PAINWeek Journal Vol 6, Q3

vol. 6 q 3 2018

fascial distortion model: what your patients are telling you that you’re not hearing p.14 a wrinkle in the plan: metabolic changes and pain management in the older adult p.22 crisis=opportunity: reducing medication burden while managing chronic pain p.32 darknet on the edge of town p.48 dangerous liaisons: regimens. regimes. rapprochements p.58

THe PeNDULUM SWiNGS iN BOTH DiReCTiONS.

eDUCaTiON GOeS FORWaRD.

eXeCUTiVe eDiTOR KEViN L. ZaCHaROFF md, facpe, facip, faap PUBLiSHeR PaINWeeK aRT DiReCTOR DaRRYL FOSSa eDiTORiaL DiReCTOR DeBRa WeiNeR eDiTOR HOLLY 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 Paul Arnstein rn, phd, acns-bc, fnp-c, faan Clinical Nurse Specialist for Pain Relief Massachusetts General Hospital Boston, ma Said R. Beydoun md, faan Professor of Neurology Director of the Neuromuscular Program Keck Medical Center of University of Southern California Los Angeles, ca Jennifer Bolen jd Founder Legal Side of Pain Knoxville, tn 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

eDiTORiaL BOaRD

Peter A. Foreman dds, daapm Consultant Rotorua Hospital and Private Practice Rotorua, New Zealand Gary W. Jay md, faapm, facfei Clinical Professor Department of Neurology Division: Headache University of North Carolina Chapel Hill, nc 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 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 Bruce D. Nicholson md Clinical Associate Professor Department of Anesthesia Penn State College of Medicine Hershey Medical Center Hershey, pa Director of Pain Specialists Lehigh Valley Health Network Department of Anesthesiology Allentown, pa

Marco Pappagallo md Director of Medical Intelligence Grünenthal usa Bedminster, nj Director Pain Management & Medical Mentoring New Medical Home for Chronic Pain New York, ny Steven D. Passik phd VP, Scientific Affairs, Education, and Policy Collegium Pharmaceuticals, Inc. Canton, ma Joseph V. Pergolizzi md Chief Operating Officer nema Research Inc. Naples, fl Robert W. Rothrock pa-c, mpa University of Pennsylvania Department of Anesthesiology and Critical Care Pain Medicine Division Philadelphia, pa Michael E. Schatman phd, cpe, daspe Editor-in-Chief Journal of Pain Research Adjunct Clinical Assistant Professor Tufts University School of Medicine Department of Health & Community Medicine Boston, ma Sanford M. Silverman md, pa CEO and Medical Director Comprehensive Pain Medicine Pompano Beach, fl Thomas B. Strouse md Medical Director Stewart and Lynda Resnick Neuropsychiatric Hospital at ucla Los Angeles, ca

Copyright © 2018, 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.

vol. 6 q 3 2018

14 22 32 48 58 67 68 69 70 72 6

physical therapy

facial distortion model what your patients are telling you that you’re not hearing

by matthew r. booth thomas pentzer

pharmacotherapy

a wrinkle in the plan metabolic changes and pain management in the older adult

by tanya j. uritsky

behavioral

crisis = opportunity reducing medication burden while managing chronic pain

by ravi prasad jennifer hah

key topic

darknet on the edge of town

by kevin l. zacharoff

op-ed

dangerous liaisons regimens. regimes. rapprochements

by steven d. passik

pw next generation

with courtney m. kominek

clinical pearls

by douglas gourlay

pain by numbers one-minute clinician

with jeremy a. adler, ignacio badiola, kathleen digre, lynn mcpherson, alexandra mcpherson

pundit profile

with jennifer bolen

PWJ | www.painweek.org

Q 3 | 2018

It’s like doing hard time.

If your patients are taking opioids for chronic pain, they might be experiencing Painstipation, the constipation caused by opioids. This is more commonly referred to as opioid-induced constipation (OIC).

Prescribe RELISTOR for OIC—the only product in its class* that is not metabolized via the CYP3A4 pathway. *PAMORA (peripherally acting mu-opioid receptor antagonist) approved for OIC.

INDICATION • RELISTOR® (methylnaltrexone bromide) is an opioid antagonist. RELISTOR tablets are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

IMPORTANT SAFETY INFORMATION – RELISTOR tablets, for oral use • RELISTOR tablets are contraindicated in patients with known or suspected mechanical gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

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

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

• Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR tablets. Patients having disruptions to the bloodbrain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal.

• Avoid concomitant use of RELISTOR tablets with other opioid antagonists Relistor is a trademark of Salix Pharmaceuticals or its affiliates.

All rights reserved. RELO.0052.USA.18 April 2018 Printed in USA.

because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

• In a clinical study, the most common adverse reactions for RELISTOR tablets (≥ 2% of RELISTOR patients and at a greater incidence than placebo) in patients with chronic non-cancer pain were: abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%), hyperhidrosis (3%), anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%).

• The use of RELISTOR tablets during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Advise pregnant women of the potential risk to a fetus. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR tablets.

• A dosage reduction of RELISTOR tablets is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets is needed in patients with mild renal impairment.

• A dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A).

To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Brief Summary for RELISTOR tablets and injection on adjacent page and for more information go to www.relistor.com.

REFERENCE: RELISTOR [prescribing information]. Bridgewater, NJ: Salix Pharmaceuticals.

BRIEF SUMMARY OF PRESCRIBING INFORMATION This Brief Summary does not include all the information needed to use RELISTOR safely and effectively. See full prescribing information for RELISTOR. RELISTOR (methylnaltrexone bromide) 150 mg tablets, for oral use.

RELISTOR (methylnaltrexone bromide) injection, for subcutaneous use.

8 mg/0.4 mL methylnaltrexone bromide in single-dose pre-filled syringe.

12 mg/0.6 mL methylnaltrexone bromide in a single-dose pre-filled syringe, or single-dose vial.

Initial U.S. Approval: 2008 INDICATIONS AND USAGE Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR tablets and RELISTOR injection are indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR injection is indicated for the treatment of OIC in adult patients with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care.

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

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

Severe or Persistent Diarrhea Discontinue if severe or persistent diarrhea occurs during treatment.

Opioid Withdrawal Consider the overall risk benefit in patients with disruptions to the bloodbrain barrier. Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Monitor closely for adequacy of analgesia and symptoms of opioid withdrawal.

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 clinical practice.

Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR tablets was evaluated in a double-blind, placebo-controlled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 12-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR tablets 450 mg orally (200 patients) or placebo (201 patients). After 4 weeks of double-blind treatment administered once daily, patients continued 8 weeks of double-blind treatment on an as needed basis (but not more than once daily).

The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR tablets are shown in Table 4.

Adverse reactions of abdominal pain, diarrhea, hyperhidrosis, anxiety, rhinorrhea, and chills may reflect symptoms of opioid withdrawal.

Table 4: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Tablets in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 1) RELISTOR Tablets Placebo Adverse Reaction n = 200 n = 201 Abdominal Pain** 14% 10% Diarrhea 5% 2% Headache 4% 3% Abdominal Distention 4% 2% Vomiting 3% 2% Hyperhidrosis 3% 1% Anxiety 2% 1% Muscle Spasms 2% 1% Rhinorrhea 2% 1% Chills 2% 0%

*Adverse reactions occurring in at least 2% of patients receiving RELISTOR tablets 450 mg once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness.

The safety of RELISTOR injection was evaluated in a double-blind, placebocontrolled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 2) included a 4-week, doubleblind, placebo-controlled period in which adult patients were randomized to receive RELISTOR injection 12 mg subcutaneously once daily (150 patients) or placebo (162 patients). After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR injection 12 mg subcutaneously was administered less frequently than the recommended dosage regimen of 12 mg once daily.

The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR injection are shown in Table 5. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

Table 5: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Injection in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 2) RELISTOR Injection Placebo Adverse Reaction n = 150 n = 162 Abdominal Pain** 21% 7% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% <1% Chills 1% 0%

*Adverse reactions occurring in at least 1% of patients receiving RELISTOR injection 12 mg subcutaneously once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness.

During the 4-week double-blind period, in patients with OIC and chronic non-cancer pain that received RELISTOR every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR injection 12 mg subcutaneously every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 2) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%).

The safety of RELISTOR injection was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with OIC and chronic non-cancer pain (Study 3). Patients were allowed to administer RELISTOR injection 12 mg subcutaneously less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 2. Additionally, in Study 3, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR. Opioid-Induced Constipation in Adult Patients with Advanced Illness The safety of RELISTOR injection was evaluated in two, double-blind, placebo-controlled trials in adult patients with OIC and advanced illness receiving palliative care: Study 4 included a single-dose, double-blind, placebo-controlled period, whereas Study 5 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common adverse reactions in adult patients with OIC and advanced illness receiving RELISTOR injection are shown in Table 6 below.

Table 6: Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR Injection in Adult Patients with OIC and Advanced Illness* (Studies 4 and 5) RELISTOR Injection Placebo Adverse Reaction n = 165 n = 123 Abdominal Pain** 29% 10% Flatulence 13% 6% Nausea 12% 5% Dizziness 7% 2% Diarrhea 6% 2%

*Adverse reactions occurring in at least 5% of patients receiving all doses of RELISTOR injection (0.075, 0.15, and 0.3 mg/kg) and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness.

The rates of discontinuation due to adverse reactions during the double-blind, placebo-controlled clinical trials (Study 4 and Study 5) were comparable between RELISTOR (1%) and placebo (2%).

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

Gastrointestinal Perforation, cramping, vomiting.

General Disorders and Administration Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported.

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

Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.3 mg/kg of RELISTOR did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

USE IN SPECIFIC POPULATIONS Pregnancy The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier and should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus. Advise pregnant women of the potential risk to a fetus.

Lactation Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR. In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

Geriatric Use In clinical studies of RELISTOR tablets, no overall differences in effectiveness were observed. Adverse reactions were similar; however, there was a higher incidence of diarrhea in elderly patients. In clinical studies of RELISTOR injection, no overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dosage adjustment based on age is recommended. Monitor elderly patients for adverse reactions.

Renal Impairment In a study of subjects with varying degrees of renal impairment receiving RELISTOR injection subcutaneously, there was a significant increase in the exposure to methylnaltrexone in subjects with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated

by Cockcroft-Gault) compared to healthy subjects. Therefore, a dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets or RELISTOR injection is needed in patients with mild renal impairment (creatinine clearance greater than 60 mL/minute as estimated by Cockcroft-Gault).

Hepatic Impairment Tablets In a study of subjects with varying degrees of hepatic impairment receiving a 450 mg dose of RELISTOR tablets, there was a significant increase in systemic exposure of methylnaltrexone for subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment compared to healthy subjects with normal hepatic function. Therefore, a dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A).

Injection There was no clinically meaningful change in systemic exposure of methylnaltrexone compared to healthy subjects with normal hepatic function. No dosage adjustment of RELISTOR injection is needed for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions.

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

If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect.

NONCLINICAL TOXICOLOGY Carcinogenesis Oral administration of methylnaltrexone bromide at doses up to 200 mg/kg/day (about 81 times the subcutaneous maximum recommended human dose (MRHD) of 12 mg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the subcutaneous MRHD of 12 mg/day) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the subcutaneous MRHD of 12 mg/day) for 104 weeks did not produce tumors in mice and rats.

Mutagenesis Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test.

Impairment of Fertility Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the subcutaneous MRHD of 12 mg/day; about 3.3 times the oral MRHD of 450 mg/day) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Animal Toxicology and/or Pharmacology In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone caused concentration-dependent inhibition of hERG current.

PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Patient Information).

To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Based on 9502502 12/2017 Salix Pharmaceuticals 400 Somerset Corporate Blvd.

Bridgewater, NJ 08807 USA www.salix.com Manufactured for:

Under license from:

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591 U.S. Patent Information: For Injection - U.S. Patents: 6,559,158; 8,247,425; 8,420,663; 8,552,025; 8,882,490; and 9,180,125 For Tablets - U.S. Patents: 6,559,158; 8,420,663; 8,524,276; 8,956,651; 9,180,125; and 9,314,461 Relistor is a trademark of Salix Pharmaceuticals or its affiliates.

REL.0088.USA.18

The national conference on pain for frontline practitioners.

2019

SePTeMBeR 3â&#x20AC;&#x201D;7

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)â&#x201E;˘. 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.

When we access the internet, it turns out we are only scratching the surface of everything When I think about chronic pain, I think available, legal and illegal. I have written an Kevin L. Zacharoff about constants and variables. One conarticle about an unfortunate and increasingly stant is “We are all the same animal” and prevalent illicit channel of distribution for if we examine the same type of pain in different people, we will likely opioids and other drugs—the Darknet. Without being tracked, people can be able to identify distinct similarities in pathophysiology. On the other access “dark” websites that offer transactions for anything illegal you might hand, the biopsychosocial aspects and context of chronic pain in the “pain think of. As you can imagine, with the Darknet becoming more powerful than experience” are so different, individual, and variable that it would be inac- street-corner selling drug dealers, this is a significant contributing factor curate to assume there are similarities between chronic pain patients at to the opioid overdose epidemic we are witnessing. Detailing unlikely and all. In both the clinical and regulatory world of pain management, we have unwitting partners, this article provides a pertinent look at something that, witnessed the seemingly perpetual swings of the “opioid pendulum” and if you’re anything like me, you didn’t know existed as a major contributor shifting value propositions of the role of prescribing of these analgesics. to the nation’s substance abuse problem. It may scare you, but sometimes Couple this with the release of new and sometimes conflicting pain treat- reality is something to be afraid of. I hope the article is of value to you. ment guidelines, often including a plethora of “silver bullets” directed at the increasingly prevalent opioid overdose epidemic, and it can get pretty The name Dr. Steven Passik should invoke thoughts of knowledge, wisdom, confusing. Certainly a guaranteed constant is that as our population ages, and experience in the field of pain management. I have known Dr. Passik the prevalence of chronic pain is likely to continue to increase in direct for many years, and have quoted him more times than I can keep track of, proportion. Lastly, two things that are examples of blends of constancy with complete respect for him and his opinions regarding the use of opioid and variability are how patients with pain can be assessed objectively in analgesics for the treatment of chronic pain. Dr. Passik has reliably and eloa reproducible fashion, and how illicit substances including opioids are quently helped many expert and frontline practitioners navigate the changes obtained by substance abusers and people with addictions. All of this is in perspectives about opioid prescribing as they have occurred. His Op-Ed covered in this issue of the PWJ so get ready, there is a lot to take in. entitled Dangerous Liaisons: Regimens, Regimes, and Rapprochements is typical Passik, and a must for you regardless of anything you might think you Matt Booth and Thomas Pentzer who present a way to objectively assess know, or don’t know about opioids, patients in need, and their relationship patients with musculoskeletal pain through an interesting method, the to today’s opioid epidemic. After you read it, share it—it’s that important. fascial distortion model, that looks for nonphysiologic alterations in the matrix of the fascia. A case is made that, using a reproducible approach, This issue’s Pundit Profile spotlights Jennifer Bolen, JD, the Founder of interpretation of “body language” in response to defined directions may the Legal Side of Pain in Knoxville, Tennessee. Having known Jennifer for open a window into assessing the presence of fascial distortions and pro- many years, I can say that there’s no other nonclinical individual I can think vide information to yield a more targeted approach to earlier return to of who has contributed so much to the pain management atmosphere. function, which should likely be priority one. Although not new, with proper Always with an eye to “staying on the rails” of good and safe practice, training, this approach for uninformed clinicians has the potential to be she is a rock, and it’s just plain good to know she is out there teaching, innovative and thought-provoking, providing a safe and noninvasive way writing, and helping. to complement the assessment of a normal history and physical.

Our Next Generation focuses on pharmacist Courtney Kominek. Having the Drs. Ravi Prasad and Jennifer Hah address an intersection of the opioid epi- pleasure of knowing Courtney personally, I can tell you she means it when demic: clinician concern over regulatory scrutiny, while continuing to provide she says that she’s most proud when helping patients get the care they care for patients with chronic pain. Pointing towards the inherent hazards need. What more could we ever expect from a healthcare provider? We of continuing long-term opioid therapy without definable benefits, this need a few thousand more like her, and our future might be in good shape. article offers valuable “food for thought” regarding opioid tapering, the role of nonpharmacological treatments, and a true multidisciplinary approach I’m hoping this issue is just a supplement to the education you’ll receive at to managing chronic pain. This piece is timely as we see state mandated the national PAINWeek conference in Las Vegas. I hope to see you there. If opioid dose-limiting gaining more traction. We need more discussion about you see me, say hello and give me feedback for the pwj, and suggestions for future issues. Remember that you are the reason I am here. a “Plan B” and this article provides a valuable spark for that dialogue.

