PWJ - PAINWeek Journal Vol 8, Q3 | 2020 by PAINWeek

vol. 8 q 3 2020

man on fire syndrome (erythromelalgia): a review of a rare and painful disorder p.20 armageddon: managing acute postoperative pain in an opioid sparing environment p.28 frankie says relax: the ins and outs of skeletal muscle pain P.36 stem cells and regenerative medicine P.46

pg.72

FOR ADULT CHRONIC NON-CANCER PAIN PATIENTS WITH OPIOID-INDUCED CONSTIPATION (OIC)

Take a proactive approach to OIC RELISTOR helps restore gut function by increasing the number of spontaneous bowel movements (SBMs)1 Patients with OIC are frequently cycling through over-the-counter (OTC) options with little benefit. Many OIC patients suffer for years without adequate relief2,3 OTC options may help some patients manage their symptoms, but they do not treat the underlying cause of OIC1,4 In a survey of 322 patients taking opioids orally on a daily basis:

of patients taking oral opioid therapy and OTC laxatives reported still being constipated5

OIC is different than other forms of constipation • OIC is caused by opioids binding to mu-opioid receptors in the gastrointestinal (GI) tract, significantly slowing GI motility.6 Three effects that can contribute to OIC include: – Decreased peristaltic motion7

– Increased fluid absorption from gut7

– Decreased fluid secretion into gut7

• OIC often persists throughout patients’ opioid therapy; it is usually not dependent on dose or duration of opioid use6

YOU HAVE THE POWER TO INTERVENE EARLIER AND HELP ADDRESS THE UNDERLYING CAUSE OF 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 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 blood-brain 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 because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

The RELISTOR Triple-Action Binding System (T.A.B.S™) HELPS TO:

REACTIVATE PERISTALTIC MOTION1,7

3 RESTRICT FLUID ABSORPTION1,7

RESTORE FLUID SECRETION1,7

Choose RELISTOR to help restore gut function by increasing the number of SBMs1 In a clinical trial of adult patients with OIC and chronic non-cancer pain (CNCP)

of patients (n=200) taking RELISTOR tablets experienced at least 3 SBMs* per week vs 38% of patients (n=201) taking placebo (P=.005)1,8,†,‡

• In a clinical study of adult patients with OIC and CNCP taking RELISTOR tablets, the most common adverse reactions occurring in at least 2% of patients receiving 3 RELISTOR 150-mg tablets once daily and at an incidence greater than placebo 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%)1 *SBM is defined as bowel movement without the use of any laxative in previous 24 hours.1,8 † Responder is defined as a patient with 3 or more SBMs per week, with an increase of 1 or more SBM(s) per week over baseline, for 3 or more out of the first 4 weeks of the treatment period.1 ‡ Study Design: In a 4-week, randomized, multicenter, double-blind, placebo-controlled, phase 3 study, the efficacy of RELISTOR tablets was evaluated in 401 patients (200 RELISTOR tablets, 201 placebo) with CNCP for which they were taking opioids. All patients had OIC, defined as <3 SBMs per week and at least one additional symptom of constipation.1,8

TAKE A PROACTIVE APPROACH TO OIC AND CHOOSE RELISTOR FOR YOUR ADULT PATIENTS WHO ARE NOT RECEIVING ADEQUATE RELIEF FROM OTC LAXATIVES.1,4 LEARN MORE AT RELISTORHCP.COM IMPORTANT SAFETY INFORMATION • 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 of full Prescribing Information on the following page. REFERENCES: 1. RELISTOR [prescribing information]. Bridgewater, NJ: Salix Pharmaceuticals. 2. Wakefield Research. Relistor OIC Survey: QuickRead Report. Conducted August 15-August 22, 2017. 3. Coyne KS, LoCasale RJ, Datto CJ, Sexton CC, Yeomans K, Tack J. Opioid-induced constipation in patients with chronic noncancer pain in the USA, Canada, Germany, and the UK: descriptive analysis of baseline patient-reported outcomes and retrospective chart review. ClinicoEcon Outcomes Res. 2014;6:269-281. 4. Webster LR. Opioid-induced constipation. Pain Med. 2015;16(suppl 1):S16-S21. 5. Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med. 2009;10(1):35-42. 6. Pergolizzi JV Jr, Raffa RB, Pappagallo M, et al. Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy. Patient Prefer Adherence. 2017;11:107-119. 7. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562. 8. Data on file. Clinical study report MNTX3201. Salix Pharmaceuticals; 2015.

www.salix.com 400 Somerset Corporate Boulevard, Bridgewater, NJ 08807 Tel 800-321-4576 Relistor is a trademark of Salix Pharmaceuticals or its affiliates. ©2020 Salix Pharmaceuticals or its affiliates. RELO.0026.USA.20

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 or Pain Caused by Active Cancer 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 gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Cases of gastrointestinal perforation have been reported in adult patients with 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 If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider. Opioid Withdrawal Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients. ADVERSE REACTIONS Clinical 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. 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 or severe 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 Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). For more information, go to www.Relistor.com or call 1-800-321-4576. Based on 9493104 11/2018 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. Patent Numbers: 8,247,425; 8,420,663; 8,552,025; 8,822,490; 9,180,125; 9,492,445 and 9,669,096 For Tablets: U.S. Patent Numbers: 8,420,663; 8,524,276; 8,956,651; 9,180,125; 9,314,461; 9,492,445 and 9,724,343 Relistor is a trademark of Salix Pharmaceuticals or its affiliates. REL.0082.USA.19

pg.72

365 days a year.*

*Except Leap Year which give you an extra “bonus” day.

Executive Editor Kevin L. Zacharoff md, facpe, facip, faap Publisher Painweek Art Director Darryl Fossa Editorial Director Debra Weiner Editor Holly Caster

Editorial Board

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 Jennifer Bolen jd Founder Legal Side of Pain Knoxville, tn Martin D. Cheatle PhD Associate Professor Director, Pain and Chemical Dependency Program Perelman School of Medicine University of Pennsylvania Center for Study of Addiction Philadelphia, pa 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 Associate Professor of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore, md Chair of Psychiatry Inova Health System Falls Church, VA

David Cosio PhD, ABPP Psychologist Jesse Brown VA Medical Center University of Illinois at Chicago College of Medicine, Pain Medicine Northwestern Feinberg School of Medicine, Psychiatry and Behavioral Sciences Chicago, il

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

David M. Glick DC, DAAPM, CPE, FASPE CEO & Medical Director HealthQ2 Richmond, va

Steven D. Passik phd Vice President Scientific Affairs, Education, and Policy Collegium Pharmaceuticals, Inc. Canton, ma

Douglas L. Gourlay MD, MSc, FRCPC, DFASAM Educational Consultant Former Director, Wasser Pain Centre Pain and Chemical Dependency Division Toronto, Ontario Gary W. Jay md, faapm Clinical Professor University of North Carolina Department of Neurology Chapel Hill, nc Jay Joshi MD, DABA, DABA-FM, FABA-FM CEO and Medical Director National Pain Centers Vernon Hills, il Theresa Mallick-Searle MS, NP-BC, ANP-BC Nurse Practitioner Stanford Health Care Division of Pain Medicine Stanford, ca

Joseph V. Pergolizzi md Chief Operating Officer nema Research Inc. Naples, fl 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 Kathryn A. Schopmeyer PT, DPT, CPE Physical Therapy Program Coordinator Pain Management San Francisco va Healthcare System San Francisco, ca

Mary Lynn McPherson pharmd, ma, mde, bcps Professor and Vice Chair University of Maryland School of Pharmacy Department of Pharmacy Practice and Science Hospice Consultant Pharmacist Baltimore, md

Copyright © 2020, 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.8 q3 2020

neurology

man on fire syndrome (erythromelagia) a review of a rare and painful disorder

acute pain management

by joseph v. pergolizzi jr armageddon robert b. raffa managing acute postoperative pain in an opioid sparing environment

pharmacotherapy

frankie says relax the ins and outs of skeletal muscle relaxants

by amanda m. mullins

interventional pain management

stem cells and regenerative medicine

by jay joshi

pain basics

pathophysiology of pain

by kevin l. zacharoff

36 46 59

by charles e. argoff sarah e. o’brien carrie b. tram

charles e. wollmuth

pw next generation

with jorge f. carrillo

64 65 66

clinical pearls

by martin cheatle

one-minute clinician

with jessica geiger, courtney m. kominek, abigail t. brooks, emily hurstak, jennifer bolen, douglas gourlay, gary w. jay

68 71

pundit profile

with lynn r. webster

puzzled?

by wendy caster

pain by numbers

pg.72 12

When conventional lidocaine patches don’t stick, do they work? PROBLEM

PROVEN 12-HOUR ADHESION

SOLUTION

Did you know? HALF of patients surveyed report that other lidocaine patches detach ≥3 times in 12 hours?1*

Only ZTlido® delivers 12-HOUR adhesion in a non-opioid therapy (zee-tee-lie-doh)

VISIT THE SCILEX PHARMACEUTICALS EXHIBIT to see the lidocaine patch reinvented. *According to a 2016 Harris Poll among PHN patients (n=153) and nurses (n=151). Reference: 1. Harris Poll Conducted Online from May 2-25, 2016. PHN Patients & Nurses Study: Final Report. June 9, 2016. Supported by funding from Scilex Pharmaceuticals Inc.

Indication ZTLIDO is indicated for relief of pain associated with post-herpetic neuralgia (PHN). Important Safety Information Contraindications ZTLIDO is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product. Warnings and Precautions Accidental exposure can occur even after a ZTLIDO patch has been used. Small children or pets could suffer serious adverse effects from chewing or ingesting a new or used ZTLIDO patch. Store and dispose of patches properly and keep out of reach of children and pets. Excessive dosing or overexposure to lidocaine can occur. Longer duration of application, application of more than the recommended number of patches, smaller patients, or impaired elimination may all contribute to increased blood concentration levels of lidocaine. If lidocaine overdose is suspected, check drug blood concentration. Management of overdose includes close monitoring, supportive care, and symptomatic treatment. Cases of methemoglobinemia have been reported with local anesthetic use, although patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, or concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. Signs and symptoms include cyanotic skin discoloration and/or abnormal coloration of the blood and may occur immediately or may be delayed after exposure. Methemoglobin levels may continue to rise leading to more serious central nervous system and cardiovascular adverse effects. Discontinue ZTLIDO and any other oxidizing agents. Depending on severity of the symptoms, patients may respond to supportive care or may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

Application site reactions can occur during or immediately after treatment with ZTLIDO. This may include development of blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours. Inform patients of these potential reactions and that severe skin irritation may occur with ZTLIDO if applied for a longer period than instructed. Hypersensitivity cross-reactions may be possible for patients allergic to PABA derivatives. Manage hypersensitivity reactions by conventional means. Eye exposure with ZTLIDO should be avoided. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye (eg, eye glasses/eye wear) until sensation returns. Adverse Reactions Side effects of ZTLIDO include application site reactions such as, irritation, erythema, and pruritus. These are not all of the adverse reactions that may occur. Please see full Prescribing Information for more information. Use in Specific Populations Use of ZTLIDO during lactation should be used with caution as lidocaine is excreted into breast milk. The limited human data with lidocaine in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. To report SUSPECTED ADVERSE REACTIONS, contact SCILEX Pharmaceuticals Inc. at 1-866-SCILEX3 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary of Prescribing Information on following page. SCILEX® and ZTLIDO® are registered trademarks of SCILEX Pharmaceuticals Inc. All other trademarks are the property of their respective owners. © 2020 SCILEX Pharmaceuticals Inc. All rights reserved. ZTL-00289 01/20

ZTLIDO® (lidocaine topical system) Rx only Brief Summary: This information is not comprehensive. Visit www.ZTlido.com/hcp to obtain the FDA-approved product labeling or call 1-866-SCILEX3 (1-866-724-5393). INDICATIONS AND USAGE ZTLIDO contains lidocaine, an amide local anesthetic, and is indicated for relief of pain associated with post-herpetic neuralgia (PHN). DOSAGE AND ADMINISTRATION Apply up to three topical systems only once for up to 12 hours in a 24-hour period. CONTRAINDICATIONS Contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product. WARNINGS AND PRECAUTIONS Accidental Exposure Even a used ZTLIDO topical system contains residual lidocaine after use. A small child or pet may suffer serious effects from chewing or ingesting a new or used ZTLIDO. It is important for patients to store and dispose of ZTLIDO properly and keep out of the reach of children, pets, and others. Excessive Dosing/Overexposure The following may contribute to higher blood concentration of lidocaine, leading to adverse effects: longer duration of application; application of more than the recommended number of ZTLIDO; smaller patients; hepatically impaired patients; use on non-intact skin; or applying heat sources to ZTLIDO. Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Signs may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Discontinue ZTLIDO and any other oxidizing agents. Application Site Reactions During or immediately after treatment with ZTLIDO, application site reactions may develop including blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. Inform patients that severe skin irritation may occur with ZTLIDO if applied for a longer period than recommended. Hypersensitivity Reactions Cross sensitivity to ZTLIDO in patients with a history of drug sensitivity to para-aminobenzoic acid (PABA) derivatives is possible. Eye Exposure Immediately wash out the eye with water or saline and protect the eye until sensation returns. ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail elsewhere in the labeling: • Methemoglobinemia • Application Site Reactions • Hypersensitivity Reactions

The following adverse reactions from voluntary reports or clinical studies have been reported with lidocaine. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissues: blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erosions, erythema, exfoliation, flushing, irritation, papules, petechia, pruritus, vesicles, and abnormal sensation. Immune system: angioedema, bronchospasm, dermatitis, dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria. Central Nervous System: lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, somnolence, respiratory depression and arrest. Cardiovascular: bradycardia, hypotension, and cardiovascular collapse leading to arrest. Other: asthenia, disorientation, headache, hyperesthesia, hypoesthesia, metallic taste, nausea, pain exacerbated, paresthesia, taste alteration, and vomiting. DRUG INTERACTIONS Drugs That May Cause Methemoglobinemia When Used with ZTLIDO Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drug classes: nitrates/nitrites; local anesthetics; antineoplastic agents; antibiotics; antimalarials; anticonvulsants; other drugs (e.g., acetaminophen, metoclopramide, quinine). Antiarrhythmic Drugs When ZTLIDO is used in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine), the toxic effects are additive and potentially synergistic. Consider risk/benefit during concomitant use. Local Anesthetics When ZTLIDO is used concomitantly with other products containing local anesthetic agents, the effects are additive. Consider the amount of drug absorbed from all formulations when local anesthetic agents are administered concomitantly. OVERDOSAGE Lidocaine overdose from cutaneous absorption is rare but could occur. If there is any suspicion of lidocaine overdose, check drug blood concentration. The management of overdose includes close monitoring, supportive care, and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdose with lidocaine.

This brief summary is based on ZTLIDO prescribing information revised November 2018. ZTL-00118 01/19 Manufactured for: Scilex Pharmaceuticals Inc. Palo Alto, CA 94303 USA SCILEX® and ZTLIDO® are registered trademarks of Scilex Pharmaceuticals Inc. © 2020 Scilex Pharmaceuticals Inc. All rights reserved.

