PWJ - PAINWeek Journal Vol 9, Q1 | 2021

vol. 9 q 1 2021

being held hostage? use psychological strategies for resolving difficult patient behaviors p.18 puff & anarchy: vape technology and its consequences p.26 doubling down: polysubstance abuse and associated respiratory depression p.34 opioids and mental health: suicide prevention as highest priority P.42

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

Take a proactive approach to OIC RELISTOR helps restore gut function by increasing the number of spontaneous bowel movements (SBMs)1 INDICATIONS • RELISTOR® (methylnaltrexone bromide) 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 on the last page.

You have the power to intervene early and help address the underlying cause of OIC In 2 clinical trials of adult patients with OIC and chronic non-cancer pain (CNCP) 52% of patients (n=200) taking 59% of patients (n= 150) taking RELISTOR injection RELISTOR tablets experienced at least 3 12 mg experienced at least 3 SBMs* per week vs. 38% SBMs* per week vs. 38% of patients of patients (n=162) taking placebo (P<0.001) for (n=201) taking placebo (P=.005) (Study 1)1,3,†,‡

each of the 4 weeks in the double-blind period (Study 2) 1,2^

*SBM is defined as bowel movement without the use of any laxative in previous 24 hours.1,2,3 † Responder is defined as a patient with 3 or more SBMs per week, with an increase of 1 or more SBM(s) per week over baseline, for 3 or more out of the first 4 weeks of the treatment period.1 ‡ Study Design: Study 1 was a 4-week, randomized, multicenter, double-blind, placebo-controlled, phase 3 study, the efficacy of RELISTOR tablets was evaluated in 401 patients (200 RELISTOR tablets, 201 placebo) with CNCP for which they were taking opioids. All patients had OIC, defined as <3 SBMs per week and at least one additional symptom of constipation.1,3 ^ Study 2 was a 4-week, multicenter, double-blind, randomized, placebo-controlled, phase 3 study. The efficacy of RELISTOR injection was evaluated in 312 patients 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

THE FIRST AND ONLY PAMORA OFFERING TWO ROUTES OF ADMINISTRATION FOR CNCP PATIENTS 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 on the following page.

REFERENCES: 1. RELISTOR [prescribing information]. Bridgewater, NJ: Salix Pharmaceuticals. 2. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562. 3. Data on file. Clinical study report MNTX3201. Salix Pharmaceuticals; 2020.

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.0048.USA.20 V3.0

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

RELISTOR (methylnaltrexone bromide) injection, for subcutaneous use.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

*Adverse reactions occurring in at least 1% of patients receiving RELISTOR injection 12 mg subcutaneously once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness During the 4-week double-blind period, in patients with OIC and chronic non-cancer pain that received RELISTOR every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR injection 12 mg subcutaneously every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 2) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%).

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

The most common adverse reactions in adult patients with OIC and advanced illness receiving RELISTOR injection are shown in Table 6 below.

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

*Adverse reactions occurring in at least 5% of patients receiving all doses of RELISTOR injection (0.075, 0.15, and 0.3 mg/kg) and at an incidence greater than placebo **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness The rates of discontinuation due to adverse reactions during the double-blind, placebo-controlled clinical trials (Study 4 and Study 5) were comparable between RELISTOR (1%) and placebo (2%).

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

Gastrointestinal Perforation, cramping, vomiting.

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

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

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

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

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

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

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

In clinical studies of RELISTOR injection, no overall differences in safety or effectiveness were observed between elderly patients and younger patients.

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

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

Therefore, a dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment.

No dosage adjustment of RELISTOR tablets or RELISTOR injection is needed in patients with mild renal impairment (creatinine clearance greater than 60 mL/minute as estimated by Cockcroft-Gault).

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

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

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

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

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

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

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

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

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

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

Based on 9493104 11/2018 Salix Pharmaceuticals 400 Somerset Corporate Blvd.

Bridgewater, NJ 08807 USA www.salix.com

Manufactured for:

Under license from:

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591 U.S. Patent Information: For Injection: U.S. Patent Numbers: 8,247,425; 8,420,663; 8,552,025; 8,822,490; 9,180,125; 9,492,445 and 9,669,096 For Tablets: U.S. Patent Numbers: 8,420,663; 8,524,276; 8,956,651; 9,180,125; 9,314,461; 9,492,445 and 9,724,343 Relistor is a trademark of Salix Pharmaceuticals or its affiliates.

REL.0082.USA.19

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

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

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

Editorial Board

Charles E. Argoff md, cpe Professor of Neurology Albany Medical College Department of Neurology Director Comprehensive Pain Center Albany Medical Center Department of Neurology Albany, ny Jennifer Bolen jd Founder Legal Side of Pain Knoxville, tn Martin D. Cheatle PhD Associate Professor Director, Pain and Chemical Dependency Program Perelman School of Medicine University of Pennsylvania Center for Study of Addiction Philadelphia, pa Paul J. Christo md, mba Associate Professor Johns Hopkins University School of Medicine Department of Anesthesiology and Critical Care Medicine Baltimore, md Michael R. Clark MD, MPH, MBA Professor of Psychiatry and Behavioral Sciences George Washington University School of Medicine and Health Sciences Washington, dc Chair Department of Psychiatry and Behavioral Health Services Inova Health System Falls Church, VA

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

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

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

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

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

Joseph V. Pergolizzi md Chief Operating Officer nema Research Inc. Naples, fl Michael E. Schatman phd, cpe, daspe Editor-in-Chief Journal of Pain Research Department of Diagnostic Sciences Tufts University School of Dental Medicine Department of Public Health and Community Medicine Tufts University School of Medicine Boston, ma Kathryn A. Schopmeyer PT, DPT, CPE Physical Therapy Program Coordinator Pain Management San Francisco va Healthcare System San Francisco, ca

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

Copyright © 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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NEW Clinical Findings From RELIEF Study available for download at dovepress.com

FROM A RECENTLY PUBLISHED OBSERVATIONAL STUDY:

Patients treated with Salonpas Patch reported an almost 50% reduction in pain severity and a substantially better quality of life. ®

1

BPI (Brief Pain Inventory) Severity and Interference Scores Interference

Severity

(Mean % Decrease w/ Salonpas) Overall Pain Severity

(Mean % Decrease w/ Salonpas) Overall Pain Inteference

-49.0%

General Activity

Mood

Ability to Walk

Normal Work

Social Relationships

-60.4%

-60.7%

-61.9%

Sleep

Life Enjoyment

-50.0% -58.1%

-58.8%

-58.3% -69.8%

©2020 Hisamitsu America, Inc. Use as directed.

1 Gudin JA, Dietze DT, Hurwitz PL. Improvement of Pain and Function After Use of a Topical Pain Relieving Patch: Results of the RELIEF Study. J Pain Res. 2020;13:1557-1568

vol.9 2021

18

behavioral

being held hostage? use psychological stategies for resolving difficult patient behaviors

by david cosio

cannabinoids

puff & anarchy vape technology and its consequences

by douglas l. gourlay lantie e. jorandby

pharmacotherapy

doubling down polysubstance abuse and associated respiratory depression

by joseph v. pergolizzi, jr robert b. raffa

key topic

opioids and mental health suicide prevention as highest priority

by elizabeth m. olivia suzanne mcgarity robert sproul friedhelm sandbrink

52

pain basics

pain assessment part 2

by kevin l. zacharoff

59

pw next generation

with ginevra liptan

60 61 62

clinical pearls

by kate schopmeyer

one-minute clinician

with brian f. kaufman, christopher m. herndon, tanya j. uritsky, maria c. foy, leigh ann wilson, colllin v. montgomery, sawsan as-sanie, jeffrey fudin, michael r. clark

64 69

pundit profile

with robert b. raffa

puzzled?

by wendy caster

26 34 42

pain by numbers

12

“Meetings

come to an end, but learning never stops.

PWJ keeps you going all year long.”

—Michael R. Clark md, mph, mba

this issue of the PWJ, I When one thinks about opioid analgesee common threads in the relationsics and “saving a life,” it is reasonable ships between our brains, our thinking, that one might automatically think Kevin L. Zacharoff and our perspectives regarding pain, about opioid antagonism (ie, naloxone). its treatment, and substance use. It Drs. Elizabeth Oliva, Suzanne McGarmay sound far-fetched for there to be an article about violence in ity, Robert Sproul, and Friedhelm Sandbrink explore a different a journal devoted to pain, but it is in this issue. Do healthcare pro- life-saving issue entirely: suicide prevention. Providing a basis for fessionals think about the value proposition of coaching as part of the linkage of chronic pain, opioid prescribing, and mental health, a pain treatment plan? Maybe not so much, but maybe they should. the authors substantiate the value of clinically considering the risk Is respiratory depression something discussed in the field of pain of suicide, which often exists in the Veteran population. The case is management? Yes, but what about mitigating its often-fatal out- made to think about the patient’s eyes and minds, identifying the come? Do current trends such as vaping link to pain and substance need for true patient-centered care to include the “missing P” in use? Maybe they do. Look for these connections to better under- pain care, psychiatry. stand their relationship in the context of our mission of improving the quality of life in people with chronic pain. Indeed, it is often a This issue’s Pundit Profile spotlights someone with many levels of complex relationship. complexity below the surface, Dr. Robert Raffa. While we may think we know a person by their writings or lectures, we may not be I never expected to see the word “hostage” in the PWJ, but in his correct. Read about how chance encounters led Dr. Raffa towards article, Dr. David Cosio portrays an imperfect world where, in some becoming one of our pain pundits, and how the many aspects of his situations, frontline healthcare professionals feel as if they are being life’s journey, from a background in biomedical engineering to his “held hostage” by their chronic pain patients. More importantly, he love of languages, have influenced him in profound ways. discusses the possibility of clinicians living in fear of violent repercussions resulting from “difficult” patient interactions. Amazingly, Our Next Generation interview is with Dr. Ginevra Liptan. A trethis piece shows that healthcare workers may be victims of physical mendous advocate for patients with fibromyalgia, she also is a violence more frequently than one might think, due to aberrant drug person with the diagnosis. The ability to relate to patients and behaviors, overall dissatisfaction, and everything in-between. Dr. educate healthcare providers about fibromyalgia is one of her key Cosio valuably provides strategies for helping us deal with these missions, which blends well with the other aspects of her life. I difficult and harmful situation. hope you enjoy getting to “meet” Dr. Liptan and learning about her professionally and personally.

The anesthesiologist in me has always looked at novel routes of administration for pain medications, but I must admit that I have This issue has the sixth installment of the recurring segment Back not considered vape technology as a possibility. On the other hand, to the Basics for people seeking basic foundational pain education.

I have considered the addictive nature of nicotine delivered by electronic cigarettes. Drs. Doug Gourlay and Lantie Jorandby look at This issue points out that our brains, our minds, our thoughts really the technology, its possible negative outcomes and potential impact do play much more of a role in the “story” of chronic pain than just a from a public health perspective. One particular focus of this article neurophysiological one. How we process, how we make clinical deciis the possible effect on developing brains in teens and young adults. sions, and even how we regulate likely require more attention. While We must consider the use of these products to be, in many cases, we may often reach for the prescription, maybe we also should reach instances of substance abuse, and our approaches to dealing with for identifying the context; it could be equally and, in many cases, this condition are likely similar to those currently employed for other more important. Stay safe. types of substance use. After all, it may be all about the brain.

When we talk about “risk” in the context of pain management, although we may automatically think about aberrant drug related behaviors, there are other potential adverse effects that fall into the category. Regarding opioid analgesics, while many adverse effects may significantly and negatively impact patient quality of life, none is likely more serious than the blunting of the centrally mediated reflex to breathe—respiratory depression—which may lead to fatality.

Drs. Joseph Pergolizzi and Robert Raffa look at the current state of the “opioid overdose epidemic,” pointing out that very often fatal overdoses are the result of respiratory depression caused by multiple substances. The authors highlight specific challenges related to this fact and focus on existing and new agents specifically designed to address polysubstance-induced respiratory depression.

14

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.

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September 7–11 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 39.0 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.

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David Cosio PhD, ABPP

David Cosio is a Licensed Clinical Health Psychologist, Jesse Brown VA Medical Center, at the University of Illinois at Chicago College of Medicine, Pain Medicine, and at the Northwestern Feinberg School of Medicine, Psychiatry and Behavioral Sciences. He achieved specialist certification in Clinical Health Psychology by the American Board of Professional Psychology in 2017. He is the author of Pain Relief: Managing Chronic Pain Through Traditional, Holistic, & Eastern Practices.

Douglas L. Gourlay MD, MSc, FRCPC, DFASAM

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Doug Gourlay trained as a physical chemist and anesthesiologist, focusing his practice on the assessment and treatment of chronic pain patients suffering from concurrent substance use disorders. He has written extensively on the subject of pain and addiction, especially in the realm of drug testing and monitoring. He coauthored his article with Lantie E. Jorandby, MD, dfapa, Chief Medical Officer for Lakeview Health, an addiction and recovery treatment program in Jacksonville, Florida. She completed her addiction psychiatry fellowship at Yale and served as Medical Director of the Dual Diagnosis unit at McClean, Harvard University-affiliated psychiatric hospital.

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Elizabeth M. Oliva PhD

Elizabeth Oliva is the VA National Opioid Overdose Education and Naloxone Distribution Coordinator (VA Office of Mental Health and Suicide Prevention) and an Investigator at the VA Center for Implementation to Innovation (VA Palo Alto Healthcare System). She coauthored her article with Friedhelm Sandbrink, MD, National Program Director for Pain Management, Opioid Safety and PDMP (PMOP; VA Specialty Care Services); Suzanne McGarity, phd, Clinical Psychologist at the Rocky Mountain MIRECC for Suicide Prevention; and Robert Sproul, pharmd, VA National PDMP Pharmacy Specialist, PMOP (VA Specialty Care Services).

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Joseph V. Pergolizzi, Jr md

Joseph Pergolizzi is Director of Research at NEMA Research Inc and Senior Partner at the Naples Anesthesia and Pain Associates in Florida. Has published over 200 peer-reviewed articles, and coauthored this article with Robert B. Raffa, phd, Professor Emeritus and Past Chair, Temple University School of Pharmacy (Philadelphia); Adjunct Professor, University of Arizona (Tucson); CSO, Neumentum (Summit, NJ); and Co-founder, Enalare Therapeutics (Princeton, NJ).

16

120 CE/CME CREDITS

EDUCATION IS THE BEST ANALGESIC

By David Cosio PhD, ABPP

By David Cosio PhD, ABPP

behavioral

In an ideal world,

providers would meet the expectations of their patients—to be thoughtful and listen, be empathic and nonjudgmental, and to do no harm and be competent. Patients would meet the expectations of their providers by being open and honest, obedient and motivated to get better, and display gratitude and pleasure at improvement.

However, in the real world, all these expectations can be challenged.