Adults 65 years and older account for utilization of 30% of all prescription medications and 50% of otcs. Dr. Tanya Uritsky’s article points to something I think about all the time: Every prescription and intervention we employ carries some type of risk, especially in the older patient population who are likely taking 4 or more medications daily. Focusing on the hazards of drugdrug interactions, along with the pharmacokinetic and pharmacodynamic changes that could potentially increase risk, this article reminds us that as our patients age and their bodies change, we need to carefully evaluate the risk/ benefit ratio for this ever-increasing patient population with chronic pain.

10

PWJ | www.painweek.org

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

Kevin L. Zacharoff 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.

Q 3 | 2018

2018

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visit www.painweekend.org for more info.

This activity is provided by Global Education Group. 6.0–12.o AMA Category 1 Credits™ ● This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard.

Matthew R. Booth PT, DPT

p.14

Matt Booth is the clinic director of Therapeutic Associates Physical Therapy—Southeast Boise; Clinical Faculty for the Family Medicine Residency of Idaho and the University of Washington Medical School. He is also an Instructor of Fascial Distortion Model through the American FDM Association, and teaches with FDM Academy, which he co-founded. Mr. Booth coauthored his article with Thomas Pentzer, an osteopathic medical student and undergraduate fellow in the Osteopathic Principles and Practice department at Pacific Northwest University in Yakima, Washington.

Steven D. Passik PhD

p.58

Steven Passik is Vice President of Collegium Pharmaceuticals, Inc., Scientific Affairs, Education and Policy, in Canton, Massachusetts. He is currently working to complete a book about and insider’s view of the opioid epidemic, started with Ken Kirsh, who passed away in 2017.

Ravi Prasad PhD

p.32

Ravi Prasad is a Clinical Associate Professor in the Division of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine at Stanford University in California. He coauthored his article with Jennifer Hah, MD, MS, Instructor in the Division of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine at Stanford University in California. Her NIH-funded research spans the intersection of mood, pain, and addiction. She is a pain medicine specialist, anesthesiologist, and clinical epidemiologist.

Tanya Uritsky PharmD, BCPS, CPE

p.22

Tanya Uritsky is a Clinical Pharmacy Specialist in Pain Management and Palliative Care at the Hospital of the University of Pennsylvania. She has been practicing in the inpatient hospital setting and serves as the pharmacist on the Palliative Care Service and for the health-system, as well as a pain management specialist within the pharmacy department and throughout the hospital. She has published literature on the subject of pain and symptom management and speaks nationally and internationally on the topic. She was awarded Palliative Care Practitioner of the Year in 2015 by PAINWeek.

Kevin L. Zacharoff MD, FACPE, FACIP, FAAP

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Kevin Zacharoff is a Board-Certified Anesthesiologist with over 25 years of clinical experience in anesthesiology and pain medicine. He is an active Faculty Member and Clinical Instructor at SUNY Stony Brook School of Medicine, the Executive Editor of PWJ­—PAINWeek Journal, Chairperson of the Ethics Committee at St. Catherine of Siena Medical Center in Smithtown, New York, and a member of the Anesthetic and Analgesic Drug Products Advisory Committee to the Food and Drug Administration.

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home with youâ&#x20AC;&#x201D;

By Matthew R. Booth pt, dpt & Thomas Pentzer

PHYSiCaL THeRaPY

The fascial distortion model (FDM) is a model of assessment and treatment based around the unifying concept of fascia being ubiquitous and playing a vital role in structural integrity as well as facilitating movement. Dr. Stephen Typaldos, the physician who developed FDM, posited that nonphysiologic alterations in the normal layout of the fascial matrix (referred to here as distortions) are at the heart of many musculoskeletal complaints. Further, applying corrective forces to said fascial distortions facilitates a return of the fascial matrix to a normal state, rapidly improving function and reducing pain. The FDM is also patient centered, as during the nascent days of FDM, Typaldos observed distinct patterns of hand gestures that were associated with fascial distortions.

When a patient describes their musculoskeletal complaint, they instinctively localize and classify the distortion for the practitioner, who, through observation of the patient, can then treat the distortion appropriately.

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Imagine a patient has been referred to your practice for musculoskeletal pain. The patient doesn’t speak English and you have a translator on the phone, but the phone connection is bad. How can you help this patient? The patient is speaking in their native language and gesturing with their hands to their painful area, but you can’t get a good translation of the words they are saying. How can you help them?¶Perhaps your patient’s hands move around the cervicothoracic junction, pushing on a spot with multiple fingers and tracing an unseen line that begins at their occiput and extends down to their elbow. While most providers may see this movement as a vague display of the area of discomfort, FDM-trained providers glean valuable insights about musculoskeletal complaints that can immediately guide treatment.

There are 6 patterns of body language considered to be associated with distortions affecting the fascia1: ○○ Drawing a line of tightness with their fingertips ○○ Pointing to a single point of pain on a bony landmark ○○ Pushing multiple fingers or a thumb into a soft-tissue area ○○ Holding their hand over a joint ○○ Sweeping over a body part with the pads of the fingers ○○ Loss of range of motion in a joint, often with language suggesting the affected area is stuck or would feel better if “popped” The goal of FDM based treatment is to restore normal motion and reduce fear of movement in the patient, allowing them to return to function faster, while reducing reliance on traditional treatment modalities.

Q 3 | 2018

Published Literature Scientific literature on FDM is sparse, but shows some efficacy above that of a placebo. Fink et al provides a published clinical trial in which FDM demonstrated improvements in pain and motion greater than that of standard passive mobility treatment in 60 patients diagnosed with adhesive capsulitis of the shoulder.2 In Germany, a recent trial compared FDM to the German National Disease Management Guidelines for the treatment of acute low back pain.3 The patient group that received the FDM assessment and treatment showed reduced use of pain medications compared to the group receiving treatment in accordance with German National Disease Management Guidelines, which included active exercise prescription, opioid analgesic or anti-inflammatory pharmacotherapy, thermotherapy, and/or relaxation/behavioral approaches.3 This is especially significant with the opioid crisis raging in the United States: the FDM could be used by a variety of healthcare providers, and might potentially reduce opioid analgesic overuse. www.painweek.org | PWJ

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Chronic pain can also be successfully treated using the FDM, but results typically take longer than for acute injuries. Anecdotal feedback from practitioners trained in FDM includes successful employment of FDM based treatment on sciatica, carpal tunnel syndrome, and complex regional pain syndrome.

Assessment using the FDM relies on taking a patient history, observing patient hand gestures when describing their symptoms, and performing an objective examination. Recently, studies have shown acceptable reliability (multirater kappa [κ] = 0.51) and substantial reliability (κ = 0.61) using the patient’s body language for pain.4,5 Following assessment of the patient, if there are no contraindications, FDM treatment can be employed. Relative contraindications to FDM based treatment include, but are not limited to, active infections, tumors, or hematomas at the site of the distortion, bleeding disorders, and some collagen vascular diseases.

These contraindications are highly dependent on the location of the distortion. As mentioned above, treatment choices are correlated to the distinct hand gestures of the patient, with manual therapy by the practitioner being the primary modality. Injections (prolotherapy, hydrodissection) and surgeries may also fit within the FDM both as causes of and treatments

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for fascial distortions if one considers the effects of said interventions on the fascial matrix.

Some common injuries that anecdotally appear easily resolved with FDM-based manual treatments include: “pulled” muscles and muscle tears, ankle sprains, shin splints, Osgood-Schlatter disease, whiplash, headaches, shoulder pain, frozen joints, kidney stones, plantar fasciitis, sprains, strains, and tendonitis in other parts of the body, and chronically tight muscle groups6 including those involved in certain types of low back pain.3 Treating acute sprains/strains with FDM can elicit exceptionally fast resolution. Chronic pain can also be successfully treated using the FDM, but results typically take longer than for acute injuries. Anecdotal feedback from practitioners trained in FDM includes successful employment of FDM based treatment on sciatica, carpal tunnel syndrome, and complex regional pain syndrome. A growing number of case reports are being Q 3 | 2018

published that detail the encouraging results. At the time of this writing, the latest published case report7 details the resolution of a frozen shoulder that had persisted for 18 months. While other osteopathic manual therapies (counterstrain, soft tissue, muscle energy, and high velocity/low amplitude) brought some pain relief, they failed to restore normal range of motion. Application of FDM based approach to assessment and treatment brought complete resolution of pain and restoration of full ROM in two cases. These improvements were sustained at follow-up 3 months later.7

What Is Different About FDM? This pattern-based assessment may be considered to essentially be another mode of communication, which healthcare providers may have been previously unaware of. Practitioners using the FDM may be able to expand their differential diagnoses to include fascial distortions, which, when identified and treated accordingly, potentially reduces the need for imaging, laboratory studies, and even medication. The FDM-based approach to treatment is not just interventional techniques: although it does incorporate techniques that have been around for a long time, but also provides a framework to potentially develop new techniques that could facilitate return to baseline function. Almost all manual techniques, whether they are joint mobilization, joint manipulation, osteopathic, or soft-tissue/fascial techniques, may fit into FDM. The end goal of the pain treatment is restoring range of motion, function, pain reduction, and reducing fear of movement in the patient. As there is overlap with other manual therapies, it is often asked how FDM is different.

The difference with FDM is often the order of treatment, possibly the intensity of the treatment, and usually a reduced time until the patient reports improvement. Ultimately, the FDM puts more power back into listening (or observing) the patient’s immediate needs vs the practitioner believing that they know what is best. Correcting a fascial distortion may potentially deliver rapid improvement in range of motion, strength, and pain levels. This, in turn, boosts the therapeutic alliance between practitioner and patient, and lends itself to encouraging a return to movement and function with confidence.

Multidisciplinary Aspects of Care FDM can be integrated with virtually any healthcare practice.

Practitioners can use FDM along a wide spectrum—from assessment and referral only to full hands-on care, and anywhere along the continuum to help guide the thinking behind injections, surgery, or other interventions. The FDM can complement the biopsychosocial model, often recommended for appropriate assessment and treatment of chronic pain. Medical professionals in almost any specialty can use the FDM for assessment and treatment. FDM also fits perfectly into rehabilitation regimens for physical therapists and athletic trainers seeking to separate themselves from their competitors via faster results and improved outcomes. Many professional sports teams also have staff trained in FDM. The German National Soccer Team, Q 3 | 2018

winners of the most recent World Cup, has a physical therapist who treats players on the field with FDM. With no reliance on extensive medical infrastructure, advanced medical technology, or even consumable medical supplies, FDM is also uniquely suited for application in developing countries and austere environments where traditional approaches to management of musculoskeletal complaints grind to a halt in the face of power outages, supply shortages, and absence of medical equipment.

When blended with orthopedic thinking and pain neuroscience, FDM can fill in the holes of traditional treatment that can often leave patients dissatisfied.

First-Hand Results FDM is currently being used in at least 2 family medicine residencies in the US: the Family Medicine Residency of Idaho in Boise and the University of Minnesota Mankato Residency Program which is supported by the Mayo Clinic. Erin Westfall, DO, the Osteopathic Director of Medical Education for the Mankato Residency, said, “We love FDM and are becoming known as the residency that trains their residents in this great model! My goal for each resident who comes through our program is for them to be able to adequately address the needs of the patient at that visit if possible. I view osteopathic manipulative treatment as another tool in my pocket. In reality, this is where FDM is key. I can have a diabetic, hypertensive patient come in for a 15-minute visit, and when his agenda is for back pain, and my agenda for him is chronic disease management, we can each have our goals met! We quickly treat his triggerband or herniated triggerpoint, and there is still time to take care of his chronic disease during the visit. FDM allows us to address the concerns of the patient, whether ankle pain, back pain, headaches, etc, at the time of the visit. So, we love it. Every resident knows how to do it.”

Teaching Through the American Fascial Distortion Model Association (AFDMA), FDM is taught in the US to physicians (MD and DO), physician assistants, nurse practitioners, physical therapists and PT assistants, occupational therapists, chiropractors, athletic trainers, dentists, podiatrists, and Rolfers (certified in structural integration). It is currently being taught at medical schools, and at institutions such as the Cleveland Clinic and the Mayo Clinic.

FDM is typically taught in 3 modules: ○○ A 20-hour introduction module that covers ankle, knee, and shoulder treatments ○○ A 20-hour module that covers the axial spine ○○ A 16-hour module covering hands, elbows, feet, hips, and head

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The 3rd module may be taught as an introduction, but is often offered to those who have already taken one or both of the first 2 modules. There are also special advanced FDM courses on a variety of topics not covered in these 3 modules. An International FDM Certification examination is available for those practitioners that have taken all 3 modules and have at least 1 year experience practicing in the FDM. FDM instructors certified by the AFDMA must meet several criteria, including time spent practicing FDM, assisting with module instruction, and presenting cases at modules. Certified instructors by default have years of experience using and teaching FDM.

Conclusion The fascial distortion model offers promise as a means of efficiently and quickly returning patients to full activity with faster results than traditional methods, while also reducing need for pain medication and imaging. This noninvasive model of assessment and treatment is easily learned, easily implemented in any practice, and stands to enhance the relationship between patient and practitioner. The body of case reports is growing and future research stands to enhance our understanding of this effective model of treatment.

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References 1. European Fascial Distortion Model Association (EFDMA) 2012. Das Fascziendistorsionsmodell nach Stephen Typaldos D.O. Die Typaldos-Methode. European Fascial Distortion Model Association, Wien.

2. Fink M, Schiller J, Buhck H. [Efficacy of a manual treatment method according to the fascial distortion model in the management of contracted (“frozen”) shoulder.]

Z Orthop Unfall. 2012;150(4): 420–427. [Article in German] 3. Richter D, Karst M, Buhck H, et al. Efficacy of fascial distortion model treatment for acute, nonspecific low-back pain in primary care: a prospective controlled trial.

Altern Ther Health Med. 2017 Jun 23. pii: AT5522. [Epub ahead of print] 4. Anker S. Interrater reliability in evaluating the body language based on the Fascial Distortion Model (FDM). Masterthesis. Vienna School of Osteopathy, Danube University Krems – Centre for Traditional Chinese Medicine and Complementary Medicine.

2011. Available at: afdma.com/wp-content/uploads/2016/11/23_Anker.pdf.

5. Stechmann K. Interrater-reliability within the fascial distortion model using patient’s body language and subjective verbal complaint for pain. 2011. University of Applied Science and Arts, Hildesheim. Available at: www.fasciacongress.org/2015/ Abstracts/48_Stechmann.pdf.

6. Baird CJ, Shumate SM, Tancredi MPJ, et al. The effects of the fascial distortion model on chronic hamstring tightness. Topics Integr Health Care. 2014;5(3):ID: 5.3004.

7. Boucher JD, Figueroa J. Restoration of full shoulder range of motion after application of fascial distortion model. J Am Osteopath Assoc. 2018;118(5):341-344.

Q 3 | 2018

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NAR4-US-0309 Adapt Pharma, Inc. Radnor, PA

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abstract: Adults aged 65 years and older account for utilization of 30% of prescription medications and 50% of over-the-counter (OTC) medications.1 Of this population, more than 80% take more than one medication daily. The community dwelling older adult takes an average of 4 medications daily and those living in nursing homes take an average of 9 medications daily. As many as 12% of older adults use 10 or more different medications.1 Accordingly, medication regimens should be reviewed at the onset of any new symptom in an older adult for potential adverse drug reactions (ADR). An ADR is defined as “an appreciably harmful or unpleasant reaction resulting from an intervention related to the intentional use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen or withdrawal of the product.”2 An understanding of the pharmacokinetic changes and principles of pain management in the older adult will inform decision making around medication selection and dosing.