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

—Michael R. Clark md, mph, mba

box” for years, even if we do not have the foundational knowledge of their difis a word I usually try to avoid… We tend ferences, similarities, and peculiarities. Kevin L. Zacharoff to categorize what is happening based Virtually every prescribed medication on what has happened, then measurcarries a risk/benefit ratio, and these ing things on an equitable basis with the ultimate intention of drugs are no different. This article is a must-read and a must-keep determining what is normal or abnormal. I think this also applies with fantastic at-a-glance tables. Choices about pharmacologic pain to healthcare, certainly for people with chronic pain. It has been treatments seem to be getting more complex, and it can be chalrelatively easy for me to teach others that the word “cure” does lenging for us to know about adverse effects, potential for abuse, not belong in the context of chronic pain treatment because it and drug interactions. It is all here. is unlikely, and often an unrealistic expectation. Essentially, that means telling patients with chronic pain that “normal” is out of I must admit that when I think of terms like stem cells and regenreach and a fact which must be understood and accepted to then erative medicine, my mind does not automatically think about pain attempt successfully to negotiate between pain and suffering. As and its management. Dr. Jay Joshi opens the subject for discusI reflect on the pandemic, I think how in some ways we all may be sion. Positing that we have to accept that, in certain cases, the like patients with chronic pain. Is normal ever coming back? Will causes of inflammation, tissue damage, and lack of healing may some variation of normal return, but not quite? Maybe we should not be reversible, we may need to be forward-thinking regarding view this and every issue of PWJ in a different way: an empathetic someday harnessing strategies to treat chronic pain. This piece way. A way which helps us see that any one or all of us could be just provides us with a detailed analysis how these technologies work steps away from never seeing normal again and needing help ne- and gives us food for thought about how the future of pain mangotiating a new future, the motivation to function optimally, and agement might be very different sooner than we expect. most importantly the ability to have hope. The Pundit Profile spotlights someone for whom I have the utmost Can you imagine the suffering associated burning pain, temperature respect, Dr. Lynn Webster. If I were to use two words to sum up lability, and intense erythema of the lower extremities? Dr. Carrie Dr. Webster, the first would be credible, followed by authentic. Tram, Sarah O’Brien, and Dr. Charles Argoff focus on the often When it comes to pundits in pain medicine, he has been omnipresdevastating “man on fire syndrome” or erythromelalgia. Occurring ent in the pain education landscape for as long as I can remember, in patients as young as a year old and two times more frequently in earning the respect and trust of virtually everyone he interacts women, this condition may not be part of our standard differential with. It is a treat to have the opportunity to learn more about the diagnosis. The authors provide a detailed analysis of its incidence, person behind the persona.. pathophysiology, assessment strategies, and management. Presenting in both primary and secondary variations, with either idio- Dr. Jorge F. Carrillo is the focus of this issue’s Next Generation. pathic or genetic causation, this painful condition—characterized The fact that he is a huge fan of Rocky means we are kindred spirback in 1878—may need to be more prominent in our everyday its. Add that he is driven to educate, values his family, and understands the idea that the practice of medicine is really a “navigamindset than before. tion” means that we see things the same way. It is comforting to In my opinion, there is no better acute pain model than postsurgical know more about passionate clinicians like him who will lead us pain. The causal aspect is consistent, the treatment setting is con- into the future. trolled, and one of the few variables is the patient. Despite significant scientific evidence demonstrating the adverse effects of poorly Also, of worthy of mention in this issue of PWJ is the fourth installtreated postsurgical pain on both short-term and long-term recovery, ment of the recurring segment titled Back to the Basics for people adequate analgesia for this patient population continues to be elusive. seeking basic foundational pain education. Drs. Joseph Pergolizzi Jr, Robert Raffa, and Charles Wollmuth explore this conundrum in detail, including challenges associated with “Normally” I now would be saying I hope to see you at the PAINWeek postsurgical pain in the face of today’s “opioid epidemic.” The reader National Conference. With this year’s meeting being virtual, all I can is provided with thought-provoking material about risk factors that say is that the education will be consistent and the subject matter may predict a patient’s postoperative pain course, the likelihood of clinically relevant. We will miss being together in person, but hope developing chronic postoperative pain, and strategies to try to raise next year we will approach the place we’d all like to be—normal. the bar. This article is relevant, for virtually all of us have patients who undergo surgery… and pain is part of that package. Kevin L. Zacharoff MD, FACIP, FACPE, FAAP Dr. Amanda Mullins provides an in-depth look at a nonopioid class of medications we may often prescribe/coprescribe for treatment of the most common type of pain: musculoskeletal pain. Skeletal muscle relaxants have been part of our pain management “tool-

Kevin L. Zacharoff is Faculty and Clinical Instructor at suny Stony Brook School of Medicine in New York, and is Ethics Committee Chair at St Catherine of Siena Medical Center in Smithtown, New York.

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Charles E. Argoff MD

Charles Argoff is a professor of neurology at the Albany Medical College, and director of the Albany Medical Center Department of Neurology in New York. His article was coauthored with Carrie B. Tram, dnp, and Sarah E. O’Brien, fnp-c, both of whom are nurse practitioners at Albany Medical Center, Department of Neurology, and work directly with Dr. Argoff on the pain management team.

p.46

Jay Joshi MD

Jay Joshi is a board certified anesthesiologist and fellowship trained interventional spine and pain management physician. Dr. Joshi has served as the medical director of pain management at a large hospital in the Chicago area while maintaining a private practice, where he performs interventional spine and pain procedures including selective nerve root blocks, radiofrequency ablation, and stem cell therapy. He has presented over 600 times to a variety of audiences.

Amanda M. Mullins PharmD, BCPS

p.36

Mandy Mullins is a Clinical Pharmacy Specialist - Pain Management and Palliative Care at the va St. Louis Medical Center, Jefferson Barracks Division, in Missouri. She completed her pgy2 Pain Management and Palliative Care Pharmacy Residency at Hospice of Southern Illinois, Inc., and serves as adjunct faculty at Southern Illinois University Edwardsville School of Pharmacy.

p.28

Joseph V. Pergolizzi Jr md

Joseph Pergolizzi is Director of Research at NEMA Research Inc and Senor Partner at the Naples Anesthesia and Pain Associates in Florida. Has published over 200 peer-reviewed articles, and coauthored this article with Robert B. Raffa, phd, Professor Emeritus and Past Chair, Temple University School of Pharmacy in Philadelphia, and Charles E. Wollmuth, Research Associate at NEMA Research Inc.

Not only can you take our faculty home with youâ&#x20AC;&#x201D; now you can also bring them to the gym 365 days a year!

By Charles E. Argoff MD/ Sarah E. O’Brien FNP-C/Carrie B. Tram DNP

neurology

characterized in 1878 by physician Silas Weir Mitchell, erythromelalgia, otherwise known as â&#x20AC;&#x153;man on fire syndrome,â&#x20AC;? is a rare and painful condition that can be devastating to those affected by it.1 The hallmark symptoms consist of episodic flare-ups of burning pain, temperature lability, and intense erythema of the distal extremities. This condition is diagnosed most often in patients between the ages of 50 and 60, but there are cases of pain expression reported in patients as young as 1 year old.2 The estimated annual incidence of erythromelalgia is 1.3 per 100,000, with about 2 women diagnosed to every man.1 While recognition of this rare condition has improved since its initial discovery, a thorough understanding of the clinical presentation, pathophysiology, and management may lead to a more prompt diagnosis, better treatment plan, and improved quality of life for patients.

There are two types of erythromelalgia, primary and secondary, that are classified based on the underlying etiology. Primary erythromelalgia is idiopathic or genetically inherited and is due to mutation of the SCN9A gene, located on chromosome 2q31â&#x20AC;&#x201C;32. Over 20 mutations on the SCN9A have been reported in patients with primary erythromelalgia. One such mutation affects Nav1.7, a sodium channel that plays a key role in the sensation of pain. Nav1.7 is expressed in the peripheral nervous system on the dorsal root ganglion neurons and the sympathetic ganglion neurons. Sodium channel Nav1.7 is also expressed in small-diameter nociceptive neurons and can be upregulated during an inflammatory response. The SCN9A gene codes for the Nav1.7 voltage-gated sodium channels, and therefore contributes to the â&#x20AC;&#x153;threshold gate,â&#x20AC;? to generate action potentials in nociceptors. Molecular alterations in Nav1.7 due to the SCN9A mutations lead to nociceptor dysfunction causing pain disorders, like gain of function disorders (primary erythromelalgia) and loss of function disorders (congenital insensitivity to pain). In primary erythromelalgia, increased sensory neuron excitability through altered or deactivated ramp currents leads to an amplified pain state.3 Additionally, it has been theorized that because the Nav1.7 channels are active in the central nervous system, specifically in the areas of pain perception and emotional integration, a mutation on this sodium channel may lead to a higher rate of misinterpretation of

pain. This mutation on Nav1.7 may also result in functional compensation within other sodium channels, leading to a wide variety in age at onset of symptoms and phenotypic presentation. While patients with primary or secondary erythromelalgia may present with phenotypic similarities, patients with primary erythromelalgia may be more likely to state that their symptoms began within the first decade of life compared to secondary erythromelalgia. Secondary erythromelalgia on the other hand, occurs as a result of myeloproliferative disorders stemming from multiple causes, such as hematologic conditions caused by platelet activation, drug reactions, poisoning from certain substances, connective tissue disorders, musculoskeletal disorders, and neurological disorders.4

Completing a thorough patient history and physical exam is essential to ensure early recognition of erythromelalgia in order to promptly and accurately diagnose and treat this condition. While taking a complete medical history from the patient, clinicians should ask about any comorbid conditions, specifically any conditions that can lead to secondary erythromelalgia, such as myeloproliferative disorders including polycythemia vera, leukemia, systemic macrocytosis; idiopathic thrombocytopenia, neoplasms, rheumatologic diseases; and possible medication

side effects or overdose.3,4 Medications that can directly contribute to the development of secondary erythromelalgia include bromocriptine, certain calcium channel blockers such as nifedipine, felodipine, and nicardipine, and topical isopropanol. It is also important to assess for poisoning from substances such as mushrooms or mercury, both of which can also lead to the development of erythromelalgia. The presence of erythromelalgia-associated poxvirus (an epidemic that was first uncovered among secondary school-age children in rural China in the late 1980s) should also be noted when taking a medical history. The presence of any of these underlying conditions assist the clinician in differentiating between primary and secondary erythromelalgia, and further demonstrate the importance of spending time with patients to complete a full medical history. Due to its idiopathic nature or genetic inheritance, primary erythromelalgia can be more difficult to diagnose, and can be misdiagnosed due to the similar phenotypic presentation to other common disorders such as Fabry disease. This is a genetic disorder that causes irregular lipid metabolism, manifesting in burning pain and paresthesias in the extremities. A decreased level of alpha-galactosidase A within the plasma of patients with Fabry disease differentiates it from erythromelalgia. Other disorders that present phenotypically similarly to erythromelalgia include

peripheral neuropathy, arterial or venous insufficiency, frostbite, vasculitis, erysipelas, dermatitis, osteomyelitis, gout, cellulitis, complex regional pain syndrome type 1, and Raynaudâ&#x20AC;&#x2122;s phenomenon.3 Patients with erythromelalgia presenting to a clinic will typically describe experiencing flare-ups of redness, burning pain, and warmth in the distal extremities, which can last anywhere from several minutes to days prior to improving. Symptoms are more common in lower extremities but can occur in upper extremities, and, most often, this condition presents bilaterally. If the patients are presenting in the early stages of this condition, they may complain of itching that will then progress into burning pain in the later stages of the disease process. It is not uncommon for patients to be asymptomatic while in the clinic, due to the episodic nature of this condition. Additional symptomatic presentation can include tender, mottled, and dusky skin, and acrocyanosis has also been observed in those with erythromelalgia. Typically, erythromelalgia episodes are triggered by exposure to heat, physical exercise, prolonged sitting with legs positioned below the heart, ambulation, and wearing shoes or gloves (covering the extremities). The symptoms are described as being overall worse in the summer and at night, and can be relieved by cooling, uncovering the affected extremities, elevating the extremities,

and immersing the affected extremities in water or ice.3 However, consistently submerging extremities in water or ice can present an additional problem, as development of ulceration or gangrene can occur. A study by Parker et al was completed via telephone survey to better characterize unifying signs and symptoms of erythromelalgia among 46 participants.1 Of these 46 participants, 41 (89%) were female, and the mean age of participants was 57. The average age of onset of symptoms was 41, and age at official diagnosis ranged between 8 and 84. Raynaud’s phenomenon was present in 80% of patients and appeared just over 7 years prior to the onset of erythromelalgia symptoms. Of the participants, 18% had a diagnosed connective tissue disorder, and 57% of the patients were past or present smokers. Within family history, 12 participants reported having a first-degree relative with diagnosed Raynaud’s phenomenon, and 6 reported having a first-degree relative with a diagnosed connective tissue disease.1 The most commonly reported symptoms were burning (96%), heat (93%), pain (87%), redness (83%), swelling (65%), and numbness (54%). Continuous symptoms were present in 48% of participants; 52% reported intermittent symptoms. The lower extremities were affected in 98% of patients, while 76% reported increased symptoms in their upper extremities, and 20% reported symptoms that primarily affected their face. Exacerbating factors causing symptom onset included being in a hot environment (85%), participating in vigorous exercise (78%); 76% reported increased symptoms at night.1

Diagnostic workup of a patient with suspected erythromelalgia can be difficult. Secondary erythromelalgia continues to be more of a diagnosis of exclusion, and there are no specific established biologic markers for primary erythromelalgia. Clinicians should therefore pay close attention to their patient’s physical exam and medical history to determine if there is any family history of similar symptoms, any associated underlying etiologies present, or if the presenting symptoms are more likely related to a different, phenotypically similar condition. A diagnosis of primary erythromelalgia is closely based on this history and physical exam, and is supplemented by the detection of a mutation on SCN9A, via a simple genetic blood test.3 This is indicated especially with regard to family planning purposes, as there is a 50% probability that this condition would be passed down to offspring. No specific imaging is necessarily helpful to make a diagnosis of erythromelalgia, but certain testing can rule out differential diagnoses. Myeloproliferative disorders including polycythemia or thrombocythemia may be diagnosed based on complete blood count results, thermography can be useful to assess for Raynaud’s phenomenon, and capillaroscopy can be done to assess for a connective

tissue disease.1 Histological examination can be useful only in severe cases of erythromelalgia, due to the somewhat limited specificity of such testing. Skin punch biopsies in patients with erythromelalgia may demonstrate a significant reduction in the number of small nerve fibers, perivascular lymphocytic inflammation, perivascular edema, and hyperplasia of the arteriolar smooth muscle.3

Primary erythromelalgia is largely refractory to pharmacotherapy, possibly owing to the variance in genotype between patients who are diagnosed with this condition. Encouraging conservative measures to prevent symptomatic episodes can significantly improve patients’ quality of life. Patients should be encouraged to avoid standing for long periods of time, avoid warm temperatures or vigorous exercise, and avoid keeping their extremities in a prolonged, dependent position. Elevating the extremities, and cooling any affected extremities, may temporarily reduce symptoms. Complementary and alternative measures may aid in symptomatic relief by working on patients’ responses and coping with their painful condition. Biofeedback in particular may be helpful to patients. If a myeloproliferative disorder is identified, it is important to treat that specific disorder to provide fewer and less severe episodes of pain, erythema, and warmth in the extremities.3 Pharmacological treatments that may successfully address patients’ symptoms include gabapentin, intravenous local anesthetics, propranolol, sodium nitroprusside, magnesium, compounded midodrine cream, and prostacyclin. The mutation on the SCN9A alters the binding location of local anesthetic agents; therefore, sodium channel blocking medications that use this mechanism to improve pain typically have limited efficacy in these patients. A common example of this would be lidocaine, which in 1 study provided only pain relief in 55% of patients with primary erythromelalgia.3 When this medication has provided pain relief to patients, the reported benefits are limited to fairly short durations. Mexiletine is an anti-arrhythmic agent that is similar to lidocaine and has been shown to provide lasting relief from pain in younger patients diagnosed with erythromelalgia. Studies have shown favorable outcomes when patients were given a bolus of intravenous lidocaine, and were then transitioned to mexiletine to provide long-lasting pain relief.5 Additionally, carbamazepine, an anti-epilepsy medication, has been shown in several cases to provide pain relief by decreasing voltage dependence of fast inactivation of sodium channels to more hyperpolarized potentials.3 Finally, topical therapies such as midodrine and botulinum toxin are occasionally used for pain relief, as well as the more invasive endoscopic thoracic sympathectomy procedure, which can provide relief particularly from the sympathetic nervous system dysfunction in erythromelalgia.3

In the study by Parker, the participants reported several common methods of alleviating flare-ups of pain, erythema, and warmth, including cooling (78%) and elevating (52%) the affected extremity. Intravenous iloprost, a prostacyclin analogue commonly used to treat pulmonary arterial hypertension, was the treatment that demonstrated the highest efficacy within this study population.1 Often, clinicians may find that off-label treatments, as well as a combination of treatments, may provide the greatest efficacy in reducing pain and associated complaints of erythromelalgia. There are also clinical trials being completed to assess for Nav1.7-selective agents that may be useful in treating patients, with promising results reported thus far.

diagnosis is difficult. Clinicians should note any of the triad of symptoms on physical exam and should pay close attention to detail when taking a medical and family history from patients. Certain testing can be useful to aid in the diagnosis of these patients, namely genetic testing to evaluate for a SCN9A mutation, blood work or imaging studies to rule out differential diagnoses confused with erythromelalgia, and skin punch biopsy in severe cases. This condition is largely refractory to any single pharmacotherapy aimed at reducing painful episodes, but with ongoing research being done to find a more effective treatment, the prognosis is becoming increasingly positive, and patients with erythromelalgia may be closer than ever to enjoying a satisfying quality of life. References 1. Parker L, Ponte C, Howell K, et al. Clinical features and management of erythromelalgia: long-term follow-up of 46 cases. Clin Exp Rheumatol. 2017;35:80–84.

