, in part because providers often find it hard to identify potential ruptures in their relationships with patients.2,3 And sometimes, what a patient may want may not be what they need, and the practitioner saying “No” may be the therapy. There is, however, a gentle art to saying “No.” abstract:

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Q4 | 2016

“

Patients who have rewarding relationships with their providers have better outcomes and are less likely to seek assistance from other sources, which in turn reduces the risk of conflicting treatment plans and further confusion.”

Since the beginning of the new millennium, the field of pain medicine has witnessed the pendulum of change. At first, national organizations were directing providers towards the use of opioid therapy in pain management. About 5 decades ago, governments around the world adopted the 1961 Single Convention on Narcotic Drugs which, in addition to addressing the control of illicit narcotics, obligated countries to work towards universal access to the narcotic drugs deemed necessary to alleviate pain and suffering. Henceforth, effective pain management was deemed “a right to health” according to international human rights law.4 As a consequence, patients believed they were entitled to opioids, and providers felt pressured to provide adequate treatment.5 As a result, this reinforced patient’s beliefs and sole reliance on medications for chronic pain management.6

Q4 | 2016

www.painweek.org | PWJ | 21

BEHAVIORAL

“

T oday, the health community and the general public

has witnessed how the sole reliance on narcotic medications has become an opioid epidemic.7 Politicians have even started acknowledging the need for additional substance use treatment centers in the United States to address the problem. Approximately 80% of opioids are consumed in the US alone, while most other countries do not rely as much on these medications for pain management. This overuse has led to an increase in prescription drug medication deaths, including some high profile individuals, such as Anna Nicole Smith, Heath Ledger, and Prince.8 In March 2016, the Centers for Disease Control released new guidelines about the use of opioid medications for chronic pain management in response to the crisis.9 This has caused a lot of frustration among providers, as well as patients who are seeking some relief from their chronic pain.

The Working Alliance In reality, the right to effective pain management comes with shared responsibilities between the patient and the provider.2 The benefits of building collaborations, or a “working alliance,” outweigh the challenges faced typically in the exam room. This concept originated from psychology in the 1990s,10 and has been validated by strong research support.11 Patients at times are deemed “difficult” due to personality conflicts, lack of trust, poor communication, cultural differences, severe mental health/addiction concerns, cognitive impairment, and/or concerns related to secondary gain. Providers may also have common failures, including using jargon, avoiding certain topics, making jokes, and acting like a police officer, judge, or deal-maker. The working alliance comes with some expectations: patients are expected to be open, honest, obedient, motivated, and gracious, while providers are projected to be competent, thoughtful, empathic, nonjudgmental, and good listeners.12,13 Remember, there are

22 | PWJ | www.painweek.org

…it is important to recognize that a boundary is not a threat or an attempt to control the behavior of others, and that setting appropriate limits will ultimately improve relationships with patients.”

no difficult patients, just patients with difficulties. Patients who have rewarding relationships with their providers have better outcomes and are less likely to seek assistance from other sources,11,14 which in turn reduces the risk of conflicting treatment plans and further confusion. The success of this working alliance often determines whether a patient will adopt self-management strategies.6 Essential elements of a healthy patient-provider relationship include compassion, clear expectations (or boundaries), adequate explanations on the provider side, and active participation and involvement in decision-making on the part of the patient.15 Increased emphasis on communication has been proposed as a way to improve the patient-provider relationship, and communication training for providers has been shown to be beneficial.14,15 There are 5 essential components to good communication: really listening, expressing empathy, being concise, asking questions and reflecting, and watching one’s body language.

Setting Boundaries Early on in my career, I worked with a young returning Veteran who had come to the pain clinic asking to have his opioids refilled. I remember discussing the risks and benefits of the opioid medication with him, and educated him about the comprehensive approach to pain management. The patient seemed receptive and nodded his head, which I interpreted as understanding and agreement. However, later that day I received a call from his private psychologist arguing with me about discouraging the use of his pain medications. The patient apparently did not agree with the treatment plan and had gone to him complaining of the care he received from our clinic. I had to re-educate that provider about this new approach and the need for him to provide a consistent message to the patient. The patient was appropriately weaned off the opiates in the pain clinic, but then he moved away to Q4 | 2016

another state and we lost contact. About a year later, I was [Name] “You are requesting a dose escalation for your opioid at a concert venue and this individual approached me and medication and are reporting a decrease in physical activity.” thanked me for what we had done for him. He admitted being addicted to the opioid medication at that time, and said [Express] “The role of these medications is to assist you in being we provided the boundaries for him to stop taking them— more active. The risks for these medications outweigh the benefits, boundaries he could not hold himself. and I do not see any reason to continue them.” Establishing appropriate boundaries is a skill that requires a lot of thought and practice. Yet many providers have learned little about it in medical school or clinical training. Ask yourself, “Is it hard for me to say no? Do I take on patients’ problems or pain? Am I unable to tell people what I want, need, or feel?” If you said “Yes” to any of those inquiries, then you may have some difficulties setting boundaries. To master this skill, it is important to recognize that a boundary is not a threat or an attempt to control the behavior of others, and that setting appropriate limits will ultimately improve relationships with patients. There are 4 steps involved in setting appropriate boundaries16:

[Decide] “I would like you to complete this assessment tool.” [The screener indicates the patient is at high risk and may need additional monitoring or may not be a good candidate for opioid therapy.] “The plan then will be to titrate the opioid down unless you begin increasing your current level of exercise.” [Validate] “In addition, I am going to refer you to physical therapy for an assessment and will possibly add that treatment to your current pain management plan.”

eXPeRieNCe #2

boundaries is important work and that your rights are important

A pain care agreement, signed by both you and the patient, helps patients understand the provider’s expectations, the short-term nature of opioid therapy, the risks that may be incurred, and the way various scenarios will be handled. For example, a pain care agreement might outline how lost or stolen opioids, requests for early refills, noncompliance with scheduled appointments, and other aberrant behaviors (eg, diversion, doctor/pharmacy shopping, violence and threats) will be handled. As previously mentioned, it may also be useful to consult the prescription drug monitoring electronic database, which collects designated data on controlled substances dispensed within participating states.

These skills can best be illustrated by common experiences faced in pain clinics in the US, such as dealing with opioid therapy.17

Example #1: The patient comes to your clinic as a walk-in and is reporting someone has stolen their opioid medications. The patient has shown up without a copy of the police report. You could then say:

1 Name or describe the behavior that is unacceptable

2 Express what you need or expect from the patient 3 Decide what you will do if the patient does not respect the boundaries you’ve established

4 Validate your actions by recognizing that setting

[Name] “Today you came in as a walk-in and are reporting that someone has stolen your opioid medications.”

eXPeRieNCe #1

[Express] “You, as the patient, have a shared responsibility for the safety of these opioid medications.”

There are several tools providers may use, including opioid risk assessment tools, pain opioid agreements, random urine toxicology screens, state prescription monitoring programs, decision trees, and patient pain education. An opioid risk assessment tool, such as the Screener and Opioid Assessment for Patients with Pain, or SOAPP, can be used to determine the extent of monitoring required based on the patient’s relative risk for developing problems when placed on long-term opioid therapy.18

[Decide] “In accordance with the pain opioid agreement we both signed, I will not refill that prescription without a copy of the police report.”

Example: The patient presents with increasing pain complaints and requests for opioid dose increases while reporting he/she has decreased physical activity. There is no indication that opioid therapy is helpful per your assessment. You could say: Q4 | 2016

[Validate] “In addition, with your permission, I plan to consult the state prescription monitoring database.” Example #2: The patient urgently calls you reporting an increase in their pain and then shows up to your clinic for an unscheduled appointment asking for an early refill. You could then say: [Name] “Today you have shown up without a scheduled appointment reporting an increase in your pain.” www.painweek.org | PWJ | 23

BEHAVIORAL

[Express] “If the pain is emergent, you should seek treatment in an emergency department or urgent care clinic.” [Decide] “As outlined in the pain opioid agreement we both signed, unscheduled visits are not to be used for opioid refills or escalations.”

[Decide] “I need to see your medication bottles in order to conduct a pill count. I also would like for you to have a urine tox screen. Is it okay if I speak to your family about whether they have noticed your sleepiness since taking this medication?”

[Validate] “As my patient, you deserve to have a full visit and I encourage you to schedule a follow-up appointment.”

[Validate] [The urine tox screen comes back positive for an illicit substance and there may be safety concerns.] “I would also like to consult with specialists in addiction services about your case or refer you to the emergency department.”

eXPeRieNCe #3

eXPeRieNCe #4

A urine toxicology screen should be obtained regularly from all chronic pain patients. If a patient tests positive for an illicit substance (eg, cocaine, heroin, amphetamines, prescription medications not prescribed), then a face-to-face discussion outlining the conditions that must be met in order to initiate or continue opioid therapy is crucial.

Although there are complex guidelines for the management of opioid therapy, simplified support tools, or “decision trees,” can guide providers through difficult discussions and assist in determining a course of treatment for chronic pain patients.19 Using these tools will present an opportunity for providers to educate patients about the range of nonopioid pain management strategies that are available, attempt to integrate patient preferences, and encourage joint decision-making. It may also be helpful to expand the conversation to include treatment outcomes that do not focus solely on the reduction or control of pain but also on effective functioning within the context of continued pain.11

Example #1: You ordered a urine toxicology screen during your patient’s last visit and it comes back either negative for a substance you are prescribing or positive for a substance you did not prescribe. You could then say: [Name] “The results from your last urine tox screen indicate that you are either not following your prescription and/or using illicit substances/nonprescribed medications.” [Express] “I am concerned about you and the safety of the community. These medications are controlled substances and need to be restricted. Would you consider seeking addiction services to address your use of [insert illicit substance/nonprescribed medication name here]?” [Decide] “Would you agree to me conducting another urine tox screen today?” [After the urine tox returns with the same result.] “This is the second time this has occurred, and I will not be refilling the opioid medication again.” [Validate] “There is a concern that you may be diverting, sharing, or self-escalating your dose of your medications.” Example #2: The patient comes to your visit appearing intoxicated or somnolent/ overmedicated. He/she also continues to report taking his/her opiates as prescribed. You could then say: [Name] “I am concerned that the medications I prescribed for you may be causing some sedation. Are you using more than I prescribed or have you used any illicit substances today?” [Express] “I am concerned about your safety as the patient and the safety of the community. The opioid medication I am prescribing is a controlled substance and we are both committed to making sure you are taking them responsibly.”

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Example: The patient is upset and making suicidal/homicidal threats after being told opiate therapy is being discontinued at this time. You could then say: [Name] “It is my understanding that you are making threats to yourself [or someone else].” [Express] “I am concerned about your safety [or the safety of the specified individual or the community at large].” [Decide] “I have a duty to warn, so I am going to page a psychologist [or call the police for assistance or escort you to the emergency department].” [Validate] “I am also planning to consult with the other providers on the pain clinic team about your case.”