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Q 3 | 2018

and the older adult

One study found that when compared with persons taking 4 or fewer medications, the risk of an ADR nearly doubled (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.35–2.68) for persons taking 5 to 7 medications, and quadrupled (OR 4.07, 95% CI 2.93–5.65) for those taking 8 or more medications.3 In patients 65 years of age and older, the actual incidence of ADR with 2 medications is 13%, with 5 medications 58%, and with more than 7 medications 82% to 87%.4 As with increasing medication utilization, increasing age is also associated with an increased risk of ADR. The risk of ADR in young children (less than 10 years old) is 30 ADRs per 10,000 persons and steadily climbs over the decades as people age into their 80s, up to as many as 60 ADRs/10,000 people.5 Older adults are at higher risk of using potentially inappropriate medications, having decreased adherence to medication regimens, increased risk for medication errors, increased cost, and increased morbidity and mortality.6 There are many reasons why polypharmacy may happen, many of which can be mitigated by streamlining prescribing as well as implementing deprescribing practices. Many older adults have multiple chronic diseases for which disease-specific guidelines recommend different treatments for each disease state.7 In the ever-specializing world of medicine, patients may have multiple specialists prescribing for their focused problems. There is a shortage of healthcare professionals trained in geriatric pharmacotherapy as well. Finally, the pharmacokinetic and pharmacodynamic changes of the older adult put them at an inherent increased risk for sensitivities to many medications.8,9

Q 3 | 2018

Pharmacokinetic Changes

There are many changes in the older adult’s pharmacokinetic parameters that result in increased sensitivity and altered responses to medications. Routes of administration can affect the absorption of drugs differently than might be expected in the younger adult.8 Changes in body composition and protein binding lead to increased distribution of lipid soluble medications and increased free-fraction of highly protein-bound drugs.8,9 Metabolism is slower and drugs that rely on phase 1 reactions are more likely to accumulate, especially given that the renal elimination of any metabolites will be slower.9 The aging kidney loses about 30% of its mass, including a 60% loss of glomeruli, between the ages of 30 and 90.10 For a summary of the more specific pharmacokinetic changes in older adults, see Table 1 on following page.

Many medications used in the treatment of pain and other associated symptoms require renal dose adjustment. Of the analgesics, morphine, codeine, tramadol, and NSAIDs all should be used with caution or avoided in renal impairment. Gabapentin, pregabalin, topiramate, and oxcarbazepine also require renal dose adjustment. Antidepressants, including buproprion, duloxetine, paroxetine, and venlafaxine, also require dose adjustment. In general, decrease initial doses of medications (50%) and consider longer dosing intervals for those medications that are highly lipophilic or renally excreted. www.painweek.org | PWJ

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Table 1. Pharmacokinetic Changes in the Older Adult 7-9 Pharmacokinetic Parameter

Biologic Changes in the Older Adult

Absorption

Oral (PO): ●● Increased gastric pH ●● Decreased motility, intestinal blood flow, and gastric output Intramuscular (IM): ●● Decreased muscle mass and peripheral circulation ●● Increased connective tissue Topical: ●● Decreased skin hydration, surface lipids, peripheral circulation ●● Increased keratinization

Distribution

Body composition: ●● Increased body fat (18% to 45 %) ●● Decreased muscle mass, cardiac output, water Protein binding: ●● Decreased serum albumin and protein affinity ●● Increased alpha-1 glycoprotein

Metabolism

Reduced phase 1 reactions: ●● Diazepam, amitriptyline, chlordiazepoxide Active metabolites: ●● Benzodiazepines: diazepam, chlordiazepoxide ●●TCAs: amitriptyline, imipramine ●● Antipsychotics: chlorpromazine, thioridazine ●● Opioids: morphine, meperidine

Excretion

Renal function: ●● Decreased renal blood flow, renal tubular secretion ●● Decreased muscle mass; decreased drug clearance

Pharmacodynamic Changes

While pharmacokinetic changes account for most of the alterations seen in the older adult, pharmacodynamic changes are more variable and not as well understood. There are changes seen in the numbers and sensitivity of receptors as well as counter regulatory mechanisms.9 Examples of pharmacodynamic changes include increased risk of tardive dyskinesia and Parkinsonism with antipsychotics, increased sensitivity to the anticholinergic effects of medications, as well as increased sensitivity to warfarin and NSAIDs.

There are many medications on the Beers list that are commonly used in pain management and palliative care. General types of medications to avoid, or to use with considerable caution include: ○○ Medications with anticholinergic burden— such as tricyclic antidepressants (TCAs) ○○ Muscle relaxants—such as cyclobenzaprine ○○ First generation antihistamines—such as diphenhydramine ○○ Anticholinergics—such as dicyclomine, hyoscyamine

Potentially Inappropriate Medications (PIMs)

PIMs are medications or classes of medications that should generally be avoided in persons 65 years of age and older. These medications are either ineffective or pose an unnecessarily high risk and there is a safer alternative available.11 The prevalence of these medications in older adult outpatients is estimated to from 20% to 65%.12 The American Geriatric Society has developed the Beers List of medications, which is the most widely used consensus data for inappropriate medication use in the older adult.13 The original was created in 1991, with the most recent update in 2015. This reference is readily available and serves to identify the categories of high-risk agents and individual offenders in the older adult population.

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○○ Medications with significant sedative central nervous system properties—such as opioids, barbiturates, benzodiazepines, sedative hypnotics ○○ Medications with orthostatic properties—such as clonidine, spironolactone ○○ Appetite stimulants—such as megestrol acetate, mirtazapine ○○ Dopamine receptor antagonism—such as antipsychotics, metoclopramide When reviewing or recommending a medication, considerations should also include medication interactions with other elements, such as food, OTC medications, alcohol, caffeine, Q 3 | 2018

There are many changes in the older adult’s pharmacokinetic parameters that result in increased sensitivity and altered responses to medications.

Q 3 | 2018

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and smoking. A medication would also be inappropriate if it is too expensive for the patient to acquire, not accessible to the patient, or in a formulation that they cannot administer.

Pain Management Considerations

Pain occurs in 45% to 85% of older adults.14 There is no gender difference in global pain amongst 65 to 80 year olds but there is sparse data in this age group, as it is considered a vulnerable population and not included in many studies.15 Pain may be underreported as it may be attributed to getting older or for fear of looking like a “complainer.” Caregivers may give a more accurate report based on their observations.16,17 Pain may also be undertreated for fear of the older adult’s intolerances to medications, leading to reduced quality of life, decreased socialization, sleep disturbance, cognitive impairment, disability, and malnutrition.14 Undertreated pain can also lead to altered mental status and an increased risk of falls.

General Principles

There are general recommendations to keep in mind when treating the older adult. A good pain assessment is essential and a procedure for pain assessment should be established. The hierarchy of pain assessment includes, first, a self-report if achievable.18 For those patients able to self-report, use of behavioral pain assessment tools should be implemented, as appropriate. For communicative patients, this includes the visual analogue scale, the numerical rating scale, the visual rating scale and the Faces scale. The Behavioral Pain Scale (BPS) and the Face, Legs, Activity, Cry, Consolability Scale (FLACC) are options when relying on behavioral observations. Searching for potential causes is the next step, to help assess for the possible presence of pain leading to change in patient behaviors, which is the next tier. Finally, relying on proxy report to help guide assessment, and if all else fails, an analgesic trial can help assess for the possible presence of pain. Reassessment and documentation should be frequent, throughout the shift, after interventions, and at transitions.

There are general clinical principles to rely on for any older adult or any very sick and frail individual. For all analgesics, start low and go slow, but go: titration of dosing is essential to achieve symptom control. The goal is the lowest effective dose for the shortest duration possible. Polypharmacy should be avoided if possible, although there are times that it may be very rational and needed (eg, senna along with opioids). Make every effort to start only one medication at a time and if there is an agent that can treat more than one indication, aim to use this option first to decrease pill burden. Always include and optimize nonpharmacologic options, including, but not limited to, heat/cold, massage, and exercise.19

Opioids

The American Geriatric Society has recommended the use of opioids in older adults as an addition to acetaminophen.13 Older adults generally require lower doses of opioids for pain management, starting with 50% of the recommended initial adult dose.

Knowledge of the pharmacokinetics, equianalgesic dosing, and relevant adverse effects will help with agent selection. Adjuvants should also be considered and will be explored in more

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detail below. Treatment goals should be discussed at initiation of therapy and frequently reassessed along the way.

Opioid selection should be congruent with the properties of the individual medication being considered. Codeine should only be utilized in pain management for older adults after close consideration. It is a prodrug of the cytochrome P450 2D6 enzyme, has prolonged half-life in older adults, is associated with significant nausea and constipation with use, and has a dose limit for analgesic efficacy (60 mg codeine/dose).20 Tramadol and tapentadol are weak opioids with serotonin and noradrenergic effects. These agents should be used with caution in older adults as they may be associated with increased dizziness and risk of falls, as well as a propensity to lower seizure threshold.21 Although a somewhat common belief, older age does not preclude use of morphine. Morphine does rely on the kidney to eliminate its metabolites, which can have toxic effects when not efficiently eliminated. Given the known changes to the older adult’s renal function, morphine can still be used. In fact, it is less potent than many of the alternatives, so it can be dosed very conservatively and still provide analgesia. The dosing should start lower (about 50% of the recommended adult dose) and the dosing interval may be extended at first, if desired. The extended release products are associated with a greater risk of accumulation in renal dysfunction. Hydromorphone and oxycodone have metabolites as well, but they are not as clinically significant as with morphine. Lower initial doses and extended intervals may still be considered, and titrated as needed. Hydrocodone can be considered, paying close attention to the acetaminophen content of the combination products. The extended release hydrocodone product, as with the extended release hydromorphone product, is newer and may not be accessible for many patients without utilizing alternatives first. Fentanyl and methadone are highly lipophilic drugs, so potential for changes in absorption and distribution in older adults must be carefully considered. Fentanyl patches may not be as reliably absorbed if the patient is cachectic, and methadone has complicated kinetics and should only be used by clinicians trained and skilled in its use. Buprenorphine is available in patch form for chronic pain management. Given its lipophilicity, patch formulation, and extended duration of action, this agent should be carefully considered before recommending for use in the older adult.

Opioid adverse effects are a class effect. Of note in the older adult, the central nervous system effects will be more pronounced in many patients. Constipation is a predominant issue for the older adult, as well as possibly urinary retention. Other common adverse effects may occur, including nausea, pruritis, and respiratory depression. Careful agent selection, dosing, and monitoring is recommended. Maximizing nonopioid and nonpharmacologic modalities should be part of the pain management plan to help minimize the adverse effects.

Acetaminophen

Acetaminophen is indicated the treatment of pain and fever.

Evidence for acetaminophen in chronic pain is variable, but generally a first-line recommendation for pain in older adults.22 A recent Cochrane review found that acetaminophen was not beneficial for the treatment of low back pain.23 Some evidence supports that there may only be short term benefit in Q 3 | 2018

Case of an Older Adult:

What can be done?

Mrs. H. is a 75-year-old widow who lives with her daughter and was recently diagnosed with lung cancer with bone metastases. She presents with uncontrolled pain and confusion.

Past medical history: Irritable bowel syndrome (IBS), depression, hypertension, recurrent UTIs, stress incontinence, anemia, osteoarthritis Meds: sucralfate 1 gm PO TID, ranitidine 150 mg PO daily, aspirin 325 mg PO daily, alprazolam 0.5 mg PO QHS, naproxen 500 mg PO TID, oxybutynin 5 mg PO BID, dicyclomine 10 mg PO TID, lisinopril 10 mg PO daily, acetaminophen/codeine #3 PO q6hprn

Plan:

●● Consider alternative to alprazolam QHS–mirtazapine? ○○ Avoiding benzodiazepines as they may contribute to confusion and mirtazapine may also provide mood benefit ●● Palliative radiation for bone metastases? ○○ Treating the source of the pain is recommended and will help to minimize opioid doses and the need for polypharmacy ●● Consider dexamethasone course instead of naproxen ○○ Dexamethasone, a potent anti-inflammatory may provide improved analgesia while also providing some mood and appetite benefits. Short courses may help treat pain and minimize risk of longterm adverse effects. Lower doses are recommended in the older adult (dexamethasone 2 to 4 mg daily may be sufficient for analgesia) ○○ If continuing with naproxen, add on proton pump inhibitor (PPI)? ●● Given the increased risk of bleeding associated with nonselective NSAIDs, especially in the frail older adult, on concomitant aspirin, gastrointestinal (GI) protection will decrease risk of GI bleed and PPIs are preferred over H2-receptor antagonists32 ○○ Is there an indication for aspirin? ○○ Is this primary prevention? This could be considered as opportunity to deprescribe and decrease risk of bleeding ●● Consider alternative to oxybutynin which has significant anticholinergic effects ●● Consideration of an agent with less anticholinergic burden may help with confusion ●● Consider alternative to dicyclomine ○○ Dicyclomine is being used to treat IBS. There are newer agents on the market that are not anticholinergic, although cost is a consideration. She may also not need the dicyclomine as she is also getting opioids, which will likely decrease her motility ●● Opioid agent selection for pain (alternative to codeine) ○○ In combination with acetaminophen, the dose of codeine will be limited by the acetaminophen content. Codeine is also a prodrug to morphine and metabolism is hard to predict from patient to patient. A low dose of a more preferred agent would allow for titration as well as a more tolerable adverse effect profile

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osteoarthritis, and one must be cautious in generalizing this data as these apply mostly to patients less than 55 years old.24 Acetaminophen is generally considered a safe analgesic for use in the older adult population.25 When considering utilization of acetaminophen for the treatment of pain in the older adult, it is important to be aware of the maximum recommended total daily dose, as well as any consideration for organ dysfunction. The FDA maximum recommended acetaminophen dose is 4000 mg for adult patients.

Given the metabolic changes associated with aging, it would be recommended to allow for no more than 3000 mg daily, lowered to 2000 mg daily in the setting of liver or kidney dysfunction, to minimize risk of accidental overdose.26 Many patients do not realize that acetaminophen is included as an ingredient in combination prescription as well as OTC medications for things like sleep, cough, or cold. Patient education about these dosing recommendations and caution with use of combination products will promote patient safety.

Nonsteroidal Anti-Inflammatory Drugs

There are numerous nonsteroidal anti-inflammatory drugs (NSAIDs) on the market. NSAIDs are indicated for the treatment of somatic and inflammatory pain syndromes. Available NSAIDs fall on a spectrum of cyclo-oxygenase (COX)-1 or COX-2 selectivity. COX-2 selective agents (celecoxib) have a lower risk of bleeding compared to the more COX-1 selective agents (aspirin), with agents like ibuprofen and naproxen having a mixed COX binding profile. In considering the application of NSAID therapy, one must be mindful that older adults are at significantly increased risk of developing gastrointestinal bleed (GIB), especially over the age of 75.27 Concomitant administration of therapeutic anticoagulants, serotonergic agents such as antidepressants and selective serotonin/norepinephrine reuptake inhibitors (SSRI/ SNRI), or aspirin present a significant increase in risk of bleeding with NSAID use.28 Other associated risks include renal dysfunction and exacerbations of cardiac illness (congestive heart failure, hypertension), as well as risk of myocardial infarction, which may be higher in the more COX-2 selective agents. As risk of adverse effects is generally dose and duration dependent, using the lowest effective dose for the shortest amount of time possible is recommended.21 Topical NSAIDs may be preferred for localized pain as systemic absorption is minimal.29

Adjuvants

Other medications considered for the treatment of pain include antiepileptics, such as gabapentin and pregabalin. Generally, these are indicated for neuropathic pain syndromes, but have been used as part of a multimodal analgesia regimen for the treatment of many types of pain. These medications can have profound sedative effects, which older adults are sensitive to, so dosing should be individualized. It is generally recommended

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to start between 100 to 300 mg of gabapentin in the older adult, preferably at bedtime and slowly titrate to effect.21 Monitor closely for lower extremity edema as well.

Antidepressants, generally SNRIs and TCAs are used in the treatment of neuropathic pain, with duloxetine also having an indication for osteoarthritis. These medications are associated with nausea and vomiting as well as increases in blood pressure.

Venlafaxine has an abrupt withdrawal syndrome with missed doses; duloxetine may be preferred to increased tolerability.21 TCAs are not recommended in older adults as they are associated with significant anticholinergic burden and can thus lead to increased risk of altered mental status and falls.

Avoiding Polypharmacy

Polypharmacy can and should be addressed in a systematic way. There are many recommended ways in the literature to approach deprescribing.30 In an effort to avoid polypharmacy, certain steps can be utilized. The CARE (Caution and compliance, Adjusting the dose, Review regimen regularly; Educate) method is one possible approach.31 Caution and compliance to medications includes understanding side effect profiles, identifying risk factors for ADRs, considering the risk/benefit ratio, and simple dosing, as well as assessing adherence, cost, and ease of use. Adjusting the dose should always include starting with a low dose but titrating up as tolerated or indicated.

The regimen should be carefully reviewed regularly, avoiding automatic refills, assessing other sources of medications (OTCs, herbals, etc), using caution when there are multiple prescribers, and deprescribing as able. Education includes talking to the patients and caregivers of potential side effects and assisting them in making and updating a medication list.