Erythromelalgia is a rare and complex disorder that continues to be studied by clinicians and scientists alike, in order to be better understood. Primary erythromelalgia may be caused by a genetic mutation passed down between family members, or it may be idiopathic in nature. Secondary erythromelalgia is typically a manifestation caused by an associated underlying disorder, by medication use or misuse, or possibly poisoning. Patients with either primary or secondary erythromelalgia present with a triad of symptoms—episodic or constant flare-ups of pain, erythema, and warmth in the extremities—and

2. McDonnell A, Schulman B, Ali Z, et al. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype, and somatosensory profile. Brain. 2016;139: 1052–1065. 3. Tang Z, Chen Z, Tang B, et al. Primary erythromelalgia: a review. Orphanet J Rare Dis. 2015;10(127):1–11. 4. Mann N, King T, Murphy R. Review of primary and secondary erythromelalgia. Clin Exp Dermatol. 2018;44:477–482. 5. Elgueta F, De La Cuadra-Fontaine JC, Clede L, et al. Erythromelalgia: a rare and hard-to-treat condition: a 9-year-old boy responsive to intravenous lidocaine and oral mexiletine. Pain Med. 2013;14:311-312.

By Joseph V. Pergolizzi, Jr MD/Robert B. Raffa PhD/Charles E. Wollmuth BS

By Joseph V. Pergolizzi Jr MD/Robert B. Raffa PhD/Charles E. Wollmuth BS

Postoperative pain is prevalent, often

undertreated,1,2 and there are substantial gaps in the evidence in terms of guiding clinical care.3 Postsurgical pain is inadequately addressed in ≥80% of cases, and poorly controlled pain can adversely affect recovery, delay time to ambulation, decrease patient satisfaction, and may even set the stage for the development of chronic pain, which is far more challenging to treat.4 Postoperative pain tends to be multifactorial in nature, and multimodal analgesia can often address these multiple pain mechanisms. Multimodal or combination analgesia allows for the administration of lower doses of each individual analgesic agent, thus potentially reducing adverse effects. It can also provide enhanced benefits, if the agents work synergistically. Numerous studies have demonstrated the benefits of combination analgesia for postsurgical pain management.5–10 Multimodal analgesia relies on synergistic regimens that are comprised of ≥2 analgesics with different and complementary mechanisms of action the sum of which is greater than its parts. This includes, for example, combinations of systemic analgesics (eg, acetaminophen, nonsteroidal anti-inflammatory drugs, gabapentinoids, ketamine, lidocaine, α-2 agonists, magnesium, dexamethasone, tramadol, opioids), peripheral nerve blocks, intrathecal and epidural neuraxial analgesia, and local infiltrative methods. acute pain management

may be treated effectively with local anesthetics, anti-inflammatory agents, topical products, cold therapy, etc. Centralized pain (spinal cord and brain) may be addressed, for example, with local anesthetics, opioids, Îą-2 agonists, and anti-inflammatories.11 Opioids are effective pain relievers but their use is complicated by opioid-associated side effects, potential toxicity, and well-founded concerns about their abuse potential. In light of the current public health crisis of opioid morbidity and mortality, there is heightened scrutiny on the use of opioids even in the in-hospital perioperative setting. In turn, this has led to an exploration of alternative methods of postoperative pain management.12 31

…the acute pain of surgery can precipitate the sequence of events leading to chronic pain. For this reason, it is important to treat postoperative pain quickly, completely, and effectively.

Despite an armamentarium of analgesics, a wealth of literature and guidelines from the American Society of Anesthesiologists, and a desire on the part of clinicians to treat postoperative pain safely and effectively, pain after surgery remains inadequately treated. Enhanced recovery after surgery (ERAS) applies evidence-based practice to facilitate postsurgical recovery with an eye to containing costs and meeting patient expectations with regard to expedited recovery and rapid return to the activities of daily living.13 It involves steps prior to surgery, so-called “pre-habilitation,” that involve muscle strengthening, adequate nutrition and hydration, and psychological preparation; adequate anesthesia during surgery including “front-loading” of perioperative opioid analgesics; and multimodal analgesia following surgery along with prophylaxis to prevent postoperative nausea and vomiting.14 These fast-track programs represent major paradigm shifts in patient care with the potential to improve outcomes. The barriers to more effective postoperative analgesia include insufficient clinician training, inadequate knowledge of postoperative pain control by staff, lack of clear guidance for the healthcare team, inadequate pain control metrics, and less than full engagement from the interdisciplinary care team.15,16 A common problem in postoperative pain management is the emergence of analgesic gaps or specific time periods following surgery when serum concentrations

of analgesics fall below levels needed to provide adequate analgesia.17 By-the-clock or as-needed (PRN) dosing of analgesics can result in analgesic gaps as one dose wears off before the next can take effect. For other forms of analgesia, analgesic gaps can occur at any point in patient care and may be driven by shift changes. Patient-controlled analgesia (PCA) pumps are often used to help smooth analgesic gaps; about a third of in-hospital patients (33%) wish to restart PCA within 24 hours of stopping it, saying that it was more effective at managing pain than other methods.18 However, the decision as to how long a postoperative patient has a PCA pump is rarely a qualitative or evidence-based one, but is often scheduled for the convenience of the hospital or on an arbitrary basis. Arbitrary reasons might be empirical, for instance: “The patient gets PCA for one day after surgery.” It might be based on staffing—when the hospital has adequate personnel available to disconnect the pump. Or if there are enough pumps available or if they are needed elsewhere: some hospitals have few PCA systems and might wish to deploy them to postsurgical patients. The best way to visualize analgesic gaps is to consider an oral or intramuscular dose of an analgesic every 4 or 6 hours. At each dose, the patient ingests a specific amount of analgesic agent, which enters the bloodstream causing drug concentrations to peak after a certain period. Following peak serum concentrations, the concentration of the agent declines. It is only after the serum

concentration has declined markedly that the patient takes the next dose.19 Thus, intermittent dosing allows for good analgesic relief for certain periods of time, but pain control may be interrupted by analgesic gaps. Bolus intravenous dosing likewise creates peaks and troughs in serum concentration. After administration of the bolus, there is a rapid increase in the serum concentration of the agent followed by a decline; the next bolus resumes the pattern.

The surgical trajectory of a given patient involves preoperative, intraoperative, immediate postoperative, and delayed postoperative periods, each of which has its own particular challenges and defining characteristics. During the preoperative phase, the patient’s comorbidities should be considered along with environmental issues such as stress, trauma, or relevant mental health conditions such as excessive anxiety, stress, or catastrophizing. During the surgery, nerve and tissue damage as well as surgical complications are possible. After surgery, the patient will be in a pro-inflammatory state. The anesthetic technique, type and duration of surgery, and comorbidities can play a role in healing. Following surgery, there is what may be known as a delayed postoperative period where psychosocial factors, hyperalgesia, and persistent pain may play a role. Additional surgical interventions, chemotherapy, radiation, or other medical procedures can exacerbate the pain related to the original surgery.20 Note that surgical outcomes (positive or negative) and disease prognoses can markedly affect patient attitude, emotional response, recovery trajectory, and pain levels. In particular, risk factors for developing chronic postoperative pain have been identified and include capacity overload, preoperative pain in the operating field, other forms of preoperative chronic pain, intense acute postsurgical pain, and comorbid stress syndromes. In patients with all those risk factors, 71% had chronic postoperative pain 6 months after surgery compared to 12% of patients who had none.2

Chronic postoperative pain starts with the stimulus of acute injury to bodily tissue. This triggers a nociceptive cascade of events with landmark responses of neurotransmitter release, electrophysiological responses, intracellular stress responses, structural responses, and neuropsychological events.21 Thus, the acute pain of surgery can precipitate the sequence of events leading to chronic pain. For this reason, it is important to treat postoperative pain quickly, completely, and effectively.

● When treating any type of pain, but in particular postoperative pain, it is important to take and document regular pain assessments. A number of validated pain metric tools are available for use. Many clinicians use the 11-point scale where 0 is no pain at all and 10 is the worst pain imaginable. ● Acute postoperative pain is often undertreated, and steps must be taken to assure it is addressed. ● Undertreated or untreated postoperative pain can be associated with significant, even life-altering, long-term consequences. ● Analgesic gaps can cause postoperative pain to be undertreated. ● Despite our understanding of postoperative pain and a wealth of analgesic options, there still remain many barriers to effective postoperative pain control. ● Enhanced recovery after surgery (ERAS) is a paradigm-shifting strategy that has the potential to improve outcomes. ● Multimodal analgesia is a good analgesic strategy to address multifactorial pain (which is typical for postsurgical pain) and it allows relatively low doses of the individual agents. These lower doses may help to reduce side effects associated with those agents. ● Multimodal analgesia should use ≥1 agent with complementary mechanisms of action and a synergistic analgesic effect. Many 2-drug combinations are known, such as acetaminophen plus oxycodone, hydrocodone/acetaminophen, codeine/acetaminophen, tramadol/acetaminophen, and oxycodone/ibuprofen. ● Emerging treatment options— reconsidering older nonopioid drugs such as ketorolac, nonopioid combination therapy such as celecoxib/ gabapentin or celecoxib/pregabalin—may remove barriers to postoperative pain treatments currently in development.

Pain following surgery varies among patients depending on the type of surgery and the patient’s underlying condition. Pain management may be best approached with a multimodal strategy and opioid-sparing techniques to provide effective and safe pain control. Adequate acute postoperative pain management is essential to mitigate the potential of persistent chronic pain. The current opioid crisis has spawned renewed interest in, and assessments of, the best approaches to treat pain in its variety of types and healthcare settings. This includes the assessment of the best treatment of acute pain in the postoperative setting.

The importance of treating acute pain in this setting is not only for contemporaneous pain relief, but also the mitigation of possible progression of acute pain to chronic pain, a much more difficult pain to treat. Fortunately, accepted clinical strategies described in this article are available for the healthcare provider to optimize pain treatment even in the current opioid crisis.

13. American College of Obstetricians and Gynecologists. Perioperative Pathways: Enhanced Recovery After Surgery. Obstet Gynecol. 2018;132(3):e120-e129. 14. Melnyk M, Casey RG, Black P, et al. Enhanced recovery after surgery (ERAS) protocols: time to change practice? Can Urol Assoc J. 2011;5(5):342-348. 15. Meissner W, Huygen F, Neugebauer EAM, et al. Management of acute pain in the postoperative setting: the importance of quality indicators. Curr Med Res Opin. 2018;34(1):187-196. 16. d’Amours RH, Ferrante FM. Postoperative pain management. J Orthop Sports Phys Ther. 1996;24(4):227-236.

Acknowledgements

The authors acknowledge the assistance of Jo Ann LeQuang as medical writer and editor to help create this article from the authors’ presentations.

17. Carr DB, Reines HD, Schaffer J, et al. The impact of technology on the analgesic gap and quality of acute pain management. Reg Anesth Pain Med. 2005;30(3):286-291.

References

19. Ferrante FM, Orav EJ, Rocco AG, et al. A statistical model for pain in patientcontrolled analgesia and conventional intramuscular opioid regimens. Anesth Analg. 1988;67(5):457-461.

18. Chen PP, Chui PT, Ma M, et al. A prospective survey of patients after cessation of patient-controlled analgesia. Anesth Analg. 2001;92(1):224-227.

1. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157.

20. Wu CL, Raja SN. Treatment of acute postoperative pain. Lancet. 2011;377(9784):2215-2225. 21. Carr DB, Goudas LC. Acute pain. Lancet. 1999;353(9169):2051-2058.

2. Meissner W, Coluzzi F, Fletcher D, et al. Improving the management of postoperative acute pain: priorities for change. Curr Med Res Opin. 2015;31(11):2131-2143. 3. Gordon DB, de Leon-Casasola OA, Wu CL, et al. Research gaps in practice guidelines for acute postoperative pain management in adults: findings from a review of the evidence for an American Pain Society clinical practice guideline. J Pain. 2016;17(2):158-166. 4. Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017;10:2287-2298. 5. Chen M, Feng D, Han P, et al. Analgesic efficacy of combination therapy versus monotherapy on postoperative pain control in percutaneous nephrolithotomy: a meta-analysis of randomized controlled trials. Urolithiasis. 2020;48(2):185-186. 6. Chandanwale AS, Sundar S, Latchoumibady K, et al. Efficacy and safety profile of combination of tramadol-diclofenac versus tramadol-paracetamol in patients with acute musculoskeletal conditions, postoperative pain, and acute flare of osteoarthritis and rheumatoid arthritis: a Phase III, 5-day open-label study. J Pain Res. 2014;7:455-463. 7. Cho C-H, Song K-S, Min B-W, et al. Multimodal approach to postoperative pain control in patients undergoing rotator cuff repair. Knee Surg Sports Traumatol Arthrosc. 2011;19(10):1744-1748. 8. Daniels SE, Atkinson HC, Stanescu I, et al. Analgesic Efficacy of an acetaminophen/ibuprofen fixed-dose combination in moderate to severe postoperative dental pain: a randomized, double-blind, parallel-group, placebocontrolled trial. Clin Ther. 2018;40(10):1765-1776e5. 9. Habibi M, Kim PY. Hydrocodone and acetaminophen. In: StatPearls. Treasure Island, FL: StatPearls Publishing LLC.; 2019. 10. Rawal N, Macquaire V, Catala E, et al. Tramadol/paracetamol combination tablet for postoperative pain following ambulatory hand surgery: a double-blind, double-dummy, randomized, parallel-group trial. J Pain Res. 2011;4:103-110. 11. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63(10):1979-1984. 12. Mitra S, Carlyle D, Kodumudi G, et al. New advances in acute postoperative pain management. Curr Pain Headache Rep. 2018;22(5):35.

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S CP The viewpoints in this article are those of the author and not necessarily that of the VA.

Skeletal muscle relaxants (SMRs) are a group of medications commonly used to treat spasticity and/or spasms and, as a group, vary vastly in mechanisms of action.1 Generally speaking, SMRs target sensory fibers in the periphery that are comprised of type 1a, type 1b, and type 2 fibers, each responsible for a different effect. Type 1a: Stemming from primary sensory endings on the muscle spindle, these fibers are responsible for motor neuron excitation, which results from the stretch reflex. Type 1b: Originating from the Golgi tendon body, these fibers are responsible for inhibitory interneuron excitation, meaning they activate the interneuron to release glycine, an inhibitory mediator, eventually leading to hyperpolarization of the motor neuron. Type 2: Originating from secondary sensory endings on the muscle spindle, these fibers are responsible for interpreting proprioception.2 The overarching effect of this class of medications is prevention of skeletal muscle excitability and contraction via the monosynaptic and polysynaptic reflex pathways.1

Table 1. Classifications of skeletal muscle relaxants3 Antispasmodics

Spasmolytics

Direct Acting

Carisoprodol Chlorzoxazone Cyclobenzaprine Metaxalone Methocarbamol Orphenadrine

Baclofen Diazepam Tizanidine

Dantrolene OnabotulinumtoxinA

in this class, commonly classified as either antispasmodics or spasmolytics, are listed in Table 1.3 Antispasmodics treat musculoskeletal spasms originating in the periphery, while spasmolytics treat spasticity from upper motor neurons.4 A third commonly referred to classification is direct-acting SMRs, which exert their effects directly on the muscle itself.4 Although these separate classifications of muscle relaxers exist, recent data suggest an overlap in documented benefit for conditions related to both spasticity (multiple sclerosis, spinal cord injury, cerebral palsy) and spasms (fibromyalgia, low back pain). However, prior to discussing evidence to support use of these agents, a brief refresher on the history of muscle relaxers is crucial.

The Kefauver-Harris Amendment, which mandated that manufacturers must document safety and efficacy of medications, was passed in October 1962.5 Methocarbamol, chlorzoxazone, carisoprodol, orphenadrine, and metaxalone were all approved prior to this amendment. Dantrolene, cyclobenzaprine, baclofen, and

tizanidine were approved after October 1962, meaning that they had both safety and efficacy documented prior to their approval by the U.S. Food and Drug Administration (FDA).6 Diazepam and onabotulinumtoxinA were also approved after the Kefauver-Harris Amendment, and although these two medications arenâ&#x20AC;&#x2122;t classified as skeletal muscle relaxants, they still have utility when treating conditions related to spasticity and spasms and are often included in literature and guidelines as treatment options.

