PWJ - PAINWeek Journal Vol 9, Q3 | 2021

vol. 9 q 3 2021

bup’ed or duped? is buprenorphine for everyone? p.18 golden girls dilemma: genitourinary syndrome of menopause p.28 long-haul covid: a pain physician’s perspective p.38 when east meets west: using an integrative approach to treat chronic overlapping pelvic pain disorders p.44

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

Take a proactive approach to OIC with RELISTOR ®

RELISTOR helps to restore gut function by increasing the frequency of SBMs1,* In a clinical trial of adult patients with OIC and CNCP, 52% of patients (n=200) taking RELISTOR tablets experienced at least 3 SBMs* per week, with an increase of at least 1 SBM(s) per week over baseline, for 3 or more of the 4 week treatment period vs 38% of patients (n=201) receiving placebo (P=.005).1,2

STUDY 1: In a 4-week, randomized, 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.1,2

*SBM (spontaneous bowel movement) is defined as bowel movement without the use of any laxative in previous 24 hours.1

INDICATIONS • RELISTOR® is an opioid antagonist. RELISTOR tablets and RELISTOR injection 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.

• RELISTOR injection is also indicated for the treatment of OIC in adults with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care.

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

• 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 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. 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 with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

Please see Brief Summary of full Prescribing Information for RELISTOR following this advertisement.

The only 2 routes for adults with CNCP1,3-6 The OIC firsttreatment and only with PAMORA withof2administration routes of administration for CNCP RELISTOR tablets: A once-daily, oral treatment at home.1 • RELISTOR tablets should be taken with water on an empty stomach at least 30 minutes before the first meal of the day1 • RELISTOR therapy should be continued only during opioid use. Re-evaluate the need for RELISTOR if the opioid regimen is changed to avoid adverse reactions1

RELISTOR subcutaneous injection RELISTOR injection is the only product indicated to treat OIC in adults with advanced illness or active cancer pain who require opioid dosage escalation for palliative care.1,3-5

LEARN MORE AT RELISTORHCP.COM

IMPORTANT SAFETY INFORMATION (continued) • 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. 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.

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

• 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). 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 and dose adjust per Prescribing Information as may be indicated.

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

– RELISTOR injection (≥ 1% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (21%), nausea (9%), diarrhea (6%), hyperhidrosis (6%), hot flush (3%), tremor (1%), and chills (1%).

• OIC in adult patients with advanced illness – RELISTOR injection (≥ 5% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (29%) flatulence (13%), nausea (12%), dizziness (7%), and diarrhea (6%).

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 for RELISTOR following this advertisement.

REFERENCES: 1. RELISTOR [prescribing information]. Bridgewater, NJ: Salix Pharmaceuticals. 2. Data on file. Clinical study report MNTX3201. Salix Pharmaceuticals; 2015. 3. AMITIZA (lubiprostone) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals America, Inc; 2012. 4. MOVANTIK® (naloxegol) [prescribing information]. Raleigh, NC: RedHill Biopharma Inc; 2020. 5. SYMPROIC® (naldemedine) [prescribing information]. Raleigh, NC: BioDelivery Sciences International, Inc; 2020. 6. Pergolizzi JV Jr, Christo PJ, LeQuang JA, Magnusson P. The use of Peripheral μ-Opioid Receptor Antagonists (PAMORA) in the management of opioid-induced constipation: an update on their efficacy and safety.

Drug Des Devel Ther. 2020;14:1009-1025. doi:10.2147/DDDT.S221278

www.salix.com 400 Somerset Corporate Boulevard, Bridgewater, NJ 08807 Tel 800-321-4576 Relistor is a trademark of Salix Pharmaceuticals or its affiliates. © 2021 Salix Pharmaceuticals or its affiliates.

RELO.0027.USA.21

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 1 INDICATIONS AND USAGE 1.1 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.

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

4 CONTRAINDICATIONS RELISTOR is 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 [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS 5.1 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 [see Contraindications (4)].

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

5.3 Opioid Withdrawal Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR [see Adverse Reactions (6.1)]. 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.

6 ADVERSE REACTIONS Serious and important adverse reactions described elsewhere in the labeling include: • Gastrointestinal perforation [see Warnings and Precautions (5.1)] • Severe or persistent diarrhea [see Warnings and Precautions (5.2)] • Opioid withdrawal [see Warnings and Precautions (5.3)] 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.

Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR tablets was evaluated in a double-blind, placebocontrolled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 12-week, doubleblind, placebo-controlled period in which adult patients were randomized to receive RELISTOR tablets 450 mg orally (200 patients) or placebo (201 patients) [see Clinical Studies (14.1)]. After 4 weeks of double-blind treatment administered once daily, patients continued 8 weeks of doubleblind 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, PlaceboControlled Period of Clinical Study of RELISTOR Tablets in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 1). Adverse reactions for RELISTOR Tablets (n=200) and Placebo (n=201) were abdominal pain** (14% v.10%), Diarrhea (5% v. 2%), Headache (4% v. 3%), Abdominal Distention (4% v. 2%), Vomiting (3% v. 2%), Hyperhidrosis (3% v. 1%), Anxiety (2% v. 1%), Muscle Spasms (2% v.

1%), Rhinorrhea (2% v. 1%), Chills (2% v. 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) [see Clinical Studies (14.1)]. After 4 weeks of doubleblind 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). Adverse reactions for RELISTOR Injection (n=150) and Placebo (n=162) were abdominal pain** (21% v.

7%), Nausea (9% v. 6%), Diarrhea (6% v. 4%), Hyperhidrosis (6% v. 1%), Hot Flush (3% v. 2%), Tremor (1% v. <1%), Chills (1% v. 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 [see Dosage and Administration (2.2)]. 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, openlabel, uncontrolled trial in 1034 adult patients with OIC and chronic noncancer 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 [see Clinical Studies (14.2)].

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). Adverse reactions for RELISTOR Injection (n=165) and Placebo (n=123) were abdominal pain** (29% v. 10%), Flatulence (13% v. 6%), Nausea (12% v. 5%), Dizziness (7% v. 2%), Diarrhea (6% v. 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 doubleblind, placebo-controlled clinical trials (Study 4 and Study 5) were comparable between RELISTOR (1%) and placebo (2%).

6.2 Postmarketing ExperienceThe 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 [see Warnings and Precautions (5.3)].

7 DRUG INTERACTIONS 7.1 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.

7.2 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.

8 USE IN SPECIFIC POPULATIONS 8.1 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.

8.2 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.

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

8.5 Geriatric Use Of the total number of patients in clinical studies of RELISTOR tablets, a total of 136 patients (10%) were aged 65 years and older, while 23 (2%) were aged 75 and older. 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.

Of the total number of patients in clinical studies of RELISTOR injection, a total of 226 (28%) were aged 65 years and older, while 108 (13%) were aged 75 years and older. 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.

8.6 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 [see Clinical Pharmacology (12.3)].

Therefore, a dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment [see Dosage and Administration (2.4)]. 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).

8.7 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 (ChildPugh Class C) hepatic impairment compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, a dosage reduction of RELISTOR tablets is recommended in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.5)]. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A).

Injection In a study of subjects with mild or moderate hepatic impairment, there was no clinically meaningful change in systemic exposure of methylnaltrexone compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, no dosage adjustment of RELISTOR injection is needed for patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].

Patients with severe hepatic impairment were not studied. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions. If considering dosage adjustment, follow the recommendations in Table 3 [see Dosage and Administration (2.5)].

10 OVERDOSAGE During clinical trials of RELISTOR administered orally and subcutaneously, one accidental case of methylnaltrexone bromide overdose was reported and no adverse events were reported as a result of the 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. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

13.2 Animal Toxicology and/or Pharmacology In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone caused concentration-dependent inhibition of hERG current (1%, 12%, 13% and 40% inhibition at 30, 100, 300 and 1000 micromolar concentrations, respectively).

For more information, go to www.Relistor.com or call 1-800-321-4576.

Distributed by: Salix Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA

Under license from:

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591 USA

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; 10,376,584 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; 10,307,417 and 10,376,505 RELISTOR is a trademark of Salix Pharmaceuticals, Inc. or its affiliates.

Any other product/brand names are trademarks of the respective owners. © 2021 Salix Pharmaceuticals, Inc. or its affiliates Revised: 04/2020 9502505 70014843 REL.0082.USA.19 V4.0

Not only can you take our faculty home with you— now you can also bring them to the gym 365 days a year!

365 days a year.*

*Except Leap Year which gives you and 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 Professor of Psychiatry and Behavioral Sciences George Washington University School of Medicine and Health Sciences Washington, dc

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 Department of Anesthesiology, Perioperative Care, and Pain Medicine nyu School of Medicine New York, ny 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 © 2021, 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.

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It’s Good Medicine. ©2021 Hisamitsu America, Inc. Use as directed. *Topical Analgesic Patch Data, IQVIA ProVoice 2021 **Source: CDC guidance for prescribing opiates for chronic pain

vol.9 2021

18 28 38 44 56 60 71 72 73 74 76 80

pharmacotherapy

bup’ed or duped? is buprenorphine for everyone?

by timothy atkinson, jeffrey fudin

women’s health

golden girls dilemma: genitourinary syndrome of menopause

by chensi ouyang, jessica feranec, georgine lamvu

key topic

long-haul covid: a pain physician’s perspective

by joseph pergolizzi, jr.

pelvic pain disorders

when east meets west: using an integrative approach to treat chronic overlapping pelvic pain disorders

by kathryn witzeman

op-ed

perspectives on the revised definition of pain

by kevin zacharoff

pain basics

pain assessment 8

by kevin zacharoff

pw next generation

with heather poupore-king

clinical pearls

by ravi prasad

pain by numbers one-minute clinician

with kevin zacharoff, scott powers, theresa mallick-searle, ethan russo leigh ann wilson collin montgomery, edward lee, michael kurisu

pundit profile

with charles argoff

puzzled?

by wendy caster

12

“Meetings

come to an end, but learning never stops.

PWJ keeps you going all year long.”

—Michael R. Clark md, mph, mba

preFew would argue that chronic pain is cognitive thinking, and nomenclature “simple,” but many might not know about are involved with virtually everything the complexities of assessing and treatKevin L. Zacharoff we do in caring for patients with acute ing chronic or persistent pelvic pain. In and chronic pain. Current times require the first of a 2-part series, Dr. Kathryn us to be more sensitive to the fact that actions matter, words mat- Witzeman provides a detailed analysis of the assessment and treatter, individuality matters, and that we need to have the capacity ment of complex and overlapping pelvic pain disorders (COPPDs). Afto reflect upon and recognize what motivates us to automatically fecting approximately 20% of women at some point, this condition process information before it is completely presented, digested, can have a major impact on quality of life, as it’s often unrecognized or even completely understood. This is likely the path to delivering and undertreated by frontline practitioners. Particular attention is pain care with a higher degree of autonomous, informed, shared paid to how mind-body approaches may be of complementary value decision-making with the intention of improving both outcomes in not only treating pain symptoms, but also comorbid mental health and patient satisfaction. In one way or another, each article in this conditions. issue of PWJ highlights these ideas—important and relevant topThis issue’s Pundit Profile spotlights someone I am proud to call my ics to every one of us. friend, Dr. Charles Argoff. While we are given a glimpse of what Drs. Timothy J. Atkinson and Jeffrey Fudin provide us an article goes on inside the genius-level, “90 mph” mind of his, you can take which, in typical fashion for these experts, accomplishes what they it from me that his level of dedication to the practice of medicine can always be relied upon to do—debunk things that we hear a lot is virtually unparalleled and present in everything he does. Couple about in the world of pain management and substance use disor- that with what motivated him towards a career in Neurology, and der, with the intention of simplifying and informing our treatment you have one memorable profile to read. Enjoy. planning in a positive and more informed manner. In this article, the subject is buprenorphine, and its role in treating chronic pain Dr. Heather Poupore-King is the focus of this issue’s Next Genand opioid use disorder (OUD). The authors aptly discuss the move eration. An associate professor at the Stanford Division of Pain towards expansion of access to buprenorphine treatment and the Medicine in Redwood City, California, she is dedicated to training societal stigma that persists surrounding using medications to treat academic leaders of the future and considers transforming the OUD, and related ethical dilemmas that clinicians need to consider fellowship training program to likely be her most meaningful contriwhen choosing this course of treatment. bution. Read more about her and get to know her better.

The next article, by Drs. Chensi Ouyang, Jessica Feranec, and Also in this issue is an Op-Ed from me about the clinical implications Georgine Lamvu, is about genitourinary syndrome of menopause of the recently released revised definition of pain, from the Inter(GSM). It begins with the decision in 2014 by the International Society national Association for the Study of Pain. Additionally, worthy of for the Study of Women’s Sexual Health and the North American mention in this issue of PWJ is the 8th installment of the recurring Menopause Society to destigmatize the name of a condition that segment titled Back to the Basics for people seeking basic foundaaffects many women and may have contributed to feelings of embar- tional pain education. rassment, shame, fear, and feeling minimized. The goal of this nomenclature change was to increase awareness and change the fact that I hope this issue of pwj leaves you with some food for thought and many women surveyed never discussed their symptoms with their sparks critical thinking and self-reflection about the intersection of healthcare professionals, likely because of feeling some degree of stigma, bias, precognitive thinking, and above all the fact that words stigma. The rational case is made for clinicians to screen appropriate matter. As we approach the 16th PAINWeek Annual Conference in patients for the condition, to be able to discuss its symptoms openly September in Las Vegas, I am excited to be there in person and hope without shame, and to educate women about treatment methods. to see you there. Please stop me to say hello!

Next is an article by Dr. Joseph V. Pergolizzi, Jr. about a topic we are all likely to precognitively think about as soon as it is mentioned: COVID-19. While thoughts about symptoms of acute infection and its implications and outcomes may immediately come to mind, Dr. Pergolizzi sheds light on the fact that patients and the healthcare system are being challenged by “long-haul COVID-19.” One symptom profile of this persisting illness is the presence of pain, including chest pain, myalgia, joint pain, neuropathy, and myelopathy. Much like other chronic medical conditions, attention might be hyperfocused on the “typical” symptom profile, and not on other disabling symptoms such as pain. It is imperative that clinicians consider pain as a possible and even likely symptom in patients with chronic, persistent COVID-19.

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Kevin L. Zacharoff MD, FACIP, FACPE, FAAP

Kevin L. Zacharoff is Faculty and Clinical Instructor; Course Director, Pain and Addiction; and Distinguished Visiting Scholar in Medical Humanities, Compassionate Care, and Bioethics in the Department of Family, Population, and Preventive Medicine at the Renaissance School of Medicine at Stony Brook University.

The national conference on pain for frontline practitioners.

2022 100+ Ce/CMe Credit Hours Presented

September 6–10 Register @ www.painweek.org

Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 34.0 AMA PRA Category 1 Credit(s)™. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing, and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.

Timothy J. Atkinson PharmD, BCPS, CPE

p.18

Tim Atkinson is a Clinical Pharmacy Specialist and Pain Management Director at the pgy-2 Pain & Palliative Care Pharmacy Residency Program of the va Tennessee Valley Healthcare System in Murfreesboro, Tennessee. He is on the va pbm National Residency Advisory Board. Dr. Atkinson cowrote his article with Jeffrey Fudin, pharmd, fccp, fashp, ffsmb; ceo/cmo of Remitigate llc, Delmar, New York; Clinical Pharmacy Specialist, Director: pgy2 Pharmacy Pain & Palliative Care Residency, Stratton va Medical Center (woc), Albany, New York; Adjunct Associate Professor at Albany College of Pharmacy and Health Sciences, and Western New England University College of Pharmacy and Health Sciences, Springfield, Massachusetts.

p.28

Chensi Ouyang MD

Chensi Ouyang is a minimally invasive gynecology surgeon and pelvic pain specialist. She coauthored her article with Jessica Feranec, md, who is a urogynecologist and chief of surgery at Orlando va Medical Center, and Georgine Lamvu, md, mph, chair of the Board for the International Pelvic Pain Society. All three doctors are affiliated with the Orlando va Healthcare System, Surgery Division, Gynecology Section; and the University of Central Florida College of Medicine, Department of Clinical Sciences, in Orlando.

p.38

Joseph V. Pergolizz Jr.

Joseph Pergolizzi is a co-founder and Director of Research at NEMA Research Inc. and Senior Partner at the Naples Anesthesia and Pain Associates in Florida. He has presented on leading issues in medicine around the world, authored over 200 peer-reviewed articles, numerous scientific posters, and contributed to many medical books on the topic of pain.

p.44

Kathryn Witzeman MD, FACOG

Kathryn Witzeman is the Director of the Women’s Integrative Pelvic Health Program at Denver Health in Colorado. She is an Associate Professor of obgyn at the University of Colorado School of Medicine and the immediate Past-President of the International Pelvic Pain Society.