Maximizing Safety/Minimizing Risk Especially in cases involving opioid therapy, it is important to establish boundaries early on, be consistent with your message, document the restrictions made, use policy and procedures as backup, review the pain opioid agreement, and use other tools available. The most common concern expressed by providers working in chronic pain management is how to handle patient refusals. It is important to Q4 | 2016

remember that it is the patient’s decision and right, and that they need to take responsibility for their choices. Providers should avoid making decisions based on emotions instead of facts. Providers are not obligated to provide opioid therapy, but are obligated to provide the best level of clinical care as outlined by the 1961 Single Convention on Narcotic Drugs. The goal for providers should always be to maximize safety and minimize risk for the patient and the community at large. Therefore, efforts should be shifted from simply rejection to redirection—pointing people in a healthier direction. Providers are in the best position to educate and coach patients who suffer from chronic pain about all the different types of nonopioid treatments available for pain management. Essentially, providers are trying to put pain management back into the patient’s hands. There are 4 general classifications to these treatments:

1 Traditional medical treatments: nonopioid

medications, injections/procedures, recreation, and physical medicine and rehabilitation

2 Psychological interventions: hypnosis, biofeed-

back, cognitive behavioral therapies, and mindfulness based therapies

3 Complementary and alternative medicine modalities: acupuncture, relaxation, spinal manipulation, healing touch, and massage therapy

4 Adjustment to lifestyle imbalances caused by

the pain: nutrition, sleep hygiene, mental health, physical activity, weight gain, sexual health, vocational rehabilitation, and spiritual needs

medicine: a rational approach to the treatment of chronic pain. Pain Med. 2005;6:107–112. 4. Hall J, Boswell M. Ethics, law, and pain management as a patient right. Pain Physician. 2009;12:499–506. 5. Zgierska A, Miller M, Rabago D. Patient satisfaction, prescription drug abuse, and potential unintended consequences. JAMA . 2012;307:1377–1378. 6. Dorflinger L, Kerns R, Auerbach S. Providers’ roles in enhancing patients’ adherence to pain self management. Transl Behav Med. 2013;3:39–46. 7. Centers for Disease Control and Prevention. Drug overdose in the United States: fact sheet. 2013. Available at: www.cdc.gov/ homeandrecreationalsafety/overdose/facts.html. 8. Ives T, Chelminski P, Hammett-Stabler C, et al. Predictors of opioid misuse in patients with chronic pain: a prospective cohort study. BMC Health Serv Res. 2006;6:46. 9. Centers for Disease Control and Prevention. Guideline for prescribing opioids for chronic pain— United States 2016. Recommendations and Reports. 2016;65(1):1–49. 10. Bordin E. The generalizability of the psychoanalytic concept of the working alliance. Psychother Theory Res Pract. 1979;16:252–260. 11. Vowles K, Thompson M. The patient-provider relationship in chronic pain. Curr Pain Headache Rep. 2012;16:133–138. 12. Bergman A, Matthias M, Coffing J, et al. Contrasting tensions between patients and PCPs in chronic pain management: a qualitative study. Pain Med. 2013;14:1689–1697. 13. Gulbrandsen P, Madsen H, Benth J, et al. Health care providers communicate less well with patients with chronic low back pain: a study of encounters at a back pain clinic in Denmark. Pain. 2010;150:458–461. 14. Frantsve L, Kerns R. Patient-provider interactions in the management of chronic pain: Current findings within the context of shared medical decision making. Pain Med. 2007; 8:25–35. 15. Street R, Makoul G, Arora N, et al. How does communication heal? Pathways linking clinician-patient communication to health outcomes. Patient Educ Couns. 2009;74:295–301. 16. Setting personal boundaries. Learning and Violence. Available at: www.learningandviolence.net/violence/disclosure/boundaries.pdf.

Conclusion Clinical trials have indicated the comparable efficacy of the treatments mentioned above.20 Overall, the current evidence provides little support for choosing one treatment approach over another. The provider and the patient have to determine what’s best for the patient. It’s important to note that using these other options as opposed to opioid therapy is better for everybody—the patient, the provider, and the community at large. Remember, saying “No” to opioid therapy remains one of those options.

17. Robeck I. Introduction: it’s never too late to start all over again. Available at: www.painedu.org/articles_timely.asp?ArticleNumber=50. 18. Inflexxion. Screener and Opioid Assessment for Patients with Pain (SOAPP). Available at: www.pain.edu.org/soapp.asp. 19. Cosio D. How to set boundaries with chronic pain patients. J Fam Pract. 2014;63:S3-S8. 20. Keller A, Hayden J, Bombardier C, et al. Effect sizes of non-surgical treatments of non-specific low-back pain. Euro Spine J. 2007;16:1776–1788.

References 1. Walters G. Boundaries. Out of the Fog. Available at: outofthefog.net/ CommonNonBehaviors/Boundaries.html. 2. Gourlay DL , Heit HA . Pain and addiction: Managing risk through comprehensive care. J Addict Dis. 2008;27:23–30. 3. Gourlay DL , Heit HA , Almahrezi A. Universal precautions in pain

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www.painweek.org | PWJ | 25

the role of

special

in pain management

Brooks PHarmD, bcps Courtney Kominek PHARMD, BCPS, CPE

By Abigail

Special K refers to one of the many street names for ketamine when used illicitly via various routes for its dissociative and hallucinatory effects.

PHARMACOTH RAPY

abstract: Ketamine, known on the street as “special K,” is a dissociative anesthetic with hallucinogenic properties and is classified as a controlled substance. Its unique mechanism as an N-methyl-D-aspartate (NMDA) receptor antagonist is thought to be responsible for many of the drug’s most promising properties. Stimulation of the NMDA receptor results in central sensitization (wind up phenomenon), hyperalgesia, reduced sensitivity to opioids, and the development of opioid tolerance. This can result in allodynia, hyperalgesia, and prolonged pain response. Ketamine partially reverses the previously mentioned complications that can restore the effectiveness of opioids in various settings and often allows for reduced opioid doses and improved pain control. With appropriate clinical knowledge and patient monitoring, ketamine at subanesthetic doses can play a role in the treatment of complex regional pain syndrome (CRPS), cancer pain, and even neuropathic or chronic pain refractory to typical treatment options. Depending on the clinical setting, ketamine can be administered via intravenous (IV ) or oral (PO) routes, among others. Clinical monitoring is required to ensure that side effects, such as dysphoria, do not adversely impact the patient.

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With appropriate clinical knowledge and patient monitoring, ketamine at subanesthetic doses can play a role in the treatment of complex regional pain syndrome, cancer pain, and even neuropathic or chronic pain refractory to typical treatment options.

INTRODUCTION

Also, ketamine activates the descending pain pathway.1 Ketamine, an anesthetic structurally related to phencycli- Dopamine and serotonin reuptake are inhibited, and there dine (PCP), is a Schedule III controlled substance, according are increased levels of epinephrine and norepinephrine.3 to the Controlled Substances Act, that has both licit and The anti-inflammatory effects of ketamine are unclear and illicit uses.1,2 Special K refers to one of the many street names additional studies are needed on the potential anti-tumor for ketamine when used illicitly via various routes for its effects of ketamine.6 Table 1 lists some of the proposed indidissociative and hallucinatory effects.2 In addition to its dis- cations for the use of ketamine, including several nonpain sociative anesthetic properties, ketamine also has analgesic, related conditions.1 sedative, and amnesic characteristics.2,3 Anesthetic doses of ketamine range from 0.5 to 4.5 mg/kg/h while subanesthetic doses are generally in the range of 0.1 to 0.3 mg/kg/h.4 This article reviews the use of ketamine at subanesthetic doses in CONTRAINDICATIONS pain management, as presented at PAINWeek 2016. There are some situations in which ketamine is contraindicated. Absolute contraindications include uncontrolled seizure disorder, severe symptoms related to increased intracranial pressure, active psychosis, or previous adverse reacMECHANISM OF ACTION tion to ketamine. Uncontrolled hypertension, congestive Though ketamine interacts with multiple receptors in heart failure, recent stroke, severe neurologic impairment, the central and peripheral nervous systems, ketamine’s and a history of psychosis are relative contraindications.4,8 primary mechanism of action is through noncompetitive NMDA receptor antagonism. This reduces the release of the excitatory neurotransmitter, glutamate, involved in afferent pain transmission.5 It is through the antagonistic ROUTES OF effects on NMDA receptors that ketamine is thought ADMINISTRATION to reverse hyperalgesia, opioid tolerance, and central Several routes are available for the administration of ketsensitization.3,6 amine including IV, PO, intramuscular ( IM ), subcutaneous (subQ), intranasal, and topical.7,9 Typically, the IM route In addition, ketamine binds to mu-, kappa-, and delta-opioid is discouraged for pain management due to the discomfort receptors. Hirota et al 1996 suggested that ketamine is a associated with the injection. The subQ route can be irritatmu-opioid receptor antagonist and a kappa-opioid receptor ing and require frequent rotation of injection sites.3,8 There agonist.5 Later in 2011 Hirota et al proposed that ketamine is no oral formulation available, so the injectable formulation is a mu-opioid receptor antagonist and a kappa-receptor is used orally.3,7 This has a bitter taste so it is usually mixed antagonist at anesthetic doses.6 However, others classify with juice, soda, or gelatin.3,7 Preservative induced neurotoxketamine as a mu-opioid receptor agonist.7 The analgesic icity can occur with intrathecal administration, and as the effect of ketamine is stereoselective with the S(+)-enantio- preservative-free formulation is not available in the United mer yielding more analgesia than the R(-)-enantiomer.6 States, intrathecal administration should be avoided.7,9

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PHARMACOTHERAPY

Table 1. Proposed Indications for Ketamine1 Opioid induced hyperalgesia Complex regional pain syndrome Neuropathic pain Posttraumatic stress disorder Migraine headaches Depression Trauma pain Anxiety Malignant pain Burn pain Opioid refractory pain Bipolar depression Chronic pain Abdominal pain Hospice Fibromyalgia Postoperative pain

PHARMACOKINETICS

There is a significant hepatic first pass effect with oral administration of ketamine leading to delayed and incomplete absorption.7 Due to its high lipid solubility, ketamine rapidly crosses the blood brain barrier.1,3 When injectable formulation is given orally, the onset of effect is 30 minutes, duration of action is 4 to 6 hours, and half-life is 3 hours.10 The half-life of IV ketamine is 2 to 3 hours with a duration of analgesia of about 2 to 6 hours.3 With long-term infusions of ketamine, the duration of infusion determines the half-life, with an estimated half-life of 11 days in complex regional pain syndrome Type 1 patients.1 Ketamine is metabolized through cytochrome P450 (CYP) 2B6, CYP2C9, and CYP3A4 via N-demethylation to norketamine, an active metabolite, with one-third the analgesic potency of its parent.1 Elimination occurs through the kidney and bile.1

effects—such as auditory hallucinations, paranoia, anxiety, inability to control thoughts, derealization in time and space, and increased awareness of sound and color—are dose related though may occur at even low doses used for pain.1,3 With the discontinuation of ketamine, the psychomimetic effects quickly disappear.1 Ketamine may also contribute to memory and cognitive impairment that typically resolves with short-term use though data with long-term use is not available.1 Cardiovascular effects are another concern with ketamine use. Low dose ketamine leads to cardiac stimulation mostly through sympathetic nervous system activation. Tachycardia, systemic or pulmonary hypertension, increased cardiac output, and increased myocardial oxygen consumption may ensue. Therefore, monitoring of vitals is essential when administering low dose ketamine for pain.1

Hepatic effects involve elevation in the liver enzyme profile including alanine transaminase, alkaline phosphatase, ADVERSE EFFECTS aspartate transaminase, and gamma-glutamyl transferase. The adverse effects of ketamine fall into 3 main groups: The risk of hepatotoxicity increases with prolonged or central nervous system (CNS), cardiovascular, and hepatic.1 repeated exposures to ketamine in a short period of time. CNS effects include psychomimetic as well as dizziness, With cessation of ketamine, the liver enzyme profile typiblurred vision, nightmares, and others. Psychomimetic cally normalizes within 3 months.1

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Table 2. Example Patient Monitoring Parameters* Fitzgibbons 20054

Heart Rate

Blood Pressure

Respiratory Rate

»» Monitor 30 minutes after initial dose and each dose increase

Monitor 30 minutes after initial dose and each dose increase

»» Subsequent monitoring every 4 hours or as clinically required

»» Subsequent monitoring as clinically required

National Health Service, »» Check baseline pulse Scotland »» Check 1 hour after first dose 20138 »» Check 24 hours after first dose