Numerous studies have evaluated the safety and efficacy of SMRs; however, most are poor/fair quality and have substantial limitations such as small sample sizes, single-centered participation, and un- or underreported adverse events and p-values. Lastly, there is no strong evidence that one skeletal muscle relaxant is better than the others, particularly due to the paucity of existing high-quality head-to-head trials. Of the existing observational, placebo-controlled, and head-to-head trials, along with additional meta-analyses, Chou et al produced a comprehensive review on the data supporting use of each skeletal muscle relaxant.7 Studies evaluating efficacy related to spasticity have shown fair quality evidence in favor of tizanidine, baclofen, and dantrolene compared to placebo. Head-tohead studies have shown fair quality evidence for similar efficacy between tizanidine, baclofen, dantrolene, and diazepam.7 Studies evaluating efficacy related to musculoskeletal conditions have shown fair quality evidence for the benefit of cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine compared to placebo, and head-to-head trials have shown fair quality evidence suggesting cyclobenzaprine and diazepam are similarly efficacious.7

Safety surrounding chronic use of SMRs is a long-standing concern, undoubtedly due to the lack of available data and underreporting. Studies evaluating the safety related to spasticity have shown that tizanidine is associated with lower rates of weakness when compared to baclofen; however, tizanidine does come with a risk of asymptomatic, and reversible, hepatotoxicity. 7 Baclofen may have lower incidence of dry mouth when compared with tizanidine. Dantrolene carries a risk of serious hepatotoxicity.7 Safety concerns are similar with musculoskeletal conditions, with the additional risk of reversible hepatotoxicity with chlorzoxazone. Furthermore, with the current concerns of chronic opioid therapy, it must be mentioned that skeletal muscle relaxants, due to their central nervous system depression, carry the potential for abuse and respiratory depression when used with other central nervous system depressants.8 Carisoprodol, specifically, is part of the â&#x20AC;&#x153;Holy Trinity,â&#x20AC;? along with an opioid and benzodiazepine.9 Carisoprodol is metabolized to meprobamate, which displays barbiturate-like properties and can be fatal when given with other medications known to have depressant effects.9 Although carisoprodol is the muscle relaxant most thought of as dangerous, I encourage careful consideration and monitoring of any individual on SMRs

in combination with opioids or other medications with known risk of central nervous system depression. If urine drug screens are performed for any reason, special attention must be given to any unexpected results while an individual is taking a muscle relaxer. For example, since cyclobenzaprine is so closely related to tricyclic antidepressants (TCAs), it may cause a false positive screen if tricyclic antidepressants are included in that panel.10 Additionally, TCAs, specifically amitriptyline, may cause a false positive for lysergic acid diethylamide (LSD).11 While there have been no case reports of cyclobenzaprine causing false positives for LSD, it is theoretically possible due to the structural similarities of cyclobenzaprine and amitriptyline.

If the above paragraphs regarding safety and evidence for use of these agents gave you a headache, youâ&#x20AC;&#x2122;re not alone. Blurred and scarce data surrounding the safety, efficacy, and monitoring of SMRs all contribute to the challenge of confidently utilizing them in clinical practice. Clinically, SMRs will likely not prove to be beneficial unless tension and/or spasms are a complaint. If a spasticity condition is suspected, such as multiple sclerosis or spinal cord injury, I highly recommend a referral to the appropriate provider. Perhaps the simplest way to choose a skeletal muscle relaxant in clinical practice is to combine guideline recommendations with caveats for use of each medication. Cyclobenzaprine is the preferred skeletal muscle relaxant for adjunct therapy in individuals with fibromyalgia, while baclofen is preferred in those with a neuropathic pain component.12 If using a skeletal muscle relaxant for acute low back pain, it is recommended to consider any agent except baclofen or dantrolene.13 If utilizing a skeletal muscle relaxant for low back pain in primary care, it is recommended to consider cyclobenzaprine as adjunct therapy to a first- or second-line agent.14 When considering use in spasticity associated with multiple sclerosis, baclofen is the preferred first-line agent, with tizanidine and dantrolene as preferred second-line options.15 In those with amyotrophic lateral sclerosis (ALS), baclofen is recommended as second-line treatment after physical therapy.16 Lastly, we cannot omit brief recommendations regarding utilization of SMRs in children and adolescents. For those with nonprogressive brain disorders, baclofen is preferred.17 If a diagnosis of cerebral palsy is present, tizanidine is recommended as first-line therapy.18 Anecdotally, in my role as a pain management clinical pharmacy specialist at the St. Louis va Medical

Interpreting available literature doesnâ&#x20AC;&#x2122;t come easily and, with each clinical trial contradicting the next, forming a conclusive recommendation is nearly impossible.

Center, I typically see most benefit with tizanidine and baclofen, with cyclobenzaprine coming in third. The most common adverse effect I see with tizanidine is decreased blood pressure, but most individuals tolerate this quite well due to a high incidence of comorbid hypertension. It may also be useful to initially start with a dose at bedtime as tizanidine often comes with drowsiness. Baclofen is generally tolerated well and the most common complaint I receive is sedation. Cyclobenzaprine is structurally similar to tricyclic antidepressants so be mindful of drug interactions and anticholinergic side effects. These side effects often prevent me from starting cyclobenzaprine if the individual is also on a TCA. Different healthcare providers will find benefit with different SMRs and most will admit to a trial and error method when using these medications in clinical practice. When in doubt, I recommend briefly consulting a pain specialist or someone with experience in pain management to assist with your decision. The most important lesson to keep in mind is that, because SMRs vary significantly in their mechanisms of action, failure of one muscle relaxer does not indicate nor predict failure of future therapies. For this reason, two or three muscle relaxers are often trialed before finding one that works for an individual.

Selecting a skeletal muscle relaxant for use in clinical practice can be a daunting task due to conflicting evidence and underreported adverse effects. Interpreting available literature doesnâ&#x20AC;&#x2122;t come easily and, with each clinical trial contradicting the next, forming a conclusive recommendation is nearly impossible. So, when you finally make the decision to initiate a skeletal muscle relaxant, how do you choose? Table 2 includes each of the agents, along with their available routes of administration, possible side effects, mechanism of action, and clinical pearls. This table is meant as a guide to help select the most appropriate agent for any given patient, considering other comorbidities, drug interactions, and further patient specific factors. Other things to consider include general tolerability of the selected medication, cost, and the potential for abuse of some of these agents, particularly when co-prescribed with other central nervous system depressants, such as opioids. Only after considering all these factors should you make an informed choice to initiate a skeletal muscle relaxant.â&#x20AC;&#x201A;

Table 2. Considerations when selecting a skeletal muscle relaxant19-29 Medication*

Possible Adverse Effects

Mechanism of Action

Clinical Pearls

Baclofen (PO, IT)

Sedation, dizziness, weakness, hypotension, nausea, respiratory depression

▸ Gamma-aminobutyric acid (gaba)B selective agonist ▸ Voltage-gated calcium channel α2δ antagonist (weak)

▸ gaba derivative ▸ Renal dosing recommendations ▸ Possible seizures and hallucinations with abrupt discontinuation

Carisoprodol (PO)

Drowsiness, psychological and physical dependence

▸ Unclear, likely via nonbenzodiazepine ▸ High abuse potential gabaA agonism ▸ Withdrawal symptoms with abrupt discontinuation

Chlorzoxazone (PO)

Drowsiness, dizziness

Inhibits spinal reflexes likely through corticospinal input or interneurons

▸ Centrally acting ▸ Possible hepatotoxicity

Cyclobenzaprine (PO)

Anticholinergic effects

▸ Inhibits both alpha and gamma motor neurons via activation of the locus coeruleus ▸ 5-hydroxytryptamine and norepinephrine reuptake inhibition ▸ Voltage-sensitive sodium channel inhibition

▸ Tricyclic antidepressant-like, centrally acting ▸ Hepatic dosing recommendations ▸ Contraindications: hyperthyroidism, congestive heart failure, arrhythmias

Dantrolene (PO, IV)

Flushing, nausea, vomiting, diarrhea, somnolence

Attenuates muscle response to stimulation and reflexes through directly interfering with calcium release from sarcoplasmic reticulum

▸ Black Box Warning for hepatitis ▸ Hepatic dosing recommendations

Diazepam (PO, IM, IV, SC)

Paradoxical reactions, confusion, hypotension

GABAA benzodiazepine selective agonist (a1–3,5)

▸ Centrally acting ▸ Contraindications: severe respiratory/hepatic disease

Metaxalone (PO)

Hypersensitivity reactions, Unknown drowsiness, dizziness, headache, nausea, vomiting, nervousness, gastrointestinal upset

▸ Centrally acting ▸ Increased absorption with food ▸ Contraindications: severe renal/hepatic disease

Methocarbamol (PO, IM, IV)

Drowsiness, dizziness, lightheadedness

General central nervous system depression

▸ Centrally acting ▸ Possible dark urine

OnabotulinumtoxinA Headache, extremity pain, (IM, SC) dysphagia, injection-site reaction

Blocks neuromuscular conduction by inhibiting release of acetylcholine

Medical emergency if respiratory, swallowing, or speech difficulties

Orphenadrine (PO, IM, IV)

Dry mouth, drowsiness, urinary retention, tachycardia, palpitations; aplastic anemia (rare)

▸ Significant anticholinergic, antihistaminergic activity ▸ Voltage-sensitive sodium channel antagonist ▸ Norepinephrine transport inhibitor ▸ N-methyl-D-aspartate (nmda) antagonist

▸ Structurally related to diphenhydramine ▸ Contraindications: glaucoma, prostatic hypertrophy

Tizanidine (PO)

Somnolence, dry mouth, hypotension, weakness

▸ Alpha-2 centrally acting agonist ▸ Modulates presynaptic interneuron

▸ Possible hepatotoxicity ▸ Renal dosing recommendations

*Available routes of administration: IM = intramuscular; IT = intrathecal; IV = intravenous; PO = oral; SC = subcutaneous

References 1. Fudin J, Raouf M. A review of skeletal muscle relaxants for pain management. Pract Pain Manag. 2016;16(5). 2. Barnett KE, Barman SM, Boitano S, et al. Ganong’s Review of Medical Physiology. 24th ed. NY, NY: McGraw-Hill; 2012. 3. See S, Ginzburg R. Choosing a skeletal muscle relaxant. Am Fam Physician. 2008;78(3):365–370. 4. Martínez-Pérez EF, Juárez ZN, Hernández LR, et al. Natural antispasmodics: source, stereochemical configuration, and biological activity. Biomed Res Int. 2018;2018:3819714. 5. U.S. Food and Drug Administration. Consumer Updates. Kefauver-Harris Amendments Revolutionized Drug Development. 2012. Available at: www.fda.gov/consumers/consumer-updates/kefauver-harris-amendmentsrevolutionized-drug-development. 6. Frydrych V, Oderda G. Skeletal Muscle Relaxants. University of Utah College of Pharmacy. 2016. Available at: medicaid.utah.gov/pharmacy/ptcommittee/ files/Criteria%20Review%20Documents/2016/2016.02%20Skeletal%20Muscle%20 Relaxant%20Class%20Review.pdf.

15. Perry M, Swain S, Kemmis-Betty S, et al. Multiple sclerosis: summary of NICE guidance. BMJ (Online). 2014;349:g5701. 16. Andersen PM, Abrahams S, Borasio GD, et al, and the EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis. et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) - revised report of an EFNS task force. Eur J Neurol. 2012;19(3):360–375. 17. Mugglestone MA, Eunson P, Murphy MS, et al. Spasticity in children and young people with non-progressive brain disorders: summary of NICE guidance. BMJ (Online). 2012;346:e4845. 18. Delgado MR, Hirtz D, Aisen M, et al, for the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Practice Parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review). Neurology. 2010;74(4):336–343. 19. Lioresal (baclofen) [prescribing information]. Titusville, NJ: Janssen Pharmaceutical Companies; 2019. 20. Soma (carisoprodol) [prescribing information]. Somerset, NJ: Meda Pharmaceuticals Inc.; 2009. 21. Chlorzoxazone [prescribing information]. Atlanta, GA: Mikart Inc; 2014.

7. Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004;28(2):140–175.

22. Flexeril (cyclobenzaprine) [prescribing information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc.; 2013.

8. Elder NC. Abuse of skeletal muscle relaxants. Am Fam Physician. 1991;44(4):1223–1226.

23. Dantrium (dantrolene) [prescribing information]. Rochester, MI: JHP Pharmaceuticals; 2011.

9. Fudin J, Wolf AA. The perfect storm: opioid risks and “the Holy Trinity.” Pharmacy Times. September 24, 2014. Available at: www.pharmacytimes.com/ contributor/jeffrey-fudin/2014/09/the-perfect-storm-opioid-risks-and-theholy-trinity.

24. Valium (diazepam) [prescribing information]. Nutley, NJ: Roche Products, Inc.; 2008.

10. Moeller K, Lee K, Kissack J. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83:66–76. 11. Saitman A, Hyung-Doo P, Fitzgerald R. False-positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol. 2014;38(7):387–396. 12. Hooten WM, Timming R, Belgrade M, et al. Institute for Clinical Systems Improvement. Assessment and Management of Chronic Pain. Updated November 2013. Available at: cufamilymedicine.org/chronicpain/wp-content/ uploads/sites/4/2015/10/ICSI-ChronicPain-11–2013.pdf. 13. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147(7):478–491. 14. Toward Optimized Practice. Institute of Health Economics. Guideline for the evidence-informed primary care management of low back pain. National Guideline Clearinghouse. 2011. Available at: www.guidelinecentral.com/summaries/ guideline-for-the-evidence-informed-primary-care-management-of-low-back-pain/.

25. Skelaxin (metaxalone) [prescribing information]. Hobart, NY: Mallinckrodt Inc.; 2008. 26. Robaxin (methocarbamol) [prescribing information]. Malvern, PA: Endo Pharmaceuticals Inc.; 2019. 27. Botox (onabotulinumtoxinA) [prescribing information]. Irvine, CA: Allergan, Inc.; 2010. 28. Norflex (orphenadrine) [prescribing information]. Northridge, CA: 3M Pharmaceuticals; 2006. 29. Zanaflex (tizanidine) [prescribing information]. Ardsley, NY: Acorda Therapeutics Inc.; 2013.

By Jay Joshi MD

interventional pain management

Humans have been searching for the Fountain of Youth for millennia. Some people feel that regenerative medicine may be that magical fountain, while others believe it is a fad. As with many emerging topics, there is curiosity and confusion. While the regenerative medicine field is relatively new to most people, there is already a wide variety of treatments and technologies available including, but not limited to, stem cells.

deals with the process of replacing, repairing, and restoring normal tissue and function. It also includes the possibility of growing tissues and organs in the laboratory and implanting them when the body cannot heal itself. Regenerative medicine options may be useful, for example, in decreasing inflammation. Chronic inflammation, when unresolved due to injury or lack of healing, can increase stress; decrease appetite, function, sleep, and the ability to exercise; and delay healing.1 ¶ Regenerative medicine treatment options fall into 2 categories, healing environment and cellular products. Healing environment products include:

Cellular products include:

● NSAIDs ● Steroids ● Synthetic hyaluronic acid ● Platelet rich plasma (prp) ● Amniotic fluid ● Umbilical cord and amniotic membrane growth factors ● Exosomes

● Lipoaspirate concentrate ● Bone marrow aspirate concentrate ● Umbilical cord blood ● Umbilical cord mesenchymal stem cells (MSC)

Mesenchymal stem cells (MSCs) may differentiate into the cells that make up bone, cartilage, tendons, and ligaments, as well as muscle, neural, and other progenitor tissues. In the future, there will be FDA approved MSC products already differentiated into specific tissue, such as disc material and cartilage. Many are already under development. The major categories of stem cells are umbilical cord stem cells, placenta derived stem cells, and adult stem cells. Stem cells can be classified into broad categories, based on their ability to differentiate. ● Totipotent stem cells are found only in early embryos. Each cell can form a complete organism (eg, identical twins). ● Pluripotent stem cells exist in the undifferentiated inner cell mass of the blastocyst and can form any of the over 200 different cell types found in the body. ● Multipotent stem cells are derived from fetal tissue, cord blood, and adult stem cells. Although their ability to differentiate is more limited than pluripotent stem cells, they already have a track record of success in cell based therapies.2,3

Autologous Stem Cells

Stem cells can be autologous and nonautologous. Some advantages of autologous sourced stem cells include that they are coming from a known source, there is a reduced risk of rejection or inflammation, and there is a reduced potential for bacteria or virus transmission, again due to the known source. Disadvantages: the harvesting requires a surgical procedure; it requires additional capital due to disposable goods, surgical labor, and facility time costs; and there are potential morbidity complications, such as infection, bleeding, and pain. Two types of autologous stem cells are lipoaspirate concentrate and bone marrow aspirate concentrate. Lipoaspirate concentrate is isolated from the patient’s adipose tissue. There are protocols and tools available for lipoaspirate concentrate that vary in quality and viable cell counts. The number of stem cells transplanted into damaged tissue may alter efficacy of treatment. Typically, lipoaspirate concentrate yields between 4,500 to 450,000 MSCs per mL. Bone marrow aspirate concentrate has been used mainly for orthopedic purposes, such as knee and hip joints. It produces a very dilute MSC population and yields between 30 to 300 MSCs per mL.

Nonautologous Stem Cells

Nonautologous stem cell treatment options may have some advantages, including higher concentrations of MSCs, epigenetically young cells, quick and reproducible cells, and no equipment capital or surgical costs.