Many frontline practitioners describe often feeling like they are being “held hostage” by their chronic pain patients. The graver concern is that these situations may lead to violence if not handled appropriately. There is evidence to suggest that these concerns are valid. Frontline providers may, in fact, be at high risk for patient perpetuated violence. The U.S. Bureau of Labor Statistics reports that more workplace assaults and violent acts occur in healthcare and social service industries than in any other.1 According to the Occupational Safety and Health Administration, incidents of serious workplace violence are 4 times more common in healthcare than in private industry.2

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LEARNING FROM THE STRATISTICS

Protesting residents of a city in Liberia, West Africa resist the removal of neurosurgery equipment from the local hospital, holding the only brain surgeon at the facility hostage. Their action is based on information they gathered that the only neurosurgery machine at the hospital was to be transferred to another city. The citizens’ resistance brought normal activities at the hospital to a standstill with the only brain surgeon there held hostage by the angry crowd for fear that he could smuggle the equipment out of the hospital.3 The World Health Organization has found that between 8% and 38% of healthcare workers suffer physical violence at some point in their careers, but many more are threatened or exposed to verbal aggression.4 According to the American College of Emergency Physicians, nearly 70% of emergency physicians believe that emergency department violence is increasing and is taking a toll on other patients.5 About 30 physicians in the US were the victims of work-related homicides in a single decade.6 According to the U.S. Department of Labor, 12% of the injuries sustained by registered nurses are from violent acts.7 The most common reasons for the violence8-10 are: ● Drug-seeking behaviors ● Confrontations over drug-seeking behaviors ● Long waits for service in physician offices ● Dissatisfaction or displeasure with

care or outcomes ● The perpetrator’s relationship with

religion or God ● The physician’s refusal to endorse

a report of disability The risk factors most consistently associated with patient perpetuated violence include history of opioid abuse, poor impulse control, past antisocial conduct, and past violence.11

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LEARNING FROM HOSTAGE NEGOTIATIONS

On July 1, 2020 in Manila, Philippines, a doctor at a medical center was held hostage by a patient whom he was attending to in the emergency room. At around 5:52 a.m., the patient who was being treated following a vehicular accident, grabbed a syringe and pointed it at the doctor’s neck. Police who were in the hospital saw the incident and talked to the perpetrator. The suspect was pacified and later apprehended.12 There are several aspects to a hostage negotiation. There is the hostage-taker who wants to obtain something. The “something” in the environment of a pain clinic is usually pain medications. There is the target of the hostage-taker that may not be the hostage but rather whoever can provide what they want. And there is the hostage, who is usually the bargaining chip. In the environment of a typical pain clinic, the bargaining chip may be less severe, for example, the provider’s time, a complaint, and/ or a dissatisfaction score.13

counterpart. These skills comprise the Behavioral Change Stairway Model developed by the Federal Bureau of Investigation’s international hostage negotiation unit.16

BEHAVIORAL CHANGE STAIRWAY MODEL

There are 4 phases that occur during a typical hostage negotiation. The initial phase begins at times with anger and may be volatile and ends with the hostagetakers’ demands. The negotiation phase is the “standoff” and where the relationship develops. The termination phase is brief and sometimes volatile and results in either the patient giving up, the provider giving up, or termination or discharge from the clinic. The final stage, or post-incident phase, is when the effects of the incident play out and one may witness shifts in relationships.13 A lot can be learned from reviewing hostage negotiation techniques used in real-life crisis situations.14 These negotiation strategies typically yield a 95% success rate, which is a remarkable statistic for any form of intervention strategy. Hostage negotiation is all about psychology.15 Knowing these psychology skills is critical for any “negotiator” faced with high-tension conflicts that occur during shared medical decision making. The goal of such negotiations is to work with people in crisis towards a peaceful resolution that previously seemed impossible.

It entails influencing a behavioral change in someone in order to gain voluntary compliance. The unifying factor in crisis situations is that the person’s actions are being dictated by their emotions at the detriment of rational thinking. Therefore, an effective negotiator seeks to reduce the negative emotions and bring back a more rational thinking process by employing a set of skills to influence one’s

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A tense standoff was reported in Atlanta at Georgia Medical Center where both a nurse and an internist were held captive in a room of a patient for at least twelve hours, unable to escape his banter, dialogue, and questions. The patient had decided to keep talking, which left the nurse and internist paralyzed.17 Modern hostage negotiation principles were established in 1972 when a New York Police Department detective who was also a psychologist recognized the need for trained personnel in crisis intervention. The first hostage negotiation teams were often created as elements of Special Weapons and Tactics (SWAT) teams and merely created a diversion while SWAT deployed. In modern usage, hostage negotiation teams are often deployed in conjunction with SWAT. The FBI Crisis Negotiation Unit is an example of a specialized unit trained in the Behavioral Change Stairway Model techniques. More likely than not, most frontline providers will be faced with situations similar to the one described above.

The following is a review of the specific steps of the model providers can use to diffuse these types of situations.

The First Step:

Active Listening.

Active listening demonstrates empathy and rapport and reduces the patient’s negative emotions. Listening is not ordering, directing, or commanding; warning or threatening; giving advice, making suggestions, or providing solutions; persuading with logic, arguing, or lecturing; moralizing, preaching, or telling patients their duty; judging, criticizing, disagreeing, or blaming; agreeing, approving, or praising; shaming, ridiculing, or name calling; interpreting or analyzing; reassuring, sympathizing, or consoling; questioning or probing; or withdrawing, distracting, humoring, or changing the subject. Active listening is effective when used with other microskills18: Using open-ended questions that are not easily answered with a “yes/no” or short answer, invite elaboration and thinking more deeply about an issue, and create forward momentum Emotional labeling identifies emotions, such as anger, which include symptoms like having a short temper/ being inpatient, restlessness/agitation, hitting things/slamming things, verbal outbursts, and increasing pain

Mirroring/reflecting allows the patient to hear for themselves what they have said and evaluate the logic or reasoning behind their own statements Silence gets the provider out of the way and creates a space the patient will fill in him/herself Paraphrasing, when a provider recaps what has occurred in all or part of an appointment and communicates interest and understanding

The Second Step:

Expressing Empathy.

Empathy is the ability to understand and share the feelings of another.16 It is the act of seeing the world through someone else’s eyes. In other words, one can cognitively understand what the other person is saying and can see it from their point of view. Providers need to see their patients as human beings, without judgement and as someone who is valuable in their own right. Providers also need to get in touch with their own emotions in order to truly understand and connect with another person’s emotional state. This is an element of empathy that is often skipped because providers may not have their own emotions sorted out. Another element of empathy involves communicating understanding, which can make someone feel like they are being understood, seen, and heard. If a provider does not know what to say, they can simply state, “It sounds like you feel that [paraphrase what the patient just said]... Tell me more about it.”

The Third Step:

Building Rapport.

If empathy is what the provider feels, then rapport is when the patient feels it back.16 Building rapport involves giving the patient your full attention. It requires that the provider be positive, coordinate their communication, and ensure that their verbal and nonverbal communication is congruent.18 Once the provider is able to build rapport, the patient will start to trust them.16

The Fourth Step:

Influencing Behavior.

This is the step in which the provider is actively trying to resolve the immediate crisis at hand. The provider must have a goal in mind and not lose sight of it.18 The provider hopes to influence the patient’s behavior in a positive way by recommending a course of action.16 Frontline providers can do this by changing the conversation and by using the other risk mitigation tools available, such as providing patient education, conducting random urine tox screens, accessing the state prescription drug monitoring database, using opioid risk tools (such as SOAPP), and using a decision tree.

The following cases show examples of how to change the conversation when speaking about pain medications with a patient.

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Case 1: A patient requests oxycodone for chronic low back pain.19 Typically, the provider may say something like: “The law or policy says I cannot prescribe oxycodone any longer. We will need to use something else.”

Instead, a provider might try using the following response: “We have new information showing that opioids are not the best treatment for back pain. May I talk to you about treatments we have that may work better for you?”

Case 2: A patient has been on Norco for 3 years and requests a higher dose.19 Typically, the provider may say something like: “I know you have pain, but I cannot give you more Norco and really we should not be using it at all. I am going to reduce your monthly supply by half.”

Instead, a provider might try using the following response: “May I talk to you about other treatments that might work better for your pain and are safer in the long run?”

Case 3: A patient prescribed morphine sustained release for 8 years asks why he has been on such a dangerous drug after he hears on the news about the high rates of overdose.19 Typically, the provider may say something like: “The morphine was prescribed by another provider.

I never thought it was good for you. I am not sure how to taper you off so I will refer you to the pain clinic.”

Instead, a provider may try using the following response: “Yes, this is a concern to me also. We realize opioids are not the best option. Treatments often change for diseases. Let’s talk about other options for your pain management. How does that sound to you?”

Obviously, patients will not always agree to a change in the conversation. Providers should avoid making decisions based on their patient’s emotions and not facts. The provider, however, must remember that it is the patient’s decision and right. The patient should take responsibility to make their own choices and to follow the recommendations given to them by their provider. Providers are also not obligated to provide opioids; they are obliged to offer the best level of clinical care. The main goal for all providers is to maximize safety and minimize the risk for their patient and the community at large.

The Final Step:

Engaging in Behavioral Change.

Patients at this point may act on the suggestions given by their providers and be ready to make a deal.16 Providers will want to ensure that they are engaging in shared medical decision making, which allows the patient to be part of the decision process. The provider will need to be flexible, which means they may need to give a little to get a little. Remember, giving the patient a sense of control is not the provider giving up control. This is why this process is called negotiation. It is important that

the provider maintain a consistent message and keeps control of their emotions. Staying calm throughout this process can help de-escalate a tense situation and diffuse the patient’s anger.18

7. Wood S. Violence against health care workers: legislative responses. Harvard Law Bill of Health. October 5, 2020. Available at: blog.petrieflom.law.harvard. edu/2020/10/05/violence-against-health-care-workers/.

8.

Time.

The entirety of the Behavioral Change Stairway Model will take time. Time is the negotiator’s greatest ally. This simply means that the provider needs to slow things down. Take one step at a time when going up the steps of the model and when attempting to gain voluntary compliance. Rushing the process will only add to the negative emotions present in the situation.18

Felton J. Violence prevention at the health care site. Occup Med. 1997;12:701–715.

9. Morrison J, Lantos J, Levinson W. Aggression and violence directed toward physicians. J Gen Intern Med. 1998;13:556–561.

10. O’Connell P, Bury G. Assaults against general practitioners in Ireland. Fam Med J. 1997;29:340–343.

11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. Washington, DC: American Psychiatric Association; 1994.

12. CNN Philippines Staff. Doctor held hostage by patient at East Avenue Medical Center. CNN Philippines. July 1, 2020. Available at: www.cnnphilippines.com/ news/2020/7/1/east-avenue-medical-center-hostage-doctor.html.

13. Grabianowski E. The hostage situation: how hostage negotiation works. 2017.

Available at: people.howstuffworks. com/hostage-negotiation1.htm.

CONCLUSION

A fellow training in pediatric neurology is called to consult in the emergency room at the University of Southern California Medical Center, at midday on February 8, 1993. “Get out! He’s shooting doctors!” someone yelled. Then a man’s voice: “I don’t want nurses, I want doctors! I want white coats.” The patient and the fellow crouched on the floor.20 The above excerpt is from a personal recollection of a British physician working in the US in the 1990s. There is enough evidence to suggest that frontline practitioners are at an increased risk of patient perpetuated violence. However, more likely than not, most providers will feel like they are being held hostage by their patients rather than be in such a situation. Regardless, the steps used to resolve an actual hostage negotiation can be useful in addressing these situations. Despite the specific steps outlined, the greatest ally to the provider in these situations is time.

14. PON Staff. Police negotiation techniques from the NYPD crisis negotiations team. Harvard Law School Program on Negotiation. November 16, 2020. Available at: www.pon.harvard.edu/daily/crisis-negotiations/crisis-negotiations-andnegotiation-skills-insights-from-the-new-york-city-police-department-hostagenegotiations-team/.

15. Miller L. Hostage negotiations: psychological strategies for resolving crises.

Practical police psychology. May 22, 2007. Available at: www.policeone.com/standoff/ articles/ 1247470-histage-negotiations-psychological/.

16. Barker E. 6 hostage negotiation techniques that will get what you want.

The Week. May 7, 2014. Available at: theweek.com/articles/447394/6-hostagenegotiation-techniques.

17. GomerBlog. Nurse & doctor held hostage by patient who keeps talking.

Available at: gomerblog.com/2016/04/tense-standoff-as-nurse-doctor-heldhostage-by-patients-neverending-talking/.

18. Thompson J. The 5 core skills of hostage negotiators. Psychol Today.

Available at: www.psychologytoday.com/us/blog/beyond-words/201510/ the-5-core-skills-hostage-negotiators.

19. U.S. Department of Veterans Affairs. Transforming the treatment of chronic pain: moving beyond opioids. PBM Academic Detailing Service. August 2017.

Available at: www.pbm.va.gov/PBM/AcademicDetailingService/Documents/ Academic_Detailing_Educational_Material_Catalog/Pain_ChronicPainProvider EducationalGuide_IB101000.pdf 20. Tournay AE. Hostage. BMJ. 2000;321:1603-1604.

References 1. Toscano G, Weber W. Violence in the workplace. Washington, DC: Bureau of Labor Statistics. 1995. Available at: stats.bls.gov/iif/oshwc/cfar0005.pdf.

2. Harris-Taylor M. Facing escalating workplace violence, hospital employees have had enough. National Public Radio. April 8, 2019. Available at: www.npr.org/ sections/health-shots/2019/04/08/709470502/facing-escalating-workplaceviolence-hospitals-employees-have-had-enough.

3. Domah T, Browne J (ed). Doctor held hostage at Jackson Fiah Doe Hospital. The New Dawn. August 5, 2019. Available at: thenewdawnliberia.com/ doctor-held-hostage-at-jackson-fiah-doe-hospital/.

4. World Health Organization. Violence and injury prevention. Violence against health workers. 2020. Available at: www.who.int/violence_injury_prevention/violence/ workplace/en/.

5. American College of Emergency Physicians. Violence in the emergency department: resources for a safer workplace. 2019. Available at: acep.org/administration/ violence-in-the-emergency-department-resources-for-a-safer-workplace/.

6. Goodman R, Jenkins E, Mercy J. Workplace related homicide among health care workers in the United States, 1980 through 1990. J Am Med Assoc. 1994;272:1686–1688.

24

Lantie E. J dfapa

AM , MSc, FRCPC, dFAS

orandby MD ,

rlay MD, dfapa B y Doug L. Gou

AM , MSc, FRCPC, dFAS

Lantie E. J orandby MD , dfapa

ourlay MD, dfapa B y Douglas L. G

cannabinoids

Electronic cigarettes are growing in popularity, not just as a

response to nicotine addiction but also as vehicles for other substances such as cannabis. With recent changes at the state level, cannabinoids are being investigated for their therapeutic value, especially as a potential treatment for chronic pain. In this article, we will explore the concept of vaping of both nicotine and cannabis with particular emphasis on the potential adverse consequences of this route of administration, as well as techniques which clinicians may find useful in helping patients assess risk more completely and, where necessary, effect behavioral changes.