16

120 CE/CME CREDITS

EDUCATION IS THE BEST ANALGESIC

By Timothy J. Atkinson PharmD, BCPS, CPE / Jeffrey Fudin PharmD, FCCP, FASHP, FFSMB

pharmacotherapy

Buprenorphine prescribing and availability for chronic pain and opioid use disorder (OUD) has seen considerable growth over the past decade, directly corresponding to the reduction in opioid manufacturing and decreased emphasis on traditional opioid prescribing for chronic pain. According to the Centers for Disease Control and Prevention, opioid prescribing decreased to its lowest level in over 14 years in 2019 with 46.7 opioid prescriptions per 100 persons compared to 72.4 per 100 persons in 2006.1 In 2020, the Drug Enforcement Administration reported that total domestic opioid production had decreased by 53% since 2016 with an additional decrease of at least 10% proposed for 2021.2 From 2009 to 2018, the number of individuals receiving buprenorphine for OUD more than doubled from 1.97 to 4.43 per 1000 persons.3 The largest increase was seen in the 35 to 44 age group, which increased from 2.41 to 8.34 per 1000 persons, and the only decrease was the youngest group of 15 to 24 year olds, which decreased from 1.76 to 1.40 per 1000 persons despite significant efforts to expand access to treatment across all age groups.3 Among these efforts was CARA, or the Comprehensive Addiction and Recovery Act of 2016, that expanded buprenorphine prescribing for OUD to nurse practitioners and physician assistants.

A review evaluating the early impact of this change indicated that from 2017 to 2018, buprenorphine prescribing increased by 9.1% nationally overall: 79.6% of that increase directly linked to prescribing from nurse practitioners and physicians assistants.4

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Buprenorphine History towards further expansion of buprenorphine treatment is certain with the Department of Health & Human Services Inter-Agency Taskforce Report on Pain Management Best Practices recommending increased access to buprenorphine for both chronic pain and OUD.5 It specifically encourages payers to provide coverage and reimbursement for buprenorphine treatment and recommends primary use of buprenorphine rather than use only after failure of standard mu agonist opioids such as hydrocodone or fentanyl when opioid therapy is implemented.5 Notably, there is no incentive or mandate requiring third party payers to support this recommendation. Improving provider expertise, familiarity, and experience with buprenorphine’s unique pharmacology and pharmacokinetics has never been more critical. The societal stigma surrounding medications for OUD (MOUD) is considerable, and the decreased availability of opioids for chronic pain combined with increased emphasis on identification and treatment of OUD has had some unintended consequences and created ethical dilemmas worthy of discussion.

Buprenorphine was first introduced in Europe in 1978 as an injection for the treatment of moderate to severe pain, followed by release of Temgesic® (buprenorphine) 0.2 mg and 0.4 mg sublingual (SL) tablets for pain in 1982.6 In the United States, Buprenex® (buprenorphine injection) was approved in 1981 for management of pain severe enough to require an opioid analgesic, but it was not until 2002 that SL buprenorphine was approved in the US for the treatment of OUD as Suboxone® (buprenorphine/ naloxone), which is available in much higher doses common for opioid agonist treatment for OUD.7 The early release and acceptance of SL buprenorphine for pain in Europe but not the US has likely furthered the stigma and misconception that buprenorphine is not effective for pain. The disparity between buprenorphine availability for pain worldwide and in the US continues today with buprenorphine transdermal patches (Table 1). Buprenorphine patches ranging from 5 mcg/hour to 20 mcg/hour are available in the US, but in Europe strengths available include 35 mcg/hour to 70 mcg/ hour allowing buprenorphine to take a more prominent role in pain management.8,9 The dose disparity between

Table 1. FDA Approved Buprenorphine Formulations Available in the United States Opioid Use Disorder

Pain

Suboxone® (buprenorphine/naloxone) SL tab/film*

Buprenex® (buprenorphine) IV/IM injection*

Subutex® (buprenorphine/naloxone) SL tab/film*

Butrans® (buprenorphine) weekly patch

Zubsolv® (buprenorphine/naloxone) SL tab

Belbuca® (buprenorphine) buccal film

Bunavail® (buprenorphine/naloxone) buccal film Sublocade® (buprenorphine) SQ monthly injection Brixadi® (buprenorphine) SQ weekly or monthly injection *Available as generic formulation.

SL=sublingual; IV=intravenous; IM=intramuscular; SQ=subcutaneous.

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buprenorphine formulations in the US and in Europe has contributed to increased off-label use for pain with formulations designed and approved for OUD.

Pharmacology There are several reasons why buprenorphine is thought to reduce risk when deployed to treat pain or OUD, but it begins with its unique pharmacology. Buprenorphine is a thebaine derivative and dehydroxylated phenanthrene with a core structure similar to morphine, hydrocodone, and oxycodone.10 The additions to the core structure are extensive, resulting in a large and bulky molecule significantly impacting binding kinetics including slow receptor association and incomplete and/or delayed dissociation from opioid receptors.11 Table 2 summarizes opioid receptors and their functions when activated, along with their associated potential adverse effects.12,13 Buprenorphine is classified as a partial agonist with high binding affinity at mu-opioid receptors, full antagonist with high binding affinity at kappa and delta opioid receptors, and a partial agonist with low binding affinity at the opioid receptor-like-1 opioid receptor.13 It has a very high partition coefficient and a higher mu-opioid receptor binding affinity compared to all other traditional opioids, the former of which correlates directly to rapid passage through the blood-brain barrier. Both partition coefficient and high binding affinity create challenges in the acute pain setting when buprenorphine needs to be overcome by a traditional opioid agonist.14,15 Buprenorphine’s opioid receptor interactions are valuable for MOUD because, while it competes with other opioids to bind to mu-opioid receptors, its dissociation halflife of 166 minutes and 50% binding after 1 hour combined with its high affinity for the receptor make it nearly impossible to dislodge once bound. Therefore, the goal of MOUD is to saturate opioid receptors to prevent activation and possible

overdose with opioid use. Complete receptor saturation occurs between 16 to 24 mg/day of SL buprenorphine.16 Buprenorphine has demonstrated ability to block the effects of morphine for nearly 30 hours after administration, and opioid reversal agents such as naloxone are unpredictable with required concentrations for reversal as high as 40 times higher than required for similar opioids such as fentanyl.17-19 (For more on binding affinity, see Table 3.)

Buprenorphine’s classification as a partial agonist is being challenged because it functions as a full opioid agonist throughout the therapeutic range for pain.23,24 There is a ceiling effect on respiratory depression within the therapeutic range, but analgesic effects plateau at higher doses commonly utilized for OUD.23,24 Buprenorphine activates the opioid receptor-like-1 that attenuates analgesic effects but also the rewarding effects of opioids, and may explain the improved central nervous system clarity and tolerability of buprenorphine.24 Buprenorphine is unique in that it stimulates sufficient G-protein (guanine nucleotide-binding proteins) signaling while limiting beta arrestin recruitment, which has been associated with opioid-induced respiratory depression and abuse. The balance between G-protein and beta arrestin signaling may determine the extent of analgesia vs adverse effects.13

Pharmacokinetics Buprenorphine has poor oral absorption which is why formulations emphasize SL, buccal, transdermal, or intravenous administration.10 Buprenorphine undergoes hepatic metabolism via the CYP450 system predominantly through 3A4 to its active metabolite norbuprenorphine although CYP2C8 plays a minor role.24 Plasma concentrations of the major buprenorphine metabolites include norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide, which approximate

Table 2. Pharmacologic Activity of Opioid Receptors12,13 Opioid Receptor

Desired Activity

Disadvantages when Activated

Mu

Peripheral analgesia, euphoria?

Sedation, euphoria, respiratory depression, bradycardia, nausea/vomiting, and decreased gastrointestinal motility

Delta

Spinal and supraspinal analgesia

Decreased gastrointestinal motility

Kappa

Spinal analgesia

Diuresis and dysphoria

Opioid Receptor-Like-1

Spinal analgesia

Sedation

22

or exceed those of the parent drug. Both glucuronide marginalization, mistreatment, moral weakness, justificametabolites of buprenorphine are biologically active at tion for withholding care, and voluntary or involuntary social doses relevant to metabolite exposures. Activity of the isolation.28,29 The stigma associated with long-term opioid glucuronides may contribute to the overall pharmacology therapy for pain is similarly often characterized as weakof buprenorphine.25 Norbuprenorphine quickly undergoes ness, exaggeration, neglect, and negative social reactions, glucuronidation through the UGT1A1 and UGT2B7 gene to among others.30 The new trend of off-label prescribing of improve water solubility for elimination, but studies indi- buprenorphine formulations indicated for OUD among pain cate this conversion occurs rapidly and minimizes potential patients can, unbeknownst to patients, saddle them with impact of 3A4 mediated drug interactions.26,27 Buprenor- the additive stigma of both OUD and pain. If insufficient phine has a long terminal half-life of 24 to 42 hours after time and education is allocated to patient education and chronic administration indicating that buprenorphine may shared decision making, then the risk of patients feeling continue to have clinically significant effects on treatment “duped” into OUD treatment when they are seeking pain for days after it was last administered.7 Buprenorphine is management is very real. Even providers who make it clear excreted in the urine (30%) and feces (69%).7,27 Since nor- they are prescribing buprenorphine for pain should explain buprenorphine has an extremely high affinity for p-glyco- further: the formulation is approved for OUD, and other protein, it does not readily pass the blood-brain barrier. It providers reviewing a state’s prescription drug monitoring is for this reason that we do not appreciate the full agonist program are unlikely to understand or believe a patient is effect of buprenorphine, even though the norbuprenor- receiving treatment for anything other than OUD. This can phine metabolite is present in the blood. Since buprenor- surely complicate or prevent a patient’s ability to transfer phine is administered buccally or sublingually, in the authors’ treatment to another pain practice (see Patient Case). opinion, it is plausible, if not probable, p-glycoprotein prevents passage back into the gut where mu-receptors would be responsible for opioid-induced constipation.25 PATIENT CASE Mr. Jones is offered buprenorphine/naloxone and informed that his provider is no longer comfortable with his current treatment and no other opioids will be considered. He is told that becoming dependent on these medications is natural. Hearing that this medicine will address his pain, and with a lack of alternatives, he accepts treatment. He is quickly titrated to a moderate dose of buprenorphine/naloxone in divided doses throughout the

Discussion In the midst of the opioid overdose epidemic with roughly 130 people dying per day, stigma continues to be a key factor for treatment acceptance despite significant efforts to expand access.28 The stigma against people with substance use disorders has been described as

Table 3. Mu-Opioid Receptor Binding Affinity20,21 Opioids

Range of Ki Value

Buprenorphine

0.21–1.5

Naltrexone

0.4–0.6 (antagonist effects)

Fentanyl

0.7–1.9

Methadone

0.72–5.6

Naloxone

1.0–3.0 (antagonist effects)

Morphine

1.02–4

Pentazocine

3.9–6.9

Codeine

65–135

Ki value = binding affinity; lower Ki values indicate higher affinity.

23

day and reports pain is significantly improved. Several months later, he begins reporting that the medication isn’t as helpful for his pain, and he believes that the pain was better managed on his previous regimen with traditional opioids. His request to make a change is denied and he becomes frustrated with care. It is explained to Mr. Jones that he is not a candidate for traditional opioid therapy because of his OUD diagnosis, which he says is not accurate because he’s never had a problem with opioids and only takes them for pain. He plans to switch his care to another provider, but every practice requires either a letter of good standing or an explanation of the results of the state prescription drug monitoring program query.

Ultimately, Mr. Jones is informed by multiple clinics that due to his use of buprenorphine/naloxone he is not considered a candidate for opioid therapy. They offer to refer him to a suboxone clinic but he does not agree to treatment for OUD and is discharged. Mr. Jones now feels that he’s been tricked (duped) into this situation and didn’t realize the full impact of the stigma that surrounded treatment with buprenorphine/naloxone nor that it would render him ineligible for traditional opioid therapy in the eyes of most providers. He decides to taper and discontinue use hoping that abstinence will allow him to start over and receive a second chance from a provider viewing his situation with fresh eyes. However, now he must contend with coming off high dose opioid therapy that is reserved for OUD treatment and he likely underestimates the impact discontinuation of buprenorphine/naloxone will have on his pain.

24

Unfortunately, situations like the Patient Case are becoming far more common as buprenorphine/ naloxone use is expanded and off-label prescribing for pain increases. Even providers who take time to explain why buprenorphine/naloxone is being selected for pain and discuss all the ramifications of treatment will have patients reconsider after initiating therapy and who feel “duped” when eventually confronted with the societal stigma and few alternative treatment options. The ethical dilemmas described have contributing factors that make these types of clinical conundrums commonplace.

Complex Persistent Opioid Dependence Buprenorphine’s increased popularity has led many to believe it is a panacea, and expanded use is promoted without apparent appreciation for the potential ramifications as described in the Patient Case. Complex persistent opioid dependence (CPOD) is the grey area where patients may not be ideal candidates to continue opioid therapy but refuse a diagnosis of OUD, making treatment by pain or substance use disorder professionals difficult. In this grey area of high-risk chronic pain management, we find a variety of folks treated with long-term opioid therapy considered high-risk perhaps because of high doses, polydrug risk with benzodiazepine and opioid combinations, personal or family history of substance abuse, or

Table 4. Equivalence Based on Bioavailability of Buprenorphine Formulations32 Product

Available Strengths

Percent Bioavailability

Indication

Morphine Eq 30 mg PO

Buprenex® (injectable)

0.3 mg/mL

100%

Pain

0.3 mg

Belbuca® (buccal film)

75, 150, 300, 450, 600, 750, 900 mcg

45%-65%

Pain

Butrans® (TD patch)

5, 7.5, 10, 15, 20 mcg/hr

15%

Pain

15 mcg/hr

Subutex® (SL tab/film) Suboxone® (SL tab/film) Bunavail® (buccal film) Zubsolv® (SL tab)

2/0.5, 4/1, 8/2, 12/3 mg 2.1/0.3, 4.2/0.7, 6.3/1 mg 1.4/0.36, 5.7/1.4 mg

29% ± 10% 29% ± 10% 20% ± 10%

OUD OUD OUD

1 mg/0.25 mg* NA 0.7/0.18 mg*

Sublocade® (SQ injectable)

300, 100 mcg

NA

OUD

NA

*Strength unavailable commercially, ½ of lowest available dosage form.

TD=transdermal; SL=sublingual; SQ=subcutaneous; NA=not applicable

psychiatric diagnoses that may complicate management and require a higher level of monitoring. Clinicians often provide education on these topics and attempt to initiate change to reduce risk, but what happens when the patient struggles to make the requested changes? When patients are not adherent during a taper, this aberrant behavior is considered misuse and potentially abuse. Lack of progress combined with aberrant behavior allows transition to buprenorphine/naloxone SL through a diagnosis of CPOD. CPOD is a recent phenomenon promoted as a reasonable expansion of buprenorphine/naloxone use by those focused on the profound benefits and evidence to support use in OUD.31 For some patients that may be appropriate, but did we allow patients sufficient time to adjust? Did we pause and reassess mental health stability? Provide additional education, and engage in shared decision making to see if the aberrant behavior resolves? Perhaps creating a new term that sounds like opioid dependence will justify expansion of buprenorphine/naloxone use into the grey area of treatment that has long been uncomfortable for patients and providers.

Morphine Equivalent Daily Dose Concerns Patients are often considered for buprenorphine treatment when they have struggled with an opioid taper because the aberrant behaviors that emerge when patients struggle to stabilize on a lower dose of opioids are often interpreted as evidence of OUD. Ironically, the decision to offer them buprenorphine/naloxone in such cases serves to dramatically increase their overall morphine equivalent daily dose far beyond their previous use, further reinforcing

25

physical dependence on opioid therapy. Additionally, this transition may be promoted inadvertently by policies that remove buprenorphine from opioid metrics in population management, analytics in managed care, or other regulatory scrutiny.

Table 4 includes a proposed buprenorphine equivalence based upon bioavailability comparison that correlates to the presumed equianalgesic doses of buprenorphine injection to oral morphine. It is important to understand, however, that no true equivalence of a partial agonist/antagonist to a traditional full agonist can exist because of competitive receptor binding and other variables outside the scope of this commentary. Moreover, while critics may say that equianalgesic conversions were never intended to be applied to OUD, the comparison is useful to demonstrate that buprenorphine formulations routinely utilized for OUD would be extraordinarily high doses of traditional opioid therapy. As an example, 2 mg of SL buprenorphine would be equivalent to oral morphine 60 mg, but the most common dose of buprenorphine utilized for OUD is 16 mg per day. This proposed equivalence is consistent with methadone dosing for OUD averaging 100 mg daily, which would be between 400 to 1200 mg or oral morphine daily if reversed. Neither of these comparisons is fair because converting back to morphine is not well characterized in equianalgesic studies, and methadone and buprenorphine’s unique pharmacology contribute to their mechanism and increased potency compared to traditional opioids. However, even conservative calculations make it clear that off-label use of buprenorphine formulations designed for OUD represent substantial increases in daily opioid use and it is inconceivable to think this does not contribute to further dependence on opioids.

US vs Europe: Dose Disparity Off-label use of buprenorphine formulations designed for OUD but prescribed for pain would not be necessary if there were not such a disparity between available strengths. In addition, the long history of available buprenorphine SL tablets approved for pain in Europe likely contributed to acceptance of buprenorphine’s role in pain management and reduced stigma of treatment for pain or OUD. Today, buprenorphine SL and transdermal formulations are approved at much higher strengths for pain in Europe than are available in the US, eliminating the need for off-label use and normalizing buprenorphine acceptance as an effective analgesic.