Conclusion

Changes in the body as it ages places older individuals at greater risk for problems with their medications. Polypharmacy also increases this risk. It is important to start medications at lower doses in older individuals and to titrate up slowly while monitoring closely for adverse effects. Always consider medication and disease state interactions when prescribing or assessing an adverse effect of a medication in an individual patient.

References 1. Wallace J, Paauw DS. Appropriate prescribing and important drug interactions in older adults. Med Clin North Am. 2015;99(2):295–310.

2. Edwards R, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1212.

3. Onder G, Petrovic M, Tangiisuran B, et al. Development and validation of a score to assess risk of adverse drug reactions among in-hospital patients 65 years or older: the GerontoNet ADR risk score. Arch Intern Med. 2010;170(13):1142–1148.

4. Fulton MM, Allen ER. Polypharmacy in the elderly: a literature review.

J Am Acad Nurse Pract. 2005;17(4):123–132.

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5. Ghose K. The need for a review journal of drug use and the elderly. Drugs Aging.

1991;1(1): 2–5.

use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med. 1991 Feb 15; 114(4):257–263.

6. Boyd CM, Darer C, Boult C, et al. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay performance.

JAMA. 2005;294(6):716–724.

28. Pilotto A, Fransechi M, Leandro G, et al. Proton-pump inhibitors reduce the risk of uncomplicated peptic ulcer in elderly either acute or chronic users of aspirin/ non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2004;20:1091–1097.

7. Kornkowski MJ, Semla TP, Schmader KE, et al. Recent literature update on medication risks in older adults, 2015–2016. J Am Geriatr Soc. 2017;65:1401–1405.

29. Makris UE, Abrams RC, Gurlund B, et al. Management of persistent pain in the older patient: a clinical review. JAMA. 2014 Aug 27;312(8):825–836.

8. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology.

Pharmacol Rev. 2004;56(2):163–184.

30. Scott IA, Hilmer SN, Reeve E, et al. Reducing inappropriate polypharmacy: the process of deprescribing. JAMA Intern Med. 2015;175(5):827–834.

9. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38(8):843–853.

31. Marcu O. Bagful of pills [Microsoft Powerpoint Presentation]. 2006. Available at: https: fammed.washington.edu/network/sfm/Bagful%20of%20Pills.ppt.

10. EIDesoky ES. Pharmacokinetic-pharmacodynamic crisis in the elderly. Am J Ther.

2007;14(5):488–498.

32. Maclean CH, Pencharz JN, Saag KG. Quality indicators for the care of osteoarthritis in vulnerable elders. J Am Geriatr Soc. 2007;55:S383-S391.

11. Corsonello A, Onder G, Abbatecola AM, et al. Explicit criteria for potentially inappropriate medications to reduce the risk of adverse drug reactions in elderly people: From Beers to STOPP/START Critera. Drug Saf. 2012;35(suppl 1):21–28.

12. Davidoff AJ, Miller GE, Sarpong EM, et al. Prevalence of potentially inappropriate medication use in older adults using the 2012 Beers Criteria. J Am Geriatr Soc. 2015;63:486–500.

13. The American Geriatric Society. American Geriatrics Society updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60:616–631.

14. Prostran M, Vujovic KS, Vuckovic S, et al. Pharmacotherapy of pain in the older population: the place of opioids. Front Aging Neurosci. 2016,8:144.

15. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341:2061–2067.

16. Caltagirone C, Spoletini I, Gianni W, et al. Inadequate pain relief and consequences in oncological elderly patients. Surg Oncol. 2010;19:178–183.

17. Malec M, Shega JW. Pain management in the elderly. Med Clin N Am. 2015;99:337–350.

18. Herr K, Coyne PJ, McCaffery M, et al. Pain assessment in the patient unable to self-report: position statement with clinical practice recommendations. Pain Manag Nurs. 2011;12(4):230–250.

19. Hartjes TM, Meece L, Horgas AL. CE: assessing and managing pain, agitation, and delirium in hospitalized older adults. Am J Nurs. 2016;16(10):38–46.

20. Roxane Laboratories. Codeine sulfate tablets prescribing information. Columbus, OH. 2013 Apr. 21. Cavalieri TA. Managing pain in geriatric patients. J Am Osteopath Assoc.

2007;107(suppl 4):ES10-ES16.

22. Duncan NS, Mahan RJ, Turner SJ. Non-opiate pharmacotherapy options for the management of pain in older adults. Ment Health Clin. 2015;5(3):91–101.

23. Saragiotto BT, Machado GC, Ferreira ML, et al. Paracetamol for low back pain.

Cochrane Database Syst Rev. 2016 Jun 7;(6):CD012230.

24. Machado, GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomized placebo controlled trials. BMJ. 2015 Mar 31;350:h1225.

25. AGS Panel on Pharmacological Management of Persistent Pain in Older Persons.

Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57:1331–1346.

26. Department of Health and Human Services, Food and Drug Administration.

Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use; proposed amendment of the tentative final monograph; required warnings and other labeling. Fed Regist. 2006;71:77314–77352.

27. Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal anti-inflammatory drug

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reducing medication burden while managing chronic pain

By Ravi Prasad PhD & Jennifer Hah MD, MS

BeHaViORaL

abstract:

Chronic pain is estimated to affect approximately 100 million US adults at a cost of over half a trillion dollars per year.1 Pharmacologic treatment has historically been an integral component of managing pain and the last few decades have seen an increase in the use of opioid medication as a part of this process.2 Specific prescribing practices, including titrating to effect, open ended dose escalations, and use of medication for breakthrough pain have led to individuals being exposed to higher levels of opioids over the course of time, with a subset of this population developing opioid use disorders. Recent years have seen a dramatic increase in opioid related deaths and health complications with a concurrent rise in direct and indirect costs. The magnitude of the problem resulted in President Trump declaring the opioid crisis a public health emergency. The negative ramifications associated with opioid use have led to a critical need to change approaches to pain management. There is presently a strong impetus to help patients on high doses of opioids safely reduce their daily intake and to identify efficacious pathways to help individuals living with pain manage their conditions without relying primarily on this class of medication.

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Emerging Trends in the Opioid Epidemic

Sales of opioid medication nearly quadrupled from 1999 to 2010.3 This general time period was marked by a 500% surge in the use of oxycodone4 as well as a 5 time increase in opioid related fatalities.5 The Centers for Disease Control and Prevention (CDC) estimates 66% of drug overdose deaths in 2016 involved an opioid; furthermore, there are an average of 115 opioid related deaths in the US on a daily basis.5 Prescription opioids have been a focus of concern over the past decade. Prescription opioid overdose death rates, sales, and substance abuse treatment admissions climbed in parallel over the past decade.6 The costs associated with nonmedical prescription opioid use in the US have skyrocketed to over $50 billion annually.7 The majority of costs are related to healthcare, substance abuse treatment, and lost productivity. Consequently, opioid prescribing has received heightened scrutiny, and medical providers have begun to shy away from their liberal use for pain management. In addition, societies and professional guidelines emphasize the judicial use of prescription opioids, and indicate a need for opioid tapering when patients do not demonstrate improvements in pain and function. Legislation has been introduced and passed in some states to limit the duration of opioid prescribing for certain pain indications.

Q 3 | 2018

Until 2013, natural and semisynthetic opioids were most often responsible for overdose deaths. This category of opioids include the commonly prescribed oxycodone and hydrocodone.

However, since 2015, a new trend in opioid overdose deaths has emerged. Specifically, more opioid overdose deaths are now attributed to the category of other synthetic opioids (eg, fentanyl and tramadol) or heroin.5 This epidemic of opioid overdose deaths has increased amongst all genders and races.5 In 2016 alone, 42,249 individuals died in an overdose involving an opioid, and 40% of these deaths involved prescription opioids.5 The heightened availability of illicitly manufactured fentanyl and fentanyl analogues (eg, acetylfentanyl, furanylfentanyl, carfentanil) is demonstrated by the rising number of drug products obtained by law enforcement testing positive for fentanyl.8 A key factor in the lethality of these drugs lies in their potency, www.painweek.org | PWJ

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BeHaViORaL

as fentanyl is 50 times more potent than heroin, and 100 times more potent than morphine. The potency of these illicit fentanyl analogues is demonstrated by carfentanil, which is 10,000 times more potent than morphine. Merely using a bare hand to brush off carfentanil or inhaling minute vaporized particles of illicit fentanyl and heroin have resulted in overdoses amongst police officers. Carfentanil in particular is easily absorbed through the skin, and easily inhaled, and a single particle the size of a grain of salt may be sufficient to cause an overdose. The hazards for first responders and medical personnel have similarly increased with the rise in prevalence of these illicit opioid substances.

Consequently, in June 2017, the DEA released a briefing guide for first responders encouraging the use of personal protective equipment (gloves, safety glasses, N-95 mask, coveralls, shoe covers) when treating individuals who have overdosed. Despite the lethality of these synthetic opioids, dangerous trends have been noted in patients discharged alive from the ED or inpatient hospital settings. Specifically, ED and inpatient hospital discharges for heroin poisonings have dramatically risen and exceeded discharges secondary to prescription opioid poisonings since 2013.9 The point of ED or inpatient discharge after an overdose event represents a potential key intervention point for referral to substance use treatment programs, overdose education, and naloxone distribution.

At present, we see the intersection of the public health crises of opioid misuse, addiction, and overdose and the staggering prevalence of people suffering from chronic pain. Efforts to combat the opioid epidemic must also address the lack of effective and safe nonopioid treatments for pain management.

For patients suffering from chronic pain who have been managed with long-term opioid therapy, a singular focus on reducing access to opioids may have grave consequences in and of itself. It is possible that with reduced access to prescription opioids, patients may be driven to the use of illicit opioids with a consequent increased risk of overdose. Also, patients abruptly discontinued from opioids who are not given alternative methods for pain management may experience worsened mood and increased suicidality. More than ever, efforts to adopt the biopsychosocial treatment model of pain is needed to optimally manage pain while reducing opioids. Treatment spanning medication therapy, injections, physical therapy, and pain psychology must be promoted by all providers. Efforts to improve access to psychological care for patients suffering from pain are needed. At extremes, some patients who have received longterm opioid therapy for chronic pain are experiencing great difficulty establishing care with new providers solely due to their opioid use. In these cases, it is clear that this treatment disparity is causing great distress and despair for patients. We must not forget that we are treating patients suffering from chronic pain rather than treating opioid use in and of itself.

Hazards of Prescription Opioids

When prescribing opioids, providers should be aware of risk

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factors that increase the likelihood of prescription opioid overdose. Transitioning from another opioid to methadone increases the risk of prescription opioid overdose 7-fold. Thus, opioid rotation to methadone should be carefully monitored. Other risk factors include a prescribed oral morphine equivalent dose >50 mg per day, a history of drug or alcohol abuse, other psychiatric illness, concomitant benzodiazepine use, and use of multiple pharmacies for prescription opioid refills.10 Over 60% of patients who die in opioid related deaths received a chronic noncancer pain diagnosis in their last year of life, contrasting with only 4% who received a diagnosis of opioid use disorder.11 In addition, those decedents with a chronic pain diagnosis were more likely to have filled opioid and benzodiazepine prescriptions during the last 30 days of life and have a higher incidence of comorbid depression and anxiety.11 There are elevated rates of opioid and nonopioid abuse problems in individuals using prescribed opioids, and these results are thought to be partially influenced by the presence of other underlying mental health issues.12 The links between psychological factors and substance abuse have been well-established.13 Patients receiving longterm opioid therapy for chronic noncancer pain represent a cohort at high risk for opioid related adverse events including opioid misuse and opioid related deaths. The downstream effects of opioid misuse should not be underestimated especially as opioid misuse is independently associated with initiation of illicit opioids.14 To prevent the transition to long-term prescription opioid use and its associated adverse effects, research has focused on prescribing patterns that perpetuate opioid use. In a statewide retrospective cohort study, approximately 5% of opioid naïve patients who filled an opioid prescription became long-term users.15 This initiation of long-term use was associated with higher numbers of refills, increasing cumulative milligram morphine equivalents prescribed during the initiation month, and the initiation of long-acting opioids.15 To prevent the transition to new persistent opioid use, providers should consider limiting the number of opioid refills, curb dosages to match patient needs even when prescribing as-needed regimens, and carefully consider the need for initiating long-acting opioids.

All opioid management should co-occur in the context of optimizing pain management and initiating trials of nonopioid medications.

Crisis = Opportunity

The US Department of Health and Human Services has outlined a 5-point strategy to address the opioid crisis.16 Included in their approach is an effort to improve pain management; while this includes safer prescribing practices and encouraging the development of abuse-deterrent drugs, it also emphasizes the role of nonpharmacologic approaches to caring for individuals living with pain. Thus, in the midst of the opioid crisis, there exists an opportunity to reduce medication burden and provide evidence based, multidisciplinary care to help patients develop greater self-efficacy to manage their chronic pain conditions.

Q 3 | 2018

Clarification of Terminology A number of key terms are often erroneously used interchangeably when discussing opioid medication and development of opioid use disorders. Understanding the appropriate use of these words is critical as it can help direct treatment and can be a useful component of patient education.

Tolerance occurs when a person needs more of a substance to achieve the same effect.

Example: After starting a new rotation with late hours, Jane starts drinking coffee to help maintain alertness. After several weeks, she finds that one cup is no longer sufficient and now requires 2 cups to achieve the same degree of alertness that one cup previously provided.

She has developed tolerance to caffeine.

Physical dependence is characterized by the onset of physiologic symptoms when a substance is withdrawn.

Example: Jim has been on a beta blocker to help maintain his blood pressure for the last 5 years. He ran out of medication while vacationing abroad and developed heart palpitations and increased blood pressure.

The manifestation of these symptoms suggests the presence of physical dependence.

Psychological dependence in the context of medications refers to a perception that an individual would not be able to perform specific functions in the absence of a particular drug.

Example: Steve has maintained a number of sleep hygiene improvements to address insomnia in the last 6 months but has concurrently used a daily pharmacologic sleep aid. His PCP recently suggested that he work toward tapering his sleep medications.

Steve immediately became anxious and adamantly stated that there is no way that he would be able to sleep in the absence of the pharmacologic intervention. Steveâ&#x20AC;&#x2122;s response is suggestive of psychological dependence.

Addiction, or a severe substance use disorder, is a disease that is marked by continued engagement in a particular behavior (eg, substance use) despite the presence of adverse effects.

Example: Julie lost her job and family secondary to heroin use and acquired hepatitis C from a contaminated needle. She continues to use drugs on the street using nonsterile supplies.

Her behaviors depict heroin addiction.

BeHaViORaL

Opioid Tapering Amongst Patients with Chronic Pain

Given the hazards of long-term opioid therapy for chronic pain, recommendations to taper opioids have begun to emerge.

When patients exhibit ambivalence to reducing their opioid use, emphasize research demonstrating positive outcomes that can occur following an opioid taper. Intensive outpatient and inpatient pain rehabilitation programs conduct opioid tapering with improvements in pain severity, functioning, and mood.17-24 Patients with chronic pain who exhibit opioid misuse can undergo opioid weaning without pain escalation or decreased quality of life.25 There is a wide range in opioid weaning protocols, and many of these protocols are based on expert opinion.26-28 Indications for opioid tapering include repeated aberrant drug-related behaviors.29 It is important to note that decisions should be made in the context of a pattern of behavior rather than an isolated incident such as a single episode of inconsistent urine toxicology testing. With initial concern, restructuring of opioid therapy could include more frequent monitoring, temporary opioid tapering, or the addition of psychological therapies and other nonopioid pain treatments.29 With continued concern of repeated opioid misuse, drug diversion, lack of progress towards therapeutic goals, or demonstration of intolerable adverse effects, clinicians should consider nontemporary opioid tapering.29 Other important considerations include comorbid medical conditions, such as sleep apnea and pulmonary diagnoses, that potentiate the risk of opioid induced respiratory depression. In addition, sentinel events including medication related falls may signal the need for opioid tapering and dose reduction.