Disadvantages: the potential for bacterial or viral transmission as the cells are not sterilized (which would kill all the cells), and logistical and handling considerations, such as the fact that these products must be shipped and stored at negative 2000 C. Nonautologous tissue based stem cell products are derived from Wharton’s jelly, a mucous connective tissue found within the umbilical cord. Wharton’s jelly originates in the extraembryonic mesoderm and is composed of myofibroblast-like stromal cells, collagen fibers, proteoglycans, and has very high concentrations of hyaluronic acid and chondroitin sulfate. Wharton’s jelly-derived MSCs are immunoprivileged, meaning they are universal donors. They can be collected easily at the time of childbirth and there is no need for invasive harvesting methods. Since there are about 131 million births worldwide annually, there could be a large supply of these MSCs. Nonautologous blood based stem cell products are derived from umbilical cord blood and can yield millions of cells per milliliter of product. However, cord blood may not yield therapeutic numbers of MSCs unless the blood samples from many donors are pooled or the MSCs from a single donor are expanded in culture. There may be millions of cells within that cord blood and some may be misappropriated as stem cells although they are not. Thus, only a small fraction of the cells would be considered stem cells (either hematopoietic or MSCs). Hematopoietic stem cells are the most commonly cryopreserved stem cells, usually for autologous applications. White and red blood cells are not defined as stem cells and can be found in umbilical cord blood products, which could cause potential issues with the recipient (graft-vs-host disease).4 Nonstem cell, nonautologous products are also available. The umbilical cord tissue matrix and amniotic membrane are rich in hyaluronic acid, cytokines, growth factors, and proteins. These are a few of their biggest advantages. In addition, some physicians and companies that sell noncell products feel that the lack of cells poses an advantage due to the lower chances of infection and reaction. Although these claims have been debated, we have not seen infection and reactions with properly sourced stem cells. Various companies produce different quality products, and this variation is quite apparent in the regenerative medicine space as these products are not medications. Thus, they do not have the typical FDA approval for drugs, no National Drug Code numbers, and no universal standards for production. The amniotic membrane is the inner layer of the placenta that surrounds the baby during pregnancy, and it is a universal transplant tissue. It has shown great promise and been used extensively for wound management, burns, and soft tissue repair.5,6 Amniotic liquid suspension, or amniotic fluid, has been used to increase the volume of lubricating and shock absorbing fluid in joints. It has been used

…there is a great deal of progress that will occur in the near and long term future. …improved harvesting and manufacturing processes for products containing stem cells and growth factors will only improve outcomes and reduce costs. in cosmetic applications, specifically as an anti-wrinkle agent. It contains cytokines, hyaluronic acid, various proteins, and growth factors. It does not contain any living stem cells.7 Platelet-rich plasma is defined as “autologous blood with concentrations of platelets above baseline levels, which contains at least seven growth factors.”8,9 PRP is taken directly from a patient’s own blood and then injected into the affected area. PRP does not contain stem cells. Because it involves the patient’s own blood, PRP is relatively cheap and easy to reproduce. However, side effects such as swelling and infection can occur. In addition, unwanted products, such as white blood cells, certain cytokines, inflammatory cells, and pathogens can exist in the PRP. Exosomes are the newest category of tools within regenerative medicine. They are extracellular microvesicles that are involved in cell-to-cell communication. They are typically isolated from mesenchymal stem cells, most often from bone marrow. Exosomes contain proteins and, via cell signaling, they stimulate and modulate

multiple processes that may facilitate healing. Exosomes are not cells and do not contain cells. They are very small lipid vesicles that are secreted from MSCs and range in size from 30 to 150 nanometers.10,11

Conclusion

Regenerative medicine is a promising field with growing technologies and products. While it is not a new field, the continued evolution is exciting: there is a great deal of progress that will occur in the near and long term future. For example, improved harvesting and manufacturing processes for products containing stem cells and growth factors will only improve outcomes and reduce costs. Differentiation of MSCs will no doubt increase efficacy of the cells and may eventually provide reliable outcomes. In addition, the recent availability of exosomes derived from MSCs has already shown promising results.12 Advancements have been blunted due to necessary regulations to curb charlatans and counterfeit products and services. There have also been numerous

“stem cell clinics” that offer treatments with no stem cells. [See Side Bar.] Furthermore, people working at these clinics may deceptively market themselves as physicians when they are not. Their dishonest actions cause the public to lose faith in regenerative medicine as a whole and in healthcare providers associated with regenerative medicine. They also create regulatory investigations that further hamper legitimate physicians and providers from providing proper care. Despite these anomalies, regenerative medicine has already produced some very positive results that should only improve in the years to come.

References 1. Hescheler J. Stem cells for regenerative medicine and anti-aging. J Stem Cells Regen Med. 2019;15(2):53. 2. Hima Bindu A, Srilatha B. Potency of various types of stem cells and their transplantation. J Stem Cell Res Ther. 2011;1:115. Available at: www.longdom.org/open-access/potency-of-various-types-of-stem-cellsand-their-transplantation-2157–7633.1000115.pdf. 3. Sobhani A, Khanlarkhani N, Baazm M, et al. Multipotent stem cell and current application. Acta Med Iran. 2017;55(1):6–23. Available at: www.ncbi.nlm.nih.gov/pubmed/28188938. 4. Sanz J, Montoro J, Solano C, et al. Prospective randomized study comparing myeloablative unrelated umbilical cord blood transplantation versus hla-haploidentical related stem cell transplantation for adults with hematologic malignancies. Biol Blood Marrow Transplant. 2020 Feb;26(2):358–366. 5. Zelen CM, Serena TE, Denoziere G, et al. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502–507. 6. Cooke M, Tan EK, Mandrycky C, et al. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465–474. 7. Panero AJ, Hirahara AM, Andersen WJ, et al. Are amniotic fluid products stem cell therapies? A study of amniotic fluid preparations for mesenchymal stem cells with bone marrow comparison. Am J Sports Med. 2019;47(5):1230–1235. Available at: www.ncbi.nlm.nih.gov/pubmed/30844295. 8. Kobayashi E, Flückiger L, Fujioka-Kobayashi M, et al. Comparative release of growth factors from PRP, PRF, and advanced-PRF. Clin Oral Investig. 2016;20(9):2353–2360. 9. Pavlovic V, Milan C, Jovanovic V, et al. Platelet rich plasma: a short overview of certain bioactive components. Open Med (Wars). 2016;11(1):242–247. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC5329835. 10. Hicok K, Vangsness T, Dordevic M. Exosome origins: why the cell source matters. Stem Cells Regen Med. 2020;4(1):1–4. Available at: www.researchgate.net/publication/339136421_Exosome_Origins_Why_the_Cell_Source_ Matters. 11. Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014;15(3):4142–4157. 12. Hong P, Yang, H, Wu Y, et al. The functions and clinical application potential of exosomes derived from adipose mesenchymal stem cells: a comprehensive review. Stem Cell Res Ther. 2019;10:242. Available at: stemcellres.biomedcentral.com/articles/10.1186/s13287–019–1358-y.

There are regenerative medicine

companies that have made substandard products, false claims, and committed fraud. Understandably, seriously ill patients or those close to death are willing and eager to try anything to improve their situation. Unproven regenerative medicine products, however much desired by those in need, are not recommended by mainstream practitioners.1

False claims have been made by practitioners as well as companies. An investigative reporter in Chicago exposed a chiropractor who was making false statements about the treatments she was providing and the products she was using.2-4 Two regenerative medicine

companies that have been exposed for their false claims and substandard products are Liveyon and MiMedx. Liveyon has received multiple FDA warnings for “deviations from current good manufacturing practice and current good tissue practice” in addition to failing to meet multiple FDA standards and criteria for use. Furthermore, they were warned for “offering unapproved umbilical cord blood products that may put patients at risk.” They were also forced to recall their product due to “reported possible adverse reactions.”5-8

The award for the most

notorious regenerative medicine company easily goes to MiMedx. They have had numerous Securities & Exchange Commission (SEC) investigations, fines, FDA warnings for substandard products, channel stuffing*, bait-and switch, offlabel marketing, deceitful billing, fraud, and adverse events.9,10

The Wall Street Journal stated

that, in terms of substandard products, “MiMedx Group’s injectable wound-care products don’t meet regulatory standards, including for purity and sterility, more than two years after the company told the Food and Drug Administration it had complied with the requirements.” There have been numerous complaints about their products causing inflammation or infections.11,12

Their former CEO and COO may

be facing jail time after being charged with one count of conspiracy to commit securities fraud, make false filings with the SEC, and improperly influence the conduct of audits, and one count of securities fraud. The conspiracy charge carries a maximum prison term of 5 years. MiMedx agreed to pay a $1.5 million SEC settlement and $8 million to resolve claims of bad behavior.13

Just this year, in the midst of

the COVID pandemic, MiMedx saw no shame in illegally obtaining $10 million in small business loans (Payment Protection Program or PPP loans) even though they are a public company with over 700 employees. Earlier this year, MiMedx agreed to pay $6.5 million to resolve allegations that it “overcharged the U.S. Department of Veterans Affairs (VA) by knowingly submitting false statements and disclosures regarding inflated prices for thousands of human tissue grafts used in VA medical facilities.”14-17

*Inflating sales and earnings figures by deliberately sending retailers along its distribution channel more products than they can sell to the public.

Side Bar References

15. MiMedx announces additional access to capital and financing: includes approval of paycheck protection program loan and agreement to modify term loan. Globe Newswire. April 21, 2020. Available at: www.globenewswire.com/newsrelease/2020/04/21/2019440/0/en/MiMedx-Announces-Additional-Access-toCapital-and-Financing.html.

1. Zettler PJ. Compassionate use of experimental therapies: who should decide? EMBO Mol Med. 2015;7:1248–1250. Available at: www.embopress.org/doi/full/10.15252/ emmm.201505262. 2. Zekman P. Ads for stem cell therapies promise relief that patients say they didn’t get. CBS Chicago. November 15, 2018. Available at: https://chicago.cbslocal. com/2018/11/15/stem-cell-treatments-false-hope-unproven-injections/.

16. Silver-Greenberg J, Enrich D, Drucker J, et al. large, troubled companies got bailout money in small-business loan program. NY Times. May 13, 2020. Available at: www.nytimes.com/2020/04/26/business/coronavirus-small-business-loanslarge-companies.html.

3. Zekman P. Patients pay thousands and get no results; what is the state doing to stop unproven stem cell treatments? CBS Chicago. April 25, 2019. Available at: chicago. cbslocal.com/2019/04/25/unproven-stem-cell-treatments-complaints/.

17. Manskar N, Kosman J. Dozens of public companies got $300M in coronavirus small business loans. NY Post. April 21, 2020. Available at: nypost.com/2020/04/21/public-companies-got-300m-in-coronavirus-smallbusiness-loans/.

4. Morgenson G. MiMedx ex-senior executives indicted on fraud charges. Wall Street J. November 26, 2019. Available at: www.wsj.com/articles/ mimedx-ex-senior-executives-indicted-on-fraud-charges-11574789916. 5. FDA. Company announcement. Liveyon, LLC Issues a Voluntary Nationwide Recall of the Regen Series ® Product, Manufactured by Genetech, Inc. October 10, 2018. Available at: www.fda.gov/safety/recalls-market-withdrawals-safetyalerts/liveyon-llc-issues-voluntary-nationwide-recall-regen-series-r-productmanufactured-genetech-inc. 6. FDA. News release. FDA sends warning to company for marketing dangerous unapproved stem cell products that put patients at risk and puts other stem cell firms, providers on notice. December 20, 2018. Available at: www.fda.gov/newsevents/press-announcements/fda-sends-warning-company-marketing-dangerousunapproved-stem-cell-products-put-patients-risk-and. 7. FDA. News release. FDA sends warning to companies for offering unapproved umbilical cord blood products that may put patients at risk. December 6, 2019. Available at: www.fda.gov/news-events/press-announcements/fda-sendswarning-companies-offering-unapproved-umbilical-cord-blood-products-mayput-patients-risk. 8. FDA. Warning letter. Liveyon Labs Inc. MARCS-CMS 588399. December 5, 2019. Available at: www.fda.gov/inspections-compliance-enforcement-and-criminalinvestigations/warning-letters/liveyon-labs-inc-588399–12052019. 9. Edwards J. Auditor walks away from MiMedx, pointing to big trouble. AJC. December 11, 2018. Available at: www.ajc.com/news/state--regional/ auditor-walks-away-from-mimedx-pointing-big-trouble/1iGOo6t3V22dQCbClOMnLJ/. 10. Farrell G, Robinson M, Niquette M. SEC troubles are no bar to getting smallbusiness relief funds. Bloomberg Tax. May 1, 2020. Available at: news.bloombergtax. com/financial-accounting/sec-troubles-are-no-bar-to-getting-small-businessrelief-funds. 11. Morgenson G. MiMedx Injectables Don’t Meet Regulatory Standards Despite Claim to FDA. Wall Street J. May 24, 2019. Available at: www.wsj.com/articles/ mimedx-injectables-dont-meet-regulatory-standards-despite-claim-to-fda11558654273/. 12. Donovan B. Allograft warning letter & other news. Orthopedics. April 11, 2019. Available at: ryortho.com/breaking/fda-allograft-warning-letter-other-news/. 13. Land G. Mired in litigation, MiMedx shareholders nix ex-CEO Pete Petit return bid. Law.com. June 7, 2019. Available at: https://www.law.com/dailyreportonline/ 2019/06/17/mired-in-litigation-mimedx-shareholders-nix-ex-ceo-pete-petit-return-bid/. 14. Ilahi HF. Biopharmaceutical company agrees to pay $6.5 million to resolve false claims act allegations of false commercial pricing disclosures in government contracts. Lexology.com. Available at: www.lexology.com/library/detail. aspx?g= aa7627c6–85e3–428d-a976–981365608cab.

AJOVY® (fremanezumab-vfrm) injection IS NOW AVAILABLE IN AN EASY-TO-USE AUTOINJECTOR FEATURES OF THE AUTOINJECTOR1 Audible cues signal progress of administration

No visible needle

Window displays when dose has been delivered

Button-free, push-down mechanism Device locks after use Not made with natural rubber latex

97%

of HCP and patient evaluators found the AJOVY Autoinjector easy to use in two human factor studies (N=77)1*

AJOVY is indicated for the preventive treatment of migraine in adults.

IMPORTANT SAFETY INFORMATION

Contraindications: AJOVY is contraindicated in patients with serious hypersensitivity to fremanezumab-vfrm or to any of the excipients. Please see Important Safety Information continued on the next page. Please provide proper training to patients and/or caregivers on the preparation and administration of the AJOVY Autoinjector, as well as the preﬁlled syringe. Available resources include Instructions for Use in the full Prescribing Information, and an IFU video that can be accessed at AJOVYhcp.com. *Two human factor studies assessed evaluators’ ability to complete critical tasks in order to demonstrate use of the AJOVY Autoinjector in simulated-use sessions. When asked, “Was the autoinjector easy to use?”, 97% in study 1 (N=30) and 98% in study 2 (N=47) answered “Yes.” 1

Only 4 injection days per year with quarterly dosing† Available in an autoinjector and preﬁlled syringe

To learn more about quarterly dosing with the autoinjector, visit AJOVYhcp.com IMPORTANT SAFETY INFORMATION (continued)

Hypersensitivity Reactions: Hypersensitivity reactions, including rash, pruritus, drug hypersensitivity, and urticaria were reported with AJOVY in clinical trials. Most reactions were mild to moderate, but some led to discontinuation or required corticosteroid treatment. Most reactions were reported from within hours to one month after administration. If a hypersensitivity reaction occurs, consider discontinuing AJOVY and institute appropriate therapy. Adverse Reactions: The most common adverse reactions (≥5% and greater than placebo) were injection site reactions. Please see the Brief Summary of the full Prescribing Information on the adjacent page. Reference: 1. Data on ﬁle. Parsippany, NJ: Teva Pharmaceuticals USA, Inc. †