2. Schatman M, Wegrzyn E. The United States Drug Enforcement Administration and prescription opioid production quotas: an end game of eradication? J Pain Res. 2020;13:2629–2631.

3. Olfson M, Zhang V, Schoenbaum M, et al. Trends in Buprenorphine Treatment in the United States, 2009–2018. JAMA. 2020;323(3):276–277.

4. Roehler D, Guy G, Jones C. Buprenorphine prescription dispensing rates and characteristics following federal changes in prescribing policy, 2017–2018: a crosssectional study. Drug Alcohol Depend. 2020;213:108083.

5. Department of Health & Human Services Pain Management Best Practices I nter-Agency Task Force. Pain Management Best Practices Inter-Agency Task Force Report: Updates, Gaps, Inconsistencies, and Recommendations. Final Report. 2019.

Available at: www.hhs.gov/sites/default/files/pmtf-final-report-2019–05–23.pdf.

6. UK. Public Assessment Report Decentralised Procedure: Tephine. [product information] Available at: pdf4pro.com/view/public-assessment-report-decentralisedprocedure-gov-uk-4570e4.html.

7. Drugs@FDA. Suboxone film [package insert]. Published March 4, 2021.

Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2021/022410s042lbl.pdf.

Flexibility of Treatment Setting Off-label prescribing of buprenorphine for chronic pain is only possible because of the unique approach in the United States to MOUD with office-based opioid treatment (OBOT) made possible through introduction of the DEA X-waiver with the Drug Addiction Treatment Act (DATA) 2000 legislation. One of the purported advantages to OBOT was reduction in stigma due to the ability to receive care in a generalized medical setting. While this certainly expands access to treatment for OUD to meet an urgent public health need, overlap into off-label use was inevitable with increasing popularity of off-label prescribing of buprenorphine/naloxone for pain or comorbid OUD and pain. Methadone, for example, by regulation cannot be used for the treatment of OUD outside of a facility registered and accredited both nationally with SAMSHA and locally with mental health services for that state. One solution is to follow Europe’s example of deregulation and allow all MOUD to be prescribed without special license by any provider in any medical setting with clear benefits for removing underlying stigma of treatment.

Conclusion With dramatic increases to buprenorphine prescribing and mandatory reductions in opioid manufacturing, it is natural that many patients previously stable on long-term opioid therapy will find themselves in OBOT clinics receiving buprenorphine/naloxone. Emphasizing shared decision making and patient education can assist providers in reducing stigma or patients feeling “duped” into treatment. With any major shift in the treatment paradigm, we must be cognizant of the patient-specific concerns and/ or ethical dilemmas that arise as the unintended consequences.

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23. Dahan A. Opioid-induced respiratory effects: new data on buprenorphine.

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28. Adams VJ, Volkow ND. Ethical imperatives to overcome stigma against people with substance use disorders. AMA J Ethics. 2020;22(8):702–708.

24. Lutfy K, Cowan A. Buprenorphine: a unique drug with complex pharmacology.

Curr Neuropharmacol. 2004;2(4):395–402.

29. Perry BL, Pescosolido BA, Krendl AC. The unique nature of public stigma toward non‐medical prescription opioid use and dependence: a national study. Addiction.

2020;115(12):2317–2326.

25. Brown S, Holtzman M, Kim T, et al. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active.

Anesthesiology. 2011;115(6):1251–1260.

30. Waugh OC, Byrne DG, Nicholas MK. Internalized stigma in people living with chronic pain. J Pain. 2014;15(5):550-e1.

31. Manhapra A, Arias A, Ballantyne J. The conundrum of opioid tapering in longterm opioid therapy for chronic pain: a commentary. Subst Abus. 2018;39(2):152–161.

26. Chang Y, Moody DE, McCance-Katz EF. Novel metabolites of buprenorphine detected in human liver microsomes and human urine. Drug Metab Dispos.

2006;34:440–448.

32. Bettinger JJ, Fudin J, Argoff C. Buprenorphine and surgery: what’s the protocol?

In Kean N, 2nd ed. Opioid Prescribing and Monitoring—How to Combat Opioid Abuse and Misuse Responsibly. 2nd ed. Vertical Health, LLC. September 2017:73–78.

27. Chang Y, Moody DE. Glucuronidation of buprenorphine and norbuprenorphine by human liver microsomes and UDP-glucuronosyltransferases. Drug Metab Lett.

2009;3:101–107.

27

olden

irls

By Chensi Ouyang MD / Jessica Feranec MD / Georgine Lamvu MD, MPH

women’s health

In 2014, the International Society for the Study of Women’s Sexual Health and the Board of Trustees of the North American Menopause Society made an important decision to change the term vulvovaginal atrophy/atrophic vaginitis to genitourinary syndrome of menopause (GSM). The change to a more medically accurate terminology avoided the stigmatizing connotations associated with the old nomenclature.1 Vulvovaginal atrophy/ atrophic vaginitis implies that the condition is limited to the vulvovaginal area, incorrectly assumes that the etiology is infectious and/or inflammatory, and that the patient is responsible for the condition due to underuse or other negative actions. The term vulvovaginal atrophy/atrophic vaginitis fails to include the wide variety of changes in the vulva, vagina, and bladder that are associated with estrogen deficiency in menopause. Negative societal attitudes regarding women’s sexuality, patient’s feeling of embarrassment, shame, and fear, and minimization of sexual problems inhibit discussions about GSM between patients and clinicians.2-5 The VIVA—vaginal health, insights, views, attitudes— study found that among 3,520 participants from 6 countries, only 2% felt comfortable with the term vaginal atrophy.6 The EMPOWER survey of 1,858 women with GSM found that 72% of women had never discussed their symptoms with their clinician and 81% were not aware of the condition.7 The goal of the nomenclature change was to increase awareness and decrease stigmatization of a condition that often goes untreated despite significant quality of life degradation.8,9 This article will define the current terminology, describe the prevalence, physiology, and impact of GSM, and provide an overview of available treatments.

VULVOVAGINAL SYMPTOMS

is a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids with accompanying changes to the vulva, vagina, urethra, and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections.1 Unlike vasomotor symptoms of menopause that generally improve over time, GSM is a chronic progressive condition with symptoms that persist unless treated. The prevalence of symptoms in early menopause is 4%, rising to 47% three years after menopause.10 About 50% of peri- and postmenopausal women report GSM symptoms; of those, another 50% report moderate to severe symptoms.9,11-13 Symptoms of GSM are not limited to the perimenopausal years but also occur when women experience other hypoestrogenic states including the postpartum and lactation periods, hypothalamic amenorrhea, tobacco usage, premature ovarian insufficiency, or when taking antiestrogen medications such as gonadotropin antagonists/ agonists or aromatase inhibitors.14-17 Symptoms are also associated with nonwhite race, diabetes, lower body mass index, and younger age.18

Vulvovaginal symptoms are reported by half of midlife and older women.9 The common symptoms are vaginal dryness (55%–75%), itching and irritation (18%–37%), and soreness and pain (18%–29%).6,9,18-20 Women may also experience vaginal spotting from sexual intercourse or even with minimal trauma of daily activity.

Because vulvovaginal tissue is estrogen responsive, the loss of estrogen during menopausal transition contributes to the changes seen and experienced by patients.

Vulvovaginal tissue becomes thinner and more friable due to multiple physiologic changes including thinning of the vaginal epithelium and lamina propria, smooth muscle atrophy, decreased collagen and glycogen, and reduction of physiologic discharge and vascularization.21,22 On external genital exam, there is decreased pubic hair and vulvar skin elasticity, a narrowed vaginal introitus, fusion or resorption of the labia minora, decreased skin moisture, and loss of the labial fat pad. On internal vaginal exam, reduction in vaginal rugae can be seen. The epithelium appears pale, smooth, and shiny. The result is decreased vaginal length, width, and elasticity. Additionally, the cervix is smaller and may be flush with the vaginal fornices. Sometimes, blood vessels and petechiae are visible through the thinned epithelium. Signs of severe GSM include ulcerations of the labia majora and fissures at the posterior fourchette.16 Occasionally, symptoms do not correlate with exam findings.23 Vulvovaginal changes can cause severe pain and distress at time of vaginal exam.

Small or pediatric sized speculums, adequate lubrication, gentle palpation, explaining the reason for the exam, and working with the patient to set the pace or extent of the exam can prevent a physically and emotionally traumatizing experience.

Diagnosis of GSM is based on history and physician exam findings. Laboratory studies are not needed to confirm vulvovaginal symptoms of GSM, although other vulvovaginal conditions can present with similar symptoms. Vaginitis cultures may be useful to exclude acute vaginitis, and a vulvar skin punch biopsy may be necessary to diagnose other skin conditions like lichen sclerosis, lichen simplex chronicus, and lichen planus.

SEXUAL DYSFUNCTION

Sexual pain—dyspareunia—is one of the 2 most common symptoms of GSM, affecting 38% of perimenopausal women and 56% of postmenopausal women.24 Dyspareunia is the reason why 58% to 87% of women and 30% of women’s partners stop engaging in sex.13,25 While the exact cause of the increase in pain sensation is not known, it may be related to increased innervation of vaginal mucosa in hypoestrogenic states. Vestibular pain has been reported by postmenopausal women with lower serum estradiol levels.26,27 Vulvovaginal dryness, introital narrowing, fissures, and decreased elasticity may also cause dyspareunia.

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72% of women had never discussed their symptoms with their clinician…

Vulvovaginal symptoms of GSM not only result in sexual pain but also emotional distress. Women with vulvovaginal symptoms have a 4-fold higher risk of sexual dysfunction including difficulty with desire, arousal, and orgasm.28 Low libido and dyspareunia in women are strongly associated with unhappiness.29 Among the 500 American women surveyed in the VIVA study, 75% felt adverse effects on sexual intimacy, 64% reported decreased libido, 33% felt their symptoms were preventing them from having a loving relationship, and 26% reported negative self-esteem.25 Women may feel that they have to choose the lesser of 2 evils: experience relationship deterioration or even break-up with their partner due to cessation of sex, or continue to have sex despite the pain. Unfortunately, 72% of perimenopausal women with dyspareunia continue to engage in sexual intercourse at least once a month and 34% at least once weekly.13 Because GSM is chronic and progressive, continued sexual intercourse with dyspareunia and vaginal dryness may lead to persistent or worsened sexual dysfunction. Most women do not discuss dyspareunia and vaginal dryness with their clinicians, leading to needless pain and suffering since improvement of GSM-related vulvovaginal symptoms are associated with improvement in sexual function.30-32

LOWER URINARY TRACT SYMPTOMS

In addition to reductive effects on the vulva and vagina, hypoestrogenization impacts the lower urinary tract. The nomenclature change better reflects the inclusion of these genital areas. The urethra, bladder, vulvar vestibule, and the upper vagina are all embryologically derived from the urogenital sinus tissue.33 Estrogen receptors have been found in the urethra, bladder and

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pelvic floor muscles, and exogenous estrogen has been shown to increase urethral closure pressure.34,35 After menopause, the vaginal pH becomes elevated (pH > 5) due to the decrease of beneficial vaginal lactobacilli and results in disruption of the vaginal microbiome with subsequent increase in uropathogens.36,37 The shift from a lactobacillus-dominant microbiome could be one of the reasons for frequent vaginal or urinary tract infections.

Dysuria and recurrent urinary tract infections affect 13% and 4% of postmenopausal patients, respectively,38,39 and there is a 7-fold greater risk of sexual pain disorders in women with lower urinary tract symptoms.34

QUALITY OF LIFE

In addition to genitourinary symptoms, women with GSM report a significant decrease in quality of life. The ReVIVE study found that among 3,064 postmenopausal American women, 29% reported negative effects on sleep and 27% reported negative effects on enjoyment of life.20 Another study found that for every increment in severity of GSM symptoms, there was a clinically significant incremental decrease in quality of life scores, comparable to other chronic conditions such as chronic obstructive pulmonary disease and irritable bowel syndrome.9

BARRIERS TO CARE

GSM is an underdiagnosed and undertreated condition despite the common occurrence and severity of symptoms. Women and their clinicians are often reluctant to initiate conversations regarding GSM due to social and cultural taboos regarding female genitalia and sexuality.40 Women with GSM may feel embarrassment, shame, and

loss of self-esteem that may further prevent them from seeking care.6 In the ReVIVE study, only 25% of women initiated discussion regarding genitourinary concerns with their clinicians and only 54% of women were willing to respond when their clinicians asked about their symptoms.20 When women do seek treatment, they feel that they are often dismissed by their clinicians.7,25 To overcome these barriers, clinicians should routinely screen for GSM symptoms in perimenopausal and menopausal women in a supportive and nonjudgmental fashion. Clinicians can decrease stigma and assuage feelings of isolation by sharing information such as the high prevalence of GSM. For example, “Women in their 40s or older often experience vaginal dryness, urinary problems, and pain with sex. Are you experiencing any of these symptoms?”

Similar to principles of trauma informed care, it is important to foster a compassionate environment that is sensitive and respectful of the patients’ negative experiences thus far with GSM symptoms.

Lack of awareness regarding symptoms of GSM is another major barrier. Women often think that the symptoms are a natural part of aging, that prescription treatments are not available, or that there is not enough information available about the safety of medications.13 Women may suffer silently and needlessly. Patient visits with primary care/family physicians, gynecologists, and urologists are all opportunities to improve awareness, destigmatize the condition, facilitate detection, and direct appropriate treatment.

TREATMENT

Symptoms of GSM should be treated given the condition’s chronic and progressive nature. Clinicians should counsel patients on the natural course of the condition, emphasizing that continued treatment is necessary to prevent future recurrences or relapses. Treatment strategy depends on symptom type and severity, and is usually multimodal. Women with mild vulvovaginal symptoms and dyspareunia can apply vaginal moisturizer every 2 to 3 days to relieve vaginal dryness and discomfort. There are a variety of over-the-counter vaginal moisturizers although there is paucity of research on their efficacy. The World Health Organization recommends vaginal moisturizers with osmolarity of less than 1,200 mOsm/kg due to concern for epithelial cell damage.41 Vaginal lubricants for all partners prior to and during sexual activity are essential to decrease tissue trauma from friction, though relief is only temporary and does not address the underlying changes caused by a hypoestrogenic state. Women who use condoms for contraception should avoid oil-based moisturizers and lubricants as oil will damage condoms.

Continuation of nonpainful sexual intercourse on a regular basis can help maintain vaginal elasticity.42 Women can also use a vibrator with or without a partner to stimulate vulvovaginal blood flow.43 Pelvic floor physical therapy

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with dilator therapy can help women with introital narrowing or pelvic floor hypertonicity.44 Mindfulness exercises and topical lidocaine applied to the vaginal introitus prior to sexual activity may decrease dyspareunia.45,46 Women with sexual dysfunction and associated psychosocial effects such as intimacy avoidance, low self-esteem, and body image concerns may also benefit from sex therapy.

Couples psychotherapy may facilitate education, communication, and exploration of other ways to achieve satisfying sexual activity.47 Clinicians should discuss starting lowdose vaginal estrogen therapy for women with moderate to severe GSM or those who have persistent symptoms despite nonhormonal treatment. Low-dose vaginal estrogen therapy is preferred over systemic hormone therapy when only GSM symptoms are present.16 Low-dose vaginal estrogen therapy is available in cream, capsule, pill, and ring form, and all are FDA-approved. A 2016 Cochrane review found similar efficacy between the different formulations.48 Low-dose vaginal estrogen has been shown to be effective for reducing urinary incontinence, frequency of urinary tract infections, dysuria, dyspareunia, and vaginal dryness.49,50 It has also been shown to decrease the vaginal pH, increase vaginal lactobacilli counts, and increase blood flow.51,52 Symptom improvement occurs within a few weeks of treatment, although full improvement may not be seen for 8 to 12 weeks.16 Bothersome symptoms will recur with cessation of treatment. Low-dose vaginal estrogen therapy is safer than systemic estrogen therapy, and serum estrogen levels with low-dose vaginal estrogen therapy stay within postmenopausal range.53 Vaginal bleeding, vaginal discharge, breast tenderness, and nausea rarely occur with vaginal estrogen therapy.54 Low-dose vaginal estrogen therapy has not been shown to increase risk of endometrial cancer, thromboembolism, cardiovascular disease, or breast cancer.55,56 However, caution should be exercised for women with history of estrogen-dependent cancers as little data are available regarding the safety of vaginal estrogen therapy in estrogen-dependent cancer survivors. Nonhormonal therapy should be first line for these patients, and the decision to initiate vaginal estrogen therapy should be made in conjunction with the patient and her oncologist.

Ospemifene and dehydroepiandrosterone (DHEA) are nonestrogen medications that are FDA-approved for treatment of vaginal dryness and dyspareunia due to GSM. Ospemifene is a selective estrogen receptor modulator that is an estrogen agonist in the vagina. Although ex vivo studies in human breast tissue showed that ospemifene is an estrogen antagonist,57 it has not been studied in women with or at high risk for breast cancer and is not approved

by FDA for women with breast cancer. Risks of ospemifene include increased incidence of thromboembolism and hot flushes. DHEA is a sex hormone precursor for estrogen and androgen synthesis. The most common side effects are vaginal discharge and an abnormal pap test result.58 DHEA

Symptoms of GSM are not limited to the perimenopausal years…

is not FDA-approved for women with breast cancer due to lack of safety data. The efficacy and safety of vulvovaginal energy-based devices including lasers and radiofrequency devices are still under investigation, and these therapies are not FDA approved for treatment of GSM.