»» Check baseline BP »» Check 1 hour after first dose

If RR decreases to 10 breaths/ minute, inform provider

»» Check 24 hours after first dose

»» Check daily

»» If pulse increases to ≥20 bpm or >100 bpm, inform provider

»» If BP increases ≥20 mm Hg above baseline, notify provider *Monitoring parameters vary depending on the protocol

Monitoring parameters vary depending on the protocol. Association for the Study of Pain ( IASP) has diagnostic criteTable 2 provides examples of the monitoring parameters of ria for CRPS that requires “the presence of initiating noxious 2 protocols.4,8 Adverse effects of ketamine can be managed event or cause of immobilization; continuing pain, allodynia, in various ways. To prevent opioid toxicity due to the res- or hyperalgesia, with which the pain is disproportionate to toration of opioid sensitivity, it is recommended to reduce any inciting event; evidence at some time of edema, changes opioid dose by 25% to 50% upon initiation of ketamine.3,4 in skin blood flow, or abnormal sudomotor activity in the CNS adverse effects can be managed with reducing the region of pain; and the diagnosis is excluded by the existence dose, slowing the titration of medication, or treatment of of conditions that would otherwise account for the degree symptoms.3 Benzodiazepines, antipsychotics, propofol, and of pain and dysfunction.”13 CRPS can be categorized into clonidine have been used to mitigate CNS adverse effects.1,3 Type 1 or Type 2 based on the absence or presence of clinical Cardiovascular effects are managed through ketamine dose signs of major peripheral nerve injury, respectively.12 The reduction.1 Budapest Criteria was developed to address limitations with the IASP CRPS diagnostic criteria; however, most of the The cost of a ketamine infusion can be substantial. Since literature discussed in this article utilizes the IASP CRPS ketamine is being used in an off-label fashion, patients are diagnostic criteria.14 generally paying out-of-pocket. Data from 2015 suggests a ketamine infusion can range in price from $400 to $1700 Sigtermans and colleagues15 conducted a randomized, per infusion.11 double-blind, placebo-controlled, parallel-group trial in 60 patients with CRPS -1 based on IASP criteria. Patients received either a 4.2-day IV infusion of low-dose S(+)-ketamine or placebo (normal saline). Ketamine was KETAMINE initiated at 1.2 mcg/kg/min and titrated based on tolerability AND COMPLEX REGIONAL and effect up to a maximum of 7.2 mcg/kg/min. The primary PAIN SYNDROME (CRPS) outcome was pain scores reported via numerical rating scale CRPS, previously known as reflex sympathetic dystrophy ( NRS) from 0 to 10 at baseline and weekly until week 12. (RSD), was first recognized in the American Civil War. It has Results showed that ketamine led to a statistically significant an incidence rate of 5.46 to 26.2 per 100,000 persons.12 The reduction (P<0.001) in pain compared to placebo during the hallmark of CRPS is central sensitization. The International 12-week study, but the significance was lost at week 12. There Q4 | 2016

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PHARMACOTHERAPY

was no statistically significant change in function with ketamine. Adverse effects were common, with 93% of ketamine patients compared to 17% of placebo patients experiencing psychomimetic effects. Nausea (63% ketamine vs 17% placebo), vomiting (47% vs 10%), and headache (37% vs 33%) were also reported. Only 2 patients discontinued the study due to psychomimetic effects.15

case reports, clinical experience, etc.] Examined research incorporated many different routes of administration, doses, and outcome measures. There were also variable inclusion and exclusion criteria. Other concerns with the literature were the relatively small sample sizes involved and large placebo response observed. Due to wide range in treatment duration and doses utilized, the authors were unable to comment on the most effective route or dose. There were also concerns with safety and tolerability because of the side effect profile. Overall, it was determined that evidence is inconclusive and only weak evidence exists for the use of ketamine in CRPS. Ketamine is not considered a first-line treatment option in CRPS.9 Further rigorous research is recommended.18

Another double-blind, randomized, placebo-controlled study was completed by Schwartzman and colleagues.16 The investigators planned to enroll 40 patients in the study. Enrollment was discontinued after 19 patients because an interim analysis showed little placebo effect and the researchers had increased experience and efficacy with higher doses of ketamine (50 mg/h). Patients were included if they had a diagnosis of CRPS based on IASP criteria. A 4-hour infusion for 10 days of low dose ketamine or placebo (normal saline) was administered to patients according to KETAMINE the following schedule: 5 days on, 2 days off, and 5 days AND MALIGNANT PAIN on. Ketamine was titrated up to a maximum 0.35 mg/kg/h. The National Comprehensive Cancer Network ( NCCN ) Patients also received midazolam and clonidine. Overall, guidelines reiterate that pain management is an essential there was statistically significant reductions in pain in the component of oncologic management and that adequate pain ketamine group compared to placebo (P<0.01), but there management positively contributes to quality of life improvewas no change in the level of activity when comparing pre- ment, most likely for both the patient and the patient’s loved and posttreatment values. There was a statistically signif- ones.19 Regarding the use of ketamine in malignant pain, the icant reduction in nighttime awakenings in the ketamine following studies and publications were highlighted during group compared to placebo (P<0.05). No patients in the the PAINWeek 2016 presentation. study reported agitation, blurred vision, or psychomimetic effects, but 6 of 19 patients experienced nausea, headache, The randomized, double-blind, placebo-controlled trial tiredness, or dysphoria (4/9 in ketamine group, 2/10 in pla- by Salas and colleagues20 investigated the use of ketamine cebo group).16 continuous IV infusion (CIVI ) in combination with morphine IV compared to placebo CIVI with morphine IV for Noppers and colleagues17 reported on drug induced liver the treatment of cancer pain refractory to standard opioids injury with ketamine treatment for CRPS -1 based on IASP (defined as pain score ≥4/10 after 24 hours of morphine criteria. There were 6 patients enrolled in the group who CIVI ). The patients (N=20; 11 ketamine, 9 placebo) were were to receive 100 hour infusions of S(+)-ketamine twice treated at a group of adult palliative care units in the south separated by 16 days. Ketamine was initiated at 1.2 mcg/ of France. Neither group had a predefined maximum dose kg/h and titrated to a maximum of 7.2 mcg/kg/h. All but for morphine IV; for ketamine treatment, therapy was inione patient in this group experienced a side effect, including tiated at 0.5 mg/kg/day then increased to 1 mg/kg/day after hypertension (n=1), psychotropic side effects (n=1), or hep- 24 hours if the pain score remained ≥1/10. Patients were atotoxicity (n=3). All patients affected with hepatotoxicity evaluated and reassessed at the following time points: ranreceived 2 exposures to ketamine within a 4-week interval. domization (baseline), at ketamine or placebo start time (T0), Within 2 months of ketamine treatment discontinuation, and at 2 hours (T1), 24 hours (T2), and 48 hours (T3) after liver enzymes normalized. Those who received ketamine T0. The primary outcome of the study was to assess the at longer intervals did not experience hepatotoxicity. These change in the pain score between baseline and T1 (2 hours findings support the regular monitoring of liver function after baseline evaluation). The results of the study found that with ketamine.17 self-reported pain scores did not differ significantly between the 2 groups, regardless of time points compared (T2 change A systematic review of ketamine for CRPS was performed by from T0, T3 change from T0). With the use of ketamine, Connolly and colleagues.9 Many more articles from level III morphine consumption did not decrease during the study evidence (n=13) and level IV evidence (n=21) were included period; in fact, morphine doses were not different between compared to level I evidence (n=6) and level II evidence (n=5) the ketamine and placebo groups. In addition, no difference because of the lack of availability in the literature. [Level I: was found between the groups in analgesic effect, tolerabilmeta-analysis or systematic reviews. Level II: ≥1 well-pow- ity, or patient satisfaction. Overall, the study authors were ered randomized, controlled trial(s). Level III: retrospective unable to conclude that a ketamine-morphine combination studies, open-label trials, pilot studies. Level IV: anecdotes, provides superior pain relief compared to morphine alone.20

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The Cochrane Review concluded that the current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for cancer pain and that more randomized controlled trials are needed to investigate its use.

In another randomized, double-blind, placebo-controlled colleagues7 identified a total of 5 randomized controlled study by Hardy and colleagues,21 study authors investigated trials, 6 prospective nonrandomized, uncontrolled trials, and the use of subQ ketamine for malignant pain refractory to 1 retrospective review investigating the use of ketamine in standard opioids and coadjuvants at predefined dose levels adults with cancer pain. While the review also included data (pain score ≥3/10). Over a 5-day time frame, ketamine vs on the use of ketamine in children, the presenters focused placebo (normal saline) was administered to the study patient on the adult data. In all, the various trials included a total population (N=187; 149 met definition of completion). Ket- of N=483 and, due to heterogeneity, direct comparison of amine was initiated at 100 mg/24 hours and titrated up to a trials was not feasible. The routes of administration for ketmaximum dose of 500 mg/24 hours; if 80% of study drug had amine included IV, PO, subQ, intrathecal, and sublingual; been delivered and average pain improved by ≥2 units with the authors identified recommended ketamine infusion dosno more than 4 breakthrough doses, the study drug dose ages ranging from 0.05 to 0.5 mg/kg/h ( IV or subQ). In remained the same. The primary outcome was clinically addition, recommended oral dosages of ketamine range from relevant improvement in pain—defined as reduction in pain 0.2 to 0.5 mg/kg 2 to 3 times per day with a maximum dose score by ≥2 points from baseline in the absence of more than of ketamine 50 mg PO three times a day for long-term use. 4 breakthrough doses of analgesia over prior 24 hours—at The authors also advised that intrathecal ketamine infusion the end of the 5-day study period. The final results found no should be avoided due to 2 case reports of spinal cord necrosis difference in outcome in study patients who met the defi- on autopsy. Limitations identified in the literature presented nition of completion, in the subgroup that received 5 days and reviewed include the small number of total studies, few of study drug, or when all participants with baseline pain blinded randomized controlled trials, small sample sizes, and scores were included. In fact, no significant difference was short duration of follow-up compared to the chronic nature noted with multiple analysis methods though the manuscript of the pain. Overall, the review concluded that ketamine did report a number-needed-to-treat ( NNT ) and a number- should be considered as an adjuvant for refractory cancer needed-to-harm ( NNH ). The subQ route of administration pain though also called for additional research.7 is not recommended, as evidenced by this study which found that injection site reactions were significantly more likely to occur in the ketamine group (P<0.001).21 In the 2012 update to the 2003 Cochrane Review of ketamine as an adjuvant to opioids for cancer pain, no new identified studies were included in the final review. Overall, the Cochrane Review concluded that the current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for cancer pain and that more randomized controlled trials are needed to investigate its use.22 In another systemic review and synthesis of the literature, Bredlau and Q4 | 2016

KETAMINE AND NEUROPATHIC PAIN

Neuropathic pain can be challenging to manage and treat as the cause can be related to an injury, such as spinal cord injury, or postsurgical, or due to a more chronic condition, such as poorly controlled diabetes or herpes zoster. The most complex patients can experience pain that is refractory to treatment with multimodal therapy and/or highdose opioids. A 5-year retrospective, nonrandomized study www.painweek.org | PWJ | 33

PHARMACOTHERAPY

The potential future for ketamine seems bright with possibility. conducted by Marchetti and colleagues23 investigated the use of ketamine for the treatment of refractory chronic pain conditions, including neuropathic pain that was postsurgical in nature or related to fibromyalgia or other miscellaneous conditions (60% of the study population, N=55 cases with 4 patients undergoing 2 separate treatments each). Ketamine was initiated via IV in the hospital and then converted to PO for continued use as an outpatient; however, with time, a simpler process was adopted. In the simpler process, patients were admitted for a 1-day hospitalization and IV ketamine infusion before conversion to PO route and others were simply started on PO ketamine as an outpatient. The maximum dose of PO ketamine that patients could titrate to was 3 mg/kg/day over the course of 1 to 3 months, and then patients were gradually tapered down to limit withdrawal symptoms from ketamine use. In patients prescribed opioids upon initiation of ketamine, the opioid daily dose was reduced. Several pieces of key information were tracked over the course of the study to categorize patients into 1 of 4 groups: effective (mean pain reduction ≥50% and/or quality of life significantly improved); partially effective (mean pain reduction 25% to 50%); opioid sparing only (mean pain reduction <25%, but opioid dose decreased by ≥30%); or failure (mean pain reduction ≤25%, quality of life not improved, and opioid dosage not decreased). Final results found PO ketamine to be effective in 44% of patients, partially effective in 20%, opioid sparing only in 14%, and completely ineffective or failure in 22%. Interestingly, patients without any opioid treatment during the ketamine challenge showed a 36% failure rate, whereas those receiving opioids showed only a 7% failure rate (P<0.02), suggesting that ketamine is an adjuvant to opioids rather than a stand-alone treatment. Most importantly, at the end of treatment when ketamine decreased pain intensity (P<0.05), those patients were more often working and less often off work,23 a unique finding as other studies did not necessarily report improvement in function in terms of work attendance.