As far back as recorded time, the Egyptians referred to the use of substances to alter mood. Homer’s The Odyssey recounts Helen of Troy giving her guests a drug (possibly opium) that “takes away grief and anger and brings forgetfulness of every ill.”1 Probably not the first instance of drug use in society, but certainly one that is well recorded. Drug use in society has been well documented by MarcAntoine Crocq, MD, of the Centre Hospitalier, Rouffach, France, in a paper titled Historical and cultural aspects of man’s relationship with addictive drugs.2 As well as identifying new psychoactive drugs, new methods of ingesting these drugs have, over time, been developed. Some methods, such as inhalation, have grown socially acceptable while others, like parenteral injection, have found their way into the more socially marginalized populations of society’s drug users. As with so many other habits, the pendulum swings from unacceptable to desirable and back, sometimes within one generation.

Routes of administration

Contrary to popular belief, the fastest route of administration of a drug is not parenteral. Actually, the pulmonary route of administration is the fastest, most efficient means of delivering a drug to the brain. While the pulmonary route of administration is not without limitations, particularly in terms of unit dose, it is more direct, travelling from the lungs directly into the left side of the heart and up to the brain. Contrast this with the intravenous route: the drug must pass through the right side of the heart, into the lungs, and finally on to the left side (arterial) circulation. The speed of central nervous system (CNS) delivery also impacts directly on the reinforcing nature of a drug.3 The route of administration also plays a significant role in much of the physical damage that drug users experience.

Consider the use of cocaine, for example.

When administered topically, is has minimal reinforcing qualities, largely due to the slow onset of CNS effects.

There is also minimal if any damage to the tissue to which it is applied. When the drug is applied topically, to the nasal mucosa, onset is relatively fast (compared to topical cutaneous application) with considerable damage due to the long-term effects of the vasoconstrictive properties of this drug. Nasal mucosal sloughing is commonly seen as septal cartilage deterioration and, in advanced cases, destruction of nasal cartilage and collapse of the nasal structure.4,5 When cocaine is smoked, it becomes even more reinforcing psychologically and more destructive.

Pulmonary vasoconstrictive effects of cocaine lead to a myriad of adverse effects including pulmonary fibrosis and pulmonary hypertension, to mention only two.6,7

Vaping technology

The 20th century saw an advancement in efficiency and apparent social acceptability of the tobacco habit: smoking had become electronic. The e-cigarette had come of age. Its history is quite interesting.

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Herbert Gilbert, who was a 2-pack per day smoker, patented a smokeless nontobacco cigarette in 1965.8 At the time, the invention did not become popular.

In 2003, Lik Hon, a Chinese national, developed and patented the first e-cigarette in an attempt to address the massive smoking problem in China.9 The active ingredient was nicotine in the free-base or alkaloid form, which is not the most efficient molecular form for CNS delivery.10 It didn’t take long for alkaloid chemists from the tobacco industry to refine the product to utilize nicotine salts, which are more readily absorbed.

In a relatively unregulated industry, these products found their way into a variety of hands, including cigarette smokers wishing to quit, as well as a new potential market of nonsmoking adolescents who were attracted to the products by clever marketing and the addition of flavoring compounds11 such as bubble gum, cherry, and fruit. Joe Camel™ style marketing campaigns appeared,12-14 essentially unchallenged even though they were clearly targeting a more youthful market under the guise of being a “safer” alternative to conventional tobacco use. This “safer” claim is proving to be based more on hope than the scientific evidence.

Electronic drug delivery systems— the e-cigarette

The idea behind the electronic cigarette is quite simple. When certain liquids (the carrier) are heated by resistance wire coils, the liquid atomizes essentially creating a white cloud of carrier vapor as well as anything else within that carrier. The carrier liquid typically contains a mixture of glycerol and propylene glycol. The atomized carrier liquid serves the role of smoke in delivering the active ingredient, and unfortunately any of the contaminants that may also be present. While both glycerol and propylene glycol are considered “generally safe,” this assessment applies to oral administration and does not necessarily apply when these chemicals are heated and inhaled.15,16

“Many

of these devices had no quality assurance. …they were often being produced by individual hackers with extensive guidance available on the internet. The lack of regulation and oversight became a real problem.”

The typical e-cigarette

Key elements17 of an electronic cigarette are:

1 The mouthpiece 2 The cartridge/tank: holds carrier liquid and active ingredient(s)

3 The heater/atomizer:

converts liquid into a vapor

4 The microprocessor: takes power from

the battery and delivers it to the heating element; this occurs on demand, when the user creates a negative pressure at the mouthpiece 5 The battery: typically rechargeable, providing power for the device to function

What was initially seen as a viable tool in the campaign toward smoking cessation became an opportunity to revitalize a dying industry. Many of the e-cigarette companies came under the control of large tobacco companies including RJ Reynolds. Beyond this, a counterfeit industry of unregulated manufacture and distribution of knock-off e-cigarettes appeared. Since a relatively small number of companies actually produce the components for these devices, it became difficult to distinguish the

30

original product from those manufactured offshore. These products were often obtained unfilled. This resulted in adulterated products coming onto the market, often at significantly lower prices than the retail innovator products were priced.

As a result, it became exceedingly difficult to determine if the increases in pulmonary disease in e-cigarette users was intrinsic to the technology or if it was due to adulterants and contaminants that unsuspected users were exposed to.

This novel delivery system, however, is ripe for use beyond simple nicotine. It quickly became a more socially acceptable means to consume cannabinoids. With a faster onset of action and the ability to titrate to desired effect, the e-cigarette is a nearly ideal method of drug delivery. Coupled with a world wide web of experimenters who designed and modified larger capacity vaporizers, a billion dollar industry of international scope soon appeared.

With a primary goal of pushing the limits, atomizer temperatures were increased to allow even more “juice” to be applied directly to the heating element (“dripping”), which produced enormous clouds of drug laden vapor.

Many of these devices had no quality assurance. After all, they were often being produced by individual hackers with extensive guidance available on the internet. The lack of regulation and oversight became a real problem.

Regulatory reform and impact

As we all know, well meant regulations can have both intended and unintended consequences. As an example, raising the legal age for the sale of tobacco products was intended to reduce adolescent smoking.

Unfortunately, the assumption that a law prohibiting sale to minors would address underage use did not consider the ability of these now prohibited users from switching to e-cigarettes. Now, as the pattern of use in adolescents is shifting, regulators are introducing new regulations to address vape technology from the manufacturing, marketing, and distributing perspectives. All this is being done with the hope that these new regulations will curtail the adolescent problem of nicotine dependency and the resultant harms associated with its use. Unfortunately, if nicotine dependent youth are no longer able to access their drug of choice through vape technology, they will likely go back—or in some cases begin—to use regular tobacco products.

E-cigarette contents

survey. Between 2017 through 2019, in this age group, and specifically looking at those attending college, vaping of nicotine rose from 6.1% to 22%, and from 5.1% to 14% of those who are vaping marijuana. The numbers are higher for their counterparts who are not in college. MTF 2020 data may offer some good news: though vaping of both nicotine and marijuana remains high, there was a leveling off in use for both products in teens in high school.27 Other data show that teen use of e-cigarettes comes with a majority of users having never smoked a traditional cigarette. Data also show concerning levels of conversion to combustible cigarettes.23 Additionally, teens have developed creative methods of altering e-cigarette pods to be able to vape cannabis.24 Nicotine has been shown to activate the reward centers of the brain, which can trigger addictive behaviors. In part due to the delay in the brain development of a young adult, nicotine use is considered to ”prime the pump,” increasing the likelihood for addiction to harder drugs, such as cocaine and opioids.25 Dr. Wilson Compton, the deputy director of NIDA, has remarked that vaping is becoming the “marker” for a potential increase in rates of other substances of abuse.26

E-cigarettes, as described above, use a device to heat propylene glycol and other carriers, which may or may not contain nicotine, into a smoke-like vaper. This technology has attracted adolescents and young adults in large numbers.18 The American Academy of Pediatrics and the United States Centers for Disease Control and Prevention have commented on the risks that vaping poses to adolescents and young adults. These risks include a well-studied pattern of vaping lung disease, abbreviated as EVALI—e-cigarette, or vaping, product use-associated lung injury.19 Electronic cigarette use and vaping appears to be linked to worsening of other substance use disorders, including the development of a tobacco use disorder in previously nicotine-naïve individuals. Electronic cigarette use, specifically in adolescents and young adults, may reverse gains made in the battle fought against tobacco use in the US over the past several decades.

Additionally, studies have examined the effect that nicotine has on the developing brain, considering that most brain development is not fully complete until a human reaches his/her mid-20s. Altering brain development has generated concerns for mental health disorders along with the heightened risks of developing other substance use disorders.20,21 Consider the results of Monitoring the Future (MTF),22 an annual epidemiologic study funded through the National Institute of Drug Abuse (NIDA). MTF tracks drug and alcohol attitudes and use among teenagers and young adults. Recent data shows a staggering increase in vaping among college age adults, those 19 to 22 years of age. According to NIDA, this is the largest increase in substance use in an age group ever seen in the 45-year-old

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Vaping and health issues

Vaping has been shown to weaken lungs and normal respiratory functions and cause airway and lung inflammation.18 A retrospective study run out of Stanford showed a 5 times more likely risk of contracting COVID-19 if you are an adolescent or young adult who vapes.27 The authors suggested that this risk may be linked to frequent touching of the face and mouth while smoking but could not rule out the role of toxic vapors and their effects on lung tissue, highlighting ongoing and long-term lung damage.

Nicotine has been shown to disrupt sleep patterns, which are critical for mental and physical health.

Research also shows that smoking increases the risks of various psychiatric disorders, such as depression and anxiety. Teen and young adult patients will endlessly debate the idea that smoking, either nicotine or marijuana, helps their anxiety or helps them sleep. Clearly, the data show that smoking worsens these problems.28-31 More concerning is the risk for serious mental health illnesses among this vulnerable population.

This risk comes from cannabis vaping that, according to MTF, has also risen sharply over the last 3 years.22 Specifically, cannabis vaping may be a greater risk, given that the delivery system may be more effective than combustible cannabis cigarettes and has been shown to increase the level of tetrahydrocannabinol (THC) in the bloodstream. In young adults and adolescents who carry vulnerability in their genome, evidence has suggested that cannabis use can potentially trigger more serious mental health disorders such as psychosis or schizophrenia.29,32

“Between Between 2017 through 2019…vaping of nicotine rose from 6.1% to 22%, and from 5.1% to 14% of those who are vaping marijuana.” marijuana.

E-cigarettes have a public perception as a safer alternative to traditional tobacco, and the e-cigarette market has promoted e-cigarettes as the “cleaner” substitute to smoking. These claims of a healthier alternative have yet to be definitively proven. This public perception likely plays a role as one of the drivers of higher rates of use, in both older and younger adults.33 Our world is now filled with smart phones, sexting, and social media overuse. An entire peer group exists that knows only life with constant electronic stimulation. Our national and global nicotine obsessions appear to have morphed from combusted tobacco-containing cigarettes to electronic versions. This begs the question: Are teens and young adults using e-cigarettes because of boredom? Is there a generational ADHD of restlessness that stems from a life with fewer meaningful human interactions?

Treatments

A lack of “meaningful connections” can become an appropriate segue into the effective approaches available for talking with adolescents and young adults about substance use in general and vaping in particular.

The following techniques can also be applied to those who live with chronic pain, substance use disorders, and other targeted pathologic behaviors.34,35 Prochaska and DiClemente introduced the stages of change in 1983 while exploring techniques for smokers who seek abstinence. These stages have now been applied broadly to the substance abuse world and beyond as a method to evaluate and assess where an individual is and what approach will be most effective at accomplishing change.36,37 Miller and Rollnick developed motivational interviewing as a platform to collaborate with the individual seeking change.37 The spirit of motivational interviewing builds on this concept, that instead of a confrontational

32

relationship the therapist and the patient can work together to effect change. This is meant to find and harness the patient’s motivations, not the therapists. This therapy assists with identifying the patient’s commitment and confidence for change and converts the traditional authoritarian dynamic of therapist/patient, supplanting it with the collaborative partnership that is patient centered.

Motivational interviewing has been used effectively in chronic pain populations,38 and has been shown to reduce overuse or even misuse of opioid pain medications. Additionally, motivational interviewing has proven effective in changing other behaviors, helping people motivate themselves to lose weight and stay on an exercise regiment, and can be applied effectively and easily in disadvantaged populations.39-41 Another technique effectively used in chronic pain populations is mindfulness based interventions, such as meditation and stress reduction. These have been studied and shown to provide improvement in quality of life, overall functioning, and mobility by reducing the perception of chronic pain.42 Mindfulness has been shown to be effective for mental health populations and substance abuse disorders as well. It also has been used to reduce anxiety levels and cravings of addictive substances.43,44

Conclusions

As we continue into the 21st century, with all its quantum leaps in technology, it behooves us as a society to pause and examine the new techniques that have developed around a millennial old habit and weigh the risks and benefits for multiple patient populations in a thoughtful way. E-cigarettes and vaping are potentials for substance use and all the negatives that go with it.

Approaches such as motivational interviewing and mindfulness have proven effective in populations with pain and other chronic medical conditions and may help those with an addiction to e-cigarettes and vaping.

References 1.

24. Knapp AA, Lee DC, Borodovsky JT, et al. Emerging trends in cannabis administration among adolescent cannabis users. J Adolesc Health. 2019;64(4):487–493.

Homer FR. The Odyssey. 18th ed. New York: Vintage Books; 1990.

25. Agrawal A, Madden PAF, Martin NG, et al. Do early experiences with cannabis vary in cigarette smokers? Drug Alcohol Depend. 2013;128(3):255–259.

2. Crocq MA. Historical and cultural aspects of man’s relationship with addictive drugs. Dialogues Clin Neurosci. 2007;9(4):355–361.

26. Wagner W. Study: staggering increase in vaping in 19- to 22-year-olds.

October 8, 2020. Available at: treatmentmagazine.com/study-staggering-increasein-vaping-in-19-to-22-year-olds.

3. Minogianis EA, Levesque D, Samaha AN. The speed of cocaine delivery determines the subsequent motivation to self-administer the drug. Neuropsychopharmacology. 2013;38(13):2644–2656.

27. Galha SM, Cheng J, Halpern-Feisher B. Association between youth smoking, electronic cigarette use and coronavirus disease 2019. J Adolesc Health.

2020;67(4):519–523.

4. Gatt K, Vella SM, Fenech M, et al. Infective complications of midline destruction in a cocaine user. BMJ Case Rep. 2019;12(7):e231743.

5. Garcia-Perez D, Ruiz-Ortiz M, Panero I, et al. Snorting the brain away: cerebral damage as an extension of cocaine-induced midline destructive lesions. J Neuropathol Exp Neurol. 2020;79(12):1365–1369.

28. Patton GC, Hibbert M, Rosier MJ, et al. Is smoking associated with depression and anxiety in teenagers? Am J Public Health. 1996;86(2):225–230.

29. D’Souza DC, Sewell RA, Ranganathan M. Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci. 2009;259(7):413–431.

6. Douedi S, Upadhyaya VD, Patel I, et al. Cocaine-induced giant bullous emphysema. Case Rep Med. 2020;2020:6410327.

30. Sewell RA, Ranganathan M, D’Souza DC. Cannabinoids and psychosis. Int Rev Psychiatry. 2009;21(2):152–162.

7. Tseng W, Sutter ME, Albertson TE. Stimulants and the lung: review of literature.

Clin Rev Allergy Immunol. 2014;46(1):82–100.