References 1. Portman DJ, Gass ML. Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Maturitas. 2014;79(3):349–354.

2. Sturdee DW, Panay N. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric. 2010; 13:509–522.

CONCLUSION

GSM is a chronic and progressive condition that is underdiagnosed and undertreated. The effects of GSM are broad and encompass vulvovaginal symptoms, urinary symptoms, sexual dysfunction, psychosocial distress, and decreased quality of life. Barriers to treatment include social and cultural taboo surrounding women’s sexuality, and lack of awareness regarding the condition and available treatments. The shift in terminology from vulvovaginal atrophy/atrophic vaginitis to genitourinary syndrome of menopause provides patients and clinicians a socially acceptable way to discuss and promote more research and education on this condition. Given patients’ reluctance to discuss GSM symptoms, clinicians should screen for GSM in a sensitive and respectful manner.

Patient education should emphasize the chronic nature of the condition, the need for continued treatment, and the effects on genitourinary and sexual health. Multimodal therapy should be tailored to the patient’s symptomology.

While low-dose estrogen therapy is preferred for moderate to severe symptoms in women without estrogen-dependent cancers, shared therapeutic decision making should include nonhormonal therapies such as moisturizers, lubricants, physical therapy, and individual or couples sex therapy.

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3. Townsend J. Urogenital atrophy in the in the post-menopausal woman.

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4. Lindau ST, Schumm LP, Laumann EO, et al. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357:762–774.

5. Gott M, Hinchliff S. Barriers to seeking treatment for sexual problems in primary care: a qualitative study with older people. Fam Pract. 2003;20:690–695.

6. Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views & Attitudes. (VIVA): results from an international survey. Climacteric. 2012;15:36–44.

7. Kingsberg SA, Krychman M, Graham S, et al. The Women’s EMPOWER Survey: identifying women’s perceptions on vulvar and vaginal atrophy and its treatment.

J Sex Med. 2017;14(3):413–424.

8. Nappi RE, Palacios S, Bruyniks N, et al; EVES Study investigators. The burden of vulvovaginal atrophy on women’s daily living: implications on quality of life from a face-to-face real-life survey. Menopause. 2019;26(5):485–491.

9. DiBonaventura M, Luo X, Moffatt M, et al. The association between vulvovaginal atrophy symptoms and quality of life among postmenopausal women in the United States and Western Europe. J Womens Health (Larchmt).

2015;24(9):713–722.

10. Dennerstein L, Dudley EC, Hopper JL, et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000;96(3):351–358.

11. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med. 2009;6(8):2133–2142.

12. Nappi RE, Kokot-Kierepa M. Women’s voices in the menopause: results from an international survey on vaginal atrophy. Maturitas. 2010;67(3):233–238.

13. Parish SJ, Nappi RE, Krychman ML, et al. Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy.

Int J Womens Health. 2013;5:437–447.

25. Simon JA, Kokot-Kierepa M, Goldstein J, et al. Vaginal health in the United States: results from the Vaginal Health: Insights, Views & Attitudes survey. Menopause. 2013;20(10):1043–1048.

14. Wisniewski PM, Wilkinson EJ. Postpartum vaginal atrophy. Am J Obstet Gynecol.

1991;165(4 Pt 2):1249–1254.

26. Griebling TL, Liao Z, Smith PG. Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. Menopause.

2012;19(6):630–635.

15. Baron JA, La Vecchia C, Levi F. The antiestrogenic effect of cigarette smoking in women. Am J Obstet Gynecol. 1990;162(2):502–514.

27. Kao A, Binik YM, Amsel R, et al. Biopsychosocial predictors of postmenopausal dyspareunia: the role of steroid hormones, vulvovaginal atrophy, cognitive-emotional factors, and dyadic adjustment. J Sex Med. 2012;9(8):2066–2076.

16. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 2020;27(9):976–992.

28. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active postmenopausal women. Menopause. 2008;15(4 Pt 1):661–666.

17. Pacello PC, Yela DA, Rabelo S, et al. Dyspareunia and lubrication in premature ovarian failure using hormonal therapy and vaginal health. Climacteric.

2014;17(4):342–347.

18. Huang AJ, Moore EE, Boyko EJ, et al. Vaginal symptoms in postmenopausal women: self-reported severity, natural history, and risk factors. Menopause.

2010;17(1):121–126.

19. Domoney C, Currie H, Panay N, et al. The CLOSER survey: impact of postmenopausal vaginal discomfort on women and male partners in the UK. Menopause Int. 2013;19(2):69–76.

20. Kingsberg SA, Wysocki S, Magnus L, et al. Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal Women’s VIews of Treatment Options for Menopausal Vaginal ChangEs) survey. J Sex Med. 2013;10(7):1790–1799.

21. Calleja-Agius J, Brincat M. The effect of menopause on the skin and other connective tissues. Gynecol Endocrinol. 2012;28(4):273–277.

22. Semmelink HJ, de Wilde PC, van Houwelingen JC, Vooijs GP. Histomorphometric study of the lower urogenital tract in pre- and post-menopausal women. Cytometry.

1990;11(6):700–707.

23. Davila GW, Singh A, Karapanagiotou I, et al. Are women with urogenital atrophy symptomatic? Am J Obstet Gynecol. 2003;188(2):382–388.

24. Cumming GP, Herald J, Moncur R, et al. Women’s attitudes to hormone replacement therapy, alternative therapy and sexual health: a web-based survey.

Menopause Int. 2007;13(2):79–83.

29. Avis NE, Brockwell S, Randolph JF Jr, et al. Longitudinal changes in sexual functioning as women transition through menopause: results from the Study of Women’s Health Across the Nation. Menopause. 2009;16(3):442–452.

30. Nappi RE, Lello S, Melis GB, et al. LEI (Lack of tEstosterone Impact) survey in a clinical sample with surgical menopause. Climacteric. 2009;12(6):533–540.

31. Pinkerton JV, Bushmakin AG, Komm BS, et al. Relationship between changes in vulvar-vaginal atrophy and changes in sexual functioning. Maturitas. 2017;100:57–63.

32. Erekson EA, Li FY, Martin DK, et al. Vulvovaginal symptoms prevalence in postmenopausal women and relationship to other menopausal symptoms and pelvic floor disorders. Menopause. 2016;23(4):368–375.

33. Brown JS, Vittinghoff E, Kanaya AM, et al; Heart and Estrogen/Progestin Replacement Study Research Group. Urinary tract infections in postmenopausal women: effect of hormone therapy and risk factors. Obstet Gynecol. 2001;98(6):1045–1052.

34. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281(6):537–544. Erratum in: JAMA. 1999;281(13):1174.

35. Robinson D, Toozs-Hobson P, Cardozo L. The effect of hormones on the lower urinary tract. Menopause Int. 2013;19(4):155–162.

36. Gebhart JB, Rickard DJ, Barrett TJ, et al. Expression of estrogen receptor isoforms alpha and beta messenger RNA in vaginal tissue of premenopausal and postmenopausal women. Am J Obstet Gynecol. 2001;185(6):1325–1330; discussion 1330–1331.

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50. Cardozo L, Bachmann G, McClish D, et al. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol.

1998;92(4 Pt 2):722–727.

51. Semmens JP, Tsai CC, Semmens EC, et al. Effects of estrogen therapy on vaginal physiology during menopause. Obstet Gynecol. 1985;66(1):15–18.

52. Shen J, Song N, Williams CJ, et al. Effects of low dose estrogen therapy on the vaginal microbiomes of women with atrophic vaginitis. Sci Rep. 2016;6:24380. Erratum in: Sci Rep. 2016;6:34119.

53. Lee JS, Ettinger B, Stanczyk FZ, et al. Comparison of methods to measure low serum estradiol levels in postmenopausal women. J Clin Endocrinol Metab.

2006;91(10):3791–3797.

54. Fischer G, Bradford J. Vulvovaginal candidiasis in postmenopausal women: the role of hormone replacement therapy. J Low Genit Tract Dis. 2011;15(4):263–267.

55. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause. 2018;25(1):11–20.

56. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet.

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37. Copas P, Bukovsky A, Asbury B, et al. Estrogen, progesterone, and androgen receptor expression in levator ani muscle and fascia. J Womens Health Gend Based Med. 2001;10(8):785–795.

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38. Hummelen R, Macklaim JM, Bisanz JE, et al. Vaginal microbiome and epithelial gene array in post-menopausal women with moderate to severe dryness. PLoS One. 2011;6(11):e26602.

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39. Hillier SL, Lau RJ. Vaginal microflora in postmenopausal women who have not received estrogen replacement therapy. Clin Infect Dis. 1997;25(suppl 2):S123–6.

40. Sobecki JN, Curlin FA, Rasinski KA, et al. What we don’t talk about when we don’t talk about sex: results of a national survey of U.S. obstetrician/gynecologists.

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41. Edwards D, Panay N. Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition?

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42. Jozkowski KN, Herbenick D, Schick V, et al. Women’s perceptions about lubricant use and vaginal wetness during sexual activities. J Sex Med. 2013;10(2):484–492.

43. Schroder M, Mell LK, Hurteau JA, et al. Clitoral therapy device for treatment of sexual dysfunction in irradiated cervical cancer patients. Int J Radiat Oncol Biol Phys.

2005;61(4):1078–1086.

44. Capobianco G, Donolo E, Borghero G, et al. Effects of intravaginal estriol and pelvic floor rehabilitation on urogenital aging in postmenopausal women. Arch Gynecol Obstet. 2012;285(2):397–403.

45. Goetsch MF, Lim JY, Caughey AB. A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2015;33(30):3394–3400.

46. Zarski AC, Berking M, Fackiner C, et al. Internet-based guided self-help for vaginal penetration difficulties: results of a randomized controlled pilot trial.

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47. Althof SE. Sex therapy and combined (sex and medical) therapy. J Sex Med. 2011;8(6):1827–1828.

48. Lethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2016;2016(8):CD001500.

49. Perrotta C, Aznar M, Mejia R, et al. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008;(2):CD005131.

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Practical education for specialists and frontline practitioners treating cns disorders

The Cosmopolitan of Las Vegas September 6–10 www.brainweek.org

By Joseph V. Pergolizzi, Jr. MD

key topic

The COVID-19 pandemic continues to challenge both patients and the healthcare system in the form of “long-haul COVID-19,” sometimes just called “Long COVID,” a viral persistence phenomenon that first garnered international attention when an online community started to describe and document extended symptoms after recovery from acute infection.1 One of these websites, WeAreBodyPolitic, used multiple patient self-reports to help describe upward of 50 symptoms that individuals believed had an association with a prior case of COVID-19.2 While the scientific community must exercise caution when weighing patient self-reports from often anonymous online sources, it soon became clear that Long COVID may represent a real and serious challenge to public health.

Viral Persistence

Viral persistence has been observed with other infections, such as the relapsing/remitting phases of chikungunya3 or the prolonged symptoms endured by some infected with the Ebola virus.4 Viral persistence can be explained by one or more of the following5: ● The virus’s ability to sequester and hide itself in immune-privileged sites ● Aberrant immune responses of the patient ● Autoimmunity issues Experts talk about acute COVID-19 and chronic COVID-19 with a proposed cutoff of about 3 weeks separating the acute infection from more persistent symptoms.6 A consensus definition of Long COVID has yet to been formulated, with some saying that Long COVID occurs 12 or more weeks after the acute infection.6,7 It is not known how long Long COVID typically lasts, but some reports maintain that symptoms may persist for months.8

in the meninges,13,14 this implies that the headaches characteristic of Long COVID might be caused by a viral infection of these nociceptors.12 It has also been speculated that the inflammatory response driven by cytokine storm in severe cases of acute infection adversely affects nociception.

Despite the fact that COVID is a pandemic, there has been very little study on the potential impact Long COVID might have on pain syndromes, both in chronic pain patients and in those without chronic pain.

Cytokine storm, which can drive extreme inflammatory response in severe cases of COVID-19, raises interesting considerations in light of pain syndromes associated with Long COVID.12 The results of cytokine storm in COVID-19 resemble sepsis.12 In patients who experience sepsis after critical illness, 44% developed chronic pain with sepsis the predominant risk factor.15 Further study is needed to better understand how cytokine-mediated inflammatory processes might promote or create chronic painful conditions. If cytokine storm can trigger a form of chronic pain, an after-effect of the COVID pandemic may be a new subpopulation of chronic pain patients.

Hypotheses Include Brainstem Dysfunction

Symptoms May Differ from Acute Phase

Long COVID has been associated with a wide range of symptoms that do not necessarily mirror the symptoms experienced during the acute infection.1 The most frequently reported of these effects appear to be fatigue, cough, and dyspnea.9-11 Pain has been reported with Long COVID in the form of chest pain, myalgia, joint pain,9 neuropathy, and myelopathy.5 Many Long COVID symptoms are symptoms that can typically occur in chronic pain patients; that is, fatigue, malaise, disordered sleep, depression, cognitive problems (“brain fog”), and anxiety. Thus, it is not always clear if a chronic pain patient experiencing pronounced fatigue or depression after overcoming acute COVID infection is suffering from Long COVID, typical secondary symptoms of chronic pain, or possibly a combination. Furthermore, chronic pain patients may have pre-existing painful symptoms, such as joint pain, that can be challenging to differentiate as part of Long COVID or the original painful syndrome.

Pain is one of the primary symptoms of infection, and pathogens are known to act on the sensory nervous system.12 A good example of viral effects on nociceptors is the painful condition known as postherpetic neuralgia. It is not known if the SARS-CoV-2 affects the dorsal root ganglia or the trigeminal ganglia, but this is certainly a possibility. Headache pain is a common neurological symptom of both acute COVID infection and Long COVID. Since certain forms of headache pain are caused by nociceptors

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An intriguing hypothesis about Long COVID maintains that it may involve persistent brainstem dysfunction.16 Long COVID may turn out to be more than one syndrome, such as the long-term effects of tissue damage, viral persistence, symptoms of chronic inflammation brought on by the acute infection, or some kind of a postviral syndrome.17 The notion that Long COVID is a brainstem dysfunction is predicated on the notion that the brainstem has a greater expression of ACE2 receptors than other areas of the brain, such that SARS-CoV-2 viral tropism is thus likely to occur in the brainstem, which is already vulnerable to pathological immune activation.16 Indeed, certain autopsy findings support the fact that the brainstem may be vulnerable to viral damage from SARSCoV-2.16 The symptoms of Long COVID have a degree of overlap with brainstem functions: respiratory regulation, cognitive problems, headache, fatigue, myalgia, and gastrointestinal symptoms.16 Thus, the hypothesis presented maintains that low-grade dysfunction of the brainstem caused by acute COVID may be what is now known as Long COVID, or at least one type of Long COVID.16 Brainstem dysfunction has been implicated in chronic migraine and other forms of cephalgia.18,19 For chronic pain patients, it may be challenging to differentiate symptoms of Long COVID from chronic pain and its secondary symptoms, such as poor quality sleep, fatigue, and mental fogginess. Clinicians may be prudent to ask their chronic pain patients if they had acute

…it is not always clear if a chronic pain patient experiencing pronounced fatigue or depression after overcoming acute COVID infection is suffering from Long COVID...

COVID infection and the timeline of its course. Pain patients who have recovered from acute COVID may be asked if new symptoms emerged in the post-acute period or if pre-existing symptoms were exacerbated. Regardless of the etiology, pain in chronic pain patients must be recognized, assessed, and treated with professional compassion. Clinicians should take the lead in informing patients about Long COVID and its painful symptoms rather than allowing patients to find information online, some of which is of dubious quality.

Patients need not be alarmed by Long COVID but should be informed, so that they can regard their pain care team as allies in helping them to manage this novel condition.

Conclusion

References 1.

Nath A. Long-haul COVID. Neurology. 2020;95(13):559–560.

2. Body Politic. BodyPolitic COVID-19 Support Group Newsletter. WeAreBodyPolitic.com. Available at: www.wearebodypolitic.com/bodytype/2021/1/5/ the-preprint-youve-been-waiting-for.

3. Guillot X, Ribera A, Gasque P. Chikungunya-induced arthritis in Reunion Island: a long-term observational follow-up study showing frequently persistent joint symptoms, some cases of persistent chikungunya immunoglobulin M positivity, and no anticyclic citrullinated peptide seroconversion after 13 years. J Infect Dis. 2020;222(10):1740–1744.

4. Clark DV, Kibuuka H, Millard M, et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect Dis. 2015;15(8):905–912.

5. Gorna R, MacDermott N, Rayner C, et al. Long COVID guidelines need to reflect lived experience. Lancet. 2020;397(10273):455–457.

It may be possible that certain people with no history of chronic pain are troubled by persistent painful symptoms associated with Long COVID. Guidelines for the overall clinical treatment of Long COVID do not exist, although the National Institute for Health and Care Excellence (NICE) in Britain has offered a “living guideline” for Long COVID, but it does not specifically deal with the topic of pain.20 More guidance and public awareness is important to help patients obtain accurate diagnoses and appropriate care. In particular, pain specialists must be cognizant of this novel syndrome and its potential to cause or worsen painful conditions.

