PWJ - PAINWeek Journal Vol 8, Q4 | 2020

vol. 8 q 4 2020

new frontiers in peripheral nerve stimulation: exploring the renaissance p.20 atypical opioids as frontline analgesics p.28 navigating the otc analgesic aisle: what a pain in the aspirin! p.36 the benefits of physical activity for people coping with painful diabetic neuropathy p.50

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

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

81

%

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

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

– Increased fluid absorption from gut7

– Decreased fluid secretion into gut7

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

YOU HAVE THE POWER TO INTERVENE EARLIER AND HELP ADDRESS THE UNDERLYING CAUSE OF OIC INDICATION • RELISTOR® (methylnaltrexone bromide) is an opioid antagonist. RELISTOR tablets are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.

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

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

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

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

• Avoid concomitant use of RELISTOR tablets with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

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

1

2

REACTIVATE PERISTALTIC MOTION1,7

3 RESTRICT FLUID ABSORPTION1,7

RESTORE FLUID SECRETION1,7

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

52

%

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

• In a clinical study of adult patients with OIC and CNCP taking RELISTOR tablets, the most common adverse reactions occurring in at least 2% of patients receiving 3 RELISTOR 150-mg tablets once daily and at an incidence greater than placebo were abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%), hyperhidrosis (3%), anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%)1 *SBM is defined as bowel movement without the use of any laxative in previous 24 hours.1,8 † Responder is defined as a patient with 3 or more SBMs per week, with an increase of 1 or more SBM(s) per week over baseline, for 3 or more out of the first 4 weeks of the treatment period.1 ‡ Study Design: In a 4-week, randomized, multicenter, double-blind, placebo-controlled, phase 3 study, the efficacy of RELISTOR tablets was evaluated in 401 patients (200 RELISTOR tablets, 201 placebo) with CNCP for which they were taking opioids. All patients had OIC, defined as <3 SBMs per week and at least one additional symptom of constipation.1,8

TAKE A PROACTIVE APPROACH TO OIC AND CHOOSE RELISTOR FOR YOUR ADULT PATIENTS WHO ARE NOT RECEIVING ADEQUATE RELIEF FROM OTC LAXATIVES.1,4 LEARN MORE AT RELISTORHCP.COM IMPORTANT SAFETY INFORMATION • In a clinical study, the most common adverse reactions for RELISTOR tablets (≥ 2% of RELISTOR patients and at a greater incidence than placebo) in patients with chronic non-cancer pain were: abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%), hyperhidrosis (3%), anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%).

• The use of RELISTOR tablets during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier.

Advise pregnant women of the potential risk to a fetus. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR tablets.

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

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

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

Please see Brief Summary of full Prescribing Information on the following page.

REFERENCES: 1. RELISTOR [prescribing information]. Bridgewater, NJ: Salix Pharmaceuticals. 2. Wakefield Research. Relistor OIC Survey: QuickRead Report. Conducted August 15-August 22, 2017. 3. Coyne KS, LoCasale RJ, Datto CJ, Sexton CC, Yeomans K, Tack J. Opioid-induced constipation in patients with chronic noncancer pain in the USA, Canada, Germany, and the UK: descriptive analysis of baseline patient-reported outcomes and retrospective chart review. ClinicoEcon Outcomes Res. 2014;6:269-281. 4. Webster LR. Opioid-induced constipation. Pain Med. 2015;16(suppl 1):S16-S21. 5. Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med. 2009;10(1):35-42. 6. Pergolizzi JV Jr, Raffa RB, Pappagallo M, et al. Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy. Patient Prefer Adherence. 2017;11:107-119. 7. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562. 8. Data on file. Clinical study report MNTX3201. Salix Pharmaceuticals; 2015.

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

RELO.0026.USA.20

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

RELISTOR (methylnaltrexone bromide) injection, for subcutaneous use.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Gastrointestinal Perforation, cramping, vomiting.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bridgewater, NJ 08807 USA www.salix.com

Manufactured for:

Under license from:

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

REL.0082.USA.19

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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 © 2020, PAINWeek, a division of Tarsus Medical Group.

The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff.

PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises.