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In a literature review for the pharmacologic treatment of neuropathic pain associated with spinal cord injury, 3 ketamine studies were briefly reviewed. Two of the studies used ketamine administered via IV in combination with another drug (gabapentin and alfentanil, respectively) while the third compared ketamine to lidocaine. In summary, ketamine was found to be effective for pain, though it is uncertain how long this analgesic response lasts. Further studies are needed.24 A less conventional use of ketamine is the topical application for neuropathic pain. Case reports on the use of topical ketamine for pain relief started being published in the 1990s, and efficacy is thought to be related to activity at glutamate receptors on peripheral nerve endings. A literature review published by Sawynok 25 identified both plain ketamine topical application as well as topical ketamine in combination with various other ingredients, including but not limited to amitriptyline, baclofen, lidocaine, clonidine, ketoprofen, and gabapentin. Topical ketamine products investigated ranged in concentration from 0.5% to 10%; while acute topical application of ketamine at these concentrations produced no detectable levels of ketamine or active metabolite in the plasma. There is no data after repeated doses and higher concentrations of ketamine.25 Though bypassing the potential side effects associated with systemic administration of ketamine, topical ketamine may be difficult to find at a local compounding pharmacy or may be cost prohibitive to the patient. Again, further research is needed to determine the most appropriate patient for topical ketamine application.

THE FUTURE OF SPECIAL K

Ketamine continues to be an area of interest and development in the clinical world, including but not limited to pain management. In particular, at least 2 pharmaceutical companies are studying and developing ketamine-like drugs. Janssen Pharmaceuticals is in late-stage trials of esketamine, Q4 | 2016

a ketamine variant which can be administered via nasal spray. This product was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration in 2013 for treatment-resistant depression and then again in 2016 for major depressive disorder with imminent risk of suicide.11,26 In addition, Naurex Inc., is currently working on GLYX-13, an IV glycine-site functional partial agonist (GFPA) selective modulator of the NMDA receptor that lacks ketamine’s dissociative side effects for treatment-resistant depression.11,27 As of September 2016, there were 172 studies that were open and not yet recruiting or open and actively recruiting investigating the use of ketamine.28 The potential future for ketamine seems bright with possibility.

10. Ketamine. Lexi-comp Online. Available at: online.lexi.com/lco/action/ home/switch?siteid=983. 11. Agres T. Anesthesiologists take lead as ketamine clinics proliferate. Anesthesiology News. December 2015. Available at: www.anesthesiologynews.com/PRN -/Article/12–15/Anesthesiologists-Take-Lead-AsKetamine-Clinics-Proliferate/34407/ses=ogst. 12. Bruehl S. Complex regional pain syndrome. BMJ . 2015 Jul 29;351:h2730. 13. Bruehl S, Harden RN, Galer BS, et al. External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. Pain. 1999;81:147–154. 14. Harden RN, Bruehl S, Perez RSGM , et al. Validation of proposed diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome. Pain. 2010;150(2):268–274. 15. Sigtermans MJ, van Hilten JJ, Bauer MCR , et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009;145:304–311.

CONCLUSION

Ketamine is a unique opioid with NMDA receptor antagonist activity that can be beneficial in the setting of opioid tolerance or opioid induced hyperalgesia. Ketamine administration has been investigated using various routes of administration, though most commonly studied for pain management is IV, PO, and topical. In the realm of pain management, ketamine is postulated to improve pain related to CRPS, certain types of malignant pain, intractable or treatment-resistant chronic nonmalignant pain, and neuropathic pain. At this time, more randomized, controlled trials are needed to study the potential benefits of ketamine at subanesthetic doses for pain management as well as determining the most appropriate route of administration and dosing with standardized monitoring protocol. References

1. Niesters M, Martinin C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2013;77(2):357–367. 2. Ketamine. Drug Enforcement Administration. Office of Diversion Control. Drug & Chemical Evaluation Section. Last updated 2013 Aug. 3. Pasero C. Ketamine: low doses may provide relief for some painful conditions. Amer J Nursing. 2005;105(4):60–64. 4. Fitzgibbons EJ, Viola R. Parenteral ketamine as an analgesic adjuvant for severe pain: development and retrospective audit of a protocol for a palliative care unit. J Palliat Med. 2005;8(1):49–57. 5. Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth.1996;77(4):441–444. 6. Hirota K, Lambert DG. Ketamine: new uses for an old drug? Br J Anaesth. 2011;107(2):123–126. 7. Bredlau AL , Thakur R, Korones DN, et al. Ketamine for pain in adults and children with cancer: as systematic review and synthesis of the literature. Pain Med. 2013;14:1505–1517. 8. National Health Service. Scotland Palliative Care Guidelines: Ketamine. Available at: www.palliativecareguidelines.scot.nhs.uk/ guidelines/medicine-information-sheets/ketamine.aspx. 9. Connolly SB . Prager JP, Harden N. A systematic review of ketamine for complex regional pain syndrome. Pain Med. 2015;16:943–969.

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16. Schwartzman RJ, Alexander GM , Grothusen JR , et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147:107–115. 17. Noppers IM , Niesters M, Aarts LPHJ . Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain. 2011;152:2173–2178. 18. Harden RN . Ketamine analgesia: a call for better science. Pain Med. 2012;13(2):145–147. 19. National Comprehensive Cancer Network ( NCCN) Clinical Practice Guidelines in Oncology Adult Cancer Pain Version 2.2016. Available at: www.nccn.org/professionals/physician_gls/f_guidelines.asp#pain. 20. Salas S, Frasca M, Planchet-Barraud B, et al. Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: Considerations about the clinical research in palliative care. J Palliat Med. 2012 Mar;15(3):287–293. 21. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol. 2012 Oct 10;30(29):3611–3617. 22. Bell RF, Eccleston C, Kalso EA . Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012 Nov 14;11:CD 003351. 23. Marchetti F, Coutaux A, Bellanger A, et al. Efficacy and safety of oral ketamine for the relief of intractable chronic pain: A retrospective 5-year study of 51 patients. Eur J Pain. 2015 Aug;19(7):984–993. 24. Hagen EM , Rekand T. Management of neuropathic pain associated with spinal cord injury. Eur J Pain. 2015 Aug;19(7):984–993. 25. Sawynok J. Topical and peripheral ketamine as an analgesic. Anesth Analg. 2014 Jul;119(1):170–178. 26. Johnson & Johnson, Products & Operating Company. Esketamine receives breakthrough therapy designation from U.S. Food and Drug Administration for major depressive disorder with imminent risk for suicide. Available at: www.jnj.com/news/all/Esketamine-Receives-Breakthrough-Therapy-Designation-from- US -Food-and-Drug-Administration-for-Major-Depressive-Disorder-with-Imminent-Risk-for-Suicide. Published 16 August 2016. 27. News Release from Behavioral Healthcare: Insight for Executives. Naurex initiates phase II trial of GLYX-13 antidepressant. Available at: www.behavioral.net/news-item/naurex-initiates-phase-ii-trial-glyx-13antidepressant. Published 8 July 2011. 28. ClinicalTrials.gov: A service of the U.S. National Institutes of Health. Available at: clinicaltrials.gov/ct2/results?term=ketamine&recr=Open& no_unk=Y&pg=5.

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Mallick-Searle ms, rn-bc, anp-bc

ByÂ TheresaÂ

In the United States, over 73 million surgical procedur

The role of

Mallick-Searle ms, rn-bc, anp-bc

ByÂ TheresaÂ

in the acute care setting

res are performed annually, and most patients report experiencing a high

ADVANC D PRACTiCe PROViD R

Millions of patients each year suffer from acute pain as a result of trauma, illness, or surgery, and pain is the most common reason for presentation to the emergency department.1 The prevalence of intense acute pain is similarly high among patients undergoing surgery: in the United States, over 73 million surgical procedures are performed annually, and most patients report experiencing a high degree of pain postoperatively.2 Studies indicate that treatment of acute pain remains suboptimal due to attitudes and educational barriers on the part of clinicians and patients, as well as the intrinsic limitations of available therapies.1 Inadequate management of acute pain negatively impacts numerous aspects of patient health and may increase the risk of developing chronic pain. This article reviews the role of the advanced practice provider in the acute care setting, focusing on the use of preemptive and multimodal analgesia; imparting an understanding of the importance of identifying patients at risk for poor outcomes regarding pain management in the acute care setting; and helping educate the clinician about tools available for improved pain management outcomes in the hospitalized patient. abstract:

degree of pain postoperatively”

To avoid [undermanaged pain], the advanced practice provider who delivers primary care to the patient in the acute setting…needs to have a general understanding of basic pain pathophysiology, pain pharmacology, and an appreciation for behavioral management as well as mind-body therapies.” There has been much emphasis, recognition, and education

on the public health issue surrounding undermanaged chronic pain in the United States.3 In addition, there has been much reported about the economic impact of undermanaged pain.4 What is less recognized or emphasized is the impact of undermanaged pain in the acute care setting. ¶ A landmark study of the impact of acute pain management in the hospitalized patient over a 10-year period revealed that improvement in pain management has not kept up with other advances in healthcare: reports of “any pain” and “extreme pain” were reported as higher.2 Pain continues to be a prevalent problem for medical and surgical inpatients.5,6 Additionally, Pletcher et al found in their research that 40% of the over 100 million emergency department (ED) visits annually are for acute pain.7

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ADVANCED PRACTICE PROVIDER

IN THe ACUTe CARe SeTTiNG

Research shows that patients who struggle with high catastrophizing, somatization, chronic pain, high opioid/ benzodiazepine use, poor coping, and poor social support are at increased risk for poor pain management when compared with their peers.8 Patients undergoing certain types of surgeries where there is a high risk of nerve damage or compromise, such as thoracotomy or amputation, are also at increased risk for higher levels of pain postoperatively, as well as the development of chronic pain.8