31. Leventhal AM, Strong DR, Sussman S, et al. Psychiatric comorbidity in adolescent electronic and conventional cigarette use. J Psychiatr Res. 2016;73:71–78.

8. Gilbert HA. Smokeless Non-tobacco Cigarette, in google patent search USA, Editor. Patent number: US3,200,819. 1965.

32. Radhakrishnan R, Wilkinson ST, D’Souza DC. Gone to pot - a review of the association between cannabis and psychosis. Front Psychiatry. 2014;5:54.

9. Hon L. Non combustable atomized electronic cigarette. Chinese patent number: CN1530041A. 2003.

33. National Academies of Sciences, Engineering, and Medicine. Health and Medicine Division. Board on Population Health and Public Health Practice; Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Public Health Consequences of E-Cigarettes. Eaton DL, Kwan LY, Stratton K, editors. Washington (DC): National Academies Press (US); 2018 Jan 23.

10. Barrington-Trimis JL, Leventhal AM. Adolescents’ use of “pod mod” e-cigarettes urgent concerns. N Engl J Med. 2018;379(12):1099–1102.

11. Khlystov A, Samburova V. Flavoring compounds dominate toxic aldehyde production during e-cigarette vaping. Environ Sci Technol. 2016;50(23):13080–13085.

34. Westra HA, Constantino MJ, Antony MM. Integrating motivational interviewing with cognitive-behavioral therapy for severe generalized anxiety disorder: an allegiance-controlled randomized clinical trial. J Consult Clin Psychol.

2016;84(9):768–782.

12. Seitz CM, Orsini MM, Jung G, et al. The need for a policy that bans the use of cartoons in marketing e-cigarette products. Nicotine Tob Res. 2020;22(10):1932–1933.

13. Padon AA, Maloney EK, Cappella JN. Youth-targeted e-cigarette marketing in the US. Tob Regul Sci. 2017;3(1):95–101.

35. Balan IC, Lejuez CW, Hoffer M, et al. Integrating motivational interviewing and brief behavioral activation therapy: theoretical and practical considerations.

Cogn Behav Pract. 2016;23(2):205–220.

14. Wise J. E-cigarette marketing is aimed at youngsters, says charity. BMJ. 2013;347:f7124.

36. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51(3):390–395.

15. Pankow JF, Strongin RM, Peyton DH. More on hidden formaldehyde in e-cigarette aerosols. N Engl J Med. 2015;372(16):1576–1577.

37. Miller WR, Rollnick S. Motivational interviewing is built on the stages of change research. In: Motivational Interviewing: Helping People Change. Guilford Press; 2012.

16. Jensen RP, Luo W, Pankow JF, et al. Hidden formaldehyde in e-cigarette aerosols.

N Engl J Med. 2015;372(4):392–394.

38. Nijs J, Wimja AJ, Willaert W, et al. Integrating motivational interviewing in pain neuroscience education for people with chronic pain: a practical guide for clinicians.

Phys Ther. 2020;100(5):846–859.

17. FEMA. Parts of a second generation electronic cigarette. Wiki article. 2014.

Available at: commons.wikimedia.org/wiki/File:Parts_of_an_Electronic_cigarette.png.

18. Cullen KA, Ambrose BK, Gentzke AS, et al. Notes from the field: use of electronic cigarettes and any tobacco product among middle and high school students - United States, 2011–2018. MMWR Morb Mortal Wkly Rep. 2018; 67(45):1276–1277.

39. Tuvemo Johnson S, Anens E, Johansson AC, et al. The Otago exercise program with or without motivational interviewing for community-dwelling older adults: a 12-month follow-up of a randomized, controlled trial. J Appl Gerontol.

2021;40(3):289–299.

19. Christiani DC. Vaping-induced acute lung injury. N Engl J Med. 2020;382(10):960–962.

40. Nuss K, Moore K, Nelson T, et al. Effects of motivational interviewing and wearable fitness trackers on motivation and physical activity: a systematic Review.

Am J Health Promot. 2021;35(2):226–235.

20. England LJ, Bunnell RE, Pechacek TF, et al. Nicotine and the developing human: a neglected element in the electronic cigarette debate. Am J Prev Med. 2015;49(2):286–293.

41. Suire KB, Kavookjian J, Wadsworth DD. Motivational interviewing for overweight children: a systematic review. Pediatrics. 2020;146(5).

21. Tobore TO. On the potential harmful effects of E-Cigarettes (EC) on the developing brain: the relationship between vaping-induced oxidative stress and adolescent/ young adults social maladjustment. J Adolesc. 2019;76:202–209.

42. Majeed MH, Ali AA, Sudak DM. Mindfulness-based interventions for chronic pain: evidence and applications. Asian J Psychiatry. 2018;32:79–83.

22. Johnston L, Miech R. Monitoring the future national survey results on drug use, 1975–2019: overview, key findings on adolescent drug use. Ann Arbor, Michgan; 2020.

43. Wharton E, Kanas N. Mindfulness-based stress reduction for the treatment of anxiety disorders. Int J Group Psychother. 2019;69(3):362–372.

23. Breitbarth AK, Morgan J, Jones AL. E-cigarettes-an unintended illicit drug delivery system. Drug Alcohol Depend. 2018;192:98–111.

44. Edguer MN, Taylor L. Mindfulness practices in addictive behavior prevention, treatment, and recovery. In: Murray MM, Begun AL. The Routledge Handbook of Social Work and Addictive Behaviors. New York; Routledge. 2020:355.

33

By Joseph V. Pergolizzi, Jr MD

Robert B. Raffa PhD

pharmacotherapy

, which fell in 2018 for the first

time in 25 years, rose to record numbers in 2020, and continue to rise. The resurgence is being fueled by three interrelated phenomena: stress attributable to the coronavirus pandemic, highpotency opioid agonists, and polysubstance abuse. The phenomenon of polysubstance abuse arguably presents the most far-reaching and treatment-resistant conundrum. In this article we highlight the special challenges presented by polysubstance abuse/overdose, the role of opioid antagonists (eg, naloxone) in polysubstance overdose, and discuss existing and new agents designed to address druginduced respiratory depression by stimulating respiration rather than by receptor blockade of individual overdose agents (ie, are “agnostic” to the cause of the respiratory depression).

DRUG OVERDOSE ON THE RISE

Following a hard-earned and welcome decline in drug overdose deaths in the United States in 2018, nearly 72,000 Americans died from drug overdoses in 2019, according to data released by the Centers for Disease Control and Prevention (CDC).1 More than 81,000 drug overdose deaths occurred in the US in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period.2 Over the past decade, misuse of prescription opioids has been associated with use of illicit opioids, especially heroin. Evidence for this emanated from results from various studies which showed that almost half of heroin-injecting individuals abused prescription opioids before switching to heroin.3,4 Although a causal relationship has by no means been shown, many abusers follow a trajectory leading to the abuse of more “problematic”—from a medical, psychosocial, economic, and legal perspective—substances. New data point to significant changes in drug overdose deaths. There are now more deaths from synthetic opioids (other than methadone)5; they were involved in 31,335 overdose deaths, nearly half of all drug overdose deaths in 2018.6 Illicitly manufactured fentanyl likely drove the increase in deaths.5

THE IMPACT OF COVID-19

The stresses involved with several aspects of the pandemic, such as loss of a sense of safety, loss of loved ones to death or distance, loss of job, loss of freedom, loss of personal space, have resulted in an increase in drug-related deaths (and suicide).7 The American Medical Association (AMA) issued the following prescient brief titled Reports of increases in opioid-related overdose and other concerns during COVID pandemic8: “As the COVID-19 global pandemic continues, so does the nation’s opioid epidemic. The AMA is greatly concerned by an increasing number of reports

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from national, state and local media suggesting increases in opioid-related mortality—particularly from illicitly manufactured fentanyl and fentanyl analogs. More than 35 states have reported increases in opioid-related mortality as well as ongoing concerns for those with a mental illness or substance use disorder in counties and other areas within the state.”

Synthetic opioids (primarily illicitly manufactured fentanyl) appear to be the primary driver of the increases in overdose deaths, increasing 38.4% from the 12-month period leading up to June 2019 compared with the 12-month period preceding May 2020. During this time period2: ● 37 of the 38 US jurisdictions with available synthetic opioid data reported increases in synthetic opioid involved overdose deaths ● 18 of these jurisdictions reported increases greater than 50% ● 10 western states reported over a 98% increase in synthetic opioid-involved deaths A study on national urine drug testing findings during the COVID -19 crises revealed the following increases9: ● 10.06% in cocaine ● 12.53% in heroin ● 19.96% in methamphetamine ● 31.96% in nonprescribed fentanyl

POLYSUBSTANCE ABUSE

Polypharmacy—the prescribing of multiple medications within a given period—is common in the US, particularly in the older population.10 Although polypharmacy used as part of the legitimate management of a medical condition is an important topic, the focus here is on polypharmacy as an aspect of prescription drug misuse. In a survey conducted in Indiana, almost 84% of prescription drug misusers receiving substance abuse

treatment reported that they used at least one additional substance.11 The concern is that the nonmedical use of multiple drugs can lead to adverse effects including polysubstance abuse disorder; drug-drug interactions (often synergistic on central nervous system adverse effects such as respiratory depression); and polysubstance overdose, potentially resulting in death.12 People may intentionally engage in polysubstance abuse in an effort to experience greater effects from multiple substances. Users may have a preferred substance of abuse that they combine with other substances to enhance the primary substance’s effects; for example, those who regularly abuse opioid drugs may sometimes take them with benzodiazepines to experience greater relaxation or sedative effects. Data suggest that polysubstance use has become markedly more common than opioid use alone in the population of fatal opioid overdose victims, and a number of social factors appear to be linked to the adverse outcomes in this group.13 Fatal overdose is the most severe consequence of multidrug use. A large share of drug-related deaths in which opioids (licit and illicit) are involved also involve other substances, often other opioids and benzodiazepines. The AMA Opioid Task Force calls for substance use disorder (SUD) support, using treatments with evidence of efficacy, such as medication assisted treatment.

More than 2,000,000 Americans have an untreated SUD, and one overdose is likely to lead to others.14 The report calls for the removal of barriers that impede medical care and an end to the overdose epidemic, and also calls for the help of health insurance companies, which currently may

38

hamper pain care access. The stated goals of the Task Force report are to prioritize prevention and treatment of SUD, employ surveillance strategies to identify at-risk patients, and implement proven evidence-based approaches.

THE TREATMENT CHALLENGES

Treatment of a single-agent opioid overdose is straightforward, at least in concept. Since the precipitating cause of the danger or respiratory depression is binding of the opioid agonist molecule to the opioid receptor (primarily the mu opioid receptor subtype), the immediate cause can be specifically and completely reversed by blocking access of the opioid agonist molecule to the receptor. No agonist binding = no respiratory depression.

The danger is avoided as long as the antagonist molecule is blocking access to the agonist. Naloxone is an example of an opioid receptor antagonist. It is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. The critical point is that naloxone is an opioid antagonist that antagonizes opioid effects by competing for opioid receptor sites. Consequently, naloxone will not reverse overdose resulting from non-opioid drugs, which do not act at opioid receptors, like benzodiazepines, alcohol, or propofol. As stated by the CDC, “Naloxone alone may be inadequate if someone has taken large quantities of opioids, very potent opioids, or long-acting opioids.”15

In addition to overdose reversal being limited to opioids, other limitations of an opioid receptor antagonist include the following16: ● It can be inadequate against the newer, highly potent opioids (fentanyl, carfentanil, etc).

It may require multiple doses of antagonist. ● It reverses all opioid-mediated effects, including pain relief, which may not be desired for some patients or providers. ● Patients often awaken in an agitated, combative state, requiring additional hospital and first responder resources and interfering with further treatment. It is also a danger to responder personnel during a pandemic. ● It does not address the growing issue of polypharmacy.

acetylcholine receptor antagonist), amphetamine and cocaine (sympathomimetics), carbon dioxide, picrotoxin (GABA receptor antagonist), and tetrazoles.18 Iman et al list additional agents.19 Methylxanthines have been used in the neonatal intensive care unit for more than 40 years to treat and prevent apnea of prematurity. Caffeine is the most commonly used because of its wide safety margin and long duration of action that allows once-daily administration.

RESPIRATORY STIMULANTS

The COVID-19 pandemic has made matters worse. The law enforcement department in ≥2 US states suspended administration of naloxone by police due to the coronavirus pandemic because of concerns over possible transmission of the virus to responding officers. Overdose reversals will be left exclusively to emergency medical services. As a result, more than one person was reportedly denied an overdose reversal shortly after the directive took effect. The policy has subsequently been reversed.

AN ALTERNATIVE STRATEGY: respiratory stimulation

Given the challenges of the current overdose environment, particularly polysubstance abuse, a treatment strategy that targets only a single mechanism of respiratory depression (eg, opioid receptor) is insufficient. Cotten (2014) proposes that what is needed is a “pharmacologic ventilator,” ie, a substance that should be “agnostic” to (independent of) the cause; should not block desirable opioid-mediated effects, such as analgesia (in a hospital setting); and should not precipitate withdrawal and its associated combativeness.17 Early substances used to stimulate respiration were nonselective stimulants and worked by diverse physiologic mechanisms. “Analeptic” was applied to describe the stimulating actions of these agents. In general, they produced excitation at cortical, brainstem, or spinal cord level. The use of such agents in clinical practice has mostly waned, so “analeptic” is now used to indicate “respiratory stimulant.”

Through the years, a wide variety of diverse compounds were used to stimulate respiration (directly or indirectly), including ephedrine (inhibitor of neuronal norepinephrine reuptake), strychnine (Gly receptor antagonist), tobacco smoke (nicotine), atropine (muscarinic

39

Centrally acting Ampakines (also AMPAkines) are a family of chemically related, pharmacologic class of agents that act as positive modulators of AMPA (α-amino-3-hydroxy5-methyl-4-isoxazole propionic acid) subtype of glutamate receptor. AMPA receptors are located in the pre-Bötzinger nuclei of the brainstem, a region that is important for maintenance of respiratory rhythmogenesis. Ampakine compounds have been shown to improve respiration in animals that have been treated with opioids, propofol, pentobarbital, or ethanol.20-24 Peripherally acting Doxapram not only stimulates respiration by action on the pre-Bötzinger complex, but also by stimulating chemoreceptors in the aortic and carotid bodies, thereby stimulating respiratory centers with resultant increased rate and depth of respiration.25 Doxapram is still available, and used as a respiratory analeptic. Common adverse effects are restlessness, muscle twitching, and vomiting, and seizures can occur due to stimulation of the central nervous system.