It is particularly important to note that much of the evidence to date regarding opioid tapering does not address involuntary tapering and definitive opioid discontinuation. Rather, a systematic review of 67 studies spanning 11 randomized trials and 56 observational studies of dose reduction or discontinuation of long-term opioid therapy demonstrates a heterogeneous mix of interdisciplinary pain programs and behavioral interventions used in the context of opioid tapering.30 The majority of studies report opioid dose reduction, but discontinuation rates were highly variable. More evidence is needed to differentiate between the clinical benefits of dose reduction vs discontinuation amongst patients receiving long-term opioid therapy for chronic pain. The encouraging theme of these studies echo improvement in pain severity, function, and quality of life.30 Even psychological interventions addressing the treatment of chronic pain with an optional component of opioid dose reduction can result in sustained reductions in opioid dose months after the completion of treatment.30 Similarly, a group intervention of cognitive behavioral therapy and mindfulness meditation amongst patients receiving long-term opioid therapy indirectly reduced opioid use.30 Thus, voluntary opioid dose reduction amongst patients receiving long-term opioid therapy is likely beneficial. However, the evidence base for involuntary opioid tapering or discontinuation is much less definitive, and future research must examine the downstream effects on patients.

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The details of opioid tapering regimens still largely rely on society guidelines and expert opinion. Weekly dose reductions of 10% or 25% to 50% dose reductions every few days are provided as examples.29 At doses greater than 200 mg/day of oral morphine equivalents, tapering speed can be more rapid due to tissue saturation with opioids.29 As patients reach lower doses in the range of 60 to 80 mg/day of oral morphine equivalents, clinicians should consider reducing the rate of opioid tapering as patients are more likely to experience opioid withdrawal symptoms.29 Considerations for holding opioid tapering or increasing doses should be measured in the context of increased pain, severe opioid withdrawal symptoms, or worsening mood. Pharmacologic therapy can be prescribed to reduce opioid withdrawal symptoms. For example, clonidine 0.1 to 0.2 mg PO q6hrs or clonidine 0.1 mg/24hrs TD weekly can be prescribed to curb opioid withdrawal symptoms. Concordantly, more frequent patient follow-up for assessment of opioid withdrawal symptoms with shorter refill intervals is likely beneficial for promoting patient adherence to the medication regimen.

Transitioning to long-acting opioid formulations at scheduled doses with a consistent daily schedule may minimize the psychological reliance on pill-taking behavior as a pain coping mechanism. Throughout the course of opioid tapering, providers should continue to optimize pain management through the lens of interdisciplinary pain management with consideration of nonopioid analgesics, interventions, physical therapy, and behavioral interventions.

The CDC has released guidelines for prescribing opioids for chronic pain that also address indications for opioid tapering or discontinuation. Aligned with earlier recommendations, patients demonstrating no improvement in pain and function with opioid therapy, receiving high-risk regimens (eg, ≥50 mg oral morphine equivalents daily, concomitant benzodiazepine use) without benefit, expressing a desire for opioid dose reduction or discontinuation, having a history of overdose or serious opioid-related adverse event should be considered for opioid tapering.31 Weekly dose reductions of 10% to 50% of the original dose are recommended. However, more rapid tapers over the course of 2 to 3 weeks may be indicated in the context of recent overdose events.31 It is important to note that slower tapers may be more appropriate in the context of longer durations of preceding opioid therapy.31 Although opioid withdrawal is generally safe and not associated with mortality, pregnant women are at risk for spontaneous abortion and premature labor in the context of opioid withdrawal, and the risk of continued opioid therapy vs opioid discontinuation and tapering must be balanced.31 Similarly, ultrarapid opioid detoxification under anesthesia is associated with significant risks including death.31 The decision to proceed with opioid tapering and discontinuation, and the details of the opioid taper must be a collaborative, personalized process between providers and patients. To facilitate success, providers must empathize with the patient’s experience.32 Taking the time to acknowledge emotions of frustration, anger, or anxiety will allow providers to understand Q 3 | 2018

Considerations for holding opioid tapering or increasing doses should be measured in the context of increased pain, severe opioid withdrawal symptoms, or worsening mood. Pharmacologic therapy can be prescribed to reduce opioid withdrawal symptoms.

the individual patient’s circumstances and barriers to opioid tapering. Similarly, it is important to prepare patients for opioid tapering.32 Taking the time over multiple visits to identify a patient’s own motivations for opioid tapering will enhance their commitment and adherence. Describing the details of the opioid tapering process and setting appropriate patient expectations is likely to decrease the anxiety associated with the reduction of pain medications. Individualizing the implementation of opioid tapering is another important piece.32 It is important to consider each patient’s psychosocial situation to decide on the appropriateness of outpatient vs more resource-intensive inpatient settings. It is helpful to consider key barriers in prior opioid tapering attempts. For example, removing home or work related stress during the initiation of opioid tapering may facilitate adherence. Thus, inpatient or intensive outpatient rehabilitation programs may be a better option in this situation. Conversely, it is important to explore previous successful opioid tapering attempts, and highlight the patient’s own strength and commitment. Another key piece in the opioid tapering conversation includes citing supportive guidelines and policies. Patients will benefit from this additional education in understanding the urge for opioid tapering from their providers.

As research regarding the tapering or discontinuation of longterm opioid therapy continues to evolve, future interventions must consider patient barriers to opioid tapering, and strategies to enhance patient engagement and adherence to opioid Q 3 | 2018

tapering. One important gap is consideration of less resource intensive models of opioid tapering that can be delivered in the context of interdisciplinary pain management. In addition, prospective, longitudinal studies must examine the long-term effects of opioid tapering or discontinuation with respect to overdose and suicide attempts. Furthermore, studies examining the impact of mandatory opioid tapering are needed to address the best course of action in treating patients with comorbid pain and substance use disorders. The benefits and harms of medication assisted treatment in this patient subset should be examined.

At present, patient-provider communication is a key piece to facilitating opioid tapering. Beyond generalized concerns, patients must understand their individualized indications for opioid tapering.33 Similarly, patients benefit from having direct input regarding their medication regimen.33 For example, making small adjustments in the opioid tapering rate based on patient input enhances patient engagement. Difficulties often arise when patients and providers do not reach a shared understanding of the treatment plan.33 Throughout the entire tapering process, providers should emphasize to their patients that they will not be abandoned.33 Too often, patients become defensive and fearful as they perceive their provider is planning to discontinue the treating relationship after opioid discontinuation. Acknowledgement of these fears, and communication regarding partnership in treatment and nonabandonment, is likely to enhance patient engagement during and long after opioid tapering. www.painweek.org | PWJ

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BeHaViORaL

Multidisciplinary Pain Management

All pain is not the same. Acute pain alerts individuals to harm that is occurring in a part of the body so that protective measures can be taken to minimize tissue damage. It often has a clear cause, a defined treatment pathway, and a fixed endpoint.

Conversely, chronic pain—while absolutely real—does not signify the presence of active harm that requires immediate intervention. It may be the by-product of a previous injury or an aspect of a longer standing degenerative condition. Its etiology is often ambiguous and multifactorial and it unfortunately does not have a fixed end point.

The differences between acute and chronic pain necessitate unique treatment approaches for each. Acute pain conditions can often be successfully addressed using a purely biomedical approach that focuses on organic pathology and medical interventions to address them. Chronic pain conditions are much more complex: regardless of their cause, it is recognized that substances, stressors, and emotional states can all affect the trajectory of the pain condition itself. Optimally treating chronic pain thus requires a biopsychosocial approach that addresses all of the biological, psychological, and social factors that may be playing contributory roles.34 This is most commonly characterized by a team comprised of specialists representing different disciplines working together to help patients better manage their pain symptoms so that they can achieve higher quality of life. Team members often include a combination of medical professionals (eg, MD/DO, NP, PA), rehabilitation providers (eg, physical and occupational therapists), and mental health/behavioral specialists (eg, psychologists). Such multidisciplinary approaches to pain subsequently focus on functional improvement rather than pain amelioration, although it is not uncommon for the latter to occur as a consequence of the former.

The psychological/behavioral component of multidisciplinary pain care focuses on teaching patients strategies that they can use to improve pain self-efficacy. Common curriculum components frequently include: ○○ Developing an understanding of chronic pain ○○ Stress physiology ○○ Relaxation training ○○ Sleep hygiene ○○ Activity regulation/pacing ○○ Mindfulness approaches ○○ Stress management strategies ○○ Communication skills development ○○ Flare management planning Patients learn the aforementioned skills either in individual or group based formats. Of paramount importance is application

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of the information: the ability to articulate an understanding of the material is a necessary component to cultivate behavioral change but by itself is not sufficient to make such transformation occur. Treatment subsequently involves extensive home practice. Inclusion of members of the patient’s family and social support network is encouraged whenever possible, as pain affects the entire system in which a person lives and vice-versa.35 Townsend and colleagues19 examined 373 individuals who participated in a comprehensive pain rehabilitation program that included multiple behavioral interventions. Approximately 57% of the participants were on opioids at the start of the 3 week program and their medications were reduced as they progressed through treatment. These individuals scored higher on assessments of pain severity and depression compared to nonusers. Upon completion of the program, all participants showed significant improvement on pain severity, depression, psychosocial functioning, health status, and pain catastrophizing, regardless of opioid status. All gains persisted at 6-month follow-up. Other studies have demonstrated successful opioid cessation in the context of participation in comprehensive multidisciplinary treatment programs and have similarly found improvements on a wide range of functional and psychosocial variables.36 More importantly, there is evidence that such changes are sustainable on a long-term basis.37 Taken together, the aforementioned suggests that patients who have historically had biomedically focused pain care and exhibit signs of physical or psychological dependence on opioid medication may be excellent candidates for multidisciplinary pain care, and that participation in such treatment may yield long-term benefit. There is a low likelihood that opioid reduction or cessation in the absence of other forms of treatment may yield similar results.

Substance Abuse Treatment

Individuals who have developed addiction to opioid medication will require formal substance abuse treatment. MedicationAssisted Treatment (MAT) combines FDA-approved medications with counseling and behavioral interventions to address the full spectrum of biopsychosocial factors that may be contributing to the substance use disorder. It is important to note that pharmacologic treatment by itself is not complete treatment for addiction.

Conclusion

The latter part of the 20th century was remarkable for a sharp rise in in the use of opioids to treat pain. This was accompanied by a corresponding escalation in the number of overdose deaths and has been associated with significant societal and financial impacts. The present predicament has cast a spotlight on prescribing patterns and has also renewed interest in the application of multidisciplinary approaches to pain management. The Q 3 | 2018

latter is the silver lining of a dark cloud: treatment pathways that incorporate pharmacologic and nonpharmacologic treatment interventions can not only help address the current opioid crisis, but they can provide a sustainable approach to addressing the burgeoning pain problem in this country.

19. Townsend CO, Kerkvliet JL, Bruce BK, et al. A longitudinal study of the efficacy of a comprehensive pain rehabilitation program with opioid withdrawal: comparison of treatment outcomes based on opioid use status at admission. Pain.

2008;140(1):177–189.

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Addiction. 2016;111(11):2021–2031.

15. Deyo RA, Hallvik SE, Hildebran C, et al. Association between initial opioid prescribing patterns and subsequent long-term use among opioid-naive patients: a statewide retrospective cohort study. J Gen Intern Med. 2017;32(1):21–27.

16. Services UDoHaH. National opioid crisis: Help, resources, and information.

Available at: www.hhs.gov/opioids.

17. Hooten WM, Mantilla CB, Sandroni P, et al. Associations between heat pain perception and opioid dose among patients with chronic pain undergoing opioid tapering. Pain Med. 2010;11(11):1587–1598.

20. Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients after detoxification from high-dose opioids. J Opioid Manag. 2006;2(5):277–282.

22. Younger J, Barelka P, Carroll I, et al. Reduced cold pain tolerance in chronic pain patients following opioid detoxification. Pain Med. 2008;9(8):1158–1163.

23. Cunningham JL, Evans MM, King SM, et al. Opioid tapering in fibromyalgia patients: experience from an interdisciplinary pain rehabilitation program. Pain Med. 2016;17(9):1676–1685.

24. Harden P, Ahmed S, Ang K, et al. Clinical implications of tapering chronic opioids in a veteran population. Pain Med. 2015;16(10):1975–1981.

25. Nilsen HK, Stiles TC, Landro NI, et al. Patients with problematic opioid use can be weaned from codeine without pain escalation. Acta Anaesthesiol Scand.

2010;54(5):571–579.

26. Bowens CD, Thompson JA, Thompson MT, et al. A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med. 2011;12(5):504–511.

27. Parran L, Pederson C. Effects of an opioid taper algorithm in hematopoietic progenitor cell transplant recipients. Oncol Nurs Forum. 2002;29(1):41–50.

28. Wang H, Akbar M, Weinsheimer N, et al. Longitudinal observation of changes in pain sensitivity during opioid tapering in patients with chronic low-back pain. Pain Med. 2011;12(12):1720–1726.

29. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–130.

30. Frank JW, Lovejoy TI, Becker WC, et al. Patient outcomes in dose reduction or discontinuation of long-term opioid therapy: a systematic review. Ann Intern Med. 2017;167(3):181–191.

31. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. JAMA. 2016;315(15):1624–1645.

32. Kennedy LC, Binswanger IA, Mueller SR, et al. “Those conversations in my experience don’t go well”: a qualitative study of primary care provider experiences tapering long-term opioid medications. Pain Med. 2017 Nov 4. [Epub ahead of print] 33. Matthias MS, Johnson NL, Shields CG, et al. “I’m not gonna pull the rug out from under you”: patient-provider communication about opioid tapering. J Pain.

2017;18(11):1365–1373.

34. Longnecker DE, Newman MF, Mackey S, et al. Anesthesiology. 3rd edition.

New York: McGraw-Hill Education; 2017.

35. Krahe C, Springer A, Weinman JA, et al. The social modulation of pain: others as predictive signals of salience - a systematic review. Front Hum Neurosci. 2013;7:386.

36. Gilliam WP, Craner JR, Cunningham JL, et al. Longitudinal treatment outcomes for an interdisciplinary pain rehabilitation program: comparisons of subjective and objective outcomes on the basis of opioid use status. J Pain. 2018;19(6):678–689.

37. Huffman KL, Rush TE, Fan Y, et al. Sustained improvements in pain, mood, function and opioid use post interdisciplinary pain rehabilitation in patients weaned from high and low dose chronic opioid therapy. Pain. 2017;158(7):1380–1394.

18. Hooten WM, Townsend CO, Sletten CD, et al. Treatment outcomes after multidisciplinary pain rehabilitation with analgesic medication withdrawal for patients with fibromyalgia. Pain Med. 2007;8(1):8–16.

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• • •

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

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

key topic

about appropriately utilizing opioid analgesics to treat chronic pain have taken many twists and turns over the past 25 years.

During this period, in addition to debates about longterm efficacy of chronic opioid therapy, we have witnessed what many call a growing “opioid crisis or epidemic.” Regulatory agencies, governing bodies, healthcare systems, and other stakeholders have looked towards changing prescribing practices of healthcare professionals as an important solution to battling the increasing number of opioid related overdose deaths. Law enforcement officials have ramped up efforts to hinder street-corner drug dealers. Unfortunately, technology-enabled illicit channels of distribution of opioids and other drugs via the internet seem positioned to significantly hinder these efforts. This article provides a background of the “swinging opioid pendulum” and its unlikely intersection with a virtual marketplace for all things illegal, including opioid drugs—the Darknet.

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It seems as if almost every possible permutation of attitudes towards opioid analgesics one could imagine has occurred over the past 25 years. A summarization of the big “pendulum swings” regarding opioid prescribing includes when we witnessed, in the late 1990s, criticism of the medical community for not considering chronic pain as a bona fide medical condition worthy of attention and treatment. We saw demands for compassionate treatment of people with chronic pain with the intention of ending undertreatment and the call to provide more compassionate pain care. In 2000, pain was designated the Fifth Vital Sign, and the Pain Patient’s Bill of Rights was developed and disseminated. Many feel (including this author) that the subsequent increase in opioid prescribing was a direct response to these demands, with more liberal prescribing of opioid analgesics for chronic becoming the norm.

Data has shown that over this period, the number of opioid related overdose deaths increased in parallel with increases in opioid prescribing.1 Pharmaceutical manufacturers have been accused of contributing to this problem in a number of ways, including marketing strategies which minimized—or in some cases negated—the risk and likelihood of aberrant drug related behaviors, such as abuse, dependency, and addiction. Fiery and passionate debates about opioid overuse subsequently ensued and continue today. And although it took a while, significant adverse effect profiles of nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, became less important than the number of people succumbing to overdose deaths involving an opioid of some kind. The multidisciplinary pain clinic model flourished and then dwindled because of numerous challenges including absent or dwindling reimbursement from payers.