Quarterly dosing, 675 mg (225 mg x 3) SC dose and monthly, 225 mg SC dose.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR AJOVY® (fremanezumab-vfrm) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE AJOVY is indicated for the preventive treatment of migraine in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage Two subcutaneous dosing options of AJOVY are available to administer the recommended dosage: • 225 mg monthly, or • 675 mg every 3 months (quarterly), which is administered as three consecutive subcutaneous injections of 225 mg each. When switching dosage options, administer the first dose of the new regimen on the next scheduled date of administration. If a dose of AJOVY is missed, administer as soon as possible. Thereafter, AJOVY can be scheduled from the date of the last dose. Important Administration Instructions 2.2 AJOVY is for subcutaneous use only. AJOVY may be administered by healthcare professionals, patients, and/or caregivers. Prior to use, provide proper training to patients and/or caregivers on the preparation and administration of AJOVY prefilled syringe, including aseptic technique [see Instructions for Use in full Prescribing Information]: • Remove AJOVY from the refrigerator. Prior to use, allow AJOVY to sit at room temperature for 30 minutes protected from direct sunlight. Do not warm by using a heat source such as hot water or a microwave. Do not use AJOVY if it has been at room temperature for 24 hours or longer. • Follow aseptic injection technique every time AJOVY is administered. • Inspect AJOVY for particles or discoloration prior to administration. Do not use if the solution is cloudy, discolored, or contains particles. • Administer AJOVY by subcutaneous injection into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. For multiple injections, you may use the same body site, but not the exact location of the previous injection. • Do not co-administer AJOVY with other injectable drugs at the same injection site. 4 CONTRAINDICATIONS AJOVY is contraindicated in patients with serious hypersensitivity to fremanezumabvfrm or to any of the excipients [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including rash, pruritus, drug hypersensitivity, and urticaria, were reported with AJOVY in clinical trials. Most reactions were mild to moderate, but some led to discontinuation or required corticosteroid treatment. Most reactions were reported from within hours to one month after administration. If a hypersensitivity reaction occurs, consider discontinuing AJOVY, and institute appropriate therapy. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 6.1 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. The safety of AJOVY was evaluated in 2512 patients with migraine who received at least 1 dose of AJOVY, representing 1279 patient-years of exposure. Of these, 1730 patients were exposed to AJOVY 225 mg monthly or AJOVY 675 mg quarterly for at least 6 months, 775 patients for at least 12 months, and 138 patients for at least 15 months. In placebo-controlled clinical trials (Studies 1 and 2), 662 patients received AJOVY 225 mg monthly for 12 weeks (with or without a loading dose of 675 mg), and 663 patients received AJOVY 675 mg quarterly for 12 weeks. In the controlled trials, 87% of patients were female, 80% were White, and the mean age was 41 years. The most common adverse reactions in the clinical trials for the preventive treatment of migraine (incidence at least 5% and greater than placebo) were injection site reactions. The adverse reactions that most commonly led to discontinuations were injection site reactions (1%). Table 1 summarizes adverse reactions reported in the 3-month placebo-controlled studies (Study 1 and Study 2), and the 1-month follow-up period after those studies. Table 1: Adverse Reactions Occurring with an Incidence of At Least 2% for Either Dosing Regimen of AJOVY and At Least 2% Greater Than Placebo in Studies 1 and 2 Placebo AJOVY AJOVY Monthly 225 mg Monthly 675 mg Quarterly (n=668) (n=667) (n=290) % % % Injection site reactionsa 43 45 38 a Injection site reactions include multiple related adverse event terms, such as injection site pain, induration, and erythema. Adverse Reaction

AJOVY® (fremanezumab-vfrm) injection 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to fremanezumab-vfrm in the studies described below with the incidence of antibodies in other studies to other products may be misleading. Clinical immunogenicity of AJOVY was monitored by analyzing anti-drug antibodies (ADA) and neutralizing antibodies in drug-treated patients. The data reflect the percentage of patients whose test results were positive for antibodies to AJOVY in specific assays. In 3-month placebo-controlled studies, treatment-emergent ADA responses were observed in 6 out of 1701 (0.4%) AJOVY-treated patients. One of the 6 patients developed anti-AJOVY neutralizing antibodies at Day 84. In the ongoing long-term open-label study, ADA were detected in 1.6% of patients (30 out of 1888). Out of 30 ADA-positive patients, 17 had a neutralizing activity in their post-dose samples. Although these data do not demonstrate an impact of antifremanezumab-vfrm antibody development on the efficacy or safety of AJOVY in these patients, the available data are too limited to make definitive conclusions. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of AJOVY in pregnant women. AJOVY has a long half-life. This should be taken into consideration for women who are pregnant or plan to become pregnant while using AJOVY. Administration of fremanezumab-vfrm to rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation at doses resulting in plasma levels greater than those expected clinically did not result in adverse effects on development [see Animal Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The estimated rate of major birth defects (2.2-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. Data Animal Data When fremanezumab-vfrm (0, 50, 100, or 200 mg/kg) was administered to male and female rats by weekly subcutaneous injection prior to and during mating and continuing in females throughout organogenesis, no adverse embryofetal effects were observed. The highest dose tested was associated with plasma exposures (AUC) approximately 2 times that in humans at a dose of 675 mg. Administration of fremanezumab-vfrm (0, 10, 50, or 100 mg/kg) weekly by subcutaneous injection to pregnant rabbits throughout the period of organogenesis produced no adverse effects on embryofetal development. The highest dose tested was associated with plasma AUC approximately 3 times that in humans (675 mg). Administration of fremanezumab-vfrm (0, 50, 100, or 200 mg/kg) weekly by subcutaneous injection to female rats throughout pregnancy and lactation resulted in no adverse effects on pre- and postnatal development. The highest dose tested was associated with plasma AUC approximately 2 times that in humans (675 mg). 8.2 Lactation Risk Summary There are no data on the presence of fremanezumab-vfrm in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AJOVY and any potential adverse effects on the breastfed infant from AJOVY or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of AJOVY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Manufactured by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 US License No. 2016 ©2020 Teva Pharmaceuticals USA, Inc. This Brief Summary is based on the full Prescribing Information for AJOVY AJO-004.

FRE-42210

February 2020

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

efinition of abnormal pain

Classification o

Pain associated with the functioning of the unaltered nociceptive system, such as stepping on a thumbtack or touching a hot stove, is referred to as normal pain or nociceptive pain. Pain that occurs in the context of a nociceptive system that has been altered by tissue damage or other processes may be referred to as abnormal pain. There are several different ways of classifying abnormal pain, with no universally accepted approach. The following is a classification system that represents emerging consensus. Inflammatory pain is the sensation that results from injury to a somatic tissue (eg, skin, muscle, bone), which is invariably followed by an inflammatory reaction. For example, inflammatory pain is felt as the result of an acute injury or infection. The pain produced consequent to tissue inflammation results from several different processes. The release in injured tissue of so-called algogenic substances, such as bradykinin and serotonin, results in “sensitization” of the peripheral nociceptors, leading to a lower threshold for firing and an increased frequency of firing compared with their resting state. Sensitization of nociceptive afferents means that these neurons now respond to non-noxious stimuli, such as a light touch or contact with

clothing. So-called silent nociceptors may also be recruited; these are nociceptive nerve fibers that normally are silent, but in the setting of inflammation generate “pain” signals. After tissue healing, the pain generally resolves. However, in states of ongoing inflammation, such as rheumatoid arthritis or cancer, pain persists. In cases where inflammation may resolve but leave permanent anatomic alterations, such as the joint damage produced by osteoarthritis, chronic pain may result even though inflammation disappears or becomes inconspicuous.

What mechanisms lead inflammatory pain to become chronic or severe? One proposed mechanism is central

of pain into different types and mechanisms is more than just academic interest. Data continue to emerge indicating that different types of pain respond to different types of treatment, so that accurate classification of the type of pain can support accurate selection of treatment. sensitization—referring to the process by which, as a consequence of excessive nociceptive nerve signals bombarding the central nervous system from the periphery, long-term changes occur in the central nervous system that result in persistent amplification of pain signals. One experimental paradigm resulting in central sensitization is known as wind-up, referring to the progressive increase in the magnitude of C-fiber evoked responses of dorsal horn neurons produced by repetitive activation of C-fibers.1 Central sensitization is one proposed mechanism by which, in the context of inflammation or nerve injury (such as neuropathic pain), normally innocuous stimuli produce pain, such as is seen in many cases of postherpetic neuralgia.2 The phenomenon of normally innocuous stimuli (a light touch, for example) producing pain is called allodynia. Central sensitization may also cause an exaggerated response to normally painful stimuli; this is called hyperalgesia. Primary hyperalgesia occurs at the site of injury and is characterized by a lower pain threshold, spontaneous pain, and increased sensitivity. It usually features thermal and mechanical hypersensitivity.3 Secondary hyperalgesia refers to hyperalgesia occurring outside the area originally injured and is thought usually to be a consequence of central sensitization. The significance of the distinction is that to effectively treat chronic pain, hypersensitivity must be addressed during the clinical assessment of patients. Therapy that targets the mechanisms of hypersensitivity, if present, rather than mechanisms of nociception, must be used to try to alleviate symptoms.4 Neuropathic pain is defined as pain due to damaged or dysfunctional nerves. The pathophysiology of neuropathic pain can have both peripheral and central mechanisms. There have been multiple proposed mechanisms for both peripheral and central components to the pathophysiology of neuropathic pain; it is doubtful that a single mechanism can account for all cases. Damaged primary afferents may generate signals at ectopic or abnormal locations and their excitability increases after mechanical stimulation. In

addition, nerves that are cut off from input from the periphery, as in the case of amputation, may become hyperactive. Changes in the dorsal horn after nerve injury5: ○ Reorganization ○ Modulation in sensory input ○ Enlargement of the second-order neuron’s receptive field ○ Alteration in opioid receptivity ○ Abnormal ingrowth of sympathetic nerve terminals ○ Abnormal temporal summation Thus, central nervous system changes, as well as peripheral nerve changes, may generate neuropathic pain. Woolf and Mannion categorize peripheral neuropathic pain as either spontaneous (stimulus-independent) or hypersensitive (stimulus-evoked) because of increased sensitivity after damage to sensory neurons.6 Dysfunctional pain refers to a pain syndrome in which patients experience pain and abnormal sensitivity not associated with noxious stimulus, tissue damage, inflammation, or an identifiable lesion to the nervous system. The conditions encompassed by dysfunctional pain may include fibromyalgia, tension-type headaches, migraines, and even irritable bowel syndrome. Individuals with these syndromes share several common characteristics, including hypervigilance to sensory stimuli, exaggerated experience of a diverse array of sensory stimuli (eg, pain, but also sound, light, etc), high prevalence of associated conditions (eg, the high prevalence of irritable bowel syndrome in patients with fibromyalgia), and, in some cases, abnormal biomarkers (eg, opioid peptides in spinal fluid). There are many other ways of describing pain and terms that support them. An important term is referred pain, the perception of pain in a body part in which it did not originate (eg, feeling pain from the diaphragm near the shoulder). The mechanism of referred pain is thought to be convergence

of primary afferents from different locations (eg, shoulder and diaphragm) onto the same spinal cord neurons. Because spinal neurons subserve both deep structures and skin, mislocation of sensations is possible. Classification of pain into different types and mechanisms is more than just academic interest. Data continue to emerge indicating that different types of pain respond to different types of treatment, so that accurate classification of the type of pain can support accurate selection of treatment.

There is a need to individualize therapy for every patient in order to maximize the safety and efficacy of pain treatment. Consideration of variations in pain conditions themselves, metabolic differences regarding cytochrome P-450, and genetic receptor polymorphism, further reinforces that need. References 1. Li J, Simone DA, Larson AA. Windup leads to characteristics of central sensitization. Pain. 1999;79(1):75–82.

Additionally, when considering formulating a treatment plan that includes opioid analgesics, it is important to consider that new research shows that variations in patient response may be genetically based at the receptor level. Most of the opioids used in clinical practice exert their effects through mu opioid receptors. Their potency, effectiveness, and adverse effects can vary unpredictably among patients. Researchers feel that these variations “strongly argue against a single receptor mediating their actions.”7 A single mu opioid receptor gene has been identified, but current thinking is that there are numerous mu opioid receptor subtypes that are in part responsible for this variation in response.

2. Fields HL, Basbaum AI. Central nervous system mechanisms of pain modulation. In: Wall PD, Melzack R, eds. Textbook of Pain. 6th ed. London: Elsevier; 2013:309–330. 3. Raj PP. Pain mechanisms. In: Raj PP, ed. Pain Medicine: A Comprehensive Review. 2nd ed. Missouri: Mosby-Year Book; 2003:12–23. 4. Mannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain. 2000;16(suppl 3):S144–S156. 5. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. New York: McGraw Hill, Healthcare Information Programs; 2000. 6. Woolf CJ, Mannion RJ. Neuropathic pain: etiology, symptoms, mechanisms, and management. Lancet. 1999;353:1959–1964. 7. Pasternak GW. Molecular insights into mu opioid pharmacology: from the clinic to the bench. Clin J Pain. 2010;26 suppl 10:S3–9.

article in this series will be Pain Assessment Part 1.

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Jorge F. Carrillo md, facog Associate Professor University of Central Florida College of Medicine/ Department of Obstetrics and Gynecology Minimally Invasive Gynecologic Surgeon Orlando VA Medical Center

GPS Orlando, fl Typical Day My day starts usually at 6:15a with freshly brewed Colombian coffee. Then I’m either in the clinic seeing patients or in the OR performing minimally invasive gynecologic procedures. We have residents and a fellow, so clinical and surgical teaching is embedded in my daily activities, as well as patient teaching, which to me is fundamental. After work, I play with my children, spend time with my wife, work out or run, have dinner, and read the kids a bedtime story. If time allows, I work on educational projects. Persona Dr. Fred Howard, one of fathers of chronic pelvic pain (cpp) treatment and an excellent friend, inspired my career as a cpp specialist. Dr. Ron Epstein is the reason why I’m starting a Master of Health Professions Education at Maastricht University. I share my day to day clinical practice with Dr. Georgine Lamvu—clinician, surgeon, researcher, cpp specialist—whom I consider a great friend. Social Media Habits I use Facebook and Instagram and, although I have a Twitter account, I am not savvy. Contribution As I reflect about my passions and achievements, I find a common denominator: educating. Not only myself, but high school and college students, medical students, residents, fellows, healthcare providers, and patients. I like having the opportunity to transmit knowledge and have a permanent impact on the learner. Educating is fundamental in how healthcare is provided, especially in chronic pain, and in my field. I believe educating patients is as important as educating healthcare providers. My contribution occurs every day, either seeing patients and educating them about their conditions, or when I am with students, residents, or fellows, or every time I am invited to participate in an educational event. It is very satisfying when someone remembers you for something they learned from you. I might even say it’s more satisfying than operating, and I am someone who loves operating! People I most admire my father Eduardo Carrillo (who passed in 2017): he was a Peruvian ambassador and someone whose life was always fueled by an intense love of his country, his family, and what is right and just. I do also have to mention, as a lover of soccer, Edson Arantes do Nascimento, better known as Pelé. I have always admired his skills and persistence in life. His life story is inspiring. Words I think every healthcare provider should read Dr. Ron Epstein’s Attending. It will help you navigate, or as he says “kayak,” the waters of being a healthcare professional and taking care of yourself while you take care of patients. Also, Manual of the Warrior of Light by Paulo Coelho. It’s like a cookbook on how to behave in life. Popcorn I am a huge Rocky fan. Those movies bring a lot of memories: my brothers and I could watch every day. I can proudly say my kids love the saga as well. Scrubs is a tv show that shaped my life: I identify with it and often use fragments of the show for educational purposes. PAINWeek I was first introduced to PAINWeek by Dr. Lamvu who said: “This meeting is like no other event you have attended.” She was right, not only because of how comprehensive the content is, but because of the quality of the speakers and the different educational strategies used to deliver each session. I love it! As someone who is so devoted to education, I have to say the phrase I identify with the most from PAINWeek is “Education is the best analgesic.’’ I couldn’t agree more. 63

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By Martin Cheatle

phd

Patients who have chronic pain and an opioid use disorder are particularly vulnerable to self-harm. We can be so focused on the debate— “opiates are good”/ “opiates are bad”— that we are not seeing this cry for help.

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In 2019, more than

Early onset cancer makes up >30% of stomach cancer diagnoses. A research team studied

A study looked at 2 orthobiologic therapies; platelet-rich plasma injections and stem cell injections, and found dramatic cost variability ranging from a few hundred dollars to as much as $12,000. A team surveyed

underwent minimally invasive transcatheter aortic-valve replacement (TAVR) procedures in the US, compared to about

who had aortic valve replacement with open-heart surgery.

Patients who underwent TAVR had similar key 5-year clinical outcomes of death and stroke as patients who had traditional open-heart surgery to replace the valve. The PARTNER 2A study compares 2 different approaches to treating aortic stenosis, a common heart problem affecting some 12% of people >65.1 Acetaminophen has been available

to review stomach cancer statistics from 1973 to 2015. Researchers found the incidence of late-onset stomach cancer decreased by 1.8% annually during the study period, while the early onset disease decreased by 1.9% annually from 1973 to 1995 and then increased by 1.5% through 2013. Early onset gastric cancer has doubled from 18% of all cases in 1995 to >30% of all gastric cancer cases.3

Some studies suggest marijuana can trigger heart attacks and strokes in some users. In 1 study of heart attacks in people

in the US without a prescription since 1955. State regulators reviewed

orthopedic sports medicine practices

around the United States. Roughly 2/3rds of the responding practices offered one or both of the therapies. The mean cost of platelet-rich plasma injection was $707, with a range of $175 to $4,973. Stem cell injections had a mean cost of $2,728, ranging from $300 to $12,000.5

Chronic back pain (CBP) is a major global health problem and treatment is hampered by a lack of efficacy. A trial enrolled

with CBP (pain duration >12 weeks). A state law known as Proposition 65 says California must warn people of any chemical known to cause cancer or reproductive toxicity.