Almitrine stimulates TASK-1 and TASK-3 potassium channels in the carotid body. It was never approved in the US, and its sale was subsequently banned in the European Union and the United Kingdom. It is considered unsuitable for clinical practice because of a significant incidence of peripheral neuropathy caused by its metabolites.26 ENA-001 (previously GAL-021), which is in development, has received attention as an “agnostic” respiratory stimulant for drug-induced respiratory depression. It acts on the carotid bodies by inhibiting large-conductance Ca2+/voltage-activated (big potassium) channels, BK .27 It has been shown to increase minute ventilation in a dose dependent manner, and to reverse opioid, benzodiazepine, isoflurane, and propofol induced respiratory depression in animals.28 Thus it offers a potential agent for the care of polysubstance patients. It has now been shown to antagonize opioid-induced respiratory depression in healthy volunteers.29 A further benefit of ENA-001 is rapid onset time/ offset time, which has been suggested to make “this drug an attractive alternative to naloxone.”30

CONCLUSION

In contradistinction to receptor blockade by an antagonist, which is hampered by ever-morepotent agonists and polysubstance-induced respiratory depression, an approach agnostic to the cause would be desirable. The newest drugs target specific subtypes of potassium channels located on tissue located outside the central nervous system (carotid body), accounting for significantly reduced central nervous system adverse effects. Only time will tell if the long-sought search for a respiratory analeptic is near realization.

References

16. Peppin J, Pergolizzi JJ, Dahan A, et al. Commentary: New complications make treatment of ‘opioid’ overdose challenging. Pharmacol Pharmacy. 2020;11:362–372.

17. Cotten JF. The latest pharmacologic ventilator. Anesthesiology. 2014;121:442–444.

18. Peppin J, Pergolizzi JJ, Fudin J, et al. History of analeptics and respiratory stimulants. J Pain Res. [in press] 19. Imam MZ, Kuo A, Smith MT. Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants. F1000Res. 2020;9.

20. Ren J, Ding X, Funk GD, et al. Ampakine CX717 protects against fentanyl-induced respiratory depression and lethal apnea in rats. Anesthesiology. 2009;110:1364–1370.

21. Dai W, Gao X, Xiao D, et al. The impact and mechanism of a novel allosteric AMPA receptor modulator LCX001 on protection against respiratory depression in rodents.

Front Pharmacol. 2019;10:105.

22. Xiao D, Xie F, Xu X, et al. The impact and mechanism of ampakine CX1739 on protection against respiratory depression in rats. Future Med Chem. 2020;12:2093–2104.

1. Centers for Disease Control and Prevention. Provisional drug overdose death counts. 2021. Available at: www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm.

23. Ren J, Ding X, Greer JJ. Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717. J Appl Physiol (1985). 2012;113:1004–1011.

2. Centers for Disease Control and Prevention. Overdose deaths accelerating during COVID-19: expanded prevention efforts needed. 2020. Available at: www.cdc. gov/media/releases/2020/p1218-overdose-deaths-covid-2019.html.

24. Dai W, Xiao D, Gao X, et al. A brain-targeted ampakine compound protects against opioid-induced respiratory depression. Eur J Pharmacol. 2017;809:122–129.

3. Carlson RG, Nahhas RW, Martins SS, et al. Predictors of transition to heroin use among initially non-opioid dependent illicit pharmaceutical opioid users: a natural history study. Drug Alcohol Depend. 2016;160:127–134.

25. Yost CS. A new look at the respiratory stimulant doxapram. CNS Drug Rev, 2006;12:236–249.

4. Cicero TJ, Ellis MS, Kasper ZA. Increased use of heroin as an initiating opioid of abuse. Addict Behav. 2017;74:63–66.

26. Golder FJ, Hewitt MM, McLeod JF. Respiratory stimulant drugs in the post-operative setting. Respir Physiol Neurobiol. 2013;189:395–402.

5. O’Donnell JK, Halpin J, Mattson CL, et al. Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 - 10 States, July-December 2016. MMWR Morb Mortal Wkly Rep. 2017;66: 1197–1202.

6. Centers for Disease Control and Prevention. New data show significant changes in drug overdose deaths: Overall decline in opioid-involved drug overdose deaths – but more deaths from synthetic opioids other than methadone. 2020. Available at: www.cdc.gov/media/releases/2020/p0318-data-show-changes-overdose-deaths.html.

27. McCartney CE, McClafferty H, Huibant JM, et al. A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel alpha-subunits. Proc Natl Acad Sci U S A. 2005;102:17870–17876.

28. McLeod JF, Leempoels JM, Peng SX, et al. GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers. Br J Anaesth. 2014;113:875–883.

29. Dahan A, van der Schrier R, Smith T, et al. Averting Opioid-induced Respiratory Depression without Affecting Analgesia. Anesthesiology. 2018;128:1027–1037.

7. John A, Pirkis J, Gunnell D, et al. Trends in suicide during the covid-19 pandemic.

BMJ. 2020;371:m4352.

30. van der Schier R, Roozekrans M, van Velzen M, et al. Opioid-induced respiratory depression: reversal by non-opioid drugs. F1000Prime Rep. 2014;6:79.

8. American Medical Association. Issue brief: Reports of increases in opioidrelated overdose and other concerns during COVID pandemic. 2020. Available at: www.asapnys.org/wp-content/uploads/2020/07/Issue-brief_-Reports-of-increasesin-opioid-related-overdose-and-other-concerns-during-COVID-pandemic.pdf.

9. Health M. Millenium Health Signals Report™. COVID-19 Special Edition: Significant changes in drug use during the pandemic. 2020. Available at: www.rsat-tta. com/Files/MH_Signals_Report_COVID_19.

10. Golchin N, Frank SH, Vince A, et al. Polypharmacy in the elderly.

J Res Pharm Pract. 2015;4:85–88.

11. Omenka I. Polypharmacy among prescription drug users. 2017. Available at: fsph. iupui.edu/doc/research-centers/polypharmacy-among-prescription-drug-users.pdf.

12. Peppin JF, Raffa RB, Schatman ME. The polysubstance overdose-death crisis.

J Pain Res. 2020;13, 3405–3408.

13. Compton WM, Valentino RJ, DuPont RL. Polysubstance use in the U.S. opioid crisis. Mol Psychiatry. 2021;26:41–50.

14. AMA. Opioid task force 2020 progress report. 2020. Available at: end-overdose-epidemic.org/wp-content/uploads/2020/07/AMA-Opioid-Task-Force-2020Progress-Report.pdf.

15. Centers for Disease Control and Prevention. Using naloxone to reverse opioid overdose in the workplace: Information for employers and workers. 2018. Available at: www.cdc.gov/niosh/docs/2019–101/background.html.

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Education is the best analgesic. www.painweek.org

By Elizabeth M. Oliva PhD Suzanne McGarity PhD

Robert Sproul PharmD

Friedhelm Sandbrink MD

By Elizabeth M. Oliva PhD Suzanne McGarity PhD Robert Sproul PharmD Friedhelm Sandbrink MD

key topic

increasing awareness that opioid therapy and suffering from pain and mental health comorbidities are associated with the rising number of suicides in the United States. Suicide prevention is of highest priority to the Veterans Health Administration. This article describes links between opioid therapy, suicide, and mental health; reviews suicide prevention and relevant approaches; and summarizes suicide prevention opportunities for pain management staff. We review suicide risk related to opioid therapy and opioid medication reductions

Opioid-Related Deaths and Suicide:

Chronic Pain:

Linked to Mental Health

Conditions and Suicide Risk

Multiple epidemiological studies have consistently documented the link between the presence of chronic pain and risk of suicide, and severity of pain predicts greater likelihood of subsequent suicide.1,2 In a recent meta-analysis, the presence of physical pain was found to be a consistent risk factor for suicidal thoughts and behaviors including suicide deaths.3 Suicidality in patients with chronic pain is common: about one-third contemplate or attempt suicide,4 with an almost 3-fold increased risk for suicide attempts compared to the general public. For example, the risk for suicide attempts increased more than 6-fold in the context of severe headaches, and 9-fold in patients with back pain.1,3,5 While the risk of suicide deaths is due in part to well-known correlates of pain such as depression and substance use disorders (SUD), there are aspects of chronic pain itself that add uniquely to an individual’s suicide risk profile, and the link between pain and suicide persists even after accounting for mood disorders.1,6 According to Elman et al, several mechanisms contribute to the prevalence of suicidality in patients with chronic pain, including genetic, developmental, social, psychological, and medical factors.1 Loss of hope and low expectancy for subjective well-being, conditioned fear, and avoidance behavior are contributing causes. Based on the considerable overlap between brain circuitries mediating physical and emotional pain, it is also hypothesized that patients with chronic pain exhibit alterations in reward and anti-reward pathways.

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Simultaneous Public Health Crises

There has been an increase in deaths from opioid overdoses (and poisonings of all kind) and of suicides in the US, and both occur commonly in patients suffering from chronic pain. Studies clearly document that patients with chronic pain and receipt of opioid medication for pain have an increased suicide risk, and this is likely particularly high in the context of mental health disorders, especially opioid use disorder (OUD).7,8 For the US, Centers for Disease Control and Prevention (CDC) data documents more than doubling in the age-adjusted rate of deaths from suicide and unintentional overdose between 2010 and 2017. It is estimated that about 20% to 30% of opioid overdose deaths are intentional, and the rate of suicides could be even higher.7 The associations between opioid prescribing, overdose, and suicide deaths were recently reviewed

by Bohnert and Ilgen.8 They note that the increase is likely related to both the increased demand for opioids (so-called “death of despair”) and the increasing supply of opioids in the US including prescription and illicit opioid drugs.

The Relationship:

Mental Health, Opioid Prescribing, and Suicide Risk

Recent studies suggest that adults with mental health disorders are more likely to be prescribed opioids, as was shown in patients presenting to a university

“Among

US Veterans of Iraq and Afghanistan, mental health disorder diagnoses, especially posttraumatic stress disorder, were associated with an increased risk of receiving opioids for pain, high-risk opioid use, and adverse clinical outcomes.”

clinic for chronic pain and in Veterans.9,10 According to Davis et al the 16% of Americans who have mental health disorders receive over half of all opioids prescribed in the US.11 In their analysis, having a mental health disorder was associated with twice the likelihood of prescription opioid use overall. In another study, patients with mood disorders were more likely to be started on opioid therapy and nearly twice as likely to use opioids long-term for pain than those without mood disorders.12 A study of the Veteran population receiving care in the Veterans Health Administration (VHA) showed that about 50% of Veterans with at least 1 pain condition had a mental health disorder diagnosis, and in the subset of Veterans attending pain specialty care, this number rose to 68%. The study showed that patients attending pain specialty clinics had more difficult-to-treat pain conditions and comorbid psychiatric disorders, and received a greater number of opioid prescriptions.13 Among US Veterans of Iraq and Afghanistan, mental health disorder diagnoses, especially posttraumatic stress disorder (PTSD), were associated with an increased risk of receiving opioids for pain, high-risk opioid use, and adverse clinical outcomes.10 Moreover, opioids in and of themselves may affect mental health disorder diagnoses: Scherrer et al documented an increased risk of new-onset depression in opioid naïve patients after opioid exposure in patients enrolled in 3 separate US healthcare systems.14 In the VHA population, 12% developed new onset depression, with risk increasing the longer the duration on opioids.

They estimate 1 subsequent case of depression for every 12 patients exposed to longer than 90 days of opioid analgesic use.14

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Thus, there is evidence that patients with mental health conditions are more likely to receive opioids, for a longer duration and at higher dosages, to misuse and/or abuse opioids, to overdose, and to consider and/or attempt suicide. Conversely, improvements in pain leads to improvement in mental health symptoms and vice versa.

The link between opioid prescribing and the risk of opioid overdose deaths is generally accepted and shows a clear dose dependent relationship. Similarly, there is a clear link between opioids and suicide risk that is, however, less strongly correlated with prescribed daily opioid dosage.15 High doses may be a marker for other factors that drive suicide, including unresolved severe chronic pain and mental health disorders.

Among Veterans receiving care in the VHA who had referrals to pain specialty care services, the presence of moderate to severe pain intensity was associated with suicide attempts in the following year.16 Interestingly, when that study used an adjusted model, while pain intensity had similar hazard ratios as having an opioid analgesic prescription, even higher hazard ratios were seen among those with mental health and substance use disorders. Similarly, as was shown in Veterans receiving opioid medication for pain, the presence of mental health and, in particular SUD, was a greater predictor of deaths from opioid overdose or suicide than medical factors, the type or dosage of opioid medication, or co-prescribing with benzodiazepines.17 There is a particularly strong association between suicide and the presence of OUD, far greater than for other substance use disorders.8 It is also possible that the presence of severe pain may lead to riskier use of prescription or illicit opioids.

Suicide Prevention

Death by suicide is a global phenomenon. In 2016, suicide accounted for 1.4% of all deaths worldwide, making it the 18th leading cause of mortality.18 Suicide in the US, however, is now the 10th leading cause of death, accounting for more than 48,000 deaths in 2018.19 Death by suicide is considered a public health concern in that rates of suicides have risen 33% since 1999.19 Moreover, research suggests that approximately 90% of those who attempt suicide do not die as a result of the attempt.20 In 2017, there were an estimated 1,400,000 suicide attempts.21 While loss of life is certainly a major aspect of this public health problem, suicidal behavior that does not result in death is also a significant concern. The physical, emotional, and economic impact of suicide attempts affects not only survivors, but those close to survivors and the public at large.

Although suicide occurs among all categories of individuals in the US, service members and Veterans are at especially elevated risk for death by suicide.

Based on data from the Office of Mental Health and Suicide Prevention,22 in 2018, approximately 127.4 people died by suicide each day and Veterans accounted for 17.6 (6.5 with recent VHA use and 11.1 without recent VHA use) of these deaths. Veterans who died by suicide were more likely to be male and between the ages of 18 and 34. Compared to non-Veteran adults, female Veterans were 2.1 times more likely to die by suicide vs non-Veteran female adults, and male Veterans were 1.3 times more likely to die by suicide vs non-Veteran male adults.

Research studies that examine deaths by suicide offer strong evidence that individuals who die by suicide often receive healthcare services, such as healthcare appointments, in the year prior to death. Reasons for seeking services during this time period vary greatly and are often unrelated to mental health.23 In 2016, The Joint Commission published a Sentinel Alert (used to make healthcare systems aware of serious events and conditions and associated recommendations) notifying providers of this important need to screen and evaluate patients for suicide risk.

The Joint Commission later implemented new requirements that reflect the need for expanding suicide risk screening across healthcare systems (see Table of Resources at pain. sh/mhl). Additionally, VHA’s Office of Mental Health and Suicide Prevention’s (OMHSP) National Strategy for Preventing Veteran Suicide also leveraged this new public health approach to suicide prevention by focusing on collaboration and the urgent need for prevention.24 In 2018, VHA’s OMHSP launched an effort called the VA Suicide Risk Identification Strategy (VA Risk ID) to develop and implement a national, standardized process for suicide risk screening and assessment, using high-quality, evidence-based tools and practices that would provide the type of universal, selected and indicated screening needed across VHA. The strategy offers a 3-stage approach starting with a primary screen for suicide risk

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(PHQ9 item 9).25 Those who screen positive on the primary screen receive the second level screener: the Columbia Suicide Severity Rating Scale (C-SSRS).26 The C-SSRS includes 3 to 8 questions—depending on the Veteran’s responses— that specifically query about suicidal thoughts, plan, intent, and behavior. Veterans who screen positive on the C-SSRS will receive the Comprehensive Suicide Risk Evaluation (CSRE), which allows providers to gather information about suicidal ideation, suicidal behavior, warning signs, risk factors, and protective factors to make an informed assessment of both acute and chronic risk for suicide and to develop an individually tailored risk mitigation plan for the Veteran for whom the risk has been identified. VA Risk ID is consistent with the VA/dod Clinical Practice Guideline for the Assessment and Management of Patients at Risk for Suicide (VA/dod CPG) (see Table at pain.sh/mhl).27 Notably, a consultation service is available to providers treating Veterans outside of VHA to support suicide prevention among all Veterans (see Table).