The reason for undermanaged pain in the acute care setting is multifactorial. To avoid it, the advanced practice provider (APP) who delivers primary care to the patient in the acute setting— OR , ICU, infusion center, medical/ surgical in-patient setting, ED —needs to have a general understanding of basic pain pathophysiology, pain pharmacology, and an appreciation for behavioral management as well as mind-body therapies. APPs working in trauma, oncology, palliative care, and surgery also need to have The setting of expectations and treatment goals begins in an awareness of regional analgesic techniques and thera- the clinic, and these goals should continue to be reviewed pies—a basic understanding of the peripheral and central throughout the acute care treatment period. Setting expecnervous system is necessary. What must be avoided is pro- tations up front reduces patient anxiety9 about “not being viders’ insufficient knowledge of pain pharmacology and heard” by the acute care team, reduces the possibility of other treatment options, fear of medication side effects, unmanaged pain, clarifies patient’s expectations and undernot setting expectations or discharge planning, and inad- standing about the acute care period, and gives the patient equate initial identification of patients at increased risk for an opportunity to discuss aftercare. poor outcomes. Communication must begin with the first provider to idenPreemptively, the APP who will deliver primary care to the tify patients at risk for poor pain management outcomes, patient planning a hospitalization or outpatient surgery, and and continue with all providers interacting with that the APP preparing the patient for the hospital course in patient during the course of the acute care experience. Prithe anesthesia pre-op clinics, and the APP working as part mary communication must include discussion of current of the surgical team or specialty medicine services (pul- medications that the patient is taking, including opioids, monary, oncology, transplant, etc) all have a role to play in benzodiazepines, and muscle relaxants; other adjuvant pain management. pain medications such as anticonvulsants and antidepressants; and use of other substances such as cannabinoids, Key aspects to ensuring superior outcomes at this phase ethyl alcohol, etc. Any primary mood disorders—such as in the process include identification of patients at risk for preexisting depression, anxiety, and substance abuse dispoorly managed pain; patient education, including review- orders—must be recognized and discussed. Paramount ing goals and setting expectations; and timely communica- in the communication hierarchy is the dialogue with the tion with anticipated members of the patient’s care. anesthesia provider in using advanced therapies such as IV

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infusions with lidocaine and/or ketamine for the patient The general goals of pain management in the acute care at increased risk for poorly managed postoperative pain.10 setting, first and foremost, include identifying the source The use of regional anesthetic techniques should be dis- and addressing the cause of pain. Acute pain should be mancussed as well.11 aged aggressively and in a thoughtful manner, to expedite discharge and, we hope, to reduce the incidence of persistent pain. Any intervention, be it pharmaceutical or procedural, IT’S JUST PAiN?! should aim to maintain alertness and functionality, along with minimizing side effects. Finally, the APP should aware Deleterious effects of unmanaged pain in the acute care of the sensory and affective component of pain, with an aim setting can impact a multitude of systems. Complications of reducing subjective suffering. may include: The development of treatment protocols for pain and symp●●Cardiovascular: tachycardia, decreased pulmonary tom management within particular specialty groups can vascular reserve, arrhythmias, myocardial infarction help expedite the process of treatment and reduce unnecfor susceptible patients essary suffering. Treatment protocols/guidelines can be helpful in many environments, including the ED.13-15 The ●●Pulmonary: splinting, atelectasis, infection intensive care unit, where the level of patient acuity and risk of delirium are high, is also well served by pain man●●Gastrointestinal: reduced motility, nausea, agement guidelines.16 Additionally, outside of the critical vomiting, ileus, obstruction setting and within the acute care hospital, pain management protocols and guidelines can also expedite care and ●●Renal: oliguria, urinary retention reduce suffering.17 ●●Coagulation abnormalities: altered platelet aggregation, venostasis, deep vein thrombosis/ pulmonary embolus ●●Psychological impacts: increased anxiety, fear, depression Additionally, undermanaged pain can lead to an overall delayed recovery, slower return to function, possible delayed hospital discharge, and increased cost.12 Q4 | 2016

DiSCHARGe PLANNiNG Discharge planning should begin along with the plan for admission. The APP arranging for inpatient radiation therapy for the oncology patient, for example, should have a plan for managing the patient’s increased pain posttreatment. The APP preparing the patient for a total joint replacement due to chronic osteoarthritis should have a plan for postsurgical pain management and for pain with physical therapy www.painweek.org | PWJ | 41

ADVANCED PRACTICE PROVIDER

Discharge planning should begin along with the plan for admission. The APP arranging for inpatient radiation therapy for the oncology patient, for example, should have a plan for managing the patient’s increased pain posttreatment.”

as the patient rehabilitates. The APP seeing the patient in ●●If a difficult discharge is anticipated, engage the ED or urgent care setting should help arrange for the case-management early in the admission. patient to be seen by their primary care provider. Pain is the most commonly reported reason for unanticipated admis- ●●Verify hospital follow up, preferably within 2 weeks sion or readmission.18 of discharge. Being asked to discharge a patient from an acute hospital- ●●Provide the patient with only enough discharge ization can be challenging for an APP. He or she may not medications (including opioids) to get to their have been involved in the day-to-day care of the patient, follow-up visit. Provide written instructions on any especially if there has not been adequate follow up arranged; new medication’s side effects, their safe use, and or if the patient has been started on new medications for contact information for questions. pain during the admission (that may or may not be covered by the patient’s insurance); or if the expectation is to provide the patient with a new opioid prescription or for a CONCLUSiONS much higher dose than the patient may have come into the hospital on. There should always be a good sign-out, which Millions of patients each year suffer from acute pain as a speaks to the importance of excellent communication with result of trauma, illness, or surgery. Even with the recognithe provider(s) who have been managing the patient’s care tion that undertreated pain remains a public health concern, most consistently during the admission. Hospital care-man- and that costs to the US healthcare budget are greater than agers can assist with disposition needs, some prescription most other chronic diseases combined, the management of insurance issues, and coordination of care. pain in the acute care setting still remains underemphasized. The management of pain in the acute care setting is the responsibility of all healthcare providers involved in that PeARLS OF WiSDOM patient’s care, from the decision to hospitalize the patient, to the acute care setting itself, and finally the aftercare that ●●Hospital discharges can be challenging on the may reduce the need for readmission. As advance practice weekends for all the above mentioned reasons. providers continue to provide the majority of the pre- and Aim for discharges during the week, preferably aftercare to these select patients, they are also providing an during business hours. increasing amount of the inpatient acute care as they join surgical specialty practices, working in anesthesia as primary providers and in the critical care settings of ICU and ED.

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Table. Nonopioid pain medications commonly used in the acute care setting Drug Class

Example/Typical Dosing

Major Considerations

Indication

Anticonvulsants

»» Gabapentin—300 to 1200 mg tid

Renally excreted

Neuropathic pain

»» Pregabalin—50 to 150 mg tid Antidepressants Muscle relaxants

»» Duloxetine—20 to 60 mg/day »» Desipramine—25 to 100 mg/day

Neuropathic pain/ comorbid depression

»» Baclofen—5 to 10 mg tid

Muscle spasm

»» Flexeril—5 to 10 mg tid NSAIDs

»» Celecoxib—100 to 200 mg qd-bid

Bleeding risk, renal considerations

Nociceptive pain

»» Ketorolac—10 mg oral q6h, 30 to 60 mg IV q6h Acetaminophen

n/a—1000 mg tid-qid; oral and IV dosing equivalent

Hepatic dosing; IV, oral, rectal administration

Nociceptive pain

Lidocaine

IV infusion—1 mg/kg/h

No oral equivalent; additionally beneficial when patient is NPO

Neuropathic pain

Melatonin receptor agonists

»» Melatonin—3 to 10 mg/evening »» Ramelteon—8 mg/night

References

anaesthesia. Cochrane Database Syst Rev. 2016 May 26;(5):CD 008646.

1. Sinatra R. Causes and consequences of in adequate management of acute pain. Pain Medicine. 2010;11(12):1859–1871.

10. Kranke P, Jokinen J, Pace NL , et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery. Cochrane Database Syst Rev. 2015 Jul 16;(7):CD 009642.

2. Apfelbaum JL , Chen C, Mehta SS, et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be unmanaged. Anesth Analg. 2003;97:534–540. 3. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington (DC ): National Academies Press (US); 2011. 4. Gaskin DJ, Richard P. The Economic Costs of Pain in the United States. In Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Washington (DC ): National Academies Press. 2011:301–338. 5. Helfand M, Freeman M. Assessment and management of acute pain in adult medical inpatients: a systematic review. Pain Med. 2009 Oct;10(7):1183–1199. 6. Kohler M, Chiu F, Gelber KM , et al. Pain management in critically ill patients: a review of multimodal treatment options. Pain Manag. 2016 Nov;6(6):591–602. 7. Pletcher MJ, Kertesz SG, Kohn MA , et al. Trends on opioid prescribing by race/ethnicity for patients seeking care in US emergency departments. JAMA . 2008;299:70–78. 8. Macintyre PE, Schug SA , Scott DA , et al, APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management: Scientific Evidence. 3rd ed. ANZCA & FPM , Melbourne; 2010. 9. Powell R, Scott NW, Manyande A, et al. Psychological preparation and postoperative outcomes for adults undergoing surgery under general

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Sleep difficulty

11. Curatolo M. Regional anesthesia in pain management. Curr Opin Anaesthesiol. 2016 Oct;29(5):614–619. 12. Joshi GP, Ogunnaike BO. Consequences of inadequate postoperative pain relief and chronic persistent postoperative pain. Anesthesiol Clin North Am. 2005 Mar;23(1):21–36. 13. Thomas SH . Management of pain in the emergency department. ISRN Emerg Med. 2013(2013);Article ID 583132:19 pages. 14. The American Academy of Emergency Medicine: Model Emergency Department Pain Treatment Guidelines. Available at: www.aaem.org/publications/news-releases/model-emergencydepartment-pain-treatment-guidelines. 15. Ohio State Recommendations: Implementing Prescribing Guidelines in the Emergency Department. Available at: www.healthy.ohio.gov/-/media/ HealthyOhio/ASSETS/Files/ED/ Implementing-Prescribing-Guidelines-in-the-Emergency-Department. pdf?la=en. 16. Hajiesmaeili MR , Safari S. Pain management in the intensive care unit: do we need special protocols? Anesth Pain Med. 2012 Spring;1(4):237–238. 17. Society of Hospital Medicine: improving pain management implementation guide. Available at: tools.hospitalmedicine.org/resource_rooms/ imp_guides/Pain_ Management/PainMgmt_Final3.4.15.pdf 18. Coley KC , Williams BA , DaPos SV, et al. Retrospective evaluation of unanticipated admission and readmissions after same day surgery and associated costs. J Clin Anesth 2002;14(5):349–353.

www.painweek.org | PWJ | 43

By Donna

D. Alderman do

abstract: Prolotherapy is a method of regenerative injection treatment that stimulates healing.1 This therapy has been in practice for decades in the treatment of musculoskeletal pain and osteoarthritis, and has evolved to include the use of platelet rich plasma (PRP) and autologous adult stem cell sources, such as bone marrow and adipose (fat) stem/stromal cells. Chronic musculoskeletal pain is the most common medical complaint in the United States, and one of the most common reasons for primary care visits.2 The American Academy of Orthopedic Surgeons estimates that 1 in 2 adults—126.6 million people—are affected by a musculoskeletal condition, comparable to the total percentage of Americans living with a chronic lung or heart condition, costing an estimated $213 billion in annual treatment, care and lost wages.3 Osteoarthritis (OA) is also a major health issue, and the most common joint disease, affecting millions of people in the United States.4 Typical medical recommendations for these conditions include prescription medications, which offer temporary relief but may have addiction potential or other unwanted side effects; cortisone, which sometimes helps but can have adverse effects on joints and joint tissue; hyaluronic acid joint injections, which are only temporary; physical therapy, osteopathic or chiropractic treatments, which may help, but not in every case; and of course surgery, which is not always indicated, has additional risk and may fail. In May 2016 Orthopedics Today reported a high incidence of pain 1 year after total knee replacement.5 Surgeons themselves are questioning whether surgery is always the best answer. A 2016 journal article compared surgery to other more conservative treatments for knee OA and concluded: “Surgery has historically been considered the final solution for treatment of knee osteoarthritis,” however, “there are increasing concerns regarding the lack of randomized controlled studies to support this opinion.”6 Therefore the need for a safe and effective nonsurgical treatment for musculoskeletal pain and OA is evident. Prolotherapy is low risk and has a high success rate. The newer, more biologic formulas, such as PRP and stem cell sources, allow treatment of more severe chronic as well as acute issues, while use of musculoskeletal ultrasound for diagnosis and injection guidance improves accuracy and precision.