6. Baig AM. Chronic COVID syndrome: need for an appropriate medical terminology for Long-COVID and COVID long-haulers. J Med Virol. 2020;93(5):2555–2556.

7. Mendelson M, Nel J, Blumberg L, et al. Long-COVID: an evolving problem with an extensive impact. S Afr Med J. 2020;111(1):10–12.

8. COVID symptom study. How long does COVID last? COVID Symptom Study.

Available at: covid.joinzoe.com/post/covid-long-term.

9. Carfì A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603–605.

10. Mandal S, Barnett J, Brill SE, et al. ‘Long-COVID: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax. 2020 Nov 10.

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11. Moreno-Pérez O, Merino E, Leon-Ramirez JM, et al. Post-acute COVID-19 syndrome. Incidence and risk factors: a Mediterranean cohort study. J Infect.

2021;82(3):378–383.

12. McFarland AJ, Yousuf MS, Shiers S, et al. Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain. Pain Rep. 2021;6(1):e885.

13. Jacobs B, Dussor G. Neurovascular contributions to migraine: moving beyond vasodilation. Neuroscience. 2016;338:130–144.

14. Khan S, Amin FM, Christensen CE, et al. Meningeal contribution to migraine pain: a magnetic resonance angiography study. Brain. 2019;142(1):93–102.

15. Battle CE, Lovett S, Hutchings H. Chronic pain in survivors of critical illness: a retrospective analysis of incidence and risk factors. Crit Care. 2013;17(3):R101.

16. Yong SJ. Persistent brainstem dysfunction in Long-COVID: a hypothesis.

ACS Chem Neurosci. 2021;12(4):573–580.

17. Mahase E. Long covid could be four different syndromes, review suggests. BMJ (Clinical research ed). 2020;371:m3981.

18. Marciszewski KK, Meylakh N, Di Pietro F, et al. Changes in brainstem pain modulation circuitry function over the migraine cycle. J Neurosci. 2018;38(49): 10479–10488.

19. Chong CD, Plasencia JD, Frakes DH, et al. Structural alterations of the brainstem in migraine. Neuroimage Clin. 2017;13:223–227.

20. Sivan M, Taylor S. NICE guideline on long covid. BMJ (Clinical research ed).

2020;371:m4938.

Using an Integrative Approach to Treat Chronic Overlapping Pelvic Pain Disorders

By Kathryn Witzeman MD, FACOG

pelvic pain disorders

Have you ever been stumped or frustrated in treating chronic or persistent pelvic pain? Have your patients not responded as expected to the standard hormonal or pain medications or surgical therapies?

Welcome to Part 1 of a 2-part series addressing an innovative approach to treating complex and overlapping pelvic pain disorders (COPPDs).

Part 1 focuses on the possible underlying connections between COPPDs and how mindbody modalities can tackle part of the inherent dysfunction in these coexisting disorders.

Part 2, in the next issue of PWJ, will build upon this foundation and discuss how combining mind-body modalities with manual therapies, acupuncture, nutritional approaches, and plant-based therapies in a shared decision-making framework may improve functionality and quality of life in people with COPPDs, while decreasing dependence on opioid medications and other traditional and more costly measures.

Chronic or persistent pelvic pain (CPP) affects women of all socioeconomic, racial, and cultural backgrounds worldwide. The prevalence for women during reproductive age has been reported between 14% and 24%, with approximately 20% of women experiencing some form of CPP during their lifetime.1 A more recent systematic review reported the prevalence of CPP in general ranged between 5.7% and 26.6% in women of reproductive age; however, the review noted that there was a paucity of studies from many regions of the world.2 This common condition has a major impact on quality of life and unfortunately is commonly underrecognized and undertreated by frontline healthcare providers, leading to prolongation of symptoms and increased suffering.

The term chronic pelvic pain, while used regularly in the literature and for medical coding, does little to help discern what may be contributing to the patient’s symptoms or to guide clinical care recommendations. Specifically, it describes how long and where a person feels pain. CPP is multifactorial and commonly involves not only gynecological causes, but also urological, gastrointestinal, musculoskeletal, and neurological causes, and has psychopathological and sexual dysfunction contributions.3 CPP in women is defined by the American College of Obstetricians and Gynecologists as “noncyclical pain of at least 6 months’ duration that appears in locations such as the pelvis, anterior abdominal wall, lower back, or buttocks and that is serious enough to cause disability or lead to medical care.”4 Alternatively, the International Association for the Study of Pain defines CPP as “chronic or persistent pain perceived in structures related to the pelvis of either men or women. It is often associated with negative cognitive, behavioral, sexual, and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor, or gynecological dysfunction.”5

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A growing body of literature recognizes the comorbid and overlapping nature of abdominopelvic pain disorders including dysmenorrhea, irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, vulvodynia, and lumbopelvic myofascial pain.6-9 Anxiety and depressive disorders as well as sleep disorders and posttraumatic stress disorder are also strongly associated with pelvic pain disorders.10-12 The concept of coexisting pain conditions has recently been recognized by the National Institutes of Health and the US Congress as a set of disorders that co-aggregate to include, but should not be limited to, temporomandibular disorder, fibromyalgia, irritable bowel syndrome, vulvodynia, myalgic encephalomyelitis/chronic fatigue syndrome, interstitial cystitis/painful bladder syndrome, endometriosis, chronic tension-type headache, migraine headache, chronic lower back pain, and dry eye syndrome. Collectively, these conditions are increasingly referred to as chronic overlapping pain conditions (COPCs).13 Curiously, almost half of these conditions occur in the abdominopelvic region.

Factors that affect the perception of pain affect the perception of CPP in a similar way. Extreme stress surrounding an insult may suppress pain perceptions during a crisis situation but may also lead to prolonged changes in pain perception and chronic stress. The neuroendocrine milieu of pro-inflammatory neuromodulators that coincides may also impact pain perceptions,14 and a person’s underlying thoughts and pain beliefs impact their perception as well. Gender and psychosocial processes in pain coping and early life exposure to stress play additional factors. Hormonal influences add another layer of complexity in this neuroendocrine pain soup.

Pain perceptions are influenced by a variety of factors. The nociceptive input from the periphery travels to the spinal cord via A-delta or C fibers; this can be amplified by peripheral sensitization. Both ascending (to the brain) and descending (from the brain) nociceptive modulation impact the pain experience. This nociceptive modulation can also be altered by peripheral and central sensitization, often arising from injury. Many factors centrally affect the pain experience, including chemical and structure factors such as neurodegeneration, metabolism, and maladaptive plasticity; cognitive set: hypervigilance, attention, distraction, catastrophizing; context, in the form of pain beliefs, expectations, and the power of placebo; and mood: depression, anxiety, and catastrophizing.

Each of these can be further broken down and can have a variety of effects on the pain experience.15,16

Let’s consider a common clinical scenario: BL, a cis-gendered female 42-year-old G2P2 with a 10-year history of worsening pelvic pain that now includes daily pain with routine activity, bowel movements, and urination. She currently avoids sexual intercourse due to pain (dyspareunia) and leaves work frequently because of headaches. She is distraught and concerned about potentially losing both her job and intimate partner of many years.

BL has seen many physicians in her search for a “cure” and is very frustrated with the healthcare system.

Clearly, obtaining a thorough history and performing a physical exam will be key in focusing your initial recommendations. However, an integrative approach in obtaining BL’s history is the 1st step. It is of the utmost importance to take into account the whole person and the impact symptoms have on her life, as well as the impact that life and its stressors have on her symptoms. Considering not only the potential contributing body systems—which may include gastrointestinal, urinary, reproductive, neurosensory, and myofascial—but also the impact of sleep issues, life stressors, anxiety, depression, and the possibility of PTSD will inform the clinical approach. To optimize the chances of successful treatment, it is imperative to learn about potential contributing factors to her complaints,

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their impact on not only her body but her mind and spirit.

Then through shared decision-making, potential integrative therapeutic options can be considered.

Autonomic Nervous System Dysregulation The area of the mind-body connection and modalities that address this most vital connection is quite broad. Choosing one of these modalities that your patient may be motivated to engage with can impact not only the emotive comorbidities, including depression, anxiety, and posttraumatic symptoms, but also the pain experience itself.

The autonomic nervous system (ANS) is made up of the sympathetic nervous system and parasympathetic nervous system, which have different roles in general and, of relevance here, are part of different stages of inflammation. The sympathetic nervous system is involved in the initial phases of inflammation, and it gives rise to a pro-inflammatory environment that can sensitize nerve endings through adrenoceptors. In the later stages of inflammation, there is an alteration in the balance of pro-inflammatory and anti-inflammatory nerve reactivity.

The sympathetic nervous system has been shown to be involved in both the development and severity of chronic inflammatory diseases.15,16 Enhanced pain perception experienced by people with COPCs may result from a dysregulation in peripheral systems, central systems (including the ANS), or both, that produce dynamic, time-dependent changes in the excitability and response characteristics of neuronal and glial cells, which may contribute to the central sensitization and the enhanced temporal summation (ie, wind-up) of nociceptive input observed in patients with COPCs. This dysregulation can also contribute to altered mood, motor, autonomic, and neuroendocrine responses as well as contributing to pain perception and possibly the contralateral: mood, motor, autonomic, and neuroendocrine responses contribute to altered pain perception.17

Breath Work

Although our breath is highly connected to the ANS, we also have significant conscious control over it. Many types of meditation include breath training, and breathing techniques can be applied as a separate intervention with its own effects on health and emotional outcomes. Pranayamic breathing, defined as a manipulation of breath movement, has been shown to contribute to significant physiological changes. The mechanisms of pranayamic breathing that specifically interact with the nervous system and affect metabolism and autonomic functions remain unclear. Predominant theory hypothesizes that voluntary slow deep breathing functionally

Choosing…modalities…can impact not only the emotive comorbidities, including depression, anxiety, and posttraumatic symptoms, but also the pain experience itself. resets the autonomic nervous system through stretchinduced inhibitory signals and hyperpolarization currents propagated through both neural and nonneural tissue, which synchronize neural elements in the heart, lungs, limbic system, and cortex.18 The rate of breathing has been shown to be capable of changing both the heart rate and heart rate variability.19 There is a significant body of research to support that heart rate variability is a good measure of how well the ANS is working, representing the balance between the sympathetic and parasympathetic nervous system.20 The ANS is highly adaptable and allows the organism to maintain its balance when experiencing strain or stress. Conversely, a lack of flexibility leading to a more rigid system can lead to somatic and psychological pathologies. Reduced heart rate variability seems to indicate decreased cardiac vagal tone with elevated sympathetic activity in anxious and depressive individuals, reflecting a deficit in flexibility and dysfunction of emotional and physiological mechanisms.21,22

Clinical Hypnosis

Clinical hypnosis has been recognized by the American Medical Association and the American Psychiatric Association since 1958. It’s been widely studied in chronic pain management of adults and children with consistent and significant decreases in pain associated with a variety of conditions. While it has been found to be more effective than many other interventions, there is a lack of standardization in hypnotic interventions examined in clinical trials. The number of patients in the trials is typically low, and trials frequently lack long term follow-up.23,24 Hypnosis incorporates components such as relaxation, focused attention, imagery, interpersonal processing, and suggestion. Clinical outcome studies on acute and chronic pain, as well as neurophysiological studies in the laboratory, have demonstrated that hypnosis is

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effective over and above placebo treatments and has measurable effects on activity in brain areas known to be involved in processing pain. Equally important, recent clinical trials provide significant findings useful to the clinical application of hypnosis for the management of chronic pain.25 Efficacy studies specific to pelvic pain disorders are less prolific. One abdominopelvic pain condition with solid evidence for “gut directed” hypnotherapy is irritable bowel syndrome.26 Few studies evaluate long term effects. However, a 2012 Scandinavian study retrospectively evaluated 208 patients with refractory irritable bowel syndrome. Initially 49% of participants were considered responders; 73% of these responders reported continued improvement for up to 7 years; and 87% of the 208 patient cohort considered gut directed hypnotherapy worthwhile.27 A 2014 randomized controlled trial from India was the first of its kind to evaluate clinical hypnosis in primary dysmenorrhea. Standard NSAIDs therapy was compared to a standardized clinical hypnosis treatment protocol in 56 female nursing students diagnosed with primary dysmenorrhea. Each group continued treatment for 3 consecutive menstrual cycles and then a subsequent 3 consecutive cycles with no intervention. Participants graded their quality of life based on functional restrictions of activity during their menses due to menstrual pain and other associated symptoms including nausea, vomiting, headaches, or dizziness at baseline and after each cycle.

There was significant improvement in the quality of life of both groups at 3 months; however, a waning in both groups was seen at 6 months when both therapies had stopped. Further research is needed with larger samples sizes and validated questionnaires to extrapolate these results to a general population of women with primary dysmenorrhea. These limited data suggest clinical hypnosis may be effective for people with primary dysmenorrhea who may not be good candidates for NSAID or hormonal therapies.28

Clinical hypnosis is typically taught by providers to patients as self-hypnosis, which may help to build a sense of control and empowerment. It also has important positive effects on anticipatory anxiety that often accompanies procedures, and it may be used when usual medical treatments cause adverse reactions or are otherwise not tolerated or declined. Other benefits include its flexibility with no need for technical support or expensive equipment. All that is needed is a trained and certified clinical hypnosis provider. The patient, however, needs to be engaged and put in the time and effort to practice the techniques they learn. The American Society of Clinical Hypnosis is an excellent resource, with a “find a certified provider” function, available at www.asch.net.

Typically, these images are visualized with a goal of evoking a state of relaxation and a specific outcome such as pain relief. Guided imagery has been suggested in several reports to be an effective treatment for a variety of pain conditions and has been said to modulate the immune system and facilitate mind-body healing. A 2011 systematic review of guided imagery for musculoskeletal pain noted that because it is often coupled with other modalities such as hypnosis, breathing exercises, progressive muscle relaxation, and music therapy, it is challenging to isolate its efficacy.35 A preliminary randomized pilot study in 2008 showed promising results, reporting 45% of patients with interstitial cystitis were responders with moderate to marked symptom improvement during the study. Both pain scores and episodes of urgency significantly decreased in the treatment group.29

Guided Imagery

Guided imagery is another modality that operates within the mind-body connection. It is an easy-to-use multisensory relaxation-based practice that utilizes guided affirmations and soothing music to evoke images in the mind that are then experienced in the body, employing all of the senses. Research shows that practicing guided imagery has both physiological and psychological responses, including reducing healing time after injuries and surgery, boosting short term immunity and increasing mental well-being.29-32 Some of the largest and most prominent healthcare insurers in the US have added guided imagery to their plans because it has been shown to reduce treatment costs and increase positive health outcomes.

In 2011, a University of Oxford research team concluded that women with CPP report negative pain-related cognitions in the form of intrusive mental imagery.

For example, one woman in the study reported imagining “malicious demons playing around my pelvis, pushing, pulling, and scratching.”33 Targeting such imagery has led to interesting treatment innovations in the care of emotional disorders. The use of imagery, up to this point, had been neglected in pain phenomenology, and could provide a novel target for a mind-body therapy in chronic pain.33 Additionally, Alappattu34 draws a connection between the fear avoidance model and chronic pelvic pain disorders inclusive of pelvic myofascial pain. This conceptual model theorizes in particular how certain psychological variables, including pain-related anxiety and pain catastrophizing, contribute to chronic pain disorders.

While additional research is needed, Alappattu suggests that integrating the model into the clinical approach to pelvic pain may assist in reducing both catastrophizing and anxiety.34 Psychological approaches address the fear avoidance model with a variety of therapies including cognitive behavioral therapy, dialectic behavioral therapy, and guided imagery.

Guided imagery is defined as the generation of different mental images, either sensory or affective, using the capacities of visualization and imagination.

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) is likely the mind-body modality traditional western healthcare providers are most familiar with and have recommended to other patients. The use of CBT has been studied in many of the COPPDs individually. In Lindstrom’s 2015 descriptive study, the McCoy Female Sexuality Questionnaire and the Hospital Anxiety and Depression Scale were used to evaluate efficacy of treatment for sexual pain as the primary outcome, as well as psychological distress. This study included 60 participants diagnosed with provoked vestibulodynia who underwent a 10 week period of combined mucosal desensitization and pelvic floor exercise with CBT. Study participants reported significant increases in sexual fantasies, sexual pleasure, and an increased frequency of self-stimulation and sexual intercourse. Anxiety levels were significantly reduced; depression scores, however, did not change. Improvements were sustained at 6 months.36 In 2016, Goldfinger’s study randomized 20 women with provoked vestibulodynia and sexual pain to receive either CBT or comprehensive pelvic physical therapy. The primary outcome was change in intercourse pain intensity; secondary outcomes included pain on cotton swab test, various nonsexual activities, and negative pain cognitions. Both groups demonstrated significant decrease, approximately 30%, after treatment in all outcome measures, with the exception of sexual functioning where significant improvement was observed only in the CBT group. Nearly all parameters maintained improvement at 6 months. While a small pilot, this study showed that both CBT and physical therapy can lead to clinically meaningful improvements in both pain and psychosexual function.37 Research continues to evaluate optimal protocols for the integrated use of CBT and physical therapy.38-40 Dialectical behavioral therapy (DBT) is a subtype of CBT with the main goals of teaching people how to live in the moment and develop healthier ways

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of coping with stress, regulating their emotions, and improving their relationship with others. Originally intended to treat severe borderline personality disorder, it evolved to become an evidenced-based therapy for treating conditions in which people exhibit emotional dysregulation or have self-destructive behaviors such as eating disorders and substance abuse disorders, all of which have been correlated to pelvic pain disorders.41-43 However, a recent literature review did not identify any studies evaluating the use of DBT in chronic pelvic pain disorders.