Screening and evaluation are important aspects of suicide prevention, although at times patients may spontaneously report information related to suicidal thoughts or behaviors. Responding appropriately to concerning statements or behaviors is another key aspect of preventing loss to suicide. If providers notice changes in a patient’s behavior or moods, starting a conversation with the patient about potential thoughts of suicide can help a patient feel valued and recognized while also providing education about what resources are available. The simple act of starting a conversation about suicide can mean the difference between a tragic outcome and a life saved. Providers who observe any of the following may want to initiate a conversation about the potential for increased risk of suicide:

● Talking about dying or killing oneself ● Verbalized feelings of hopelessness/ helplessness or feeling burdensome to others ● Withdrawal/isolation from family/friends ● Sudden increase in use of alcohol/drugs ● Onset or worsening of sleep problems ● Any preparatory behaviors, such as writing a note or seeking out means

It is common for providers to feel unsure about how to start these conversations. One example of initiating a conversation about suicide is “I’m hearing that you’ve been having a difficult time lately, and I’m so glad you shared this with me. Here in VA, we are concerned about Veteran suicide and we want our Veterans to know that they can discuss this topic with us. I’d like to ask, have you had any recent thoughts about wanting to die or killing yourself?” Depending on the response, the provider might feel comfortable asking follow-up questions, administering a screening tool, or conducting a warm hand-off to a mental health professional.

Widespread findings across research that examines means of suicide demonstrate that firearm injury is the leading cause of suicide among the US population, including among Veterans and all dod components (Active, Reserve, National Guard).28 Moreover, a suicide by firearm is not necessarily dependent upon owning the firearm. Residing in a household with a firearm is associated with a significantly increased risk of suicide across US regions, states, cities, and households.29 After firearms, suffocation (28%) and poisoning (including overdoses on medication, 14%) account for the next largest number of suicide deaths, followed by other means (eg, falls, cuts).30 With regard to lethality, firearms also act as the most lethal means of acting on suicidal thoughts—85% to 90% of self-inflicted firearm injuries are fatal.31 While there are many long-term and nonmodifiable factors that contribute to overall risk for suicide, the minutes to days leading up to a suicide attempt (“acute risk period”) offer an important opportunity for preventative intervention. The time between when a person decides to die by suicide and acting on that decision is often very short. A study found that 71% of attempters estimated that this process took less than an hour.32 This reality underscores the importance of reducing access to lethal means by building in time and space between the individual and the lethal means for suicide.

Because the acute phase of crisis is often brief, building in as much time and space—with gun locks/lockboxes, storing ammunition separately from gun, utilizing medication lockboxes—between impulse to act and access to lethal means can help save a life. The VA/dod CPG for suicide risk assessment and management strongly recommends assessing for the availability of specific lethal means (such as firearms, excess medication) as part of comprehensively evaluating suicide risk. VHA’s Rocky Mountain Mental Illness Research, Education and Clinical Center (MIRECC) created a Firearm Safety in Times of Community Stress tip sheet that may be helpful.33 For patients with pain, a discussion about how to maintain safety despite having access to ways to harm oneself (ie, lethal means safety) related to medications can be particularly helpful. Recommended safety practices may include: ● Blister packets for home medications ● Use of medication disposal kits and bins

for unneeded medications ● Asking a doctor or pharmacist to limit

the number of refills or the quantity

of pills prescribed ● Having a family member or friend

administer medication in the correct dosage ● Portioning out pills for a few days ● Locking away any remaining pills ● Giving any remaining pills to a trusted

family member or friend

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Resources to support lethal means safety and suicide prevention counseling are included in the Table of Resources available at pain.sh/Mhl.

Opioid Tapering and Suicide Risk

Studies clearly document that patients with chronic pain and receipt of opioid medication for pain have an increased suicide risk, and this appears to be particularly high in the context of mental health symptoms.

Thus, opioid tapering in the chronic pain patient occurs in the setting of an already vulnerable population at risk for suicide. The concern that opioid tapering or discontinuation may further exacerbate the risk of suicidal ideation, suicide attempts, and suicide deaths has received greater attention recently.

A study in Veterans whose clinicians discontinued their opioid medication documented suicidal self-directed violence (meaning suicide attempts or preparatory behavior) in 2.3%, and an additional 9.2% experienced suicidal ideation without self-directed violence.34 Of these Veterans, about half carried a diagnosis of SUD. The risk for suicidal ideation or behavior was greater in patients with a history of having a mental health disorder diagnosis, in particular PTSD and psychotic diagnoses.

The risk was not linked to opioid dosage and was similar in patients with or without SUD. Lovejoy et al found that among long-term opioid therapy patients who were discontinued based on clinician decisions (85% of their sample), 75% were discontinued due to aberrant behaviors.35 Im et al also found that drug use disorder and alcohol use disorder were both associated with increased risk of suicide attempts among patients receiving chronic short-acting opioids or long-acting opioids from VHA clinicians.36 Based on an analysis of Veterans whose opioid pain medication was discontinued in 2013 and who were followed to the end of 2014, a VHA observational study found that opioid discontinuations were associated with an increased risk of death from opioid overdose or suicide.37 Descriptive data suggested that risk was pronounced in the period immediately following opioid discontinuation; the period following opioid initiation was also an elevated risk period.

The rapid proliferation of studies showing adverse outcomes associated with chronic opioid therapy for pain (eg, overdose, addiction) is juxtaposed with increasing media reports and a growing number of studies identifying adverse outcomes—including suicide—when chronic opioid therapy is tapered or discontinued.38,39 An awareness of the potential risk related to opioid tapering, in particular inappropriately rapid tapering and abrupt opioid medication discontinuation, has resulted in safety warnings from the US Food and Drug Administration (FDA) in 2019 and a statement by the authors of the CDC opioid

“Among Veterans receiving care in the VHA who had referrals to pain specialty care services, the presence of moderate to severe pain intensity was associated with suicide attempts in the following year.”

prescribing guideline in 2016 that sought to clarify their recommendations.40 Recently, the National Academy of Medicine published a comprehensive review of issues related to opioid tapering in patients on long-term opioid therapy for chronic noncancer pain.41 With awareness of the opioid crisis, doctors with good intentions, and driven by patient safety considerations, may taper or discontinue opioid therapy as a means to mitigate risks of addiction, overdose, or death.

Although efforts to rein in opioid prescribing are clearly needed, a 1-size fits all approach may be detrimental to patients. Pain management staff will likely have to use different strategies to reduce reliance on opioids and address pain when working with patients with acute vs chronic pain and in particular patients who are opioid naïve vs those on chronic opioid therapy. There is clearly a need to broaden current efforts—which tend to focus solely on opioid prescribing—towards more holistic, patient-centered care to address the myriad of issues that place patients prescribed opioids at greater risk for suicide.

Despite the robust associations between opioid dosage and risk of adverse outcomes, the vast majority of opioid overdose-related deaths among patients prescribed opioids occurred among those on low doses of opioids.42 For instance, internal VHA data found that in fiscal year 2013, among patients prescribed opioids who had died of overdose/suicide, almost 4 of every 5 patients who died were prescribed doses less than 90 mg morphine equivalent daily dose yet almost 3 of every 4 overdose/ suicide deaths were among patients with mental health or SUD diagnoses. These data underscore the importance of taking into consideration mental health and SUD when assessing risk for overdose/suicide.

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The importance of taking a patient-centered approach to improve opioid safety is underscored by the predictive analytic model underlying VHA’s Stratification Tool for Opioid Risk Mitigation (STORM), which placed opioid prescribing risk in relation to other risk factors for overdose/ suicide.43 The model found that previous healthcare utilization (eg, previous overdose/suicide, detoxification, and inpatient mental health treatment), SUD, and psychiatric comorbidities had among the highest odds ratios for overdose/suicide events. Medical comorbidities also played a role as did other evidence-based sedating pain medications (eg, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and anticonvulsants) in addition to opioids and sedatives. The STORM predictive analytic model highlighted how large healthcare systems can leverage their administrative data to identify patients at risk for overdose/ suicide. VHA is wrapping up a national randomized program evaluation that will characterize STORM implementation and its impact on patient outcomes.44-46

Conclusion

Providers and/or supporting staff must consider an individual’s risk not just from continuing opioids in the face of an epidemic, but also from opioid tapering, whether due to compensatory dose reduction or discontinuance. Based on a comprehensive biopsychosocial risk assessment and discussion with the patient, the provider should consider a clinical determination based on best probable outcomes for that patient, leveraged with appropriate risk mitigation strategies, follow-up, and thoughtful, empathetic care. If a taper is deemed medically indicated and initiated, there should be heightened awareness for

the potential manifestations of OUD, increasing pain and despair, further loss of self-worth/esteem, and/or an elevated sense of disconnection or abandonment, potentially culminating in significant suicide risk and lethal outcome.

As pain management providers, it is important to acknowledge, study, and learn from data. It is also imperative to act on them through the prism of patient-centered care, taking into consideration the impact on the individual, and the need for an individualized, holistic care plan. Taken in whole, our review heralds the necessary adoption of the biopsychosocial model to meet complex patient needs, harkening to Howe and Sullivan’s assertion that psychiatry is the “missing P” in chronic pain care.47

Acknowledgments

We thank Bridget Matarazzo for her feedback on drafts of this paper, Justina Wu for her editorial assistance, and acknowledge the sacrifices of men and women who have served in the US military.

12. Halbert BT, Davis RB, Wee CC. Disproportionate longer-term opioid use among U.S. adults with mood disorders. Pain. 2016;157(11):2452–7. Available at: journals.lww.com/00006396–201611000–00010.

13. Arout CA, Sofuoglu M, Rosenheck RA. Rates and correlates of pain specialty clinic use nationally in the Veterans Health Administration. Pain Med. 2017;pnw206.

Available at: academic.oup.com/painmedicine/article-lookup/doi/10.1093/pm/pnw206.

14. Scherrer JF, Salas J, Copeland LA, et al. Prescription opioid duration, dose, and increased risk of depression in 3 large patient populations. Ann Fam Med. 2016;14(1):54–62.

15. Ilgen MA, Bohnert ASB, Ganoczy D, et al. Opioid dose and risk of suicide. Pain.

2016;157(5):1079–1084. Available at: journals.lww.com/00006396–201605000–00013.

16. Ashrafioun L, Kane C, Bishop TM, et al. The association of pain intensity and suicide attempts among patients initiating pain specialty services. J Pain. 2019;20(7): 852–859. Available at: linkinghub.elsevier.com/retrieve/pii/S1526590019300872.

17. Oliva EM, Christopher MLD, Wells D, et al. Opioid overdose education and naloxone distribution: development of the Veterans Health Administration’s national program. J Am Pharm Assoc. 2017;57(2):S168-S179.e4. Available at: linkinghub.elsevier. com/retrieve/pii/S1544319117300250.

18. World Health Organization. Suicide data. World Health Organization.

Available at: www.who.int/mental_health/prevention/suicide/suicideprevent/en/.

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21. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: results from the 2018 National Survey on Drug Use and Health. Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration; 2019.

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4. Ilgen MA, Zivin K, McCammon RJ, et al. Pain and suicidal thoughts, plans and attempts in the United States. Gen Hosp Psychiatry. 2008;30(6):521–527.

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23. The Joint Commission. Sentinel Event Alert #56: Detecting and treating suicide ideation in all settings. 2016. Available at: www.jointcommission.org/-/media/ deprecated-unorganized/imported-assets/tjc/system-folders/assetmanager/ sea_56_suicide_infographic_2_10_16_finalpdf.pdf.

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24. Office of Mental Health and Suicide Prevention. National Strategy for Preventing Veteran Suicide 2018–2028. Office of Mental Health and Suicide Prevention. Available at: www.mentalhealth.va.gov/suicide_prevention/docs/ Office-of-Mental-Health-and-Suicide-Prevention-National-Strategy-forPreventing-Veterans-Suicide.pdf.

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8. Bohnert ASB, Ilgen MA. Understanding links among opioid use, overdose, and suicide. N Engl J Med. 2019;380(1):71–79. Available at: www.nejm.org/doi/10.1056/ NEJMra1802148.

25. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–613. Available at: link.springer.com/10.1046/j.1525–1497.2001.016009606.x.

9. Goesling J, Henry MJ, Moser SE, et al. Symptoms of depression are associated with opioid use regardless of pain severity and physical functioning among treatment-seeking patients with chronic pain. J Pain. 2015;16(9):844–851. Available at: linkinghub.elsevier.com/retrieve/pii/S1526590015007026.

26. Posner K, Brent D, Lucas C, et al. Columbia-suicide severity rating scale (C-SSRS).

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27. Department of Veterans Affairs, Department of Defense. VA / DOD Clinical Practice Guidelines for the Assessment and Management of Patients at Risk for Suicide. Department of Veterans Affairs, Department of Defense. Available at: www. healthquality.va.gov/guidelines/MH/srb/VADODSuicideRiskFullCPGFinal5088919.pdf.

10. Seal KH, Shi Y, Cohen G, et al. Association of mental health disorders with prescription opioids and high-risk opioid use in US Veterans of Iraq and Afghanistan.

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28. Office of Mental Health and Suicide Prevention. 2019 National Veteran Suicide Prevention Annual Report. Veterans Health Administration, Office of Mental Health and Suicide Prevention; 2019. Available at: www.mentalhealth.va.gov/docs/datasheets/2019/2019_National_Veteran_Suicide_Prevention_Annual_Report_508.pdf.

11. Davis CS, Burris S, Beletsky L, et al. Co-prescribing naloxone does not increase liability risk. Subst Abuse. 2016;37(4):498–500. Available at: www.tandfonline.com/doi/full/10.1080/08897077.2016.1238431.

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29. RAND. The relationship between firearm availability and suicide. RAND; 2018.

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46. Rogal SS, Chinman M, Gellad WF, et al. Tracking implementation strategies in the randomized rollout of a Veterans Affairs national opioid risk management initiative.

Implement Sci. 2020;15(1):48. Available at: implementationscience.biomedcentral.com/ articles/10.1186/s13012–020–01005-y.

30. Suicide Prevention Resource Center. Scope of the Problem. Means of Suicide.

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47. Howe CQ, Sullivan MD. The missing ‘P’ in pain management: how the current opioid epidemic highlights the need for psychiatric services in chronic pain care. Gen Hosp Psychiatry. 2014;36(1):99–104. Available at: linkinghub.elsevier.com/retrieve/pii/ S0163834313002600.

31. Wang J, Sumner SA, Simon TR, et al. Trends in the incidence and lethality of suicidal acts in the United States, 2006 to 2015. JAMA Psychiatry. 2020;77(7):684.