For many today, the “opioid pendulum” has swung in the opposite direction of liberal prescribing, towards only prescribing these opioid analgesics when all other modalities have been tried and failed. Amid the Q 3 | 2018

controversy, pain education has remained something that uniformly is sparse, fragmented, inconsistent, and voluntary despite pain being the most common reason that people seek medical attention.2 In fact, educational deficits continue to exist despite the fact that almost every regulatory stakeholder (and there are a lot of them) has recommended healthcare professional, patient, and community level education as an important pillar of battling the opioid crisis/epidemic.

Many other silver bullets to battle this “crisis” other than education have been proposed, implemented, and even mandated with the goal of doing one thing: stopping or at least stemming the seemingly ever-increasing number of opioid related deaths. Risk mitigating efforts and tools and tactics—such as new guidelines, opioid agreements, obtaining informed consent, utilizing urine drug screening and other opioid risk-predicting tools, querying prescription drug monitoring programs, and increased availability of naloxone—have been promoted as ways of undoing the damage of increased prescribing.

These changes and updates make sense if we presume that opioid related overdose deaths are only related to things that directly take place in the context of a healthcare linked environment; things that are related to chronic pain patients and legitimate healthcare provider opioid prescribing. Current thinking of many supports the idea that there is a direct causal relationship between prescribing and overdose deaths. Recommendations include more prudent assessment and prescribing, less opioid medication being dispensed with each prescription, using lower doses and shorter periods of duration when opioid prescribing is appropriate, and relying more on nonopioid based pain treatments and techniques. Admittedly, and argued by many, one significant negative outcome of these trends may be unintentionally denying access of opioids to those who need them, making chronic pain patients pay a drastic price resulting from those who misuse, abuse, and become addicted, and die from unintentional overdoses. www.painweek.org | PWJ

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key topic

fraction of what exists on the internet. The visible and familiar part of the web is referred to as the surface web.

But there is much more to the web than what we typically access and the information we retrieve through search engines, online shopping websites, and electronic communications. Surprisingly, there is an entire universe of the web (some estimate as much as 96% of it) below the surface that is virtually invisible to our commonly used web browsers. It is known as the deep web.

It turns out that there another contributor to the opioid epidemic that is far removed from what we know, think, and recognize in a clinical world, a significantly darker dimension which ignores regulatory, clinical, and law enforcement efforts.

It is fair to say that the World Wide Web (or the internet) is ubiquitous for most if not all of us around the world.

We probably have some familiarity about the basics of the web: that it’s actually a combination of resource materials (identified by uniform resource locators or URLs) and users linked to each other by Hypertext Transfer Protocol (http). While this is a bit of an oversimplification, for all intents and purposes, the internet is the network or platform that provides a place for the web to exist, and for information to be exchanged. From a privacy perspective it is important to know that whether we realize it or not, when we “surf the web” our identity and location are often discoverable through individual Internet Protocol (IP) addresses linked to our computers, modems, or routers.

You may be asking yourself what this all has to do with healthcare, opioids, and overdose deaths. Well as it turns out, what we think we know about the web is just a small

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The deep web is home to a dark virtual marketplace where one can go to find pretty much anything desired and/or illegal for sale. As if this isn’t scary enough, inside this deep web is a cavernous niche that users can visit and operate with complete anonymity: the Darknet or dark web.3 Inside the confines of the Darknet, without being tracked, people can access “dark” websites that have everything from assassins for hire to illegal weapons, fake IDs, and drugs. Think of an unlimited black-market for just about anything against the law you can imagine.

Unlike the web browsers most of us use, like Firefox®, Edge®, or Chrome®, to access the Darknet multiple steps are taken to ensure that the user remains anonymous. The most common Darknet web browser is called The Onion Router or Tor. Perfectly legal and free to download, Tor looks and performs just like a standard web browser. Ironically and much like the internet itself, Tor was created by the government at the U.S. Naval Research Laboratory with the initial purpose of protecting sensitive military communications. In fact, emphasizing privacy through encryption was the main goal of developing Tor. When connecting to a dark website through Tor, your computer’s identity goes through enough of a series of relays to other computers on the internet and gets “cleaned” until it reaches complete anonymity, ultimately arriving at the destination website.

Even though the dark website you visit has the ability to see which parts of the site are being accessed, it cannot identify who you are, with the path back to the user being a virtually blind trail.

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In the midst of a worsening opioid overdose epidemic, with many looking to healthcare providers to solve it and prevent it from spiraling further out of control, is this deep, dark, and anonymous valley on the web where things illegal are freely available. This includes access to drugs, all types and formulations of opioid drugs, mainly synthetic ones like fentanyl, but also counterfeit ones and, to a lesser degree, natural ones, like heroin.

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of Darknet-acquired synthetic or counterfeit drugs containing illicit fentanyl.

In the midst of a worsening opioid overdose epidemic, with many looking to healthcare providers to solve it and prevent it from spiraling further out of control, is this deep, dark, and anonymous valley on the web where things illegal are freely available. This includes access to drugs, all types and formulations of opioid drugs, mainly synthetic ones like fentanyl, but also counterfeit ones and, to a lesser degree, natural ones, like heroin.4 Estimated to be rapidly becoming even more powerful than streetcorner selling drug cartels and dealers, Darknet online shopping for illicit synthetic opioids is reaching every corner of the country and the rest of the world outside of the purview and control of the healthcare system, in many cases with the unwitting assistance of our very own United States Postal System (USPS), paid for with untraceable encrypted digital currency like Bitcoin.5 A recent New York Times article quoted Kathryn Haun, a prosecutor in San Francisco, stating that the dark web has become an important source of illegal sales of synthetic opioids because it has enabled illicit distribution channels which previously did not exist.6 In fact, when the article was written, June 2017, one of the leading Darknet market sites, AlphaBay, had more than 21,000 individual listings for opioids for sale, including 4,100 just for fentanyl and similar drugs in a variety of formulations, including pills, powders, and sprays.

In May of 2017, federal authorities charged a 6-person operation in Utah that was purchasing fentanyl in bulk from China, and then selling it on the Darknet. With a high level of sophistication, Darknet websites like AlphaBay are full service websites complete with social media forums, buying recommendations, and everything else you might expect to see on an online shopping website.

From states like South Carolina, New Jersey, and Ohio, across the Pacific to Asia and everywhere in between, Darknet vendors are freely selling dangerous and potentially fatal illicit opioids to completely anonymous purchasers. Members of the Drug Enforcement Administration (DEA) have been quoted as saying that the Darknet has taken on a key role in the opioid overdose crisis in our country, outside the purview of law enforcement officials.7 This is a global problem, and while the US is not the only country dealing with the impact of mail-order opioids and fatalities, it has significantly more fentanyl related overdoses compared to other countries. In many cases this tracks back to Darknet websites and the unwitting help of commercial delivery services like the USPS or United Parcel Service (UPS).8 High profile overdose deaths like the one involving Prince are thought to be the result

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With Darknet marketplaces continuing to thrive and multiplying despite the recent dismantling of 2 of the most high-profile and prolific opioid-selling sites, Silk Road and AlphaBay, a new government task force has been created, the Joint Criminal Opioid Darknet Enforcement team or J-CODE. Targeting vendors who sell illicit fentanyl by mail9 J-CODE more than doubles the FBI’s involvement in fighting opioid trafficking. Some organizations have expressed concerns about preserving the right to privacy on the Darknet in the face of fighting the opioid epidemic and illicit drug sales, and this is poised to be another fiery and passionate debate. For now, it seems that the sheer number of Darknet websites and the ease of manufacturing synthetic opioids pose a difficult challenge.10 One study about the impact of the Darknet on substance abuse and harm trajectories yielded concerning findings.11 Purchasers of illicit drugs were surveyed and queried about their experiences of purchasing illegal drugs the Darknet way and were freely willing to answer. Responses included:

“We no longer need a drug dealer” “We essentially knew the quality would be good based on reviews” “Whatever we had the cash for, we knew we could have it the next day” “It was like being a kid in a candy store” These researchers concluded that, from an epidemiological perspective, while there is no question that increased availability is related to increased harm, inversely the ability to purchase “portions” of drugs at will may have contributed to some degree of harm reduction. They also noted that the closure of one Darknet website did not deter purchasers from finding a replacement.

Q 3 | 2018

realize there may be much more to solving this problem than prescribing guidelines or dosing limits alone are able to fix.

Fighting in the dark can be difficult. We need to be scared of this “dark,” but with no end to the opioid crisis in sight, we cannot let fear inadvertently deny people with chronic pain the treatments they need.

References: 1. The Opioid Epidemic: by the numbers. Department of Health and Human Services. 2016. Available at: www.hhs.gov/sites/default/files/Factsheetopioids-061516.pdf.

2. Mezei L, Murinson B. Pain education in North American medical schools.

J Pain. 2011;12(12):1199–1208.

3. Going dark: the internet behind the internet. NPR – All Things Considered.

Available at: www.npr.org/sections/alltechconsidered/2014/05/25/3158214 15/going-dark-the-internet-behind-the-internet.

4. Duxbury SW. The network structure of opioid distribution on a darknet cryptomarket. J Quant Criminol. June 2017:1–21.

As the marketplace on the Darknet and manufacturers of synthetic opioids continue to proliferate, we are left with lingering questions. How can authorities and law enforcement successfully combat a global internet based platform like the Darknet? What role, if any, can/ do healthcare professionals play in combating the Darknet and its role in increasing the number of opioid overdoses? Is there a link between purchasers of illicit opioids on the Darknet, legitimate prescribing practices, and patients with chronic pain? Will more and more opioid abusers turn to the Darknet to acquire these medications if other sources become less available? Is increased regulation of the internet and risk of sacrificing privacy a tenable solution to stop this illicit channel?

The unexpected intersection of technology and healthcare in the battle against the opioid overdose problem presents a unique set of challenges that may be surprising, unexpected, and unrecognized by clinicians, regulatory agencies, and law enforcement officials. It is always our responsibility when prescribing opioid analgesics to be aware of what may happen in high risk situations where abuse or misuse may be likely. This potential contributor to the opioid overdose epidemic requires us to be aware and vigilant of people obtaining illicit opioids via the Darknet, and for all stakeholders to Q 3 | 2018

5. Masoni M, Guelfi MR, Gensini GF. Darknet and Bitcoin, the obscure and anonymous side of the internet in healthcare. Technol Health Care.

2016;24:969–972.

6. Popper N. Opioid dealers embrace the dark web to send deadly drugs by mail. The New York Times, DealBook Business and Policy. June 10, 2017.

7. Singer JA. While politicians cut opioid prescriptions, fentanyl – with the help from the “dark web” and the USPS – becomes the number one killer.

The Cato Institute, Cato at Liberty. May 23, 2018.

8. CBS News. It’s easy to buy opioids on the so-called darknet, FBI says.

April 13, 2018. Available at: www.cbsnews.com/news/opioid-fentanyl-darknetdrugs-fbi/.

9. United States Department of Justice. Attorney General Sessions announces new tool to fight online drug trafficking. January 29, 2018.

Available at: www.justice.gov/opa/pr/attorney-general-sessions -announces-new-tool-fight-online-drug-trafficking.

10. Pergolizzi JV, LeQuang JA, Taylor R, et al. The “darknet”: the new street for street drugs. J Clin Pharm Ther. 2017;42(6):790.

11. Barratt MJ, Lenton S, Maddox A, et al. ‘What if you live on top of a bakery and you like cakes?’-Drug use and harm trajectories before, during and after the emergence of Silk Road. Int J Drug Policy. 2016;35:50-57.

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By Steven D. Passik phd

This light of history is pitiless; it has a strange and divine quality that, luminous as it is, and precisely because it is luminous, often casts a shadow just where we saw a radianceâ&#x20AC;Ś Victor Hugo, Les MisĂŠrables

Steven D. Passik PhD, is Vice President of Collegium Pharmaceuticals, Inc., Scientific Affairs, Education and Policy, in Canton, Massachusetts.

Along with regime change often comes

regimen change. And with regimen change there is a tendency to abandon all the tenets of the prior prevailing thought. With the changes in the mores surrounding opioid prescribing is it really the case that observations grounded in the clinical work of experts about the nature of pain management with opioids need to be ignored, superseded, or abandoned? Some observations were true but taught incorrectly. Some were overly simplified, and tied too closely to raising or lowering doses, or quite possibly overly naïve regarding taking subjective pain reports at face value. Doing so led to clinical problems that are well known (ie, escalation of doses in nonadherent patients; clinicians being too quick to escalate opioids rather than consider other adjuvant treatments).

What is not well known is what will happen if we ignore some of these notions, many of them as wise as they were self-effacing, taking the onus for poor outcomes on ourselves as clinicians. Do we risk worsening the lot of people with severe pain? Losing our empathy? Failing in our roles as advocates? Quite possibly. Perhaps rethinking these concepts will lead to a rapprochement and reconciliation of where we have been and where we are going philosophically and with regard to opioid policy.

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drug dealing “patients” who used doctors’ good faith bias against them. And other parts of the supply chain are alleged to have put profits over people (this is being litigated): drugs were supplied to small communities in quantities large enough for a small country, and some pharmacy professionals failed to abide by their own code of professional ethics and filled dubious prescriptions.

ollowing a revolution,

it is not uncommon for the new regime to erase all traces of its predecessor.

Statues are pulled down in the public square and writings are destroyed. The revolution of increased opioid prescribing that led to 400% to 500% increases in opioid prescribing in just over a decade did so in a healthcare system ill prepared to accommodate this surge. Many people suffering from pain were helped, and many were hurt. My view has always been that opioids are capable of bestowing great benefits and are also capable of causing great harm, and the failures in containing the harms inherent in opioid use exposed many of the critical weaknesses in our healthcare system.

Where once the potential benefits of “liberating” opioids were the focus of those eager to relieve suffering, and the harms of such liberation were trivialized, now the harms are emphasized by those interested in preventing addiction, overdose, and death, and the potential benefits to patients suffering from pain are minimized.

This oversimplification tends to worsen the suffering of those getting the short end of the rhetorical stick: now, people with pain are being abandoned, tapered off therapies on which many have been stable (voluntarily and even involuntarily) and, in some dire cases, driven to consider suicide. The pendulum has clearly swung from opiophilia to opiophobia and as prescribing levels have dropped, a series of important pain management concepts have fallen out of favor. Some of these important tenets are now the subject of scorn and derision or seen as mere platitudes to sell drugs.

There are many facets to the complicated story of pain and addiction and the genesis of the opioid crisis. The main theme of the most commonly told version is greed.

Charges of corporate greed have been the predominant form discussed in the media, best-selling books and even in a searing analysis provided by comedian John Oliver on his HBO show Last Week Tonight. The truth be told, there was more than enough greed to go around: from the greed of pill mill-running professionals and others who saw an opportunity to make money while behaving like little more than drug dealers, to the greed of doctor-shopping,

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Where there was no maleficence, frequently, there was system failure. Failure to create a generation of, as Dr. Doug Gourlay coined, “Talented amateurs in addiction medicine” trained to use opioids safely; failure to coordinate treatment; failure to raise the standard of care so that the majority of Americans wouldn’t go on to receive their opioids in ever-increasing amounts with little monitoring; failure to recognize the indications for other forms of pain therapies; failure to teach prescribers to assess a set of risk factors and tailor the parameters of opioid therapy differently in concert with the results of this risk stratification. Reimbursement for opioid therapy based on thoughtful analysis, risk stratification, and other best practices was suboptimal; by implication, it suggested that “doing opioids right” was not valuable.

The part of the opioid story that has not often been told is that of beneficence. The opioid revolution was built on principles and concepts that have their roots in the hospice and palliative care movements, which posit that patients’ suffering should be taken seriously and that it should be assessed, believed, and expertly addressed with any and all available tools. Those movements suggest that if efforts to address patients’ pain were unsuccessful and the pain persisted, that patients wouldn’t be blamed for the therapies’ failure, and the clinician would own the responsibility to continue to try everything in their power to relieve the patients’ misery. I have elsewhere compared some of the suspension of disbelief that surrounded the trivialization of addiction risk, among other issues, to that which is sometimes seen in religious movements, driven by the zealous desire to relieve pain and suffering. There is, no doubt, an intellectual dishonesty inherent in this suspension of disbelief, no matter how well intentioned it might have been. However, intellectual dishonesty is never justified, regardless of which direction it tends toward, and I believe that many of the arguments in support of widespread bans or restrictions on opioid therapy are motivated by exactly such intellectual dishonesty, albeit applied in the other direction in the opioid debate.

And this is exactly what has occurred in the dismissal and derision of some of the tenets of the opioid movement and in the enshrining of distortions of opioid pharmacology into practice. As I will argue below, we dismiss some of these concepts at our peril. At risk is not just the perpetuation of suffering and loss, but also our very humanity and empathy as clinicians.