The state’s list has grown to about

it was noted that 10% of young heart attack patients had used marijuana and/or cocaine. Among the 5 highlights from the review: 2 million people with heart disease have used marijuana; it’s estimated that

have used the drug at least once in their life; Evidence for acetaminophen’s link to cancer has been weak enough that the International Agency for Research on Cancer declined to list it as a possible carcinogen following reviews in 1990 and 1999.2

have used the drug in the past year.4

with CBP were randomized to the openlabel placebo group (N = 63) or TAU group (N = 59). Open-label placebo application led to a larger reduction of pain intensity (-0.62 ± 0.23 vs 0.11 ± 0.17, all M ± SE, P = 0.001, d = -0.44) as well as patient-reported functional disability (3.21 ± 1.59 vs 0.65 ± 1.15, P = 0.020, d = -0.45) and depression scores (-1.07 ± 0.55 vs 0.37 ± 0.39, P = 0.010, d = -0.50) compared with TAU only.6

1. pain.sh/5rm 2. pain.sh/tre 3. pain.sh/3pj 4. pain.sh/v3d 5. pain.sh/jgx 6. pain.sh/nce

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Risk Mitigation: Strategies

Courtney M. Kominek PharmD, BCPS, CPE; Abigail T. Brooks PharmD, BCPS Two VA Clinical Pharmacy Specialists, Courtney Kominek and Abigail Brooks, offer a quick list of strategies for risk mitigation. ● Opioid informed consent and opioid agreement ● Urine drug monitoring ● Prescription drug monitoring program checks ● Naloxone ● Education and distribution ● Pill counts ● Formal tools for assessment and reassessment, such as the Opioid Risk Tool or SOAPP-r

Always Improving: Advocate and Collaborate

Jessica Geiger PharmD, ms, BCPS, CPE

Advocating—for your patients, for your colleagues, for yourself—is important, but not always easy. Take an active role: ask and answer questions!

An Integrative Pain Management Program: Expanding Options for Chronic Pain Treatment Emily Hurstak MD, MPH, MA

If you encounter a barrier to patient care, perhaps an insurance company…

In 2016, a multimodal pain management program was created and evaluated at Tom Waddell Urban Health primary care clinic in the Tenderloin neighborhood of San Francisco, a community experiencing high rates of opioid overdose. Dr. Hurstak, an assistant director at the San Francisco Free Clinic in California, tells of the motivation and backstory for this integrative pain program.

● Go through all the steps necessary to get past that barrier ● Provide all your rationale for whatever it is you want to do ● Provide documentation for why you think it’s appropriate to continue that person on whatever they’re on ● Never think “Oh well, they said no, so I guess we’re done”

Backstory ● Very high rates of opioid-related overdose affecting communities served by Department of Public Health clinics ● Safety-net patient populations ● Affected by high rates of chronic pain, substance use disorders, and opioid-related risks ● A program born out of crisis ● Trying to meet patient needs in a more comprehensive way ● Minimizing risks associated with some treatments in use

Get out of your silo ● Walk across the aisle ● Progress can’t be made without help ● If you’re a hospitalist caring for someone in a pain clinic, don’t assume the pain clinic is going to take over what you’ve recommended to do ● Make that follow-up phone call: “Hey, don’t know if you knew this… your patient is here… here’s what’s going on… here are the changes we’re hoping that you will continue. What can we give you to justify changing the plan you may have made?”

Leaders came together and ● Designed, implemented, and evaluated an integrative pain management program ● Utilized a quality improvement framework known as a pdsa cycle (plan, do, study, act) developed by W. Edwards Deming ● Engaged in continuous evaluation and adaptation of our program to meet needs of patients, and providers on the ground ● Conducted a quasi-experimental study of a proportion of patients who participated in our program to look at pain outcomes, quality of life outcomes, and functional status

Advocate/collaborate ● Others may have contacts ● If a patient goes outside of what’s prescribed, they could be discharged from the pain clinic ● I would never want someone to lose their pain provider because of something we change in the hospital ● Make that extra step: give the professional courtesy of that extra phone call to make sure we really make the smoothest transition we can

Expert Witness Testimony

Cannabinoids: What We Don’t Know Can…

Jennifer Bolen, JD; Douglas Gourlay MD, MSC, FRCPC, DFASAM

Gary W. Jay MD, FAAPM

The expert witness testimony in the US has contributed to courtroom confusion regarding the practitioner’s duties & responsibilities; it’s led to an attempt to put some uniform recipe into all prescribing and it’s neglected the patients.

Interest in cannabinoids is at an all-time high. Does this interest impact the perceived opioid crisis? Do we know enough about CBD and THC to make decisions? What has Dr. Jay experienced? We don’t know enough to be certain of anything:

● Many experts are hired because they take gray and turn it into black & white, while everyone in clinical care knows that very rarely is a problem black & white. ● Some experts become subjective; then the standard is objective. We can get lost in that. ● Once a precedent has been accepted as a kind of standard, it becomes something people return to, sometimes resulting in having to live with bad science and bad statements. ● Many medical experts don’t really know what our roles are. I can certainly be an advocate for the person who’s hired me. But when we’re in court the challenge is to remember it’s not who paid you, it’s not who asked you to come, it’s the questions you’re asked and the information you share with the jury or the judge.

● I personally hesitate to utilize and tell patients, “Oh, you should definitely do this” ● I’m not comfortable ● I don’t know all the facts ● I don’t think anybody does What if your patient is using edibles for headache? ● My answer is, “That’s your choice” ● cbd edibles are perfectly fine ● In North Carolina, you can’t get recreational or medical marijuana; they’re both illegal, but patients can legally get CBD oil Where you run into a problem: let’s say a patient had a significant pain problem that needed an opioid. But if they had CBD or marijuana in their urine, there would be a problem trying to utilize an opioid with that patient. It’s still a Schedule 1 drug for the federal folk, which means the DEA can take a rather dim look at a doctor giving an opioid to somebody on an illegal drug.

In the courtroom it is artificial with rules of evidence or hearing rules, or boundaries. The people who are there other than the prescribing practitioner, none have seen the patient. That makes it particularly challenging when they look backward and try to apply today’s standards to yesterday’s boundaries and yesterday’s tools.

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with

lynn r.

webster

md, facpm, fasam

“My grandfather taught me tolerance, patience, and empathy. The spirit of my grandfather has guided me in all aspects of life.”

What inspired you to do what you do? It was 1980 when I completed my residency in anesthesiology. During that time, enkephalins and opioid receptors were discovered on the spinal cord. This led to an appreciation that pain could be modulated at the spinal cord level and that relieving pain was going to be an exciting area of medicine.

Who were your mentors? My grandfather has been my life’s mentor. He was my hero. My grandmother had multiple sclerosis. She was in constant pain. Sometimes, it was severe enough that she would scream and wish aloud that she could die. Grandma could not move from one position in a chair to another without assistance. From as early as I can remember, she sat frozen with her knees at a right angle to her hips. Her 90-pound frame—which looked like a skeleton—had to be carried from the living room chair to the toilet to the kitchen table to the bed. In bed, she had to lie on her side, because her legs had developed permanent contractures, preventing her from resting in any other position. During the 18 years of my childhood and youth, my grandfather rarely left my grandmother’s side except to work in the fields. He was a farmer. I never recall my grandfather speaking negatively to her or expressing anger at her dependence, nor did he ever ask anyone else in the family to help care for her.

Why did you focus on pain management? In 1990, I placed a thoracic epidural in a woman who was to have a thoracotomy and lung resection for cancer. I was never trained to place a thoracic epidural, so it was scary to do it the first time. If I made a mistake, I could cause paralysis, but I was convinced the potential benefits outweighed that risk. The procedure was successful, and the woman had no post-op pain for the three days the catheter was infusing analgesia. The success of that procedure made me feel I was at the beginning of a new frontier in medicine. I felt a new specialty was going to emerge that would vanquish the suffering so many people had to endure following surgery. I believed that if we could provide that type of relief for post-op patients, then we should be able to help people with cancer pain and chronic noncancer pain as well. In my mind, I had the opportunity to impact the lives of most of my patients in this new field.

Today, we would call my grandfather a “caregiver,” but that strikes me as too clinical. His level of generosity requires a higher level of attribution. Saint or hero—take your pick. In either case, he was my greatest mentor. He taught me tolerance, patience, and empathy. The spirit of my grandfather has guided me in all aspects of life.

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Q If you weren’t a healthcare provider, what would you be? a A rap star, perhaps. I gave my inaugural performance as a rap star when I offered the toast at my daughter’s wedding. The feedback I received was, well, not exactly encouraging, but appreciative!

of two granddaughters. They’re very young now, but they’re growing by the hour. I hope they someday will build full, successful lives outside the insulated bubble of our family. Our world has sometimes been a challenging place for women. I want my granddaughters to internalize the words of Angelou’s poem to help build the self-confidence they deserve to have. They are too phenomenal to ever allow themselves to be marginalized or devalued by any man or woman.

What is your most marked characteristic? Those who know me well would probably say my most notable characteristic is my ability to empathize with others. That may be true. However, I believe my most marked characteristic is my persistence. I am determined to pursue what I feel is right, sometimes, to my personal detriment. My wife says it is my “daunting equipoise” in the face of crises. I don’t know if that is completely true. But, even if it is partly true, I hope to teach it to my grandchildren.

What would you like your legacy to be? My greatest legacy will be my children and grandchildren. I hope my example has helped them develop their perseverance, determination, strength, and courage.

Plans for the future? I plan to continue to conduct research, and hope to find safer and more effective treatments for pain and addiction. We are at the precipice of major advances in treatment, and I hope to be among those who will make those innovations possible.

Q What do you consider your greatest achievement? a Providing validation to people in pain who have lived in the shadows. I have lived my life by trying to be like my grandfather, but it is Maya Angelou’s words that describe what I feel is my greatest achievement: “People will forget what you’ve said, people will forget what you did, but people will never forget how you made them feel.” If I have made people feel important, if I have made people feel valued, if I have made people know that someone cares, then that is my greatest achievement.

What is your motto? “I believe you.” Those three simple words can change the life of someone in pain who lives in the shadow and feels ignored.

Lynn R. Webster, MD, FACPM, FASAM, is the Vice President at PRA Healthsciences in Salt Lake City, Utah.

What is your favorite language? The language of the heart is my favorite language, because it says so much more than we can say with words, and it is universal.

Q If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be? a I would choose Maya Angelou’s Phenomenal Woman, and I would share its lessons with two of the people who are dearest to me. I am the proud grandfather

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By Wendy Caster

If a rose by any other name would smell as sweet, would a pain-associated word by any other definition hurt as much? Less, we hope. (Themed clues are capitalized) Across 1. ACTOR JOHN WHO PLAYED MR. OLLIVANDER IN HARRY POTTER FILMS 5. Glass tube used in labs 10. Dubai dignitary 14. Cookie that comes in Mini, Double Stuf, and Mega Stuf varieties 15. Large cuts of meat 16. What a male lion has that a male tiger doesn’t 17. Jump 18. Cavities in a bone or other body part 19. Prefix for European 2 0. PA GENTLEMAN’S SPOUSE? 22. NOT A SOFT CANOE 24. Buxom 26. Amount of minutes spent on a smartphone 27. The standard for time zones (abbrev) 3 0. Wiliness 31. A piece of mountain climbing equipment 32. Italian lira replacement 34. Grassland 35. You might find it in a cemetery or a book 36. May birthstone 38. Between 13 and 19 41. Easter flower 42. Honorific for Paul McCartney and Elton John 43. Someone who is full of him-/herself 44. ___ of Langerhans 4 6. Throb 4 8. Cry, a lot 49. Put in your two cents’ worth 5 0. Remove small parts of a roof or bathroom 52. GIVE A HAIRCUT 54. STEPHEN KING FILM STARRING KATHY BATES 5 8. Diva solo 59. Nasal glop 61. Turn or slide uncontrollably 62. Circus location 63. Brawl 6 4. Home to over four billion people 65. Bono’s buddy The _____ 6 6. German city 67. Desires

Down 1. Actor Ian of “Lord of the Rings” 2. The “U” in a BUN test 3. Genuine 4. November birthstone 5. In a light-hearted or humorous way 6. Charged item 7. Succinctly 8. Infuriate 9. Old time Russian bigwig 10. Discharges, e.g., of CO2 or lead 11. Cocktails of whiskey, sweet vermouth, and bitters 12. Deep blue 13. Go back into business 21. Nobelist Hammarskjold 23. In music, having two main beats to a measure 25. Even 27. “Gosh!” 2 8. Silent 29. Providing support with a lattice of wood, bamboo, or metal Puzzle solution: painweek.org/crossword.

33. Popular but not-ideal word meaning to acclimatize someone, as to a new job 35. Very sweet, very rich fruit 37. Change 38. What you shouldn’t do when playing pinball 39. Slime 4 0. Abate 42. Twilights 44. A salt or ester of iodic acid 45. Having a steeple 4 6. Nudges 47. Actor Wallach or quarterback Manning 51. Prose piece making a point 53. Gaelic 55. Stop that or _____! 56. Destroy 57. Votes in favor 6 0. Versatile truck, informally

here are several things I reflect upon as this year’s PAINWeek conference approaches. I think about the fact that I have been a member of the faculty from the first meeting and have not missed one conference. I consider that we still have a long way to go to help education overcome the controversies that exist and continue to evolve in how we approach patients with pain. My impression is that the “job” of pain education will never be done and that the discussions should never end. Most importantly, I continue to believe that we must never forget that the target does not change—to help assess and care for patients with pain as safely and effectively as we can. PAINWeek provides much more than education, it provides a forum for dialogue and thinking. This conference does have a “secret sauce” that virtually all faculty members recognize: all the presentations and discussions are collectively directed towards the multitude of disciplines that must be involved to achieve our common goals. In my opinion, what has made this the largest pain conference in the country is the recognition that we work together, we think together, and that we talk with each other. That this year’s conference is virtual instead of in-person changes nothing except the forum by which we do what must be done—providing the sustenance we need to grow and foster knowledge and continue our common mission regardless of the constraints placed upon us by current events. Kevin L. Zacharoff md facip, facip, facpe, faap Editor-in-Chief PWJ—PAINWeek Journal

ABOUT US…

A Funny Thing Happened On the Way to Las Vegas By Debra Weiner

Well, not funny at all, but certainly very unpredictable. This is the first time in 13 years that we will not be in Las Vegas, ready to roll out the red carpet and light up the marquee for the PAINWeek National Conference. That being said, we are doing the next best thing—going back into the lab and creating something entirely new, but with the same intention and gusto of our signature event. This year, we are presenting the PAINWeek 2020 Live Virtual Conference. This particular endeavor has required an enormous amount of wizardry. As unbelievable as it may seem, producing a 5-day live meeting, with 90 faculty, over 2,000 attendees, and a curriculum of over 120 hours is a piece of cake compared to the nuances, bells, and whistles of a virtual platform. Aside from being a major national conference that kicks off the academic calendar, PAINWeek is just plain fun. We have become so connected and close to everyone involved, the week at The Cosmopolitan is more like a reunion and less like a work-related enterprise. The covid-19 pandemic has affected us all in different ways. We are, for the most part, working remotely. But thanks to daily Zoom calls, we are able to maintain a meaningful degree of connectivity that minimizes isolation and maximizes the team spirit. Our Ocean’s 11 vibe continues, but in a very different time signature. Typically, in August, la-based Patrick is at our New Jersey office working with Darryl on signage and the million other things that need to be completed. Over the years, the four weeks preceding the conference have become precious touchstones, where any/all conflicts dissolve, and the collective motivation is getting the show packed and out the door. This year, Heather has not had to print onsite materials and pack 60 boxes for the Fed Ex pallet. Instead, she has worked closely with Jeffrey on abstracts and other details regarding the scientific session. Charlie has spent the majority of his time learning everything there is to know about a virtual exhibit hall and working with our sponsors on getting their assets into their designated booths. Maya has replied to hundreds of emails directed to info@painweek.org and spends a good deal of phone time reiterating things she’s already explained in the aforementioned emails. Red continues to be our resident Sam Seaborn, managing clients, their agencies, and, like Charlie, spending an enormous amount of time learning the nuances of our CadmiumCD virtual conference platform. Mike has been amazing. We didn’t officially pivot from live to virtual until late May. He had the unenviable task of educating our sponsors on the value of maintaining their presence in new, unchartered waters. It is a testament to his tenacity and focus that we have a respectable amount of commercial support with the sponsored programs and the exhibit hall. Holly has been a champ as well. She is responsible for creating our nonpersonal communications and has had to learn both a new crm system and adapting her editorial tasks within the virtual platform. Late last year, a serendipitous moment occurred: Adam joined the team as our Digital Engagement Manager. He has done a spectacular job, forensically approaching challenges inherent to an algorithmic environment. Darryl remains prolific and passionate about his design work but is very clear about missing the onsite Green Room experience. For him, it is a most special time where he photographs old friends and new faculty, extracting animated poses with antiquated phones, trumpets, and guitars. At any given moment, you could take a peek, and find him snapping away furiously to a Miles Davis soundtrack. Jeffrey and I continue to sit across from each other, though more often remotely, each at our respective dashboards. I develop the recipes; he finds the co-packer to bring our pickles to market. We recently took a MyersBriggs type of personality test, where we literally had completely different scores, illustrating totally opposite characteristics. Thereby representing a perfect whole. This is us. 74

Jen Bolen JD

Michael Clark

Abigail Brooks

MD, MPH, MBA

pharmd, bcps

PAINWeek: What can I say? Where else are you able to obtain a constant flow of highly professional and useful information on all things relating to the treatment of pain? Where else do you have a veritable library of insights from attorneys, investigators, practitioners, and expert educators on the “what” and “how to” of providing quality pain care with a focus on helping you stay current with clinical standards of care and controlled substances laws? The folks running PAINWeek, along with the continuing education leaders at Global, have put their respective hearts and souls into PAINWeek and want nothing more than to ensure practitioners nationwide have access to all this and more. COVID-19 really changes nothing in this regard. While PAINWeek’s educational platform is different this year, and requires adjustments by us all, there is so much to be gained by attending the PAINWeek 2020 Live Virtual Conference! I am honored to continue to be part of the PAINWeek faculty, and I look forward to serving you and the PAINWeek team as we do our very best to make sure you have what you need during these trying times!