Mindfulness Based Stress Reduction

What is mindfulness? Dr. Jon Kabat-Zinn, known for extensive study and popularizing of this modality, has described it as “paying attention to the present moment with intention, while letting go of judgment, as if your life depends on it.” It’s hard to pick up a magazine or surf the internet without coming across something on mindfulness. It is certainly trending, but does the evidence support it specifically in pelvic pain conditions?

Traditionally speaking mindfulness based stress reduction (MBSR) is an 8 week structured, well-defined, and systematic patient centered educational approach that uses relatively intensive training in mindfulness based meditation as the core of the program to teach people how to take better care of themselves and live healthier and more adaptive lives.44 Stress has been shown to impact perceptions of pain and function. Does MBSR reduce chronic pain and improve function, and by what mechanism? Research is active in the use of MBSR in a wide variety of chronic pain conditions including fibromyalgia and its potential mechanism.45-50 In research specific to pelvic pain disorders, the majority of outcomes resulted in only modest improvement, with barriers including patient burden, treatment preference, and motivation. MBSR has been shown to benefit women in various stages of breast cancer treatment, with significant improvement in physical functioning and improvement in psychological parameters such as anxiety, depression, and overall feeling of well-being.51-54

Medical or Therapeutic Yoga

Yoga is classified by the World Health Organization as a mind-body practice. Yoga combines physical exercise, meditation, and respiratory techniques that strengthen the muscles and relieve stress and has been shown to balance the ANS as evidenced by improved heart rate variability in multiple studies.55-58 Therapeutic yoga has also been shown to help the body and mind to modulate depression and anxiety, common comorbidities of COPPDs.59-61 Growing evidence supports that the practice of yoga can reduce reported levels of CPP and improve quality of life measures. Several studies have shown significant

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improvement in women with both proven endometriosis and with CPP of unknown source.55,57,58

Trauma-Informed Yoga

When recommending yoga therapy to patients, one must be cautious to direct them to a trauma-informed yoga therapist. A yoga class at the nearest studio or gym could be very triggering. An optimally functioning ANS returns to homeostasis after sympathetic nervous system arousal. However, individuals with PTSD-related hyperarousal symptoms may take much longer than others to self-regulate and return to a more balanced physiological state.

Yoga, as a mind-body practice, engages downregulating practices that emphasize activation of the parasympathetic nervous system as well as upregulating practices that stimulate the sympathetic nervous system.

Mindful use of up- and downregulating practices over time helps individuals learn to discern cues from their ANS, recognizing when they are either hyper- or hypoaroused, and teaches them how to recalibrate or balance their ANS.62 The aim of trauma-informed yoga is to provide students with practices that help them access the ANS in general (eg, through breath control) and re-engage the parasympathetic nervous system. However, many athletic yoga practices are geared toward inducing hyperarousal and may thus be contraindicated for individuals with trauma symptoms.63 The heterogeneity of yoga practices can make referrals by health practitioners ambiguous and misleading for clients seeking treatment for trauma related symptoms. Trauma-informed yoga can significantly reduce PTSD symptomatology as well as pain symptoms. Studies show effect sizes comparable to well-researched psychotherapeutic and psychopharmacologic approaches.62 Yoga may improve the functioning of traumatized individuals by helping them to tolerate physical and sensory experiences associated with fear and helplessness and to increase emotional awareness and affect tolerance.

We have reviewed the emerging concept of chronic overlapping pelvic pain disorders, their potential underlying etiological relationships, and also have begun exploring how mind-body modalities can work synergistically to address both pain symptoms and comorbid mental health conditions including depression, anxiety, and PTSD. Part 2 will build upon this foundation.

If you find yourself struggling with the complexity and challenging presentations of people with persistent or chronic pelvic pain disorders, you are not alone.

To learn more, check out additional resources available through the International Pelvic Pain Society (IPPS) at pelvicpain.org.

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4. Chronic Pelvic Pain: ACOG Practice Bulletin Summary, Number 218. Obstet Gynecol. 2020;135(3):744–746.

26. Palsson OS. Hypnosis treatment of gastrointestinal disorders: a comprehensive review of the empirical evidence. Am J Clin Hypn. 2015;58(2):134–158.

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16. Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron. 2007;55(3):377–391.

38. Taple BJ, Griffith JW, Weaver C, et al. Enhancing behavioral treatment for women with pelvic floor disorders: Study protocol for a pilot randomized controlled trial. Contemp Clin Trials Commun. 2020;17:100514.

17. Maixner W, Fillingim RB, Williams DA, et al. Overlapping chronic pain conditions: implications for diagnosis and classification. J Pain. 2016;17(9 suppl):T93-T107.

39. Brotto LA, Bergeron S, Zdaniuk B, et al. A comparison of mindfulness-based cognitive therapy vs cognitive behavioral therapy for the treatment of provoked vestibulodynia in a hospital clinic setting. J Sex Med. 2019;16(6):909–923.

18. Jerath R, Edry JW, Barnes VA, et al. Physiology of long pranayamic breathing: neural respiratory elements may provide a mechanism that explains how slow deep breathing shifts the autonomic nervous system. Med Hypotheses. 2006;67(3):566–571.

40. Lofrisco BM. Female sexual pain disorders and cognitive behavioral therapy. J Sex Res. 2011;48(6):573–579.

19. Li C, Chang Q, Zhang J, et al. Effects of slow breathing rate on heart rate variability and arterial baroreflex sensitivity in essential hypertension. Medicine (Baltimore). 2018;97(18):e0639.

41. Badura AS, Reiter RC, Altmaier EM, et al. Dissociation, somatization, substance abuse, and coping in women with chronic pelvic pain. Obstet Gynecol.

1997;90(3):405–410.

20. Zhu J, Ji L, Liu C. Heart rate variability monitoring for emotion and disorders of emotion. Physiol Meas. 2019;40(6):064004.

42. Ben-Porath D, Duthu F, Luo T, et al. Dialectical behavioral therapy: an update and review of the existing treatment models adapted for adults with eating disorders.

Eat Disord. 2020;28(2):101–121.

21. Servant D, Logier R, Mouster Y, et al. [Heart rate variability. Applications in psychiatry]. Encephale. 2009;35(5):423–428.

43. Altman D, Iliadou AN, Lundholm C, et al. Somatic comorbidity in women with overactive bladder syndrome. J Urol. 2016;196(2):473–477.

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44. Worthen M, Cash E. Stress management. 2020 Aug 29. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. PMID: 30020672.

45. Santarnecchi E, Egiziano E, D’Arista S, et al. Mindfulness-based stress reduction training modulates striatal and cerebellar connectivity. J Neurosci Res. May 2021;99(5):1236–1252.

46. Andersen E, Geiger P, Schiller C, et al. Effects of mindfulness-based stress reduction on experimental pain sensitivity and cortisol responses in women with early life abuse: a randomized controlled trial. Psychosom Med. 2020;doi:10.1097/PSY.0000000000000889.

47. Chavez JL, Porucznik CA, Gren LH, et al. The impact of preoperative mindfulness-based stress reduction on postoperative outcomes in lumbar spine degenerative disease: 3-month and 12-month results of a pilot study.

World Neurosurg. 2020;139:e230-e236.

48. Law H, Avins A, Stahl R, et al. Recruitment, retention, and adherence in a randomized feasibility trial of mindfulness-based stress reduction for patients with migraine.

Complement Ther Med. 2020;55:102610.

49. Marske C, Shah S, Chavira A, et al. Mindfulnessbased stress reduction in the management of chronic pain and its comorbid depression. J Am Osteopath Assoc.

2020;120(9):575–581.

50. Simshäuser K, Lüking M, Kaube H, et al. Is Mindfulness-based stress reduction a promising and feasible intervention for patients suffering from migraine? a randomized controlled pilot trial. Complement Med Res. 2020;27(1):19–30.

51. Windgassen S, McKernan L. Cognition, emotion, and the bladder: psychosocial factors in bladder pain syndrome and interstitial cystitis (BPS/IC). Curr Bladder Dysfunct Rep. 2020;15(1):9–14.

52. Smith SL, Langen WH. A systematic review of mindfulness practices for improving outcomes in chronic low back pain. Int J Yoga. 2020;13(3):177–182.

53. Naliboff BD, Smith SR, Serpa JG, et al. Mindfulness-based stress reduction improves irritable bowel syndrome (IBS) symptoms via specific aspects of mindfulness. Neurogastroenterol Motil. 2020;32(9):e13828.

54. Crisp CD, Hastings-Tolsma M, Jonscher KR. Mindfulness-based stress reduction for military women with chronic pelvic pain: a feasibility study. Mil Med. 09 2016;181(9):982–989.

55. Saxena R, Gupta M, Shankar N, et al. Effects of yogic intervention on pain scores and quality of life in females with chronic pelvic pain. Int J Yoga. 2017;10(1):9–15.

56. Gonçalves AV, Barros NF, Bahamondes L. The practice of hatha yoga for the treatment of pain associated with endometriosis. J Altern Complement Med. 2017;23(1):45–52.

57. Gonçalves AV, Makuch MY, Setubal MS, et al. A qualitative study on the practice of yoga for women with pain-associated endometriosis. J Altern Complement Med. 2016;22(12):977–982.

58. Huang AJ, Rowen TS, Abercrombie P, et al. Development and feasibility of a group-based therapeutic yoga program for women with chronic pelvic pain. Pain Med. 2017;18(10):1864–1872.

59. Ghaffarilaleh G, Ghaffarilaleh V, Sanamno Z, Kamalifard M. Yoga positively affected depression and blood pressure in women with premenstrual syndrome in a randomized controlled clinical trial. Complement Ther Clin Pract. 2019;34:87–92.

60. Price M, Spinazzola J, Musicaro R, et al. Effectiveness of an extended yoga treatment for women with chronic posttraumatic stress disorder. J Altern Complement Med. 2017;23(4):300–309.

61. Justice L, Brems C. Bridging body and mind: case series of a 10-week trauma-informed yoga protocol for Veterans. Int J Yoga Therap. 2019;29(1):65–79.

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Practical education for specialists and frontline practitioners treating CNS disorders

Regional Conference Series

WEST

Scottsdale, az

10/9–10/10

SOUTH

Tampa, fl 11/6–11/7

MIDWEST

Live Conference!

St. Louis, mo

11/13–11/14

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

PERSPECTIVES O N TH E R EVIS ED DEFI N ITI O N O F PAI N

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

At the time of this writing, 21 years is exactly one-third of my age, and I

guess it would be fair to say that for virtually all of us, 21 years is a lot of time.

Turning 21 is a rite of passage in our society as we become “legal”; you can buy alcohol, adopt a child, and gamble for example. Additionally, numerologists (for those of you who believe in these kinds of things) consider the number 21 to be symbolic of beginnings, changes, success, completion, and the fulfillment of desires, to name a few. And you likely know what 21 signifies at the blackjack table (I am not a gambler). ¶ In preparing for one of my upcoming talks (Tell Me Why It Hurts) with Dr. Patricia Tsui at the 2021 PAINWeek National Conference, I realized that 21 year periods have been very significant in the pain management world—more so than I ever realized. And believe it or not, this all has to do with the International Association for the Study of Pain (IASP), and its definition of “pain.” Who knew? I certainly did not realize any of this as it was happening. 2

In July 2020,

2020 forward could get through the course without this education, knowledge, and clinical implications. The students were quite impressed and excited to have this information and digest it, and that made me feel good. I am still waiting for the mass dissemination of this “new” definition.

the IASP formally released a revised definition of pain. An article about it was published in the IASP’s journal PAIN, and it had a tremendous impact on me. It made me hopeful about how this new and revised definition could help frontline practitioners who assess and treat patients with acute, subacute, and chronic pain better consider both its neurophysiological and neuropsychological aspects. It seemed to me that this revised definition would be the clincher, spelling it out for us very clearly and succinctly. No more quandaries, no more debates, no more denials by payers, no more feelings of ambiguity, marginalization, and stigmatization. Game over! And I was exhilarated.

What does all of this have to with the number 21? As I often state in my presentations, “So what?” Well, the revelation for me was that the last time the IASP retooled the definition of pain was in 1979. This was the moment when clinicians managing pain needed to consider that pain was not only a sensory, but also an emotional experience. 21 years later in the year 2000, pain was designated the 5th vital sign. We were all encouraged to query about a person’s pain rating on a scale of 0 to 10 (or 0 to 100 depending on preference). Virtually no recommendation was made about emotional ratings, pain’s impact on quality of life, the importance of having a biopsychosocial approach to pain management, and, in my mind, most importantly about the functional impact of pain. 2000 was also designated the beginning of The Decade of Pain Control and Research. Patients were given a Pain Bill of Rights. 21 years had passed since 1979, and although it was not perfect, it was something.

What happened during the next 12 months is interesting.

Unlike a revised definition of hyperglycemia, borderline hypertension, etc, there really was no publicity in the mainstream medical literature. In fact, in a discussion I had with the director of a pain service at one of the largest academic centers on the west coast sometime around December 2020, when I queried the impact that the revised definition of pain was having on the clinic’s practices, the response I received was “What revised definition?” I felt a bit deflated, sent along info about it to them, and then waited patiently for the news to be disseminated to the masses of frontline practitioners of every discipline so we could all be on the same page.

Certainly, as the course director of pain and addiction at my medical school I incorporated this new information into my curriculum, so no student from September

At that point, 21 years was half of my life, and my thinking was things would get better, way better, and quickly. Attention would be paid to pain, “translational” research would happen and inform best practices. Most

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…pain does not live in a vacuum, and societal issues we face today related to the opioid overdose epidemic play a significant role in how and what we do.

achieve. I am hopeful that this is not the case. I am hopeful that we can put our heads together, share information, and communicate and educate others to make it viral. Of course, it may not be easy, as change rarely is. Other factors also obviously need to be considered, as we all know that pain does not live in a vacuum, and societal issues we face today related to the opioid overdose epidemic play a significant role in how and what we do.

importantly, pain education would take front and center stage, underscoring the importance of pain education and putting it in a position to help us all do a better job in doing what we were supposed to do for patients: advocate and help them navigate the negotiation of pain and suffering. 2000 was 21 years after 1979 and IASP’s changes to the definition of pain, but things were finally happening, and I was right in the middle of it and still young-ish!

Maybe we need to take heed of the numerologists’ interpretation of the symbolism of the number 21 and consider this to be the point that we begin, implement new change efficiently, succeed at it, and fulfill the mission of the 2020 revised definition of pain sooner rather than later. I don’t know about you, but I am already doing the math about how old I will be in another 21 years…

I realized as I wrote this that here we are in 2021— 21 years after all these exciting designations, hopes, and aspirations in the field of pain management that were made in 2000. The research was supposed to have been done by now, with that designated Decade of Pain far away in the rearview mirror. Pain and substance use education should have been incorporated into all healthcare professional training programs, and everyone should have had a better footing in terms of how pain is assessed, treated, and services are reimbursed. Policymakers and regulators should have had a long enough time to coalesce, have consensus, and support us instead of being at odds with us and people with pain. After all, 21 years is a long time, isn’t it?

…21 year periods have been very significant in the pain management world…

So now here we are, just a bit over a year since the IASP revised definition of pain was released, and the question I am asking myself is whether another 21 year segment must pass before we make the significant incremental progress in pain management that it is intended to

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

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

Pain affects the patient in many ways both psychologically and socially. An overall gestalt of the most salient emotional aspects of pain can be elicited by posing a general question about the patient’s well-being, such as, “How is the pain affecting your life?” or “How are you coping with your pain and its effect on your life?” Following is some of the more common areas where patients’ concerns may lie.