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COMPLEMENTARY&ALT RNATiV

Prolotherapy has been in existence since the 1930s…

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rolotherapy has been in existence since the 1930s when Earl Gedney, DO, a general surgeon at the Philadelphia College of Osteopathic Medicine, caught his thumb in closing operating room doors, stretching and spraining it. After several months of pain and instability in that joint, he was told to just live with it and change professions. Dr. Gedney was not of the mindset to agree with this, so he started researching possible options. He knew of a common practice in those days of physician “herniologists.” These doctors treated hernias by injecting the stretched hernia connective tissue ring with an irritating solution, promoting closure of the defect. Dr. Gedney extrapolated his knowledge of nonsurgical hernia repair to the nonsurgical repair of joints, ligaments, and tendons. He concluded that ligament and tendon laxity (looseness) causes joint instability, leading to pain, and could be resolved by strengthening the joint connective tissue. Reasoning he had little to lose by being a guinea pig for this theory, he started injecting his thumb with these irritating solutions and had a dramatically successful result. Before long, he was back working as a surgeon. Excited about his result, he started on a lifelong career of research into this technique. In June 1937 he published the first known case report and journal article about the special technique,7 followed by a presentation at the February 1938 meeting of the Osteopathic Clinical Society of Philadelphia called The hypermobile joint further reports on injection method. —

A decade later another pioneer, George Hackett,

MD, coined the word “prolotherapy,” short for “proliferation therapy,” for its ability to stimulate repair and proliferation of new connective tissue at joint injury sites. Dr. Hackett went on to publish the first formal textbook on the subject in 1956.8 The medical community eventually agreed that joint instability and ligament laxity lead to pain and osteoarthritis, and in 1972, Lancet wrote that joint instability is a leading contributor not only to irregular biomechanics and pain, but Q4 | 2016

the subsequent development of OA .9 It is now well accepted that there is a significant association between joint injury, resulting joint instability, and then later OA .10 Prolotherapy is therefore an excellent treatment for OA because it not only addresses ligament injury and joint laxity, reducing instability and pain,11 but may also prevent further joint biomechanical damage and OA . Recent studies also show that all the various forms of prolotherapy have the potential to stimulate cartilage regeneration.12-14 www.painweek.org | PWJ | 47

COMPLEMENTARLY&ALTERNATIVE

Prolotherapy: which conditions?

Prolotherapy has traditionally been used for chronic injuries or pain, however it has come into use for treatment of acute injuries to stimulate faster, stronger healing. Common conditions treated15 are: →→Tendinitis/tendinosis, repetitive strain injuries, shoulder pain, rotator cuff tears →→Ligament sprains, other sports injuries →→Knee pain, meniscal tears, ligament tears →→Osteoarthritis and degenerative joint/ disc disease →→Low back pain, sacroiliac joint pain/ instability, sciatica →→Neck pain, whiplash, headache →→Elbow pain, golfer’s and tennis elbow →→Ankle and foot pain, plantar fasciitis →→Wrist and finger pain, thumb and finger OA →→High hamstring tendinopathy, iliopsoas tendinopathy →→Hip pain, iliotibial band syndrome, hip OA (as long as it’s not end stage)

the body to repair old injuries by activating a new healing cascade, raising growth factor levels and effectiveness.17 In a recent publication with pre- and posttesting and biopsies, dextrose prolotherapy was also shown effective in cartilage regeneration.12 There is a large volume of medical research including double blinded and placebo controlled studies, showing the effectiveness and safety of dextrose prolotherapy, including a recently published review.18

Platelet-rich plasma prolotherapy PRP has been used in prolotherapy for over 10 years. Many people have heard the term as a treatment for musculoskeletal and sports injuries, but do not realize it is a form of prolotherapy. Studies support the use of PRP for tendinopathy,19 chronic tendon and muscle injury,20 joint degeneration,21 and OA , including a study showing PRP to be more effective than hyaluronic acid for knee22 and hip OA .23 It is believed that PRP can also modulate action on articular cartilage lubrication and regeneration.13 There is a huge interest by orthopedic medicine physicians in PRP, with many, many journal publications and studies, as well as a recent textbook on its use in musculoskeletal medicine.24 There are also some interesting observations, including a case report of calcific tendonitis in a rotator cuff, treated with PRP. Results showed not only excellent resolution of symptoms and pain, but also X-ray evidence that calcium deposits previously present in the tendon were gone when followed up 1 year later.25

Biocellular (stem cell) prolotherapy

Biocellular (stem cell or stem/stromal cell) prolotherapy is so named because it uses adult stem cell sources as the →→Temporomandibular joint dysfunction prolotherapy treatment formula. Biocellular prolotherapy is used when a more aggressive healing process is needed →→Hypermobility or desired. In the early 1990s, adult stem cells, specifically mesenchymal stem cells (MSCs), were discovered to have →→Other musculoskeletal pain an active role in connective tissue repair after injury.26,27 MSCs are partially differentiated cells capable of continuing down the lineage to ligament, tendon, or cartilage cells.28 Types of It is also believed that these cells work by changing the prolotherapy tissue and joint microenvironment more favorably towards There are 3 general formula types in prolotherapy: tradi- healing.29 [See Figure 1 at goo.gl/guojfB.] An individual is tional (dextrose), platelet-rich plasma ( PRP) and biocellular, born with these adult stem cells, they are found throughout also known as stem cell prolotherapy, which uses autologous the body, multiply to replenish dying cells and regenerate stem cell sources, ie, typically bone marrow or adipose (fat) damaged tissues. The 2 main storage reservoirs of MSCs in stromal tissue. the human body are bone marrow and adipose (fat) tissue, and both of these can be used as stem cell sources in prolotherapy. Adipose is an interesting tissue because it conTraditional prolotherapy tains 500 to 2000 times as many MSCs as bone marrow. Traditional, also referred to as dextrose prolotherapy, uses Adipose also retains its regenerative abilities much longer hypertonic (10% to 15%) dextrose as its main proliferating as a person ages than bone marrow does,30 as well as being formula. Hypertonic dextrose creates an osmotic irritation easier to harvest, making adipose an ideal stem cell source, which then promotes positive inflammation and healing.16 especially for older patients.31,32 The first protocol for adiAt its core, this treatment could be thought of as “tricking” pose derived biocellular prolotherapy was published in 2011

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in Journal of Prolotherapy.33 Another advantage of adipose, or PRP, and in other cases biocellular (stem/stromal cell) is observed specifically when treating knees, is its potential the most practical starting point, depending on the patient’s to replenish the knee infrapatellar fat pad. This fat pad not presentation and injuries. Patient preference is also importonly provides a cushion, but also contains potent MSCs and ant as the doctor-patient relationship is a partnership, and, MSC precursors.34 It has been speculated that depletion of once the patient understands the process, his/her input is this fat pad plays a prominent role in the initiation and pro- important in this determination. Each patient is evaluated gression of OA in the knee.35 Many cases of adipose derived individually, and recovery may be faster in some cases than biocellular prolotherapy have been done in the knee since others. An average number of traditional or PRP prolother2011 and show objective ultrasound evidence demonstrat- apy treatments is 4 to 6, spaced 4 to 6 weeks apart. An avering infrapatellar fat pad improvement that correlates with age number of treatments for biocellular prolotherapy is reduction of patients’ pain and improved function. Biocel- 1 to 2, spaced 6 to 9 months apart. In some cases a patient lular prolotherapy has also been used successfully in cases may start with one form of prolotherapy, and then advance of tendon injury and for acute sports injuries where faster to a more aggressive form if results level off. See the treathealing is desired along with the possibility of reduced scar ment course algorithm (Figure) of where to start, when to tissue formation. [See Figures 2, 3, and 4 at goo.gl/guojfB.] switch, and how long the process typically takes.

Who is an appropriate patient for prolotherapy?

In the Hackett prolotherapy text book, first published in 1956 with 4 subsequent editions, the question of who was appropriate as a candidate for prolotherapy treatment was addressed.36 This book states that a patient should have:

1 An appropriate medical problem 2 A desire for improvement 3 No underlying medical condition that would significantly interfere with healing 4 A willingness to report progress 5 A willingness to receive painful injections in an effort to recover from injury These criteria are still true today. It is important for the patient to understand this is a process of healing, and that the treated area is being stimulated to heal so will often feel worse initially before it feels better. There is also an “ebb and flow”—a “4 steps forward, 2 steps back” phenomena—which occurs during the interval after treatment. This is especially true with PRP or biocellular prolotherapy because these are more aggressive formulas, stimulate deeper healing, and are often more uncomfortable than dextrose prolotherapy. The most important common denominator between patients who are successful is patience and an understanding of the treatment process.

When to use which type of prolotherapy and how long does it take?

As a physician doing prolotherapy for 20 years, it is my practice to start with the least aggressive formula that I believe will get the job done. In some cases that is dextrose Q4 | 2016

Use of diagnostic musculoskeletal ultrasound

Ultrasound as a tool in diagnosis and treatment for musculoskeletal medicine has been gaining popularity in recent years.37 The ability to immediately correlate the exact spot where a patient is having pain to an image can result in a faster and better diagnosis. While MRI has its place, ultrasound may show more detail than MRI for certain locations, multiple joints can easily (and inexpensively) be scanned including contralateral joints, and every patient can get an ultrasound, even those with metal implants.38 Dynamic (movement) imaging can also be accomplished, to correctly estimate the extent of damage of a ligament or tendon tear. MRI falls short here as scans are done with the patient motionless, and some connective tissue tears do not show up unless the joint is mobilized.39 The use of ultrasound can also be valuable as a “GPS” while injecting difficult locations. And serial ultrasounds over a treatment course can help to show progress and build patient confidence. Musculoskeletal ultrasound is fast becoming the standard of care in physical medicine and rehabilitation physician training programs.40 Better machines are being produced, and just like when computers came down in size and price, very sophisticated, high quality ultrasound machines are now available that are portable and affordable. Some have high end features, such as color tissue elastography (also called sonoelastography), which measure the stiffness or softness of tissue. This feature, previously only available on expensive ultrasound machines, is now being offered on smaller, more portable devices, such as the Konica Minolta Sonimage HS1 system. Tissue elastography, which has been used for years in other applications, is new to musculoskeletal medicine. This technology can potentially allow the practitioner to determine tears that were undetectable with standard black and white imaging, where a diagnosis would otherwise not be possible. [See Figure 5 at goo.gl/guojfB.] While there is a learning curve in beginning to use ultrasound, it is well worth the effort as any tool which can help the pain practitioner better diagnose and resolve a patient’s pain origin is invaluable. www.painweek.org | PWJ | 49

COMPLEMENTARLY&ALTERNATIVE

Figure. Typical prolotherapy treatment algorithm.

Treatment algorithim

Evaluation: patient history, physical exam, review of previous studies, musculoskeletal ultrasound in office to confirm diagnosis Determine if candidate for dextrose, PRP, or stem cell prolotherapy

Discuss options If excess degeneration, severe tendonosis, muscle tear, or if patient prefers PRP over dextrose prolotherapy, and if no contraindications PRP prolotherapy × 2 treatments, interval 4–6 weeks

Usual course 4–6 treatments should be completed and 90% – 100% improved*

If no substantial improvement or if results have plateaued Biocellular (stem cell) prolotherapy (note: may also start here as indicated by severity of problem or patient preference) × 1–2 treatments, 6–12 months apart

PRP prolotherapy if needed at recheck visits × 1–2 treatments Should be completed and 90% – 100% improved*

50 | PWJ | www.painweek.org

Dextrose prolotherapy × 2 treatments, interval 3–4 weeks

Re-evaluate If no substantial improvement or if results have plateaued

Re-evaluate

If doing well, continue re-evaluating every treatment

If average case

If doing well, continue treatment Dextrose prolotherapy × 2–4 treatments, interval 3–4 weeks Should be completed and 90% – 100% improved. If not, re-evaluate, consider PRP prolotherapy or biocellular (stem cell) prolotherapy

*Based on a combination of objective and subjective measures, such as pain reduction, better stability, increased function, and improved on orthopedic testing and ultrasound imaging.