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Pain as the 5th Vital Sign Perhaps no concept

associated with the opioid revolution has taken more of the blame for the ensuing crisis than the movement that led to the adoption of pain as the 5th vital sign. By elevating pain self-reporting, mandating its ongoing assessment, and making it as visible at the bedside as other vital signs, palliative care and pain management advocates hoped that pain control would become a standard part of good medical care and become impossible to ignore. Some would argue that by doing so, the medical community overindulged people’s subjective complaints and responded overly simplistically to those complaints with more and more opioids. There is some truth in this view: attempting to make pain assessment this visible and constant on a massive, healthcare system wide scale, there was no choice, in my view, but to employ the most simplistic, and for some patient populations unvalidated, quick and dirty pain assessment possible. The reification of the 0 to 10 pain score in the service of driving opioid doses was overly simplistic and harmful. We are not treating numbers we are treating people, complex people whose numeric pain score is not directly linked to a therapeutic response other than to drive clinician concern and thought about etiology of the untreated pain and a nonautomated, personalized recommendation of a therapeutic response. But the real damage wasn’t done until pain scores got tied to patient satisfaction, which in turn became tied to hospital/clinician evaluations and Q 3 | 2018

financing. The fastest way in some circumstances to bring these scores up was to simply prescribe more opioids.

As a professional who often had to deliver the news to a patient who was losing control of her opioid taking that we would never abandon her but that we were going to abandon opioid therapy, this conversation rarely yielded high patient satisfaction scores.

However, just because a concept meant to improve communication and empathy was co-opted and misapplied, it does not necessarily follow that the best answer is to move back to a “don’t ask, don’t tell” attitude about pain assessment and management. Especially in a time when opioid doses are being tapered and/or becoming increasingly difficult to access, and heroin and other illicit opioids are readily available, this might be the worst possible time in recent medical history to send the message to patients that we don’t care about their pain and suffering, that it isn’t a priority, and that we have nothing to offer.

Decades ago, John Bonica, the father of the modern pain management movement, decried “therapeutic nihilism” when it comes to pain.1 We need to communicate care and concern and manifest that concern and care with expertise and help—help that is not measured in milligrams.

For some patients, that help will include opioid therapy; for many others it will include a range of interventions, medical and nonmedical. The constant assessment of www.painweek.org | PWJ

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Every case in which a person is floundering and not meeting analgesic, functional, and behavioral goals requires thoughtful, nonjudgmental analysis and problem solving in which neither the patient nor the clinician take anything, least of all the possibility of loss of control of substances, for granted.

pain must not be abandoned. It is what we do with the information once we have it that counts. Not collecting the information is not an option.

Pain is what the patient says it is

Relatedly, the late great Margo McCaffrey was no fool when she declared that the patient’s pain is “whatever the patient says it is, occurring whenever the patient says it does.”2 McCaffrey knew that untold numbers of patients had manifest levels of pain and suffering that had been as disabling as they had been callously ignored and misinterpreted. McCaffrey was also too shrewd a clinician to translate a report of pain into a mandate for a particular dose of opioids. She was instead arguing that clinicians should not assume they are more expert at determining how much suffering the patient was experiencing than the patient herself. That said, the collecting of self-reports in the form of 0 to 10 scales led to taking the numbers themselves too literarily. One patient’s “8” might be driven by a combination of nociception, and depression, and tendencies to chemically cope, while the next person’s “8” might be a more direct reflection of their experience of nociception. Until we make an effort to know the person and know about their communication style and the very individualized nature of their suffering, we should not assume that the patient’s pain report has any direct relationship to any specific action to be employed by the clinician, least of all raising opioid doses in an automated way. However, ignoring Margo’s declaration and instead turning a deaf ear or a jaundiced eye toward human misery will neither end the opioid overdose crisis and the rash of suicides of abandoned patients, nor will it solve drug addiction.

Opioids (still) have no pharmacologic ceiling

Joe Shurman, MD, a pain expert and friend practicing for decades in the San Diego area, and I were once talking and he, feigning nostalgia, referred to the “no ceiling” days

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of opioid prescribing. Opioids do not now, nor have they ever had, a pharmacologic ceiling. That does not mean that they don’t have a practical or commonsense ceiling.

What that means is that there is no one dose of opioids as a group nor a particular opioid drug that is right for all.

Dr. Shurman was referring to the days when he could use his expert clinical judgment and experience to find the right, individualized dose for the suffering human being in front of him without running afoul of state or federal laws.

Indeed, whereas our old misapplication of this concept used to result in the truncating of doses on the high end of the therapeutic spectrum, morphine sulfate equivalent limits being enshrined into guidelines and laws now have had the effect of truncating the range of doses on the lower end of that spectrum. Either way, doses are not individualized, and people end up in danger of toxicity, overdose, or unrelieved pain.

Pseudoaddiction

Perhaps no concept associated with the opioid revolution is viewed more cynically than that of pseudoaddiction.

Some of that cynicism may be based on what is actually a mistaken conflict of interest: many believe that the concept of pseudoaddiction was created by a pharmaceutical executive for an opioid manufacturer. Instead, the concept was introduced in a paper published in 1989 in the journal Pain.3 One of the authors, J. David Haddox, did indeed go on to become a Purdue Pharma executive a full decade later. At the time of publication, he was a fellow of his coauthor, David Weissman. The paper is based upon a clinical observation of uncooperative and surly behavior on the part of a young man with cancer whose pain was not well managed. Frustrated staff saw his behavior as signs he was addicted. It may be clinical lore, but when Haddox saw this behavior upon being consulted in the case, he is said to have told his supervisor: “This isn’t addiction, this is pseudoaddiction.” They went on to write a paper about this experience, suggesting that poorly treated pain can lead to desperation and that desperation can lead to patients acting in ways that are not typical of Q 3 | 2018

them, and these behaviors can be confused with addiction. They called it pseudoaddiction and maintained that this syndrome was iatrogenic. It was our fault as professionals responsible for providing pain relief and it was our responsibility to fix it. They proposed that the remedy was to provide expertise leading to improved analgesia and the atypical behaviors would, as in the case of the young man with cancer, cease. The authors were not seeking to sell drugs on behalf of their employers, nor did they even suggest that applying their expertise in such instances would lead exclusively to more opioids.

It is hard to overemphasize the impact of this concept, which became overextended, oversimplified, and taught to aspiring pain providers in a naïve and incorrect fashion. Incorrect in that it was translated too directly into opioid dose adjustments; meant to include behaviors on the part of the patient far more aberrant than those in the original case (ie, the use of illicit drugs for pain control); and/or that pseudoaddiction and addiction were mutually exclusive. When you combine the notion of pseudoaddiction with ideas about the lack of a pharmacologic ceiling for opioids, a rationale appears to emerge for increasing opioid doses, in a knee-jerk fashion, and even in so-called “bad actors.” Weissman wrote at least one follow-up paper trying to narrow the use of the concept and bring it back to its roots,4 but the horse was already out of the barn.

Somewhat later, I joined Kirsh and Webster in proposing that the concept of pseudoaddiction be re-taught in a way that encourages clinicians to improve analgesia.5 That proposal contemplated that this re-education might result in higher doses for some patients, but the focus of our paper was that clinicians should never let behavioral signs of loss of control go unaddressed. I have often said, somewhat tongue in cheek, that I wouldn’t think it would be good practice to increase the frequency of someone’s meditation sessions in a knee-jerk fashion, let alone someone’s opioids. Every case in which a person is floundering and not meeting analgesic, functional, and behavioral goals requires thoughtful, nonjudgmental analysis and problem solving in which neither the patient nor the clinician take anything, least of all the possibility of loss of control of substances, for granted.

What we don’t want to lose is the humility of recognizing that pain is indeed often inexpertly, clumsily, and poorly managed and that it is our professional responsibility to remedy it as best as possible instead of deriding patients’ desperation. Recognizing that we, as professionals working within the confines of our healthcare system, sometimes fail to relieve desperation and that such situational variables drive patient behavior helps us maintain empathy and overcome the subject–observer bias so rampant in such situations. This bias is seen in how we explain the behavior of others we see acting in a certain fashion. When we ourselves are doing something, we tend to explain it Q 3 | 2018

on the basis of situational variables; but when we observe others we tend to explain their behaviors as an extension of their character or personality. So, we might say about ourselves, “I’m sorry I am being grumpy; I didn’t sleep well last night” but attribute the grumpiness of another person to a character flaw: “He is such an unpleasant, grumpy person.” So, when we see a desperate person in unrelieved pain acting aggressively and seeking medications, we might be inclined to say, “He is a drug-seeking kind of a person” whereas if we were making an observation about ourselves, we might say, “I can’t seem to access adequate pain care, which is why I am being aggressive.” Pseudoaddiction viewed as an iatrogenic syndrome reminds us to be forgiving enough to overcome this bias. The opiophobic times in which we live call for a particularly forgiving attitude on the part of clinicians toward patients’ desperation, as difficulty in accessing pain care will create, for some patients at least, a level of desperation not seen in over a decade. This forgiveness should be manifest not in milligrams of opioids, but in a thoughtful and nonjudgmental analysis of what is making the person desperate, and our empathy and humanity will be manifest in taking steps to relieve it while also safeguarding the person from any loss of control of their opioids. We do not serve the patients’ long-term best interest by ignoring their pain.

Ignoring desperation, loss of control, or any aspect of pain related suffering is not the answer to some people’s perception that we might have spent a decade overindulging it. People with pain and people with addiction have already lost so much. They will not be helped by professionals who lose their hearts.

References 1. Saxon W. John J. Bonica, pioneer in anesthesia, dies at 77. NY Times.

Available at: www.nytimes.com/1994/08/20/obituaries/john-j-bonica-pioneer-in-anesthesia-dies-at-77.html.

2. McCaffery M, Beebe A. Pain: clinical manual for nursing practice. CV Mosby, St. Louis; 1989.

3. Weissman DE, Haddox JD. Pseudo addiction: an iatrogenic syndrome.

Pain. 1989;36(3):363–366.

4. Weissman DE. Understanding pseudo addiction. J Pain Sympt Manag.

1994;9(2):74.

5. Passik SD, Kirsh KL, Webster L. Pseudoaddiction revisited: a commentary on clinical and historical considerations. Pain Manag. 2011;1(3):239-248.

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“Meetings come to an end, but learning never stops.

PWJ keeps you going all year long.”

— Michael R. Clark Md, mph, mba

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Courtney M. Kominek pharmd, bcps, cpe Clinical Pharmacy Specialist—Pain Management Harry S. Truman Memorial Veterans’ Hospital

I’m most proud when I help a patient get the care they need…and the patient is able to have a functional and meaningful life.

GPS Columbia, mo Typical Day “I start my day by doing phone follow-ups with patients then seeing other patients by

videotelehealth or in person. I have quite a few administrative responsibilities as well. Right from work I like to go to the gym for a workout. I currently belong to a mixed marital arts gym and like to box and kickbox. It’s a good way to get rid of the day’s frustrations.” Persona “I certainly am trying to prepare myself to be ‘a next generation opinion leader.’ Hopefully I can fill the shoes of my predecessors!” Social Media Habits “I follow several pharmacy organizations and pain management sites on Facebook or Instagram to keep up to date. I find useful information from Practical Pain Management (note I serve on the editorial board) as well as PAINWeek. Otherwise I follow the news and some of my favorite celebrities on Facebook and Instagram.” Contribution “I’m most proud when I help a patient get the care they need—whether that’s referring them to the interdisciplinary chronic pain program or treatment for a substance use disorder—and the patient is able to have a functional and meaningful life.” People “The public figures I most admire are no longer with us: Mother Theresa and Princess Diana for their philanthropic work.” Words “I belong to a book club; we meet once a month and read a variety of genres. I’m in a historical fiction kick with The Storyteller, All the Light We Cannot See, and The Nightingale.” Popcorn “Some of my favorite movies are Zero Dark Thirty and The Guardian.” P NWeek “I love PAINWeek because it allows me to meet many different people at the frontlines of managing chronic pain. I learn lots from presenting and attending PAINWeek and PAINWeekEnds and enjoy helping others take care of chronic pain patients.”

ai

Q 3 | 2018

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By Doug Gourlay md, msc, frcpc, fasam

“If you can’t prove I’m lying, how dare you not believe me.”

Rather than engaging the patient in their story, consider simply tightening the therapeutic boundaries.

Increasing the frequency of visits, limiting the quantity of medications prescribed at any given time, and even requesting a urine drug screen can all be indirect ways of addressing these suspicious stories.

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Of

Records

Conclusions from a study of

24,610

5,760

450

from a commercial insurance database on

interviewed in the Baltimore area,

who underwent spinal fusion surgery between 2007 and 2015 were examined.

drug users

75 %

patients

5,500 22.3

reported witnessing an overdose, and

12 %

had witnessed >5 overdose incidents.

These individuals used drugs in a greater variety of settings, such as restrooms and abandoned buildings.

Drug users have consistently demonstrated their abilities to treat overdose victims and help prevent hiv, but training users to administer naloxone and distributing it in affected areas is no guarantee that these users will have it with them when needed.1

samhsa reports that opioid use is connected to

~ 44% of ER admissions for drug toxicity among US adults aged

50 and older.

A study surveyed

130 of these patients with chronic pain.

Nearly 35 % reported misusing their opioid prescriptions within the prior month.

Risk factors for abuse included illicit drug use ( 13x greater risk) and moderate depression ( 6x greater risk) but also education level: participants with at least some college education were 2.5x more likely to misuse opioids than those with less schooling.2

—

of these

%—

had taken opioid analgesics for

>6 months prior to their procedure.

The likelihood of surgical wound complications in the -month interval postsurgery was

3

19 % greater

for the chronic opioid therapy patient cohort compared to patients who used opioids for < months or not at all.

6

Chronic opioid patients were more likely to return to the hospital or ER during the -month postsurgical period and were

3

US adults over a

24-year span suggest that chronic

inflammation experienced in middle age may be associated with > frailty and poorer overall health in later life.

Over the course of

5

medical exams starting in their

40s & 50s, participants were assessed for markers of inflammation.

5

At the th exam, the patients, now in their 70s, were categorized for degree of robustness or frailty.

% more likely to undergo repeat spinal fusion within year.3

Each standard deviation of elevated inflammation in midlife was connected to a 39% greater likelihood for frailty in later life.5

Hip replacement can add years

A retrospective analysis of

33

1

to life as well as adding life to years.

Researchers evaluated

132,000 patients

who underwent total hip arthroplasty (THA) from 1999 through 2012, with an average age of years at the time of surgery.

68

Compared to the Swedish population in general, patients who elected to undergo THA had a rate of survival % better at 1-year postprocedure, % to % better at 5 years, and % better at 10 years.

1 3 5 2

By 12 years after surgery, no discernable difference in survival rate was noted.4

277 concussion patients concluded that commonly prescribed medications for concussion sufferers have little positive impact on severity of symptoms or the course of recovery.

3

Patients were sorted into groups: no medication; receiving gabapentin; receiving either of tricyclic antidepressants.

2

2 22

Members were scored on elements of postconcussion recovery: headache & a combination of symptoms including headache.

Scores for both headache & combined symptoms declined in equal measure for all groups, suggesting that time, rather than medications, is the significant contributor to concussion recovery.6

3

1. https://bit.ly/2Fgy57E 2. https://bit.ly/2JrYcLx 3. https://bit.ly/2JowfUC 4. https://bit.ly/2HWHzI0 5. https://bit.ly/2FsC1SU 6. https://bit.ly/2HANAgC

Q 3 | 2018

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an effect. Unfortunately, we haven’t been able to study any of those yet. So, for primary care, what I would say about using cannabinoids as a treatment option is that it may be something to consider before you start putting patients on opioids. Once you start them on opioids, if they’ve been on it for a couple of months, chances are they’re going to be on it for the rest of their lives. And so medical marijuana may be an option to offer to patients and hopefully decrease the use of opioids for chronic noncancer pain.

3

The Neurobiology of Chronic Migraine Kathleen Digre MD

1

When Health Insurance May Not Be on Our Side

Jeremy A. Adler MS, PA-C

The cost of healthcare of course is a concern. The insurance companies are in the business of providing insurance, and healthcare professionals and patients are seeking out quality care. There’s an inherent conflict there because unfortunately pain is a complex biopsychosocial problem. It really does require a comprehensive team and there is a cost involved in the treatment. The approach of using things that are inexpensive may often not be the best interest and there are ramifications down the line. The people are suffering harms because of addiction and abuse; people are missing work and not able to pay insurance premiums. The insurance companies have to look at this in a multidimensional way. It’s very challenging though to have them sit down and look at a singular price of a single treatment and make a determination on it and get them to be supportive. I think there’s efforts certainly to try to leverage law and use state legislatures to pass bills that will basically demand certain access, but I haven’t really seen a whole lot of enforcement.