I first attended PAINWeek back in 2014 as a recent pgy2 pain pharmacy resident graduate, fresh out of residency, and had just started my first “real job.” That year I was also one of the lucky recipients of the PAINWeek scholarship. My first meeting had me “geeking out,” meeting famous pain pharmacists, physicians, and other providers that I had only read about. Their books, publications, and articles taught me so much during my residency training. It was the beginning of what would become my annual pilgrimage to Las Vegas for the PAINWeek Conference! This conference is so much more than a way to earn ce credit— it’s an annual meeting of friends and my pain family, learning and sharing together and bringing new members into the fold. With the bright lights of Vegas and the casino in the background, we rise for those 7am sessions and network, catch-up, and learn well into the afternoon (sometimes into the evening over cocktails and dinner). While the meeting will be virtual this year due to covid-19, there is no rest for the weary! We need to recharge our batteries and find creative ways together to reach our chronic pain patients, especially through whatever virtual modality we may be using to provide them care. 2020 is certainly a conference year that none of us will forget!

In times of challenge we talk about building resilience and avoiding burnout. Many have talked about how to achieve these goals with an emphasis on engaging in meaningful work, knowing your actions result in a positive outcome, and developing good coping skills. While these elements are admittedly crucial to being a successful practitioner, we must acknowledge that what underlies all of them is practice. The only way to define meaningful work is by doing it; the only way to accomplish a positive outcome is being an expert; and the only way to possess good coping skills is by learning what worked and what did not. PAINWeek is the forum facilitating these conversations. Our community of frontline practitioners caring for patients with pain is built with an open door, welcoming all experiences, sharing all successes (as well as failures), and developing diversity of talents. PAINWeek sends its members back to their own communities to spread that culture of expertise. And every year, we look forward to their return knowing that the conversation will deepen and enrich us. Thanks to everyone who attends PAINWeek.

David Cosio

phd, ABP

I attended my first PAINWeek in 2009 at the Red Rock Casino. It was so exciting, and I learned so much. The conference was then moved to The Cosmopolitan on the Las Vegas Strip. I will be honest: I really loved the intimacy and isolation that the Red Rock provided and was not too excited about the new location. Of course, I went to the conference and had a wonderful time. I have enjoyed being at the conference every year since, have met so many new people, and made so many new connections. This year, we are facing another change to the conference…it being virtual due to COVID-19. Once again, I approach this conference with some apprehension, but if my experience is any indication, this will be a wonderful meeting and we will experience new ways to connect with and learn from each other. I am happy to still be able to connect and meet the other attendees…even if it is virtually.

Ramon Cuevas-Trisan MD

In late July, we were under a hurricane warning in Florida and I heard someone say, “What a strange year. Just what we needed on top of all this civil unrest and COVID mess.” l couldn’t help but think that a hurricane warning in the Florida summer was about the only normal thing happening in 2020. The pandemic has turned our world upside down, affecting and changing the way that we do everything. Now, coming up is a Labor Day weekend without PAINWeek in Las Vegas—that’s unheard of! But the show must go on, and PAINWeek is no exception. No Cosmopolitan this year, but there will be an eclectic academic program second to none in the field. It will be delivered online, but I have no doubt it will be as solid as ever. I will miss seeing and hanging out with great colleagues and friends, but the latest and greatest in pain medicine will still be there.

Jeffrey Fudin

pharmd, DAIPM, FCCP, FASHP, FFSMB

I am truly looking forward to a virtual PAINWeek. The importance of continuing this impactful educational congress cannot be overstated. Education for pain providers from every discipline has always been a much needed commodity. Now more than ever, providers need up-to-date education and a chance to connect with national experts since so many patients with chronic pain syndromes have been variously affected by the pandemic, social isolation, political strife, and discord, all of which have destabilized many otherwise stable patients due to increased anxiety, depression, panic, and other biopsychosocial issues. I have every bit of confidence that the PAINWeek staff, educators, and mentors will elevate this virtual meeting to a prodigious level! I look forward to many interactions with colleagues and caregivers across the United States.

Mark Garofoli

pharmd, MBA, BCGP, CPE

Doug Gourlay

Have you ever seen Mickey Mouse not smiling? Of course not! (He’d be a terrible candidate for a patient FACES pain scale!) However, Mickey gets it: The show must go on, always. PAINWeek is the prime steak of healthcare conferences, with every detail always being top notch, whether brushing the most artistic CE presentation posters on the planet or considering passionate faculty experts so very well versed in education. We’ve come to enjoy the learning and networking environment in Las Vegas every year while also coming to rely upon PAINWeek for all that is pain management. The pandemic can take away the venue, but it simply cannot take away the passion of PAINWeek. Patients in pain need healthcare professionals’ help now more than ever, thus the show must go on.

MD, MSc, FRCPC, DFASAM

I’ve been a member of the PAINWeek family since its second year. This meeting has always been a highlight of my year, both socially and academically. The collection of speakers has always been second to none. The attendees are enthusiastic, committed, and ready to ask difficult questions that help advance our understanding of this difficult area of medicine. The move this year to a virtual, online format will be both exciting and challenging, but that’s what PAINWeek has always been about.

David Glick

DC, DAPPM, CPE, FASPE

Having participated in PAINWeek since its inception, it has been quite rewarding to see how it has evolved and grown. From the very beginning there was something special about the way that PAINWeek engaged with their attendees, focusing not just on clinical diagnosis and management of a wide variety of conditions associated with pain. There is, and always was, a unique focus on how frontline clinicians can practically apply the best assessment and therapeutic strategies, while also applying best practices to protect themselves, which we all know can be difficult to navigate in the field of pain. How we as clinicians educate our patients, and even share information with our colleagues, is the proverbial secret weapon for improving clinical outcomes and patient safety. I cannot express how much I have valued the opportunity to share my knowledge and experience and learn from faculty and attendees. Now, it has become a brave new world. We are not able to interact with those who have become our PAINWeek family. The way we practice has changed, with concerns and considerations, including the rapid adoption of telemedicine, that effect our abilities to treat our patients. While I will miss physically being at PAINWeek, thankfully PAINWeek 2020 has adapted to meet the challenge. PAINWeek 2020 Live Virtual Conference is more important than ever.

Jeffrey Gudin MD

PAINWeek is a meeting that I personally look forward to each year. It is the perfect meeting for frontline clinicians with just the right amount of academic and cutting-edge pharmaceutical research. Interested in low back pain, migraine, substance misuse, drug testing, nutrition, or behavioral pain management? PAINWeek has it. Although we cannot meet live this year due to our current pandemic, rest assured the learning will not stop. One of my goals is to help convey the critical message that we cannot let our guard down when it comes to prescription drug misuse. We have made so much progress in this area in the past decade; unfortunately, there is evidence of a resurgent opioid epidemic within the pandemic. We need to change with the times. Telemedicine visits and virtual e-prescribing have led to fewer face-to-face encounters, and less ability for us to assess risk. Stressful crises and natural disasters are known to increase drug and alcohol misuse: we cannot let our vulnerable population of pain patients go unmonitored. At the same time, we need to focus on behavioral therapies, devices, and analgesics of the future with nonaddictive properties—all topics that can be found at PAINWeek.

Jennifer Hah md

R. Norman Harden

PAINWeek represents much more than just the annual conference to me. Over the years, I have seen the evolution of the content covering the most cutting edge advancements in the treatment of pain conditions. The depth and breadth of the topics covered has always been impressive. One of the strengths of the PAINWeek conference is its truly interdisciplinary nature with a convergence of clinicians from different fields. In these unprecedented times, I believe the PAINWeek community of frontline practitioners as well as specialists will seamlessly carry the conference into its virtual platform with enthusiasm. I am really looking forward to this year’s conference.

PAINWeek is a unique and valuable alternative to society led conventions. In addition to the everso-valuable education of our colleagues in the trenches (our original purpose) we have evolved into the premier arena for interaction and communications/networking between pharma and device scientists. The abstracts are often a first look as to who is doing what, and why. Always my favorite and most informative meeting of the year.

Tracey Mallick-Searle

Gary Jay MD, FAAPM

For the past 13 years, I cannot remember NOT looking forward to going to Las Vegas in September to deliver presentations at PAINWeek. I have been involved with this incredible organization since the beginning. PAINWeek has grown to be my favorite conference of the year. It has always been a great place to see friends, network, learn from my peers, and present new talks. I always looked forward to seeing the posters that Darryl would create to go with my talks, with great names provided by Debra! The feeling of teaching a group of clinicians who really wanted to learn was wonderful. It was no surprise that PAINWeek became the largest pain conference each year. It deserved to be, and I have been honored for over a decade to be a part of this fantastic enterprise. Now, during the COVID-19 pandemic, which also involves pain patients in a multitude of ways, the inherent issues of travel make going to Las Vegas a problem. In any event, life goes on, and so does the need for education regarding pain. We are still needed, possibly more than before the pandemic, as medicine is changing how and when patients are seen and treated. So, this year, in its virtual form, PAINWeek will go on. This is much needed and definitely a good thing.

Sean Li MD

The pain management specialty has confronted the challenges of the opioid epidemic with expanded patient education, responsible opioid prescribing, and effective interventions. Now as medical professionals, we are faced with a global pandemic changing the way we deliver healthcare. PAINWeek has served and will continue to serve as the most comprehensive evidencebased information source for providers treating chronic pain. It has been an honor and a privilege to be part of this team over the years. I am looking forward to continuing this tradition for the PAINWeek 2020 Live Virtual Conference.

I am a Nurse Practitioner specializing in pain management for over 15 years. I “joined” the PAINWeek family in 2015, lecturing and eventually coordinating the Advanced Practice Provider (APP) track. I have enjoyed showcasing the contributions not only of APPs in pain management, but also exploring the contributions of multidisciplinary care in chronic pain management. I enjoy introducing new lecturers to the conference, like Ethan Russo, MD (in 2019) and Donald Abrams, MD (in 2017), sharing their work in the field of medicinal cannabis research and clinical practice. Finally, I have very much enjoyed being part of the PAINWeekEnd regional conferences, “taking the show on the road” as it were, meeting local frontline clinicians and listening to their experiences, challenges, and “home runs” in the care of patients struggling with pain. I was excited and looking forward to 2020, “The Year of the Nurse/Midwife,” which had so much potential for a memorable year! With the onset of the COVID-19 pandemic, we have seen nurses working hand in hand with their healthcare colleagues demonstrating what it means to be inventive, creative, and intuitive when it comes to meeting the needs of all their patients. This is how I view PAINWeek: ever at the forefront of innovation and creativity, intuitively finding the best way to bring insightful and quality education to the frontline clinician, making it fresh, fun, and now virtual.

Mary Lynn McPherson

pharmd, MA, MDE, BCPS

I am quite proud of the fact that I have attended and presented at EVERY single PAINWeek conference since its inception. From the very first meeting where several hundred people attended, through PAINWeek 2019 (where thousands attended), the energy has been contagious, and the education fulfilling! I find myself coming home from PAINWeek with 300 more things on my “to do” list because new ideas are bouncing around in my head like in a pinball machine! And then…along came Miss Coronavirus. To say 2020 has been a little different is the understatement of the century! Meetings cancelled, working from home, hiding under my desk… Happily, PAINWeek 2020 hasn’t been cancelled, just moved to a virtual platform. I’m delighted that I can still participate in this fabulous meeting! I regret that I won’t get to see my friends in person this year, but frankly my professional development is too important to let that stand in my way. My patients still have pain, so the show must go on! Perhaps I’ll see you in Las Vegas in September 2021, but for now, I hope to see you online!

Joseph Pergolizzi Jr MD

Robert Raffa

phd

Michael Schatman

phd

As founder and chair of the PAINWeek Scientific Session, I look forward to each annual meeting as an opportunity to meet new colleagues, hear new thoughts about pain medicine, and reconnect with the many pain specialists and pain patients I have come to know over the years. It’s always a whirlwind for me, and I have never left PAINWeek without lots of great ideas, new potential projects, and new connections. I would have never imagined anything would keep me away from PAINWeek! This year, I look forward to saluting our versatility as we use technology and resilience to still come together for the cause all of us care so deeply about: relieving pain. That is our mission. The means has changed this year, but our mission is the same and our determination is only fortified. I applaud the organizers of this year’s PAINWeek for meeting the challenge without diminishing our objectives!

There’s a pain researcher in Tucson A deep sadness has settled upon. Since as long as he can remember, Went to PAINWeek every September. At least ten times, perhaps even more. It’s part of him now, right to his core. Every year the same, new facts and fun, And just so good to see everyone. But not this year alas, Since a virus goes round, And we all have to pass. So he’s not Vegas bound. But that pain researcher need not fear, He’ll be fine as September draws near. Although the in-person fun he’ll miss, The PAINWeek group has decided this: Despite the pandemic and COVID, We are still all set and devoted.

PAINWeek is the pain related event which I look forward to most each year, having served on the faculty for well over a decade. Teaching physicians and other healthcare professionals is a joy, as our attendees are so motivated to learn how to become better pain managers. Beyond the teaching, however, is the opportunity to interact with so many providers on a human level; to hear about their struggles in treating pain effectively in their practices; and to provide them with tips regarding strategies for cutting through bureaucratic obstacles which will allow them to optimize their time in a manner that results in more positive interactions with their patients. The virtual format for PAINWeek 2020 will present some minor challenges, but I don’t see why the conference wouldn’t be every bit as rewarding as have in-person PAINWeek conferences, both for attendees and faculty.

Except in place of a talking head, We will all be doing Zoom instead!

Kate Schopmeyer

DPT, CPE

Caring for people who live and struggle with persisting pain requires community, knowledge, and enduring support. This is what the PAINWeek conference can offer to any healthcare provider no matter where they are in their career. The first time I attended the PAINWeek conference, in 2012, I considered myself to be an experienced clinician but was a novice at treating chronic pain. My feelings of apprehension and inadequacy were strong, as I had taken on a new role in a chronic pain clinic. I found inspiration and excitement for a sector of healthcare that is so often regarded with foreboding. In the years following my first attendance, I’ve grown more inspired by the network I developed at PAINWeek and I strive to give back a bit of hope as faculty. Now that social isolation is widespread, the need to connect and learn from each other is more urgent and stronger than ever. Amidst the grueling adaptation we are all undergoing as we transition into a new era of digitized healthcare, I am again inspired by the possibilities. Taking the PW conference into the virtual world will no doubt allow us to spread knowledge further and faster than in years past. I hope you can join us on this adventure!

Tanya Uritsky pharmd, BCPS

PAINWeek started for me as a pharmacy resident specializing in pain management and palliative care. I attended out in the Red Rock and, after just one session, I knew I needed to squeeze in as many more as possible while I was there. I was able to soak up a ton of learning, even squeezing in a final session that ended just as my airport transportation came to pick me up. Since then, I have been able to gain knowledge and expertise that has helped me get on the PAINWeek platform and share all I have come to know. I love that PAINWeek has focused on education for different practice settings, disciplines, levels of experience, and represents all facets of pain from chronic pain to palliative care and everything in between. It has been my great pleasure to be a part of PAINWeek, especially in these changing times. When we cannot connect in person, we can share from afar and continue to learn and grow.

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â&#x20AC;&#x192; education is the best analgesic.