Q4 | 2016

[Prolotherapy] could be thought of as ‘tricking’ the body to repair old injuries by activating a new healing cascade, raising growth factor levels and effectiveness.

Conclusion

Musculoskeletal pain and osteoarthritis are common complaints and can be a challenge for the treating physician. Traditional medical treatment options may not be straightforward, and may be only temporary, ineffective, or high risk. Osteoarthritis has been shown to develop after connective tissue injury, which leads to biomechanical change and ultimately degeneration and pain. Traditional dextrose prolotherapy, PRP prolotherapy, and biocellular (stem cell or stem/stromal cell) prolotherapy are low risk procedures with a high success rate. These procedures are regenerative in nature and work by stimulating repair of joints, ligaments, tendons, muscle and cartilage. An added benefit is that when joints are stabilized, biomechanical joint injury and further OA may be prevented. Different types of prolotherapy are appropriate for different situations and conditions, and the choice of which form of prolotherapy to use is arrived at after a thorough evaluation, diagnostic musculoskeletal ultrasound and/or other imaging, discussion with the patient, and a working diagnosis as to what is causing his/ her pain. While prolotherapy regenerative medicine is the wave of the future, now encompassing platelet and stem cell biotechnology, its origins are from the past and based on a very simple premise that the body can be stimulated to heal, reducing or eliminating pain. Q4 | 2016

References 1. Alderman D. Prolotherapy for musculoskeletal pain. Pract Pain Manag. 2007;7(1):33. 2. Uhl RL , Roberts TT, Papaliodis DN, et al. Management of chronic musculoskeletal pain. J Am Acad Orthop Surg. 2014;22(2):101–110. 3. ScienceDaily. One in two Americans have a musculoskeletal condition. Available at: www.sciencedaily.com/releases/2016/03/ 160301114116.htm. 4. Felson DT, Lawrence RC , Dieppe PA , et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann Intern Med. 2000;133(8):635–646. 5. High incidence of pain common one year following TKA . Orthopedics Today. May 2016. Available at: www.healio.com/orthopedics/knee/ news/print/orthopedics-today/%7B04809ffa-5497–42d1-a547-d2462fbb 72b6%7D/high-incidence-of-pain-common-1-year-following-tka. 6. Wehling P, Moser C, Maixner W. How does surgery compare with advanced intra-articular therapies in knee osteoarthritis: current thoughts. Ther Adv Musculoskelet Dis. 2016;8(3):72–85. 7. Gedney E. Special technic: hypermobile joint: a preliminary report. Osteopath Prof. 1937;9:30–31. 8. Hackett GS . Ligament and Tendon Relaxation Treated by Prolotherapy. 1st ed. Charles C. Thomas, Springfield; 1956. 9. Radin EL , Paul IL, Rose RM . Role of mechanical factors in pathogenesis of primary osteoarthritis. Lancet. 1972;299(7749):519–522.

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COMPLEMENTARLY&ALTERNATIVE

10. Blalock D, Miller A, Tilley M, et al. Joint instability and osteoarthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2015;8:15. 11. Soliman DMI, Sherif NM , Omar OH, et al. Healing effects of prolotherapy in treatment of knee osteoarthritis healing effects of prolotherapy in treatment of knee osteoarthritis. Egyptian Rheumatol Rehabil. 2016;43(2):47. 12. Topol GA , Podesta LA , Reeves KD, et al. Chondrogenic effect of intra-articular hypertonic-dextrose (prolotherapy) in severe knee osteoarthritis. PM&R. 2016;Apr 1. [E pub ahead of print] 13. Sakata R, Reddi AH . Platelet-rich plasma modulates actions on articular cartilage lubrication and regeneration. Tissue Eng Part B Rev. 2016;22(5):408–419. 14. Pak J, Lee JH, Kartolo WA , et al. Cartilage regeneration in human with adipose tissue-derived stem cells: current status in clinical implications. Bio Med Res Int. 2016;2016:12 pages. 15. Alderman DD. Regenerative injection therapies for pain: traditional, platelet rich plasma and biocellular prolotherapy. In: Bonakdar RA , Sukiennik AW, eds. Integrative Pain Management. In: Oxford, England: Oxford University Press; 2016:345. 16. Brody JE . Injections to kick-start tissue repair. NY Times. 2007:D8. 17. Reeves KD. Normal tendon and ligament healing. In: Lennard T. Pain Procedures in Clinical Practice. Philadelphia, PA: Hanley & Belfus; 2000:172. 18. Hauser RA , Lackner JB, Steilen-Matias D, et al. A systematic review of dextrose prolotherapy for chronic musculoskeletal pain. Clin Med Insights Arthritis Musculoskelet Disord. 2016;9:139. 19. Fitzpatrick J, Bulsara M, Zheng MH . The effectiveness of platelet-rich plasma in the treatment of tendinopathy a meta-analysis of randomized controlled clinical trials. Am J Sports Med. 2016;Jun 6. [E pub ahead of print] 20. Mishra A, Woodall J, Vieira A. Treatment of tendon and muscle using platelet-rich plasma. Clin Sports Med. 2009;28(1):113–125.

mesenchymal stem/stromal cells. PloS One. 2014;9(12):e115963. 31. Frese L, Dijkman PE, Hoerstrup SP. Adipose tissue-derived stem cells in regenerative medicine. Transfus Med Hemother. 2016;43(4):268–274. 32. Alderman DD. Advances in regenerative medicine: high-density platelet-rich plasma and stem cell prolotherapy for musculoskeletal pain. Pract Pain Manag. 2011;11(8). 33. Alderman D, Alexander RW, Harris G, et al. Stem cell prolotherapy in regenerative medicine: background, theory and protocols. J Prolother. 2011;3(3):689–708. 34. Hindle P, Khan N, Biant L, et al. The infrapatellar fat pad as a source of perivascular stem cells with increased chondrogenic potential for regenerative medicine. Stem Cells Transl Med. 2016. [E pub ahead of print] 35. Clockaerts S, Bastiaansen-Jenniskens YM , Runhaar J, et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Osteoarthritis Cartilage. 2010;18(7):876–882. 36. Hackett GS, Hemwall GA , Montomery GA . Ligament and Tendon Relaxation Treated by Prolotherapy. 5th ed. Institute in Basic Life Principles, Oak Park, Illinois; 1991. 37. Primack SJ. Past, present, and future considerations for musculoskeletal ultrasound. Phys Med Rehabil Clin N Am. 2016;27(3):749–752. 38. Patil P, Dasgupta B. Role of diagnostic ultrasound in the assessment of musculoskeletal diseases. Ther Adv Musculoskel Dis. 20124(5):341–355. 39. Lento PH, Primack S. Advances and utility of diagnostic ultrasound in musculoskeletal medicine. Curr Rev Musculoskel Med. 2008;1(1):24–31. 40. Özçakar L, Kara M, Chang KV, et al. Nineteen reasons why physiatrists should do musculoskeletal ultrasound: EURO - MUSCULUS/ USPRM recommendations. Am J Phys Med Rehabil. 2015;94(6):e45-e49.

21. Filardo G, Kon E, Roffi A, et al. Platelet-rich plasma: why intraarticular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration. Knee Surg Sports Traumatol Arthrosc. 2015;23(9):2459–2474. 22. Laudy AB, Bakker EW, Rekers M, et al. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and metaanalysis. Brit J Sports Med. 2015;49(10):657–672. 23. Dallari D, Stagni C, Rani N, et al. Ultrasound-guided injection of platelet-rich plasma and hyaluronic acid, separately and in combination, for hip osteoarthritis a randomized controlled study. Am J Sports Med. 2016;44(3):664–671. 24. Maffulli N. Platelet Rich Plasma in Musculoskeletal Practice. SpringerVerlag London; 2016. 25. Seijas R, Ares O, Alvarez P, et al. Platelet-rich plasma for calcific tendinitis of the shoulder: a case report. J Orthopaed Surg. 2012;20(1):126. 26. DiMarino AM , Caplan AI, Bonfield TL . Mesenchymal stem cells in tissue repair. Frontiers Immunol. 2013;4:201. 27. Hiroshi M. Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. J Nippon Med School. 2009;76(2):56–66. 28. Zuk PA , Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279–4295. 29. Murphy MB, Moncivais K, Caplan AI . Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Molecular Med. 2013;45(11):e54. 30. Beane OS, Fonseca VC , Cooper LL , et al. Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived

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Q4 | 2016

SHORT CUTS

By Doug Gourlay MD, MSc, FRCPC, FASAM

The diagnosis of addiction is made prospectively, over time. The diagnosis of pseudoaddiction is made retrospectively. Substance misuse is a primary care issue. Primary care practitioners need to play a key role in “demand reduction” whether it’s patient use of nicotine, alcohol, or cocaine. Through your longitudinal role with the patient, the true nature of an occult substance use disorder will become apparent. Primary care also has the ability to see the patient in a more complete sense, often through multiple situations and multiple sets of eyes— how a patient responds to your administrative staff; input from the pharmacist; and, where possible, input from the patient’s significant other— can all offer insight that a consultant may never have.

Q4 | 2015

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SHORT CUTS

1 |

Pain Practice—The Changing Landscape for Primary Care

manner using first-line medications and trying to use those therapies that are going to avoid long-term complications.

Jennifer Bolen, JD

3 |

Practitioners need a system to ensure that they’re actively current on licensing board requirements and clinical guidelines relating to the longterm use of opioid therapy. SAMHSA has a kit for prescribers, patients and family members, that relates to opioid overdose issues, and will help the provider fulfill the informed consent requirement when opioids are prescribed. It’s also useful information to use to train staff. And if there’s ever an investigation and a need to engage an attorney, this little handbook of clinical material could be a good reference resource. Most importantly, the amount of education that a provider can give to a patient on these issues is super critical. By educating the patient, you are putting them on notice that they do have responsibilities—safe use, safe storage, safe disposal of the medicine; asking questions; being engaged; and talking about any possible adverse events. Patient breathing problems might trigger a provider to say, “Hey, let me help you with this additional medicine, just in case something goes wrong. I’m not labeling you an abuser or an addict. I simply want to care for you and give you a tool, like an epinephrine pen you would have if you were an asthmatic, in case you feel like you might be having an overdose event.” That education, that sharing in responsibility, and that recognition of patient responsibility is critical. Providers who do that are really taking steps in good faith to help protect their patients.

2 |

Pain Management in Workers Compensation Matthew Foster, PharmD

Workers’ compensation ( WC) patients differ from the average group health claim: most have some kind of a physical injury that led to a chronic pain condition. In group health claims for pain therapy it’s much more focused on management of diseases of either lifestyle or aging, such as diabetes or hypertension. Within the WC system, there are specific treatment guidelines at the national level and also some at the state level that help drive towards the appropriate care of the injured worker. They are similar in some aspects, such as identifying the typical medications to be used to treat the injured worker, but they guide on what is inappropriate therapy as well, so that the physicians know which should be avoided—not only having an authorization process in place but to point out how dangerous a medication can be when used in combination with opioids. One interesting trend in WC is the push towards implementation, such as through the adoption of state-based WC formularies. There is an emphasis on identifying medications that would be considered first-line therapy vs those that are less safe, maybe less effective, and definitely more expensive, and using those as the secondor third-line therapy. And an approval or review process before moving on to the second-line therapy drugs, which would also include long-acting opioids. Whenever a patient is injured, there are appropriate treatment guidelines that we’re using in the WC market. But these also apply to patients outside of Workers’ Comp. Whether you’ve sprained your back putting up Christmas lights or because you work for a company that installs Christmas lights, each should be treated in a safe and effective

54 | PWJ | www.painweek.org

Assessing Risk Assessment

Ted Jones, PhD, CPE

Although most prescribers accept that risk assessment is important, many don’t know a lot about the tools, such as the ORT or SOAPP/SOAPP-R. The ORT is given in paper form to the patient, and it misses a lot of risk: one reason is abusers may lie, plus it’s hard to read and interpretation becomes an issue. SOAPP-R has cut-off points, and you need to understand which cut-off level you’re using and why, and what the pros and cons are. Identifying risk is more than just identifying potential addicts. Risk comes from a lot of different factors. People overtake medicine. They have impulse control issues. They’re not sleeping. They don’t understand. There’s literacy issues. There’s all kinds of reasons why people cannot take their medicine as prescribed. I actually think one of the questions that we don’t ask soon or often enough is, “Where do you keep your medicine and has it ever gone missing? Have you ever lost any or had it stolen?” Diversion is a huge issue and few of the risk tools currently ask that question, so practitioners need to. If you can approach risk in a more multidimensional fashion and address what’s driving the risk, you’re going to be a lot more effective in your treatment outcomes.