I think there’s still a large disconnect between the payers and the providers right now.

2

Cannabis as an Opioid Alternative — What do we Know So Far? Ignacio Badiola MD

Cannabis as a pharmacological agent has been used for centuries. It’s been described in China, in Asian countries dating back to well before the BC era. Ultimately it made its way to the United States where it actually was made available to patients until it was outlawed in the 1930s and ‘40s. And now obviously it’s making a comeback in the hope that we can use that as an option to opioids. But the jury is still out on that. Because it is still a schedule 1 drug, studies of medical cannabis are very difficult to do. So, we just have a lot of anecdotal evidence and some studies that show that it has some benefit in pain management, specifically in neuropathic pain conditions such as multiple sclerosis. There are also some case reports showing that in specific patients, opioids have either been significantly reduced or completely stopped using medical cannabis. The two main constituents that are thought to produce most of their pharmacological activity in terms of pain management are cannabidiol and THC, but there are well over 80 other compounds which may or may not have

70 PWJ | www.painweek.org

Both the central nervous system and the peripheral nervous system are heavily involved in starting and continuing a migraine attack, and are involved before the migraine even starts. If you divide a migraine into premonitory phases—the aura, the migraine phase, the postdrome—with modern technology including functional MRI and PET scans, we observe that there are different parts of the brain, both peripherally and centrally which are involved in each part of these attacks. For example, in the prodrome, people will experience yawning or feeling tired or being very light- or sound-sensitive before they even have a headache attack. During that time, imaging of the brain can show that some parts of the hypothalamus, the brain stem, the thalamus, and even the cortex can be involved in the process. When the aura occurs, which we think is more of a cortical spreading depression, we usually see cortical changes occurring on these functional MRIs and PET scans. During the pain attack itself, we see changes that are occurring inside the brain and the nerves around the head.

People develop allodynia, where even touching the head will be painful, another process occurring both centrally and with connections to the peripheral nervous system. Then after the pain has left, there’s a postdrome period we really haven’t studied as much; it’s clear it also has brain connections. In chronic migraine, just as in chronic pain, we’re always looking for new treatments to alleviate the suffering of patients who have not had success with traditional treatments. We’re undergoing a kind of minirevolution with the discovery that antibodies to calcitonin gene-related peptide and associated receptors can actually prevent migraine attack. Several pharmaceutical companies now are working on these new compounds that I think are going to open up a whole new avenue for some people with chronic migraine.

In summary, I want to say migraine and chronic migraine are primary care disorders, and we need to deputize every person who works with people with migraine. We need every primary care provider to understand that it’s a real condition—it has physiology and anatomy that’s anchored in brain function—and that they too can become treaters and preventers of chronic migraine.

4

What is, and who decides, the ultimate patient goal?

Lynn McPherson PharmD, MA, BCPS, CPE; and

Alexandra McPherson PharmD, MPH

Alexandra: I think absolutely the overall patient goal is enhanced functionality because it’s not always possible depending on the etiology of the patient’s pain to eliminate it completely. That’s not

Q 3 | 2018

realistic. But if we ask the patient those questions and really look at them as a partner in pain management, we can come up with a strategy to set realistic pain goals and strategies to enhance their quality of life and their functional status in a way that’s satisfactory to the patient; that they can go about their daily life and accomplish some of those things that they were doing before, without saying “We’re going to treat your pain so well you’re going to go out and run a marathon next week.” That’s probably not going to happen, but we will do our best to get you to a place that is better than where you are now.

Lynn: This conversation reminds me of a patient I’ve taken care of for years. He’s a tall drink of water, he’s a 6’8” man who was a construction

Q 3 | 2018

worker and a concrete ceiling fell on him and obliterated his right hip.

He has more hardware in his right hip than the bionic man. When he came to me, his pain was an 8 on average and it was just horrible. It kept him from doing most of his activities of daily living and I said, “Mr. Smith, I’m going to keep swinging and we’re going to try every drug in the universe with any hint of analgesic effect.” I remember clearly a year later we had tried every drug in the book and he frankly was not a whole lot better and I said, “Mr. Smith, I feel like a failure. You came to me, the pain was an 8, you told me today that pain is still an 8,” and he said, “But it’s a better 8.” I said, “You’re trying to cheer me up” and he said, “No, I don’t want to kill myself anymore. It’s still an 8 but I’m coping better with the pain.” I think getting away from focusing on that number is an important part of it.

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with

jennifer

bolen

jd

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“We’ve made a difference, but there are many miles to go for all of us in pain management.”

Q What inspired you to become a healthcare provider?

a

Haha! I’m not. I am a lawyer; a former federal prosecutor.

Q

a

Why did you focus on pain management?

One afternoon, while I was still working as a federal prosecutor, I was standing behind bulletproof glass and looking out on several patients who asked to see me. I was picking up copies of their medical records that were seized pursuant to a federal search warrant, executed at the office of a local family physician. I remember seeing some of the patients crying and others scratching and shivering. I thought to myself, “There has to be a better way.” I tried to get the board and DEA to suspend the provider’s license and registration, but they wouldn’t. This guy was a danger to himself, his son, and his patients, so we went full on federal prosecution, with search warrants and an indictment to shut him down. He had his own drug problem, and we had to get him to stop prescribing controlled substances. He was in no position to care for people, as he could barely care for himself at the time. People were dying, and the licensing boards

Q 3 | 2018

and DEA were not ready to take action. I thought education would be better than enforcement. I knew a real storm was on the horizon, so I left the government shortly thereafter and set up my own consulting and education company. That was over 15 years ago. We’ve made a difference, but there are many miles to go for all of us in pain management.

Q

Who were your mentors?

a

Michael Clark, MD; Doug Gourlay, MD; Howard Heit, MD; Andrew Hertzmark; Ted Jones, phd; Darren McCoy, FNP-BC; Bill McCarberg, MD; Joyce Meyer; and Steve Passik, phd.

Q

If you weren’t a lawyer what would you be?

a

If I weren’t a lawyer, I would be a physician.

I’d go back to school, but sadly I am a little long in the tooth.

Q

What is your most marked characteristic?

a

I’ve been told that it’s the way I take command of a room when I speak, but I think it’s my ability to translate between doctors and lawyers in the courtroom or lecture hall.

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“…tell audience members that they must never forget there is a human being in front of them when they prescribe opioids.”

Q What do you consider your greatest achievement?

a Standing up in front of a group of clinicians and telling them about the deaths of my father and my son and finding a way to tell audience members that they must never forget there is a human being in front of them when they prescribe opioids.

Q

What is your favorite language?

a

Russian

Q

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

hope to make it through life’s challenges and ups and downs, and to realize the value of family and friendship to the ultimate end: to accomplish what we were put on this Earth to do—to love.

Q

What would you like your legacy to be?

a

I helped people find their way through the crap.

Q

What is your motto?

a

Not by sight, but by faith.

Jennifer Bolen, JD, is the Founder of the Legal Side of Pain in Knoxville, Tennessee.

a

Book: Conversations with the Enemy, because PFC Garwood’s experience in the enemy’s camp taught me to look at both sides of any story.

Film: My Cousin Vinny: It always makes me laugh.

I know the lines, and I love the characters.

Music: Home We’ll Go by Walk Off the Earth: “Don’t let your head hang low/You’ve seen the darkest skies I know. Let your heart run child, like horses in the wild. So take my hand and home we’ll go… Let your soul shine bright, like diamonds in the sky… It’s a long road, but we’re not alone. Together we stand, and we’re going home.” This music allows me to

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TM

Neumentum, Inc. is dedicated to becoming a leading non-opioid analgesic and neurology specialty pharmaceutical company that develops and commercializes non-opioid pain products for post-surgical and outpatient use.

Co-Founders: Joseph Pergolizzi, MD / Executive Chairman josephpergolizzi@neumentum.com R. Scott Shively / CEO scottshively@neumentum.com

For more information, please visit www.neumentum.com

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) CONTRAINDICATIONS: NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including 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 of MAOIs 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. Because extendedrelease 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. 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 and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids 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.

Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. 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 dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Overestimating the NUCYNTA ER dosage 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 in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a or injecting the dissolved product will result in the uncontrolled potentially fatal overdose of tapentadol. delivery of tapentadol and can result in overdose and death.

Profound sedation, respiratory depression, coma, and death Opioids are sought by drug abusers and people with addiction may result from the concomitant use of NUCYNTA ER with disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, reduce these risks include prescribing the drug in the smallest muscle relaxants, general anesthetics, antipsychotics, other appropriate quantity and advising the patient on the proper opioids, alcohol). Because of these risks, reserve concomitant disposal of unused drug. Contact the local state professional prescribing of these drugs for use in patients for whom licensing board or state controlled substances authority for alternative treatment options are inadequate. information on how to prevent and detect abuse or diversion of this product.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants (continued) Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.

Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: NUCYNTA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Alternatively, consider the use of non-opioid analgesics in these patients.

Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.

Serotonin syndrome symptoms 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, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.

Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.

There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics).

Monitor these patients for signs of hypotension after initiating or titrating the dosage 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.

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

Risks of Driving and Operating 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.

Risk of Toxicity in Patients with 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.

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

Risk of Toxicity in Patients with 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.

Risk of Use in Patients With Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy.

Please see Brief Summary, including BOXED WARNING, on the following pages.

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

Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including 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.

Do not abruptly discontinue NUCYNTA ER.

© 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0001 02/18

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 (tapentadol) 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) 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 (see Warnings and Precautions), reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• 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; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS 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) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7).

CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product (see Adverse Reactions).

• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see Drug Interactions).

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.

Because extended-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 (see Drug Abuse and Dependence).

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. 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 and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids 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 (see Overdosage).

Opioid 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 (see Patient Counseling Information). Contact the 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 opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see Overdosage). 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 dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential (see Dosage and Administration). Overestimating the NUCYNTA ER dosage 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 in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see Use in Specific Populations, Patient Counseling Information).

Risk from Concomitant Use with Benzodiazepines or Other CNS 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 (see Clinical Pharmacology).

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions).

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Drug Interactions and Patient Counseling Information).

Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: NUCYNTA ER treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER (see Warnings and Precautions).

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see Warnings and Precautions).

Alternatively, consider the use of non-opioid analgesics in these patients.

Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration (see Warnings and Precautions).

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs.

Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic

antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see Drug Interactions). This may occur within the recommended dosage range.

Serotonin syndrome symptoms 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, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that.

Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage 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.

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

Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi.

Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy.

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

When discontinuing NUCYNTA ER, gradually taper the dose (see Dosage and Administration). Do not abruptly discontinue NUCYNTA ER (see Drug Abuse and Dependence).

Risks of Driving and Operating 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 (see Patient Counseling Information).

Risk of Toxicity in Patients with 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 (see Dosage and Administration and Clinical Pharmacology). Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with 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 (see Clinical Pharmacology).

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see Warnings and Precautions) • Life-Threatening Respiratory Depression (see Warnings and Precautions) • Neonatal Opioid Withdrawal Syndrome (see Warnings and Precautions) • Interaction with Benzodiazepine or Other CNS Depressants (see Warnings and Precautions)

• Serotonin Syndrome (see Warnings and Precautions) • Adrenal Insufficiency (see Warnings and Precautions) • Severe Hypotension (see Warnings and Precautions) • Gastrointestinal Adverse Reactions (see Warnings and Precautions) • Seizures (see Warnings and Precautions) • Withdrawal (see Warnings and Precautions) 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.

Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients.

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.

Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients.

Postmarketing Experience The following adverse reactions have been identified during post approval use of tapentadol.

Psychiatric disorders: hallucination, suicidal ideation, panic attack Serotonin syndrome: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in NUCYNTA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see Clinical Pharmacology).

DRUG INTERACTIONS Clinically Significant Drug Interactions with NUCYNTA ER Alcohol Clinical Impact:

Concomitant use of alcohol with NUCYNTA ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol.

Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy.

Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Due to additive pharmacologic effect, the concomitant use of Impact: benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical The concomitant use of opioids with other drugs that affect Impact: the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.6].

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

Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs) Clinical MAOI interactions with opioids may manifest as serotonin Impact: syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].

Intervention: Do not use NUCYNTA ER in patients taking MAOIs or within 14 days of stopping such treatment Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical May reduce the analgesic effect of NUCYNTA ER and/or Impact: precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Tapentadol may enhance the neuromuscular blocking action of Impact: skeletal muscle relaxants and produce an increased degree of respiratory depression.

NUCYNTA ER (tapentadol) extended-release tablets, CII BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION (continued) Muscle Relaxants (continued) Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUCYNTA ER and/or the muscle relaxant as necessary.

Diuretics Clinical Opioids can reduce the efficacy of diuretics by inducing the Impact: release of antidiuretic hormone.

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

Anticholinergic Drugs Clinical The concomitant use of anticholinergic drugs may increase Impact: risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions).

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications.

Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see Warnings and Precautions).

Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor. Opioid analgesics, including NUCYNTA ER, can prolong labor.

Lactation Risk Summary 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 serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER. Clinical Considerations Monitor infants exposed to NUCYNTA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

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.

Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see Warnings and Precautions).

Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment (ChildPugh Score 10-15) is not recommended. In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), dosage reduction of NUCYNTA ER is recommended (see Dosage and Administration).

Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended.

DRUG ABUSE AND DEPENDENCE Controlled Substance NUCYNTA ER contains tapentadol, a Schedule II controlled substance.

Abuse NUCYNTA ER contains tapentadol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA ER can be abused and is subject to misuse, addiction, and criminal diversion (see Warnings and Precautions).

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

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

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

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

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

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

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 state and federal law, is strongly advised.

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

Risks Specific to Abuse of NUCYNTA ER NUCYNTA ER is for oral use only. Abuse of NUCYNTA ER poses a risk of overdose and death. The risk is increased with concurrent use of NUCYNTA ER with alcohol and other central nervous system depressants.

With intravenous abuse the inactive ingredients in NUCYNTA ER can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

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

NUCYNTA ER should not be abruptly discontinued (see Dosage and Administration). If NUCYNTA ER is abruptly discontinued in a physicallydependent patient, a withdrawal 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 (see Use in Specific Populations).

OVERDOSAGE Clinical Presentation Acute overdosage with NUCYNTA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

© May 2017, Depomed, Inc. All rights reserved. APL-NUCX-0249

© 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0001 02/18

TIME TO DUAL

TW O O NE SOURCES SOURCE

OF PAIN 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).

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Not an actual patient.

INDICATIONS AND USAGE NUCYNTA ER (tapentadol) 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) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediaterelease 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

IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse NUCYNTA ER exposes patients and other users to the risks of opioid addiction, experts. If opioid use is required for a prolonged period in a pregnant woman, abuse, and misuse, which can lead to overdose and death. Assess each patient’s advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure risk prior to prescribing NUCYNTA ER, and monitor all patients regularly for the that appropriate treatment will be available. development of these behaviors and conditions.

Interaction With Alcohol Life-threatening Respiratory Depression Instruct patients not to consume alcoholic beverages or use prescription or Serious, life-threatening, or fatal respiratory depression may occur with use of non-prescription products that contain alcohol while taking NUCYNTA ER. The coNUCYNTA ER. Monitor for respiratory depression, especially during initiation of ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol NUCYNTA ER or following a dose increase. Instruct patients to swallow NUCYNTA levels and a potentially fatal overdose of tapentadol.

ER tablets whole; crushing, chewing, or dissolving NUCYNTA ER tablets can cause Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants rapid release and absorption of a potentially fatal dose of tapentadol.

Concomitant use of opioids with benzodiazepines or other central nervous system Accidental Ingestion (CNS) depressants, including alcohol, may result in profound sedation, respiratory Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can depression, coma, and death. result in a fatal overdose of tapentadol.

• Reserve concomitant prescribing of NUCYNTA ER and benzodiazepines or other Neonatal Opioid Withdrawal Syndrome CNS depressants for use in patients for whom alternative treatment options are inadequate.

Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, • Limit dosages and durations to the minimum required. and requires management according to protocols developed by neonatology • Follow patients for signs and symptoms of respiratory depression and sedation.

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

Nucynta ER is a registered trademark of Depomed, Inc. © 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0001 02/18