Available at: jamanetwork.com/journals/jamapsychiatry/fullarticle/2764307.

32. Simon TR, Swann AC, Powell KE, et al. Characteristics of impulsive suicide attempts and attempters. Suicide Life Threat Behav. 2002;32:49–59. Available at: doi.wiley.com/10.1521/suli.32.1.5.49.24212.

33. Veterans Health Administration. Firearm Safety in Times of Community Stress.

Rocky Mountain Mental Illness Research Education and Clinical Center for Suicide Prevention. 2020. Available at: www.mirecc.va.gov/visn19/docs/Firearm_Safety_ Times_Comm_Stress_v_9_3_20.pdf.

34. Demidenko MI, Dobscha SK, Morasco BJ, et al. Suicidal ideation and suicidal self-directed violence following clinician-initiated prescription opioid discontinuation among long-term opioid users. Gen Hosp Psychiatry. 2017;47:29–35. Available at: linkinghub.elsevier.com/retrieve/pii/S0163834317301093.

35. Lovejoy TI, Morasco BJ, Demidenko MI, et al. Reasons for discontinuation of long-term opioid therapy in patients with and without substance use disorders. Pain.

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36. Im JJ, Shachter RD, Oliva EM, et al. Association of care practices with suicide attempts in US Veterans prescribed opioid medications for chronic pain management. J Gen Intern Med. 2015;30(7):979–991. Available at: link.springer.com/10.1007/ s11606–015–3220-y.

37. Oliva EM, Bowe T, Manhapra A, et al. Associations between stopping prescriptions for opioids, length of opioid treatment, and overdose or suicide deaths in US veterans: observational evaluation. BMJ. 2020;m283. Available at: www.bmj.com/lookup/doi/10.1136/bmj.m283.

38. Treating America’s Pain: Unintended Victims of the Opioid Crackdown, Parts 1–3.

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39. Szalavitz M. When the cure is worse than the disease. New York Times. 2019.

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40. Dowell D, Haegerich T, Chou R. No shortcuts to safer opioid prescribing.

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41. RIch R, Chou R, Mariano ER, et al. Best practices, research gaps, and future priorities to support tapering patients on long-term opioid therapy for chronic non-cancer pain in outpatient settings. NAM Perspect. 2020. Available at: nam.edu/ best-practices-research-gaps-and-future-priorities-to-support-tapering-patients-onlong-term-opioid-therapy-for-chronic-non-cancer-pain-in-outpatient-settings/.

42. Bohnert ASB. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305(13):1315. Available at: jama.jamanetwork. com/article.aspx?doi=10.1001/jama.2011.370.

43. Oliva EM, Bowe T, Tavakoli S, et al. Development and applications of the Veterans Health Administration’s Stratification Tool for Opioid Risk Mitigation (STORM) to improve opioid safety and prevent overdose and suicide. Psychol Serv.

2017;14(1):34–49. Available at: doi.apa.org/getdoi.cfm?doi=10.1037/ser0000099.

44. Chinman M, Gellad WF, McCarthy S, et al. Protocol for evaluating the nationwide implementation of the VA Stratification Tool for Opioid Risk Management (STORM).

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45. Minegishi T, Frakt AB, Garrido MM, et al. Randomized program evaluation of the Veterans Health Administration Stratification Tool for Opioid Risk Mitigation (STORM): a research and clinical operations partnership to examine effectiveness.

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

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

Much of the information the clinician gleans about the patient’s pain complaint is gained in a comprehensive history and physical examination.

Here is a continuation of Pain Assessment, the first part of which appeared in the last issue of PWJ, 2020 Q4.

The presence and timing of pain exacerbations may indicate the need for increased analgesic medication or nonpharmacologic interventions.

Important questions to ask the patient include: ○ What are the variations and patterns of pain?

What factors alleviate or worsen pain? → Patterns of pain can be helpful in diagnosis and treatment. For example, patients with consistent patterns of morning pain can have their medication regimen adjusted to help accomplish morning routines. The temporal pattern of pain—that is, whether it is constant or intermittent, sudden, or gradual— is one of the most important elements in the medical history that leads to diagnosis. → Provocative factors, such as activities like bending forward or backward, may also be helpful in determining the differential diagnosis. Relief maneuvers, such as bedrest or activity modification, are important as well.

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○ When was the onset of pain? What is the history of prior pain management interventions? Were any of these interventions successful? → The onset of pain, both in terms of the duration of pain and the way the pain occurred (acute, accident, insidious), has implications for treatment and may hold meaning for the patient. For example, an insidious onset of pain with an unexplained etiology may have different implications in terms of seeking treatment and coping with pain. → Patients should also be asked about prior use of pharmacologic, nonpharmacologic, and procedural interventions for pain.

The patient may have used alternative or complementary medical approaches, such as herbal preparations, acupuncture, or magnets.

The relief experienced from each of these interventions can be measured by using a visual analogue scale (VAS) or by asking the patient to assign a percentage value of relief (eg, 50% pain relief from the use of nonsteroidal anti-inflammatory drugs) for each treatment.

○ What are the physical limitations resulting from the pain? → Patients are generally quick to describe their functional limitations due to pain. Walking, performing domestic chores, or the ability to continue working in their occupation may all be affected. Individuals in acute pain may be unable to turn over, cough, or breathe deeply, secondary to their pain. Special attention should be paid to how patients may compensate for their inability to perform physical tasks, such as walking. Be aware that compensation with another limb (eg, performing all duties with one hand) can lead to overuse syndromes and/or more serious problems in previously unaffected areas.

addition, the examination should involve an assessment of the patient’s functional abilities. A careful examination of the site of the patient’s pain, including anatomic sites of commonly referred pain, should also be performed. The general appearance of the patient, including attributes of the skin, posture, and demeanor are important aspects of the general physical examination.

Musculoskeletal Examination

The musculoskeletal examination includes an overall examination and focused palpation, or manipulation, at the site of pain. The examination needs to be tailored to the pain complaint. Muscle systems in the neck, upper extremities, trunk, and lower extremities should be tested.2 Deep or superficial muscle tenderness should be noted. The quality of the patient’s response to palpation may be considered in the assessment. Vocalizations or a display of pain behavior may be part of the patient’s cultural and/or ethnic background and can be of importance. When a more stoic individual displays pain behavior in response to palpation, it may be important.3 Range of motion, including flexion, extension, side bending, rotating, and straight leg raises, should be performed when relevant to ascertain whether pain is experienced on movement, and to note the presence of functional restrictions. The degree to which these actions are performed, and whether pain is incurred during each of these exercises, should be recorded.

○ What are the expectations of pain treatment? → Patients may have high or unrealistic expectations for treatment. Although the probability that these expectations can be met in an acute setting is high, it may decrease for chronic pain conditions. → The urgency of treatment and the expectations for it may be based on inaccurate assumptions or beliefs: for example, that pain signifies ongoing damage or the return of a cancerous tumor. Patient education about the underlying cause of the pain and the effectiveness of medications, interventional procedures, and nonpharmacologic treatments should be delivered carefully and honestly in lay language. Setting appropriate expectations of treatment can itself be of therapeutic benefit.

Neurologic Examination

PHYSICAL EXAMINATION FOR PAIN The physical examination for patients with pain should include a general physical, as well as neurologic, musculoskeletal, and mental assessments, and it is likely to be a more complex process than that of other medical patients.1 In

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A tailored neurologic examination is a key component of the physical examination for pain. The neurologic screening examination should include standard elements, with testing of the cranial nerves II–XII. Motor and sensory functioning in the limbs and an evaluation of rectal and urinary sphincter function have been recommended. Sensory deficits are tested by sensitivity to light touch, pinprick, and mechanical and thermal stimuli. Light touch, pressure, or the application of hot and cold stimuli can cause allodynia—that is, the presence of pain from a stimulus that is not normally painful. Hyperalgesia, or extreme pain from stimuli that normally do cause pain, can be tested by single and multiple pinpricks, and is evidence of pathology. A motor examination should test for motor weakness, ataxia, apraxia, and decreased endurance.3 Reflexes should be normal and symmetric. In addition, pathologic reflexive signs, such as those of Babinski, Oppenheim, Gordon, Chaddock, Schaeffer, and Hoffman, should be tested when appropriate.

DIAGNOSTIC TESTING

Neurophysiology Studies

Diagnostic testing can be useful for some pain conditions and may not be useful in other types of pain conditions.

Therefore, familiarity with general principles of diagnostic testing is important when assessing patients with pain.

Imaging Studies

Imaging studies show anatomy, not pain. Thus, there may be false-positives where “abnormalities” are revealed that are unrelated to the patient’s pain, or false-negatives where the anatomy is “normal,” yet pain continues. Computed tomography myelogram, magnetic resonance imaging, ultrasound, and radionuclide examinations are used in patients with pain to confirm or rule out a diagnosis, based on the patient’s report and the physician’s assessment. In the presence of certain signs and symptoms, such as an extremely severe headache or a history of malignancy, imaging can be critical to diagnosis and treatment. Imaging is appropriate for potentially serious spinal conditions, including spinal tumor, fracture, and cauda equina syndrome. Imaging studies are necessary for chronic pain conditions (eg, unremitting cervical or back pain) for which surgery is being considered.

However, imaging plays a limited role in some chronic pain conditions. Because suspected pathologic conditions, such as herniated or bulging disks and nerve root scarring, are frequently found in asymptomatic individuals, the need for imaging studies, and interpretation of results, must be carefully considered, lest they result in inappropriate interventions for irrelevant pathology, or in distraction from the real cause of the pain.

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Electromyography and nerve conduction studies are electrodiagnostic procedures that evaluate action potentials and conduction along peripheral sensory and motor nerves.

They are used to suggest the presence or absence of nerve entrapment, radiculopathy, trauma, and systemic neurologic disease.4 These tests can provide useful information in the evaluation of the cause and extent of peripheral nervous system disease, but they are often unnecessary in the diagnosis of neuropathic pain conditions. Because they measure the functioning of large nerve fibers, they are not useful in diagnosing many neuropathic conditions that result from small-fiber damage or dysfunction.3 Quantitative sensory testing measures the function of large and small nerve fibers in addition to pain thresholds. The technique is used for researching the mechanisms of neuropathic pain and is generally not needed for diagnosis and treatment. Analogous to the case of imaging, electromyography/nerve conduction studies show nerve damage, not pain; thus, electromyography/nerve conduction studies may be abnormal but unrelated to the pain, or normal in the presence of pain.

References 1. Swarm RA, Paice JA, Anghelescu DL, et al. Adult Cancer Pain, Version 3.

2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw.

2019;17(8):977–1007.

2. Irving GA, Squire PL. Medical evaluation of the chronic pain patient. In: Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2018:209–224.

3. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. New York: McGraw Hill Healthcare Information Programs; 2000.

4. Chang DG, Date ES. Electrodiagnostic evaluation of acute and chronic pain syndromes. In: Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2009:225-234.

365 day s a year.*

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

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Ginevra Liptan MD Founder and Medical Director , The Frida Center for Fibromyalgia

“As a physician with fibromyalgia, I feel uniquely positioned to act as an advocate for fibromyalgia patients…”

GPS Wonderfully weird Portland, Oregon. Typical Day Drink too much coffee, walk the dog, get my teenager “logged in” to school, then head to the clinic, where my first appointment is not until 10am (working with my own biorhythms is my fave part of being in private practice!). After scrambling through the clinic day, it’s home for family dinner, homework help, and catching up on that pile of charts. I’ll end the day with some gentle movement and stretching, then snuggle up with a good book. Persona As a physician with fibromyalgia, I feel uniquely positioned to act as an advocate for fibromyalgia patients, and to help other healthcare providers understand how to provide the best medical care for their fibro patients. Social Media Habits I’ll skim through Apple News, but I don’t voluntarily check any social media. My daughter sends me many TikTok videos she thinks I will like, so I am a secondhand TikTokker, I guess? Contribution My book, The FibroManual: A Complete Fibromyalgia Treatment Guide for You and Your Doctor, in which I tried to turn everything I know about treating fibromyalgia into advice both patients and providers can use. People Frida Kahlo, the Mexican artist who suffered from chronic pain and is thought to have had fibromyalgia. Her painting The Broken Column is the best visual representation of fibromyalgia pain I have ever seen, and her ability to turn incredible suffering into beauty inspires me every day. Words I love to read mysteries and thrillers, anything with a puzzle to be solved. The Girl with the Dragon Tattoo. The darker the better! Popcorn Laughter is great self-care! I love silly comedies starring women—anything with Melissa McCarthy or Kate McKinnon. I’ll pick Bridesmaids. PAINWeek Spending time with my tribe of other providers who are passionate about pain medicine is the highlight of my year. I always learn so much that I can bring home and use in my clinic.

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By Kate Schopmeyer

pt, dpt, cpe

Words that we, as clinicians, might consider innocuous could in fact directly influence somebody’s experience of pain.

Referral language is changing from “Diagnosis: Chronic low back pain or idiopathic low back pain.

Needs core stabilization” to “Please help the patient with beliefs and fear avoidance. He could benefit from some pain neuroscience education.”

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Are some flare-ups of

urologic chronic pelvic pain syndrome (ucpps) caused by pollen?

Pollen levels were compared in

participants,

Frozen shoulder— adhesive capsulitis—

Exercise is often recommended

for patients with low back pain (LBP).

is a common, painful fibroproliferative tissue fibrosis affecting 2.4 out of

In a review of

thousand

studies,

people per year. from an overall group of

From 65 studies with

4097

patients

participants,

34 studies with

in 8 studies, and assessed every 2 weeks for 1 year as part of MAPP: Multidisciplinary Approach to the study of Chronic Pelvic Pain. 1 to 2 days after pollen counts exceeded a threshold, the odds of a symptom flare increased by

22% 33%

2402

did not provide a mechanism of benefit for exercise in people with chronic LBP.

Of the remaining studies, most provided >1 mechanism, from which

30 three

participants

were included in pairwise meta-analyses and 39 studies with

2736 participants

in all patients with UCPPS, and

(33%)

in network meta-analyses.

Only intra-articular corticosteroid was

associated with statistical and clinical superiority compared with other interventions in the short-term for pain and function.3

unique mechanisms

were identified and grouped into 5 themes: neuromuscular, n=105 (44%); psychosocial, n=8 (36%); neurophysiological, n=22 (9%); cardiometabolic, n=15 (6%); and tissue healing, n=12 (5%).5

in those with allergies.1

Depression/fatigue/pain

commonly co-occur in those with multiple sclerosis (MS).

A review of 8 studies and

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Does early improvement in 1 affect the other 2?

patients patients compared opioids given alone, nitrous oxide given alone, and intranasal ketamine given with nitrous oxide to determine analgesic properties of ketamine.

The end result: treatment with IV ketamine in analgesic doses of 0.1 to 0.2 mg/kg was at least as effective as opioids administered alone in pain reduction.2

with fibromyalgia—mean age 52, 94% female—completed 14 days of actigraphy to determine how activity affected their sleep.

Average activity intervals (12:00–3:00p, 3:00–6:00p and 6:00–9:00p) were studied.