Emotional Reactions

Warning Signs for Referral to a Mental Health Professional

A variety of emotional reactions can be elicited by persistent pain. Identifying negative emotional content and assessing patients’ ability to cope with these emotions are critical to improving their functioning. Asking patients, “What’s your mood generally like?” may evoke some of the following: ○ Anger: often expressed as frustration, irritability, disgust ○ Grief: sadness, blue, loss, “I’m not me” ○ Depression: anhedonia (lack of pleasure), anergia (lack of energy), loss of interest ○ Anxiety: nervous, restless, push to be “fixed” Patients may experience negative emotions about: ○ Their circumstances (an injury or accident) ○ Their diagnosis (cancer, chronic pain) ○ The inability to perform tasks previously done with ease ○ Not being able to “handle” pain ○ Treatment providers ○ Insurance coverage ○ The inability to return to their job ○ A terminal illness

○ Suicidal ideation with or without intent or plan ○ Anergia ○ Persistent anhedonia ○ Loss of appetite ○ Sleep disturbance ○ Anxiety or panic ○ Prolonged difficulty accepting the condition ○ Angry outbursts toward self or others

Cognitions, Coping, and Beliefs About Pain

Cognitions, or the patient’s thoughts, exert powerful effects on emotional reactions, behavioral responses, and interpretations of pain. Beliefs are a foundation for cognitions. For example, the belief that the etiology of pain can be “fixed” or “cured” affects expectations of and satisfaction with treatment. Some maladaptive beliefs and cognitions according to research include the following: Catastrophizing. A cognitive and emotional process that involves magnification of pain-related stimuli, feelings of helplessness, and a negative orientation to pain and life circumstances.3-5 Examples of catastrophic statements include “I can’t handle this pain,” “There is nothing I can do about my pain,” and “My pain is uncontrollable.” The effect of catastrophizing should not be underestimated. Catastrophizing is associated with depression, decreases in physical functioning, increased pain,4 risk of death by suicide,1,2 and interpersonal distress.3-5 Recent studies suggest that

Suicidal ideation is relatively common in patients with chronic pain conditions and should be assessed in every patient and addressed immediately. The risk of death by suicide is estimated to be at least double for patients with chronic pain, compared with controls.1,2

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catastrophizing may be related to cortical responses to pain6 and, potentially, inflammatory disease activity.3 Catastrophizing predicts poor outcomes for patients with chronic pain and should be treated with cognitive behavioral therapy.

The belief that persistent pain signals ongoing tissue damage. This belief results in fear of movement, physical activity, and the future. It may be necessary to educate the patient that pain does not equal harm and that appropriate physical activity is important.

The belief that if a cause of pain can be found, a treatment will fix it. Patients are generally socialized to believe that medicine has a cure for their problems. Many believe that once a cause of the pain can be found, a treatment that results in a cure is likely (eg, removing a problematic disk always resolves pain).

For many, accepting that chronic pain can be managed but not necessarily cured is a gradual process. Encouragement to continue to be engaged in life as pain is being managed and not wait for a “cure” is often necessary.

The belief that pain is a signal to stop activities and movement. Some patients believe that pain means that they should rest and be inactive. Social activities may be curtailed or stopped because they feel pain. Although patients may not be able to perform the same physical activities as before, they should be encouraged to do as much as possible because physical inactivity increases pain.6 Constructive coping styles, such as using coping self-statements and increasing behavioral activities, have been shown to be more effective ways to manage chronic pain7 than passive coping strategies (eg, resting). The patient should be asked how he or she generally copes with pain, both cognitively (eg, “What do you tell yourself when you are having a pain flare-up?”) and behaviorally (eg, “What do you do when you are having a pain flare-up?”). Increases in drug, tobacco, and alcohol use, or taking more medication than is prescribed, can be maladaptive ways of coping with pain, which can lead to an exacerbation of the difficulties in the patient’s life.

Behavioral Reactions

○ Communicate distress ○ Cope with pain ○ Elicit solicitous behavior from others ○ Express pain in a culturally learned or valued manner ○ Express pain when verbal skills are absent or impaired The frequency with which pain behaviors are displayed, as well as an evaluation of the environmental responses received, may be helpful in assessing whether these expressions are adaptive or maladaptive in a particular circumstance. The expression of pain behaviors may be critical when an individual is unable to express pain verbally (eg, children, cognitively impaired individuals).

Some behaviors (eg, resting, taking medication) are problematic when used exclusively as a pain coping strategy.

Sleep disturbance, including insomnia and middle-of-thenight awakening, initially related to painful exacerbations, can become conditioned behavioral responses over time.

Family Functioning and Responses to Pain

The family system is affected when a person becomes unable to function in the expected manner. The responses of family members have been categorized8:

1 Solicitous (eg, providing assistance or special attention to the patient)

2 Punishing (eg, becoming angry when pain is expressed)

3 Distracting (eg, encouraging the patient to distract from the pain)

Research has shown that overly solicitous behaviors or punitive responses from family members or friends are generally not helpful. Research with patients with cancer pain and their families reveals that misconceptions about cancer and pain control on the part of the family have an adverse effect on patient care and outcome.9 Those with pain may not be able to fulfill role behavior they perceive as important to their definition of themselves as fathers, mothers, or members of a family or friendship network. For example, a father may not be able to participate in athletic activities with his children and may define this ability as an important part of his role as a father. Families may need assistance changing roles and learning to interact with a person with chronic pain on a long-term basis.

Verbal and nonverbal expressions of pain include a range of behaviors: ○ Grimacing ○ Rubbing the affected body part ○ Guarding or restricting movement ○ Sighing ○ Groaning, wailing ○ Taking medications ○ Resting These behaviors are overt and are called pain behaviors.

They can be used to do the following:

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Social and Occupational Functioning

The nature and extent of some chronic pain conditions impact the ability to work and interact in social settings.

The stress that accompanies the loss of work involves the loss of a sense of purpose, as well as loss of financial compensation. Work-related injuries are particularly difficult for workers who believed they were valued employees but became relegated to a “disabled” status after their injury.

The process of workers’ compensation is complex and sometimes adversarial. Patients might be: ○ Required to participate in independent medical examinations by nontreating physicians to review the appropriateness of treatment ○ Followed by private investigators who routinely investigate claims for fraud ○ Disregarded by coworkers because the pain cannot be seen and the patient “looks good” ○ Sent back to work prematurely ○ Asked to interview for other positions ○ Treated differently by physicians because of their litigation status ○ Denied treatment the treating physician has recommended ○ Financially stressed because of the loss of fulltime salary or wages

Psychiatric Disorders and Pain

Painful conditions, like all medical conditions, affect patients with psychiatric disorders. Selected psychiatric disorders are found in greater prevalence in medical settings and in persons with chronic illnesses. Persons with chronic pain are most often diagnosed with depression, anxiety, and substance use disorders.11 Consider the following statistics for individuals meeting criteria for major depressive disorder12-14: ○ 2% of people in the community ○ 5%–9% in ambulatory care ○ 15%–20% of medical inpatients ○ 0%–58% of persons with cancer ○ 43% with nondisabling pain and depression in primary care ○ 66% with disabling pain and depression in primary care

A Word about Somatization Disorder

Patients sometimes feel disbelieved and may feel accused of faking an injury or illness for the purpose of personal gain (eg, obtaining time off) or malingering. Of course, this process is made difficult for clinicians and patients because a few patients are malingerers. Malingering involves the intentional production of false or grossly exaggerated physical or psychological symptoms for the purpose of tangible external incentives, such as obtaining financial compensation, evading criminal prosecution, avoiding work or military duty, and obtaining drugs.10 The presence of workers’ compensation or litigation status does not mean the patient does not want to improve and return to work or is demonstrating malingering, although these factors may complicate recovery. Evaluating the obstacles to recovery or rehabilitation (eg, the patient does not want to return to a former job or employer) and addressing these obstacles during treatment (eg, with vocational counseling) are important components of treating patients with chronic pain.

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Some psychiatric disorders have as a primary characteristic the existence of abnormal illness behavior and are therefore more likely to present in medical settings. For example, somatization disorder is characterized by the following: ○ A pattern of multiple physical complaints ○ Significant social and occupational impairment ○ Symptoms that occur before age 30 ○ Symptoms that last for a period of years ○ Pervasive complaints unaccounted for by a general medical condition, including the following: → 4 pain symptoms → 2 gastrointestinal symptoms → 1 sexual symptom and → 1 pseudoneurologic symptom10

Although the presence of unexplained somatic symptoms is common, somatization disorder is rare.12 The diagnosis of undifferentiated somatoform disorder is less restrictive than somatization disorder, requiring 1 or more physical complaints that cannot be explained by a general medical condition and that cause significant social or occupational distress. Care should be taken before labeling patients with

somatoform disorder or as “somatizers” because of current limitations of diagnostic testing and disease criteria. Pilowsky15 suggested that a hallmark of abnormal illness behavior is extreme difficulty accepting advice from a physician if it does not fit the patient’s appraisal of his or her health status. Avoidance of dualism in pain (ie, the pain is either in the body or the mind) is key in assessing and treating individuals with pain conditions and is especially pertinent when treating individuals with psychiatric illnesses. t REFERENCES

7. Starr TD, Rogak LJ, Kirsh KL, et al. Psychological and psychosocial evaluation. In: Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed.

Philadelphia: Lippincott Williams & Wilkins; 2009:270–278.

8. Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain. 1985 Dec;23(4):345–356.

9. Miakowski C, Zimmer EF, Barrett KM, et al. Differences in patients’ and family caregivers’ perceptions of the pain experience influence patient and caregiver outcomes. Pain. 1997;72:217–226.

10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA; 2013.

11. Dersh J, Polatin PB, Gatchel RJ. Chronic pain and psychopathology: research findings and theoretical considerations. Psychosom Med. 2002 Sep-Oct;64(5):773–786.

1. Tang NK, Crane C. Suicidality in chronic pain: a review of the prevalence, risk factors and psychological links. Psychol Med. 2006;36:575–586.

12. Wasan AD, Sullivan MD, Clark MR. Psychiatric illness, depression, anxiety, and somatoform pain disorders. In Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:393–417.

2. Fishbain DA, Lewis JE, Gao J, et al. The pain suicidality association: a narrative review. Pain Med. 2014;15(11):1835–1849.

13. Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004;32:57–71.

3. Edwards RR, Bingham CO 3rd, Bathon J, et al. Catastrophizing and pain in arthritis, fibromyalgia, and other rheumatic diseases. Arthritis Rheum. 2006;55:325–332.

14. Arnow BA, Hunkeler EM, Blasey CM, et al. Comorbid depression, chronic pain, and disability in primary care. Psychosom Med. 2006; 68:262–268.

4. Bishop SR, Warr D. Coping, catastrophizing and chronic pain in breast cancer. J Behav Med. 2003;26:265–281.

15. Pilowsky I. The diagnosis of abnormal illness behavior. Aust N Z J Psychiatry.

1971;5:136-141.

5. Quartana PJ, Campbell CM, Edwards RR. Pain catastrophizing: a critical review.

Expert Rev Neurother. 2009;9(5):745–758.

6. Turk DC, Winter F. The Pain Survival Guide: How to Reclaim Your Life. Washington, DC: American Psychological Association; 2005.

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education is the best analgesic.

For the acute treatment of migraine and the preventive treatment of episodic migraine in adults.

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Dissolving the line between acute and preventive treatment for migraines1,2 Finally, the first and only medication proven1,2:

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• Treats or prevents for up to 48 hours at a time for many patients 1,3,7 • Reduction in mean monthly migraine days (MMDs) for many patients through 12 weeks of treatment1,2

See study results below.

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Help put the power of migraine control in your patient’s hands Visit nurtec-hcp.com to see how *Exploratory analysis. Subjects had ≥1 day of efficacy data in the observation period and in the first week of the double-blind treatment period.6

Up to 18 doses of Nurtec ODT can be taken per month.1 For the acute indication, Nurtec ODT was evaluated in a multi-center, double-blind, randomized, placebo-controlled study of 1351 patients (Nurtec ODT 75 mg, n=669; placebo, n=682), with co-primary endpoints at 2 h for Nurtec ODT vs placebo: pain freedom (21% vs 11%, P<.001) and freedom from most bothersome symptom (MBS; predefined as photophobia, phonophobia, or nausea; 35% vs 27%, P=.001).1 For the preventive indication, Nurtec 75 mg was evaluated in a multi-center, double-blind, randomized, placebo-controlled study of 695 patients (Nurtec 75 mg, n=348; placebo, n=347) with the primary endpoint being change from baseline in the mean number of monthly migraine days during weeks 9-12 (-4.3 vs -3.5, P=.01).1 Back to normal activities = return to normal function

Visit Nurtec-HCP.com to learn about the range of resources available to you, your office staff and your patients.

If you have questions or would like to connect with a representative, contact us by calling 1-833-4NURTEC or by emailing us at hcpsupport@biohavenpharma.com INDICATION Nurtec ODT is indicated in adults for the: • acute treatment of migraine with or without aura • preventive treatment of episodic migraine SELECT IMPORTANT SAFETY INFORMATION Contraindications: Hypersensitivity to Nurtec ODT or any of its components.

Please see additional Important Safety Information and the accompanying Brief Summary of Full Prescribing Information on the following pages.

Real patients like Ellie are managing their migraines with Nurtec ODT Ellie is an actual patient who takes Nurtec ODT for either acute or preventive treatment of her migraines.

“Nurtec ODT meets my personal needs.

I know that stress is a trigger during the school year—especially before college exams. I want to control my migraine on MY TERMS.” - Ellie W

INDICATION Nurtec ODT is indicated in adults for the: • acute treatment of migraine with or without aura • preventive treatment of episodic migraine IMPORTANT SAFETY INFORMATION Contraindications: Hypersensitivity to Nurtec ODT or any of its components.

Warnings and Precautions: If a serious hypersensitivity reaction occurs, discontinue Nurtec ODT and initiate appropriate therapy. Serious hypersensitivity reactions have included dyspnea and rash, and can occur days after administration.

Adverse Reactions: The most common adverse reactions were nausea (2.7% in patients who received Nurtec ODT compared to 0.8% in patients who received placebo) and abdominal pain/dyspepsia (2.4% in patients who received Nurtec ODT compared to 0.8% in patients who received placebo). Hypersensitivity, including dyspnea and rash, occurred in less than 1% of patients treated with Nurtec ODT. Drug Interactions: Avoid concomitant administration of Nurtec ODT with strong inhibitors of CYP3A4, strong or moderate inducers of CYP3A or inhibitors of P-gp or BCRP. Avoid another dose of Nurtec ODT within 48 hours when it is administered with moderate inhibitors of CYP3A4.

Use in Specific Populations: Pregnant/breast feeding: It is not known if Nurtec ODT can harm an unborn baby or if it passes into breast milk. Hepatic impairment: Avoid use of Nurtec ODT in persons with severe hepatic impairment. Renal impairment: Avoid use in patients with end-stage renal disease.

Please see Brief Summary of Full Prescribing Information on the next page.

References: 1. Nurtec ODT. Package insert. Biohaven Pharmaceuticals Inc. 2. Croop R, Lipton RB, Kudrow D, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2020;397(10268): 51-60. doi:10.1016/S0140-6736(20)32544-7. 3. Croop R, Goadsby PJ, Stock DA, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial.

Lancet. 2019;394(10200):737-745. doi:10.1016/S0140-6736(19)31606-X. 4. Data on File. RIM108. Biohaven Pharmaceuticals Inc. 5. Lipton RB, Coric V, Stock EG, et al. Efficacy, safety, and tolerability of Rimegepant 75 mg orally dissolving tablet for the acute treatment of migraine: a phase 3, double-blind, randomized, placebo-controlled trial (study 303). Abstract presented at: 61st Annual Scientific Meeting of the American Headache Society; Philadelphia, PA. Session IOR05; July 11, 2019. 6. Data on File. RIM159. Biohaven Pharmaceuticals Inc. 7. Data on File. RIM118. Biohaven Pharmaceuticals Inc. © 2021 Biohaven Pharmaceuticals, Inc. All rights reserved. Nurtec is a registered trademark of Biohaven Pharmaceuticals, Inc. BIOHAVEN and the Biohaven logo are registered trademarks of Biohaven Pharmaceuticals, Inc. US-RIMODT-2100236 05/26/2021

BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete product information, see Full Prescribing Information.)

NURTEC® ODT (rimegepant) orally disintegrating tablets 75 mg, for sublingual or oral use 1 INDICATIONS AND USAGE 1.1 Acute Treatment of Migraine NURTEC ODT is indicated for the acute treatment of migraine with or without aura in adults.

1.2 Preventive Treatment of Migraine NURTEC ODT is indicated for the preventive treatment of episodic migraine in adults.

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing for Acute Treatment of Migraine The recommended dose of NURTEC ODT is 75 mg taken orally, as needed.

The maximum dose in a 24-hour period is 75 mg. The safety of using more than 18 doses in a 30-day period has not been established.

2.2 Recommended Dosing for Preventive Treatment of Episodic Migraine The recommended dosage of NURTEC ODT is 75 mg taken orally every other day.

4 CONTRAINDICATIONS NURTEC ODT is contraindicated in patients with a history of hypersensitivity reaction to rimegepant, NURTEC ODT, or any of its components. Delayed serious hypersensitivity has occurred [see Warnings and Precautions (5.1)].

5 WARNING AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including dyspnea and rash, have occurred with NURTEC ODT in clinical studies. Hypersensitivity reactions can occur days after administration, and delayed serious hypersensitivity has occurred.

If a hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy [see Contraindications (4)].

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.

Acute Treatment of Migraine The safety of NURTEC ODT for the acute treatment of migraine in adults has been evaluated in a randomized, double-blind, placebo-controlled trial (Study 1) in 682 patients with migraine who received one 75 mg dose of NURTEC ODT [see Clinical Studies (14)]. Approximately 85% were female, 74% were White, 21% were Black, and 17% were Hispanic or Latino. The mean age at study entry was 40 years (range 18-75 years of age).

Long-term safety was assessed in an open-label extension study using a different oral dosage form of rimegepant. That study evaluated 1,798 patients, dosing intermittently for up to 1-year, including 1,131 patients who were exposed to rimegepant 75 mg for at least 6 months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month.

The most common adverse reaction in Study 1 was nausea (2% in patients who received NURTEC ODT compared to 0.4% of patients who received placebo).