4 |

Alcohol Misuse and Chronic Pain Michael Weaver, MD, FASAM

Alcohol use disorder can be responsible for development of chronic pain syndromes, due to traumatic accidents or the effect of years of alcohol use on the body leading to peripheral neuropathies, pancreatitis, and other chronic, painful conditions. It can make it much more challenging to manage any kind of pain medication, whether it’s a controlled substance, opioids, benzodiazepines, or others. All of these are challenging when paired with alcohol. It’s useful to think of alcohol as a drug in addition to the drugs prescribed. Initiate the conversation about using alcohol: it should be a question that every practitioner asks. Just bringing the problem to the attention of the patient and letting them know you have concerns is often enough. If a practitioner just says, “I’m concerned about this and I really think you should start to make a change” then lots of patients will start to make a change. What we’re trying to do is increase the patient’s motivation to change a behavior, instead of forcing them or trying to convince them to do something. What will help that person be more motivated to change a behavior? Motivational interviewing is more about the approach, the style, the laid back version of trying to get someone to change their mind or behavior and do something healthier instead of less healthy. If that’s a problem, you don’t always have to address it yourself at the primary care level. If alcohol use is leading to some dangerous behaviors or even legal consequences those are triggers to go ahead and refer to a specialist. But a PCP can still be the bridge in order to continue the motivation and make sure that the patient maintains their gains once they come back from specialty care. It’s worthwhile to address alcohol use in practice. Alcohol use disorders are treatable and treatment works. Q4 | 2016

SHORT CUTS

A study of polyneuropathy incidence examined

Anterior cruciate ligament (ACL) injury affects some

The placebo effect may be stronger than previously thought.

Americans

patients with chronic low back pain were randomized into

102

250,000

and

each year, most of whom are in their 20s and 30s.

obese individuals

About

lean controls.

50%

Polyneuropathy rates were

3.8% 11.1% 29% 34%

of these require reconstructive surgery, of whom up to

in the controls,

in the obese with normoglycemia,

groups, 1 of which received standard treatment (NSAID medications) and the other received standard treatment + medication clearly labeled placebo pills.

After weeks, the placebo group reported

60%

30%

develop osteoarthritis (OA) within

in the obese with prediabetes, and in obese patients with diabetes. The research demonstrates that obesity alone is a significant contributor to polyneuropathy risk, even in the absence of comorbid diabetes.1 According to national statistics, naloxone availability is associated with a

43%

less

5 years

typical and maximum pain, compared to

9% 16%

and respective reductions reported by the first group.5

of their procedure. A new study will investigate these anomalies in patients at 3-, 6-, and 12-months postsurgery, with the objective of developing treatment paths to prevent OA development in this population.3

opioid overdose fatalities. Birmingham, Alabama, and nearby counties have seen these deaths escalate from 12 in 2010 to 137 reported in 2014. But a crowdfunded study that raised

$11,500

to purchase and distribute naloxone kits to family and friends of at-risk opioid users reports saving 9 such individuals from overdose death.2

1.4 million Americans.

IBD increases the risk of intestinal cancer by up

94%

were given opioids for their pain, but most of the cohort took only ½ of their prescription, leaving over

1000 doses unused.

60%. Among patients with Crohn’s disease,

70% eventually have surgery. Research has not only identified a potentially useful biomarker of IBD severity, but has also isolated a key protein, called EZH2 that may be a new therapeutic target for IBD treatments.4

patients who had surgery for dental impaction found that

Inflammatory bowel disease (IBD) includes conditions such as Crohn’s disease and ulcerative colitis, and affects some

drop in

study of

By introducing an incentivized text messaging system to some of these patients, the researchers reported a

22%

increase in proper medication disposal, compared to a control group who did not get the incentive.6

1. bit.ly/2eXmRLv 2. bit.ly/2fyHHPo 3. bit.ly/2fqYBSt 4. bit.ly/2fS2GxM 5. bit.ly/2fRoawz 6. bit.ly/2f8TfIM

Q4 | 2016

www.painweek.org | PWJ | 55

SHORT CUTS

with

Paul J. Christo MD, MBA

Paul Christo is the host of the Aches and Gains radio talk show, and an Associate Professor at Johns Hopkins University School of Medicine in Baltimore, Maryland.

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Q4 | 2016

“There are many ways that we can touch the lives of others, and I was fortunate to have found medicine as the way I could best do that.”

What inspired you to become a healthcare provider? I first thought about becoming a physician in high school and college, but the desire was solidified in medical school. Medicine allowed me to make a big impact on human lives, and to help restore patients to a healthy and active state of living. There are many ways that we can touch the lives of others, and I was fortunate to have found medicine as the way I could best do that. In medical school, I was inspired by rotations in anesthesiology and pain medicine. I was intrigued by the array of analgesics available to reduce surgical pain such as anesthetic gases, IV opioids, epidurals, and regional nerve blocks. Then in residency training, I saw firsthand how pain specialists used medications and specialty procedures like nerve blocks, epidurals, and implantations to reduce pain and suffering. I knew at that time that I wanted to subspecialize in pain medicine in order to make a substantial impact on the lives of those in pain. Why did you focus on pain management? As an intern, I saw many patients with inadequately controlled pain—arthritis, low back pain, headache, and neck pain—yet I didn’t have the

Q4 | 2016

knowledge to make them better. Patient visits were quick and most of my attendings avoided any discussion of pain care. I could see the need and wanted to help meet it, realizing that those in pain were completely disenfranchised and often hopeless. My life’s work has focused on improving the lives of patients in pain through clinical care, education, and research. That drive has evolved into the creation of a national talk show on overcoming pain called Aches and Gains, which airs on Sirius XM radio. The show provides a media platform for hearing the stories of patients who have found relief, shares cutting edge treatments from contributing experts, and offers ways that people in pain can cope themselves. It’s been gratifying to hear that the show is making a meaningful impact on those in need. Who were your mentors? In middle school and high school, my scoutmaster in the Boy Scouts. He was a cardiologist and led me to the field of medicine. In college, Dr. Jeremiah Freeman (organic chemistry), and in medical school, Dr. Mike Heine (anesthesiologist). In residency, Drs. Sal Abdi (pain specialist) and Bobbie Sweitzer (anesthesiologist). Mark Hubbard (entrepreneur) has been a terrific media and business mentor.

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PUNDIT PROFILE/PAUL CHRISTO

“I knew…that I wanted to subspecialize in pain medicine in order to make a substantial impact on the lives of those in pain.”

If you weren’t a healthcare provider, what would you be? I was passionate about playing the pipe organ in high school after years of studying the piano. I also realized that I didn’t have the talent to make a living as a musician, so let that vision go. Instead, I would have liked to become a CEO of a healthcare company that delivers innovative products for treating chronic diseases.

If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be? Book: The Magic of Believing by Claude M. Bristol. Movie: The Pink Panther series Music: What a Fool Believes by the Doobie Brothers

What is your most marked characteristic?

What would you like your legacy to be?

My persistence has been the driving factor in all of my pursuits. I rarely give up, despite the barriers, and try to find alternative methods of achieving the goal.

Hope is a vital part of overcoming pain. There is no question that therapies can ease pain, but the belief that you can feel better is even more important. You must believe that things can get better, and remember that your life and well-being are worth the fight. I hope that I’m remembered for responding to human need personally and compassionately as a visible advocate for pain care.

What do you consider your greatest achievement? My greatest accomplishment has been a loving marriage, and raising two children. Professionally, it’s the development of my radio talk show, Aches and Gains. What is your favorite language?

What is your motto? “No one is immune to pain, but together we can overcome it.”

The language of music…

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Q4 | 2016

GRALISE® (gabapentin) tablets Rx Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use GRALISE safely and effectively. See full Prescribing Information for GRALISE. INDICATIONS AND USAGE • GRALISE is indicated for the management of postherpetic neuralgia. • GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. DOSAGE AND ADMINISTRATION • GRALISE should be titrated to an 1800 mg dose taken orally, once-daily, with the evening meal. GRALISE tablets should be swallowed whole. Do not crush, split, or chew the tablets. For recommended titration schedule, see DOSAGE AND ADMINISTRATION in full Prescribing Information. • If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). • Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 mL/min or in patients on hemodialysis. CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. WARNINGS AND PRECAUTIONS GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Table 1: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in GRALISE) in the Pooled Analysis

Indication Epilepsy Psychiatric Other Total

Placebo Patients with Events Per 1000 Patients 1.0 5.7 1.0 2.4

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

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed, are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that GRALISE contains gabapentin, which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and pre-existing tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness.

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

GRALISE N = 359 %

Placebo N = 364 %

1.4

0.5

3.3 2.8 1.4 1.4

2.7 1.4 0.3 0.8

3.9 1.1

0.3 0.5

2.5 1.7

2.2 0.5

1.9

0.5

1.9 1.7

0.5 1.1

10.9 4.5 4.2 1.1

2.2 2.7 4.1 0.3

The following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis, viral herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. Postmarketing and Other Experience with Other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain, and sweating. DRUG INTERACTIONS In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day). Hydrocodone Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of the interaction at other doses is not known. Antacid (containing aluminum hydroxide and magnesium hydroxide) An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by approximately 20%, but by only 5% when gabapentin immediate release was taken 2 hours after the antacid. It is recommended that GRALISE be taken at least 2 hours following the antacid (containing aluminum hydroxide and magnesium hydroxide) administration. Drug/Laboratory Test Interactions False positive readings were reported with the Ames-N-Multistix SG® dipstick test for urine protein when gabapentin was added to other antiepileptic drugs; therefore, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein. USE IN SPECIFIC POPULATIONS Pregnancy Category C: GRALISE should be used during pregnancy or in women who are nursing only if the benefits clearly outweigh the risks. See full Prescribing Information for more information about use of GRALISE in pregnancy. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCl between 15 and 30 or in patients undergoing hemodialysis. [see Dosage and Administration in full Prescribing Information]. DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies. OVERDOSAGE Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

ONCE daily with EVENING MEAL

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

ONCE daily with

EVENING MEAL

ONCE daily with

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

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

Learn more today at www.Gralise.com INDICATIONS AND USAGE GRALISE is indicated for the management of postherpetic neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. IMPORTANT SAFETY INFORMATION ADVERSE REACTIONS The most common side effects were dizziness (10.9%) and somnolence (4.5%). USE IN SPECIFIC POPULATIONS Reductions in GRALISE dose should be made in patients with age-related compromised renal function. WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

For more information about GRALISE, please see Brief Summary on the following page. References: 1. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012. 2. Sang CN, Sathyanarayana R, Sweeney M. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281-288. 3. Argoff CE, Chen C, Cowles VE. Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview. Expert Opin Drug Deliv. 2012;9:1147-1160.

Relief Uninterrupted