Results:

increased physical activity in the afternoon and early evening caused sleep disturbance, especially in individuals with higher pain levels.4

adults

with MS, 86% women, participated in an 8-week self-management (n = 69) or education (n = 85) intervention via telephone.

Early ↓ in depressive symptoms = overall ↓ in pain/fatigue impact (P<.01).

Early ↓ in fatigue = overall ↓ in depressive symptom severity (P=.04) but not pain interference. Early ↓ in pain interference did not reduce the other 2 symptoms.6

1. pain.sh/n8n 2. pain.sh/7cf 3. pain.sh/7ug 4. pain.sh/pvg 5. pain.sh/5a9 6. pain.sh/i7e

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Marijuana and the Elderly Patient

Tanya J. Uritsky PharmD, BCPS; Maria C. Foy PharmD, BCPS, CPE Is the generation of older baby boomers self-medicating with marijuana, whether medical or recreational? Pain is common in the aging population. Elderly patients, trying to avoid prescription medications, may try marijuana.

What to consider: ● Many of these patients have never used cannabis ● Evidence is lacking ● There are potential dangers ● With medical marijuana, as always, start at a very low dose; educate patients so they don’t overdo

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Challenges:

Trauma Informed Care

● What might be fine for younger patients could affect the elderly differently: they might hallucinate and become psychotic ● Older adults are often excluded from studies ● Much of our data is from younger, healthier people ● Much of our data is for single doses ● We don’t know how repeated doses affect an older adult; a single dose is easier to eliminate than 10, or 15, or multiple weeks’ worth

Brian F. Kaufman DO, FACP, FACOI

● Some biochemical/structural changes that occur due to trauma or ptsd are similar in neurobiology to those in substance use disorder and chronic pain ● Some patients don’t understand that they’ve had traumatic events in their lives because to them it was normal ● The range can be from something awful, to a less traumatic event; a divorce can be traumatic to a child, leading to developmental problems and emotional issues ● For traumatized people, the subconscious has “knowns” and “unknowns”—knowns = pleasure; unknowns = pain. If I’m asking a patient to do something they’ve never done like squats, yoga, gyrokinesis, it can be a painful unknown

It is concerning; we want to make sure that if we are recommending cannabis to our older adults that we are doing it carefully. In some states, Pennsylvania for example, there are pharmacists in dispensaries. Patients should be receiving getting good counseling, and a lot of follow-up care.

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A Clinical Decision Tool for Sickle Cell Disease Leigh Ann Wilson LCSW; Collin V. Montgomery APRN

2

An adult sickle cell clinical decision tool can standardize opioid prescribing for patients. Its algorithm addresses the following:

Evidence & Treatments & Skeletal Muscle Relaxants

Christopher M. Herndon PharmD, BCPS, CPE

● Mental health in the sickle cell patient ● Any disease-related complications, including those which can be corrected with surgery ● Nonpharmacologic, nonopioid management ● How to improve patient quality of life ● If this patient actually just has chronic pain that needs to be managed ● If opioids need to be increased or decreased

Potential nonpharmacologic treatment of spasms, spasticity, or even chronic musculoskeletal pain: ● Transcutaneous electrical nerve stimulation (tens)— some can be useful for patients experiencing pain due to spasm ● Heat and ice are still tried and true: usually acute injury=ice ● Alternative modalities for pain treatment, such as acupuncture ● Guaifenesin: small studies have debunked its use, but some believe it has muscle relaxant properties; its chemical structure is fairly similar to methocarbamol

Overall positives seen: ● 50% to 75% reductions in mmes per day ● Fewer opioids due to adjuvant therapies ● Fewer opioids due to surgery for repairs or to fix complications ● Improved mental health due to less resistance to counseling

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5

7

Chronic Overlapping Pain Conditions

Documentation: Legacy of Patient Care?

A

Sawsan As-Sanie MD, MPH

Michael R. Clark MD, MPH, MBA

A cluster of conditions that frequently co-occur, can be local or widespread, and affect women 2x more than men are referred to as chronic overlapping pain conditions. Once a patient has one, it is more likely that they’ll develop another, and may suffer from multiple conditions at one time over their life. Sometimes, when one condition gets better, another begins. They include:

Documentation: ● Started out as a way to keep track of what we’ve done, to create a record that would be a legacy to patient care ● Has transmogrified into a tool for billing, a risk management function ● Informs other professionals caring for your patient your thoughts and how you cared for that patient ● Demands have increased exponentially ● Puts additional pressures on practitioners to try and capture what they’ve been providing in terms of care.

● Endometriosis ● Fibromyalgia ● Painful bladder syndrome ● Irritable bowel syndrome ● Chronic low back pain ● Headaches ● Migraine and tension headaches ● Vulvodynia ● Chronic fatigue syndrome

“If it wasn’t documented, it didn’t happen” ● That’s an unreasonable standard and impossible to accomplish ● No note should have to stand alone

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Kratom: What Should Practitioners Know?

Jeffrey Fudin PharmD, DAAPM, FCCP, FASHP ● Kratom is not part of the standard test for urine screens ● At low doses, kratom blocks reuptake of norepinephrine, serotonin, and dopamine ● It inhibits or induces cytochrome enzymes; there’s a large chance of drug interactions ● As you raise the dose of kratom, it has opioid agonist properties; it’s actually a partial opioid agonist ● Though not technically an opiate (because it’s not derived from a poppy plant) it does have opioid pharmacology and it does affect the opiate receptors; it’s basically a naturally occurring nonopium derived opioid narcotic ● Some states have outlawed it; some countries have outlawed it ● In some states, however, you can find it in gas stations, right next to the CBD lollipops

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with

robert b.

raffa

phd

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“I have been extremely lucky to be able to mostly do what I enjoy doing…”

Q

What inspired you to do what you do?

I have been extremely lucky to be able to mostly do what I enjoy doing, and to have parents who allowed it, even when they didn’t understand what I was doing or why (and maybe I didn’t either). My mother gave us an interest in all things, particularly in the creative—mine and my brother’s turned to science, my sister’s to art. My father kept it real and obtainable. In my 2nd grade classroom, I couldn’t wait to go home. One day I sat staring at a blank outline of a landscape that we were instructed to color-in with crayons. But I had so many crayons to choose from, how could I possibly decide which one(s) to use? My teacher, a nun with more than 60 students in her class, passed by and asked why I was not coloring. I explained the dilemma. She said, “Well, it is fall. Why not color with fall colors.” I told her that I had absolutely no idea what she was talking about. She said, “Just look out the window.

Those colors you see are fall colors.” Whoa, hang on! I thought: there’s a THERE out there?

That’s when I realized that school, and learning in general, could be pretty amazing!

The next inspiration, or maybe impetus is a better word, can be traced to 12 years of religion questions. What did heaven and hell mean? How could there be a trinity? What did eternity mean? These questions spawned my interest and study in thermodynamics (conservation of mass and energy?), saints, guardian angels, original sin (ah, maybe a residual of evolution from animals?). Heady stuff for an elementary-schooler to try to grapple with. And a great training ground for critical thinking, and willingness to challenge and change long-held beliefs. Finally, chemistry class in high school. Linus Pauling’s textbook turned chemistry into a movie. The atoms and molecules whizzing past as I daydreamed—not so far from 2nd grade after all.

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Q

Q

Why did you focus on pain management?

Coincidence. I was studying for a master’s degree in biomedical engineering, thinking about the materials used for the design of artificial hips, feedback control of an artificial pancreas, and other such matters, when I took an elective course in pharmacology. It was taught by a physics/math major turned pharmacologist from Temple University School of Medicine, Dr. Ronald J. Tallarida. He taught pharmacology from the perspective of a chemist/engineer (mathematical receptor concepts). Bingo! My seemingly haphazard schooling all came together and made logical sense. School became more fun and for the first time I got a good grade. I followed my friend Dr. Frank Porreca and studied for a phd at Temple with well-known analgesics researchers and drug developers. I was then fortunate to head an analgesics drug discovery program at Johnson & Johnson.

What is your most marked characteristic?

I like to listen and learn; see both sides in everything, even when unpopular or unpleasant; but with a slavish adherence to critical thinking. I’m a good support person. I don’t need (or like) to lead. I love to follow and help.

a

a

Q What do you consider your greatest achievement? a Staying out of jail—at least so far.

Maybe being the first in my family to go to college, then graduate school. The work I did on tramadol, buprenorphine, and acetaminophen. Teaching so many terrific students in pharmacy school for 20 years.

Raising two wonderful children.

Q

What is your favorite language?

Oh my. I have taken so many language courses—Latin, French, Russian, Spanish, Japanese—and I am terrible at all of them. I have taken introductory Japanese at least six times (so far) at multiple places, and I can’t even get to level 2!

Hmm, does mathematics count as a language?

a

Q

Who were your mentors?

There is no doubt that my first mentor was my mother. She gave (not devoted, which is different) all of her time to teaching through example—by doing (for her interest and our learning) arts, crafts, reading, projects of all types, volunteering, and more. Being interested in doing became second nature to me.

My high school teachers, Frank Porreca (in graduate school and my good friend and ‘life coach’) and Jeff Vaught (my supervisor and more at Johnson & Johnson). The prime position belongs to Dr. Tallarida, who introduced me to pharmacology, gave me my specialty within the field, taught me how to do research, taught me how to teach, and set the example on how to enjoy life while doing it.

And, in particular, he started to get me out of my shyness-shell (I couldn’t even talk to check-out clerks). He is terribly missed. I think of him every day and he continues to guide my thoughts and actions.

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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: That’s a difficult choice, since reading is a long-standing hobby of mine. I can narrow it down to David Copperfield, for the sheer joy of each sentence.

Movie: To Kill a Mockingbird, as a guide to living (even in space).

Music: Another impossible choice. The Rose (Bette Midler), for the inspiration, and I Will Always Love You (Whitney Houston), for… well, it just always makes me cry happy tears.

Q

What would you like your legacy to be?

That I always enjoyed what I did, didn’t hurt anyone, and helped a few people along the way. As corny as it sounds, I’d like to be remembered as a nice guy. And maybe that I tried to do assignments a little better than what was expected or anticipated. I suspect that for a few more years my professional

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Q If you weren’t a healthcare provider, what would you be? a I would love to be an artist, but I’m not good enough. Or a racecar driver—NASCAR or drag. I pursue these as hobbies.

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“Linus Pauling’s textbook turned chemistry into a movie.

The atoms and molecules whizzing past as I daydreamed…”

legacy will be the contributions that I made to tramadol, and the teaching of pharmacy students.

Robert B. Raffa, phd, is the Professor Emeritus and Past Chair, Department of Pharmaceutical Sciences, at Temple University School of Pharmacy in Philadelphia, Pennsylvania. He is an Adjunct Professor at University of Arizona College of Pharmacy in Tucson, and Chief Scientific Officer of Neumentum Inc in Morristown, New Jersey. He co-founded Enalare Therapeutics Inc. and CaRafe Drug Innovation, both in New Jersey.

Q

Plans for the future?

I plan on doing what I’m doing right now.

Publishing, some teaching, staying active as the CSO and co-founder of two emerging start-up companies, participating in advisory board meetings for pharmaceutical companies, and hiking and enjoying my family. I have always followed the people who look happy in their personal and professional lives. I observe others, particularly with regard to whether they seem happy or not. Not just that day, but with the totality of their lives and their trajectories. And not just with a single aspect of their lives (professional vs personal, etc), but overall. If their choices are making them happy, well, it might just work for me too.

a

Q

What is your motto?

“How old will you be if you don’t do it?”

When I was 28, I was telling my mother that I really loved pharmacology, but maybe it was a pipe dream. Maybe it was just too late.

“Mom,” I said, “it takes four years to get a phd!

Do you know how old I’ll be if I get a phd four years from now?” She thought about it a moment, then said: “Well, son, how old will you be in four years if you DON’T get a phd?”

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By Wendy Caster

PAINFUL PEOPLE (THE WOMEN) Across 1. FORMER MAINE SENATOR OLYMPIA 6. Types of computer ports (abbrev.)

10. Without ice 14. Spanish appetizers 15. Waterproof cover 16. It’s a lake and a county and a city and a canal 17. Happening 18. PULITZER-PRIZE-WINNING POET 2 0. It follows Mardi Gras 21. Element 75, also known as Re 22. ___-Lorraine 24. Bunches of dancers 2 8. Stop 32. Footwear brand 33. Seeker of gold 37. Singer-activist Simone 38. Rim 39. ____ Foods 4 0. Singer-songwriter DiFranco 41. When King Lear gives away his kingdom 43. Occasionally 4 6. River through Paris 4 8. Get close to again 49. Search for 51. Empty, as in the eyes of a drunk person 55. Recluse 59. Tiny spider relative 6 0. “POPULAR” SINGER KRISTIN 63. Capital of Ghana 6 4. Affectation (as in, “Put on ____”) 65. In addition 6 6. Los Angeles basketball player 67. Just 6 8. Dutch cheese 69. “STRANGER THINGS” ACTRESS MILLIE BOBBY ____ Down 1. Inscribed pillar 2. Belly button 3. Unlocks 4. Job hunters used to read them in newspapers 5. Superlative suffix 6. Home of the Great Salt Lake 7. Ditto 8. ___ Mawr College 9. Leave

10. The first lunar phase 11. Poet’s palindromic preposition 12. Not feel well 13. ___ Aviv 19. Not theirs 21. Hemmed again, perhaps 23. Comprehensive Education Plan, in brief 25. Dickens’s ___ Heep 26. Type of pasta 27. Struck down 29. Gods’ blood 3 0. HARRIET BEECHER ____ 31. TV actor Michael of “Murder, She Wrote” 33. Ripple 34. Graduate school in Houston, in brief 35. Chose to contribute to a 401k, for example 36. Go back on 42. Passionate 44. Indian stew

Puzzle solution: painweek.org/crossword.

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45. Part of a trolley 47. French bread 5 0. North American flycatcher 52. Michael Moore documentary on the health care industry 53. Scatter 54. Long (for) 56. Vulcan mind ____ 57. “____ Wonderful Life” 58. Not us 6 0. Engine part 61. Rush 62. To do this is human 63. Priestly garment

The current estimated annual cost to American society of just nine of the most common neurological diseases is staggering, totaling $789 billion.

These conditions include Alzheimer's disease and other dementias, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury, and Parkinson’s disease.”

Gooch CL, Pracht E, Borensten AR. The burden of neurological disease in the United States: a summary report and call to action.

Ann Neurol. 2017;81(4):479-484.

Fri - Sun

18 CE/CME credit hours offered

Practical education for specialists and frontline practitioners treating CNS disorders

RECOMMEND WITH CONFIDENCE

The American College of Physicians and the American Academy of Family Physicians, have made a strong recommendation1:

Use topical NSAIDs first for acute, non-low back musculoskeletal pain.

A formulation they recommend can be found in these Salonpas Pain Relievers.

©2020 Hisamitsu America, Inc. Use as directed.

1 Amir Qaseem et al., Nonpharmacologic and Pharmacologic Management of Acute Pain From Non–Low Back, Musculoskeletal Injuries in Adults: A Clinical Guideline From the American College of Physicians and American Academy of Family Physicians, Annals of Internal Medicine (2020), available at https://www.acpjournals.org/ doi/10.7326/M19-3602.