Hypersensitivity, including dyspnea and severe rash, occurred in less than 1% of patients treated with NURTEC ODT [see Contraindications (4) and Warnings and Precautions (5.1)].

Preventive Treatment of Episodic Migraine The safety of NURTEC ODT for the preventive treatment of episodic migraine in adults has been established in a randomized, double-blind, placebo-controlled trial with an open-label extension (Study 2) using a different oral dosage form of rimegepant [see Clinical Studies (14)]. In the 12-week, double-blind treatment period, 370 patients with migraine received one 75 mg dose of rimegepant every other day. Approximately 81% were female, 80% were White, 17% were Black, and 28% were Hispanic or Latino. The mean age at study entry was 41 years (range 18-74 years of age). Long-term safety was assessed in an open-label extension study that included 603 patients who were treated for up to one year. Overall, 527 patients were exposed to rimegepant 75 mg for at least 6 months, and 311 were exposed for at least one year.

The most common adverse reactions (occurring in at least 2% of rimegepanttreated patients and at a frequency of at least 1% higher than placebo) in Study 2 were nausea (2.7% in patients who received rimegepant compared with 0.8% of patients who received placebo) and abdominal pain/dyspepsia (2.4% in patients who received rimegepant compared with 0.8% of patients who received placebo).

7 DRUG INTERACTIONS 7.1 CYP3A4 Inhibitors Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 results in a significant increase in rimegepant exposure. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 [see Clinical Pharmacology (12.3)].

Concomitant administration of NURTEC ODT with moderate inhibitors of CYP3A4 may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 [see Clinical Pharmacology (12.3)].

7.2 CYP3A Inducers Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A can result in a significant reduction in rimegepant exposure, which may lead to loss of efficacy of NURTEC ODT. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A [see Clinical Pharmacology (12.3)].

7.3 Transporters Rimegepant is a substrate of P-gp and BCRP effux transporters. Concomitant administration of NURTEC ODT with inhibitors of P-gp or BCRP may result in a significant increase in rimegepant exposure [see Clinical Pharmacology (12.3)].

Avoid NURTEC ODT with inhibitors of P-gp or BCRP. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of NURTEC ODT in pregnant women. In animal studies, oral administration of rimegepant during organogenesis resulted in adverse effects on development in rats (decreased fetal body weight and increased incidence of fetal variations) at exposures greater than those used clinically and which were associated with maternal toxicity. The evaluation of developmental effects following oral administration of rimegepant throughout pregnancy and lactation was inadequate (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated rate of major birth defects (2.2 to 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.

8.2 Lactation There are no data on the presence of rimegepant or its metabolites in human milk, the effects of rimegepant on the breastfed infant, or the effects of rimegepant on milk production. There are no animal data on the excretion of rimegepant in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NURTEC ODT and any potential adverse effects on the breastfed infant from NURTEC ODT or from the underlying maternal condition.

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

8.5 Geriatric Use In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects. Clinical studies of NURTEC ODT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment No dosage adjustment of NURTEC ODT is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Plasma concentrations of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment. Avoid use of NURTEC ODT in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dosage adjustment of NURTEC ODT is required in patients with mild, moderate, or severe renal impairment. NURTEC ODT has not been studied in patients with end-stage renal disease and in patients on dialysis. Avoid use of NURTEC ODT in patients with end-stage renal disease (CLcr < 15 mL/min) [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is limited clinical experience with NURTEC ODT overdosage. Treatment of an overdose of NURTEC ODT should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. No specific antidote for the treatment of rimegepant overdose is available. Rimegepant is unlikely to be significantly removed by dialysis because of high serum protein binding [see Clinical Pharmacology (12.3)].

Manufactured for: Biohaven Pharmaceuticals, Inc. New Haven, CT 06510 USA © 2021, Biohaven Pharmaceuticals Inc. NURTEC and Biohaven are trademarks of Biohaven Pharmaceutical Holding Company Ltd. Last modified: 5/26/2021 US-RIMODT-2100416

education is the best analgesic.

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Heather Poupore-King

phd, pharmd, bcps, cpe

Clinical Associate Professor Stanford Division of Pain Medicine

“My role as the Pain Psychology Fellowship Director at Stanford allows me the honor of training future academic leaders.”

GPS Redwood City, CA Typical Day Providing clinical services and supervision to the pain psychology fellows via telehealth; walking my 14 y/o French bulldog Betty very slowly; and spending quality time with my amazing husband. I also exercise, meditate, and text my favorite coworkers! Persona I aspire to be a leader in pain psychology through the development of innovative clinical interdisciplinary programs, training pain psychology fellows, providing wellness support for our medical fellowship, and community outreach. I provide mentorship and sponsorship across disciplines. I have been blessed to have strong female leaders in my life and try to pay it forward! Social Media Habits Twitter, Facebook. Contribution My role as the Pain Psychology Fellowship Director at Stanford allows me the honor of training future academic leaders. Transforming the program into what it is today is my most meaningful contribution. Graduates go into the world to educate, teach, innovate, research, and provide the highest quality clinical care. The impact is exponentially larger than anything I could do alone. People I admire the people I truly know more than anyone I think I might know in the public arena. Words Man’s Search for Meaning and Unbroken are favorite meaningful reads. Values based living is personally and professionally relevant to me and these books put this into perspective. I also enjoy suspense/mystery books that take my mind away from reality. Popcorn Schindler’s List impacted me in ways I am simply unable to put into words. I love Dirty Dancing and am forever teased by my friends about it. For something unique, I highly recommend Mary and Max, a touching tale that speaks to acceptance and love! PAINWeek I love connecting with friends, attending talks, and taking time to soak in the knowledge available at PAINWeek. I often wish I could hop on a plane and catch dinner with friends after a long day of giving and observing talks. Thank you for all the hard work put into this extraordinary event. I truly look forward to seeing everyone in person!

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By Ravi Prasad PhD

Genetics account for about 50% in the development of alcohol use disorder.

But really it’s a combination of genetics and environment— nature and nurture— that contribute to the onset of alcohol use disorder.

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Who wants medical cannabis for their chronic pain?

In evaluating the Practical Alternative to Hospitalization (PATH) program, of

Of the

in a study of the effects of cognitive behavioral therapy on sleep were contacted via 6 telephone sessions— each 20- to 30-minutes long over an 8-week period.

in a study,

Participants reported (through daily diaries) improved sleep, less fatigue, and decreased pain.

“Deliberate napping”

mean age, 62.5 years;

for

to relieve their pain. >42% were taking opioids at baseline; 29.3% at 12 months. ½ of those who completed the study were still taking opioids at the 12 month follow up. ~1/3 of patients remained on medical cannabis for 6 months.3

a day was recommended.1

Men and women exhibit different pain sensitivities, and many chronic pain conditions are more prevalent in 1 sex.

had non-Hispanic Black race/ethnicity.

returned to an ED within 30 days.

ED boarding time was reduced by an estimated 8.2 hours per patient.5

According to 1 study, the child of a woman who had been given an epidural during childbirth would have a

MRI data from

will develop osteoarthritis by age 65; it affects

of receiving an autism diagnosis.

The latest data from over with chronic low back pain due to ankylosing spondylitis, a form of arthritis, was studied.

Classification models

it’s the

were able to identify an individual’s sex, and whether they have chronic pain, with

5th leading cause of disability.

Antidepressant paroxetine,

an inhibitor of the enzyme G proteincoupled receptor kinase 2 (GRK2), may also help fight joint degeneration.4

born during 2005 to 2016 were analyzed.

In the follow-up period, 2.1% (985 of 47,011) exposed to epidural analgesia vs 1.7% (1272 of 76,164) of unexposed offspring were diagnosed with autism spectrum disorder.6

1. pain.sh/6a6 2. pain.sh/h9r 3. pain.sh/7s4 4. pain.sh/d4114 5. pain.sh/taj 6. pain.sh/0cb

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Migraine in the Pediatric Population: Treatments

Scott Powers PhD, ABPP, FAHS Healthy habits:

● Hydration: 2 liters of liquids a day for an adolescent, including something with electrolytes before exercise or at onset of headache ● Sleep: >6 hours, but more ideally 8 to 10 hours, fitted into their lifestyle on a consistent basis, not fluctuating too much on weekends ● Food: eating a balanced diet regularly, not skipping meals; be aware of triggering foods ● Physical activity/exercise: in young children, PLAY! Just being outside, running around, having fun is healthy and good for their migraines Cognitive-behavioral therapy for migraine?

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● For those in early preschool through primary school: with parent/caregiver coaching, basic relaxation skills can be used ● By 4th or 5th grade: skills can be developed for self-regulatory treatment involving activity pacing, cognitive reappraisal of how we think about our thinking and how it impacts mood and perception of pain ● By adolescence, the full component of cbt can be mastered by adolescents quite well

Our Future Pain Management Educators

Kevin L. Zacharoff MD, FACIP, FACPE, FAAP

● Future pain management educators and thought leaders are going to come from a different place than did my generation ● I had a certain amount of leeway and control in setting aside time, and energy, to serve as a faculty member ● Times and medicine have changed: as healthcare becomes more systematized, healthcare providers have less freedom ● I’ve noticed a big change in the medical students I’ve taught. I think they’re willing to: accept that they’re going to be working for a system; live within the confines of that system; deal with being told what they can and can’t do ● Some clinicians and hospitalists have told me they’d love to come to PAINWeek but there are too many challenges: not only the cost of attending, but being able to take the time off ● What are future leaders and faculty members likely to get out of pain management education; will it help their careers? ● It’s important to identify potential faculty members early on, even at the internship/residency stage: I have students who take my elective on pain, drugs, and ethics and who participate in special interest groups devoted to people who have substance use disorders or suffer from pain.

These students are identifying themselves as potential thought leaders

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The Potential of Cannabinoids: Epilepsy

Theresa Mallick-Searle MS, NP-BC, ANP-BC Ethan B. Russo MD ● Cannabidiol is usually the 2nd most common cannabinoid in the cannabis plant. It has things in common with THC: both are anti-inflammatory and analgesic ● However, cannabidiol actually counteracts many side effects of thc such as anxiety, panic, hallucinations; they are quite complementary to one another ● cbd has an anticonvulsant effect, first noted in the early 70s ● cbd has been the subject of investigation culminating with the 2018 fda-approval of a 98% pure cannabidiol preparation (Epidiolex®) ● The cannabidiol preparation is proven safe and effective and is a great boon to children severely affected with Dravet and Lennox-Gastaut syndrome, among others ● Epidiolex may be prohibitively expensive for people who are not specifically using it for epilepsy; the doses are high, as is the projected cost ● If someone were trying to treat their arthritic shoulder, Epidiolex might be helpful, but it isn’t likely to be practical or available

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Leigh Ann Wilson LCSW Collin V. Montgomery APRN

Michael J. Kurisu DO, ABIHM

Sickle Cell Disease: Pearls

Craving the Connection of Manual Therapies: Why?

Manual medicine—physical therapy, massage, chiropractic, osteopathic manipulation— is effective for patients in chronic pain. The Personal Touch matters:

Sickle cell disease is: ● Disrespectful: a patient can do everything perfectly and it still will mess up their day or put them in the hospital—it’s unpredictable and uncontrollable ● Unpredictable: there are really no indicators on how well a patient will do or how many diseaserelated complications they may have—it is not well understood ● On a spectrum: some patients do well, needing little pain management and little healthcare utilization; others are sick from early on in life— and we don’t always know why ● Not quickly fixable: for some, it’s a very complex disease, and it should be treated as such and managed with that level of care

In the old days ● A diagnosis was made bedside ● A doctor would “lay on the hand” to do an exam and listen with the stethoscope ● There was emphasis on hands-on diagnostic ability With the advent of modern technology ● We’re more reliant on blood work and imaging studies ● A woman with appendicitis tracked her time with practitioners: 9 were involved—and only 1 actually touched her

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These days ● Doctors sit behind the computer ● The doctor-patient relationship has faded ● Technology is efficient but personal connection is what builds rapport with patients ● Patients are craving this connection ● It helps physicians as well, because we get to understand and feel and know our patients much better

Treatments for Opioid Use Disorder Edward S. Lee MD

What treatments work for opioid use disorder? ● Best evidence is for using medication-assisted therapy ● People say it’s not sufficient to prescribe buprenorphine or methadone or naltrexone, but in many ways, those are first steps towards recovery ● In a larger setting of harm reduction, we can’t really get to recovery unless we survive long enough to acquire tools necessary for recovery ● Conventional psychotherapy ● Substance use programs ● Contingency management, which basically incentivizes not using, finding things that are more attractive, even if it’s just a very small reward ● Having accumulated some of that experience of small rewards, people become more skilled at making better choices

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with

charles e.

argoff

md

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“[my most marked characteristics:] Persistence and hard work.”

Q

What inspired you to do what you do?

I can’t say that one thing inspired me. I gravitated towards neurology and neurosurgery during medical school, realized during my residency that painful conditions are the most common neurological conditions seen, realized that there ain’t no such thing as pain without a brain and “Voila!”

York. Dr. Nick Vick: Neurology, Northwestern University Medical School. Dr. Robert Moore: Neurology, SUNY Stony Brook, New York. And of course, my parents.

a

Q If you weren’t a healthcare provider, what would you be? a A delicatessen owner or movie theme composer.

Q

Why did you focus on pain management?

During my residency, the director of our headache center became ill. I volunteered as a resident (with attending supervision) to take charge of the center and discovered how many other pain issues there were to address. I naturally gravitated towards the field going forward.

a

Q

a

What is your most marked characteristic?

Persistence and hard work.

Q What do you consider your greatest achievement? a Being happily married for more than 30 years with 3 wonderful children and 1 cool dog.

Q

Who were your mentors?

George Kapp: science chairperson at James Madison High School in Brooklyn, New

a

Q

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What is your favorite language?

I don’t have one!

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“I’d like to be remembered as someone who did not try to be someone he was not.”

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 Book: Best book available (before I go) regarding space, hydroponics, and growing food.

Movie: The Princess Bride (I guess I should say The Martian, right?).

Music: Michael Nyman, The Piano soundtrack.

Q

What would you like your legacy to be?

I’d like to be remembered as someone who did not try to be someone he was not.

a

Q Plans for the future?

I haven’t thought that far.

Q

a

What is your motto?

Chance favors the prepared mind.

Charles E. Argoff, MD, is a professor of neurology at the Albany Medical College in New York.

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Causes of major pain

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By Wendy Caster

Across

1. Belittle 6. Lip ____ 10. CHRONIC PAIN IN AN EXTREMITY FOLLOWING SURGERY OR TRAUMA (abbrev.)

14. Trite 15. Harvest 16. Scoundrel 17. PRODUCING THE NEXT GENERATION 19. Spot 2 0. Hit from yesteryear 21. “Sure” 22. Variety of endive 26. Broom made of twigs (anagram of EMBOSS) 29. Place to put luggage, as on a ship 3 0. Eroded 31. Evened 32. Website address 33. Type of lion or horse 34. CONDITION AFFECTING OVARIES, FALLOPIAN TUBES, PELVIC TISSUE, AND OTHER INAPPROPRIATE ORGANS 39. Baseball’s Mel 4 0. Be behind on the bills 41. Magnanimously 43. Related to the womb 4 6. Snitch 4 8. Bullfighter 49. Lack of fat 5 0. Consumed tofu or quinoa 51. Planet 52. Hard or soft Mexican food 54. OSTEOSARCOMA, FOR EXAMPLE 59. Choir member 6 0. Microwave, e.g.

61. Assess 62. DEGENERATIVE ____ DISEASE 63. As you ____ 6 4. Head monk

Down

1. Start of a familiar series 2. “____, humbug!”

3. Singer DiFranco 4. “Do the Right Thing” pizzeria owner 5. Mythical city of gold 6. Display resentment or anger 7. Eagle digs 8. Running behind 9. Speed measure (abbrev.)

10. Brie or cheddar

11. At fault 12. Vim 13. Canny 18. Conversational website, frequently updated, often written by one group or person 21. Thus far 22. Superlative suffix 23. Musical passage to be performed in quicker time (anagram of TOTTERS) 24. Negates 25. Gobsmacked 26. “____ Ha’i” 27. Certain oatmeal dishes 2 8. Place to get a massage 3 0. Mess up 32. Versatile truck, informally 35. Pre-stereo 36. Female with a wool coat 37. Five Nations tribe 38. Anon 39. Ump’s call

Puzzle solution: painweek.org/crossword.

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42. Thumbs-up 44. Stole a second time 45. Fury 4 6. Calm 47. Soft mineral 49. Hermit 51. Interlaced 52. Lincoln’s youngest 53. Muhammad or Laila 54. Fiddle stick 55. Bag 56. Baby bear 57. Bigheadedness 58. No longer employed (abbrev.)

As a leader in pain education, PAINWeek is pleased to announce the launch of the Advanced Education Certification series. These provide 15–25 ce/cme credit hours across both on demand and live virtual sessions with subject matter experts. The purpose of this series is to provide a practical framework for continuing professional development among frontline practitioners.

Learn more at www.painweek.org

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It’s Good Medicine. ©2021 Hisamitsu America, Inc. Use as directed. *Higashi, et al. Clinical Therapeutics/Volume 32, Number 1 **Annals of Internal Medicine, 2020. acpjournals.org/doi/10.7326/M19-3602