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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.8 q4 2020

cover illustration: paris fossà

20 28 36 50 58 68

interventional pain management

new frontiers in peripheral nerve stimulation: exploring the renaissance

by jennifer m. hah nitin k. prabhakar

pharmacotherapy

atypical opioids as frontline analgesics

by lynn r. webster

key topic

navigating the otc analgesic aisle: what a pain in the aspirin!

by laura meyer-junco

behavioral pain management

the benefits of physical activity for people coping with painful diabetic neuropathy

by courtney e. brennaman beth l. dinoff

op-ed

covid & the kidney stone

by mark garofoli

pain basics

pain assessment part 1

by kevin l. zacharoff

73

pw next generation

with sean li

74 75 76

clinical pearls

by jennifer bolen

one-minute clinician

with paul j. christo, jamie clapp, heather king, mark garofoli, wayne boice jonas, scott powers

78 83

pundit profile

with robert d. sproul

puzzled?

by wendy caster

pain by numbers

12

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

PROBLEM

PROVEN 12-HOUR ADHESION

SOLUTION

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

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

VISIT THE SCILEX PHARMACEUTICALS EXHIBIT to see the lidocaine patch reinvented. *According to a 2016 Harris Poll among PHN patients (n=153) and nurses (n=151).

Reference: 1. Harris Poll Conducted Online from May 2-25, 2016. PHN Patients & Nurses Study: Final Report. June 9, 2016. Supported by funding from Scilex Pharmaceuticals Inc.

Indication ZTLIDO is indicated for relief of pain associated with post-herpetic neuralgia (PHN).

Important Safety Information Contraindications ZTLIDO is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product.

Warnings and Precautions Accidental exposure can occur even after a ZTLIDO patch has been used.

Small children or pets could suffer serious adverse effects from chewing or ingesting a new or used ZTLIDO patch. Store and dispose of patches properly and keep out of reach of children and pets.

Excessive dosing or overexposure to lidocaine can occur. Longer duration of application, application of more than the recommended number of patches, smaller patients, or impaired elimination may all contribute to increased blood concentration levels of lidocaine. If lidocaine overdose is suspected, check drug blood concentration. Management of overdose includes close monitoring, supportive care, and symptomatic treatment.

Cases of methemoglobinemia have been reported with local anesthetic use, although patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, or concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. Signs and symptoms include cyanotic skin discoloration and/or abnormal coloration of the blood and may occur immediately or may be delayed after exposure.

Methemoglobin levels may continue to rise leading to more serious central nervous system and cardiovascular adverse effects. Discontinue ZTLIDO and any other oxidizing agents. Depending on severity of the symptoms, patients may respond to supportive care or may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

Application site reactions can occur during or immediately after treatment with ZTLIDO. This may include development of blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours. Inform patients of these potential reactions and that severe skin irritation may occur with ZTLIDO if applied for a longer period than instructed.

Hypersensitivity cross-reactions may be possible for patients allergic to PABA derivatives. Manage hypersensitivity reactions by conventional means.

Eye exposure with ZTLIDO should be avoided. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye (eg, eye glasses/eye wear) until sensation returns.

Adverse Reactions Side effects of ZTLIDO include application site reactions such as, irritation, erythema, and pruritus. These are not all of the adverse reactions that may occur.

Please see full Prescribing Information for more information.

Use in Specific Populations Use of ZTLIDO during lactation should be used with caution as lidocaine is excreted into breast milk. The limited human data with lidocaine in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage.

To report SUSPECTED ADVERSE REACTIONS, contact SCILEX Pharmaceuticals Inc. at 1-866-SCILEX3 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Brief Summary of Prescribing Information on following page.

SCILEX® and ZTLIDO® are registered trademarks of SCILEX Pharmaceuticals Inc. All other trademarks are the property of their respective owners. © 2020 SCILEX Pharmaceuticals Inc. All rights reserved. ZTL-00289 01/20

ZTLIDO® (lidocaine topical system) Rx only Brief Summary: This information is not comprehensive. Visit www.ZTlido.com/hcp to obtain the FDA-approved product labeling or call 1-866-SCILEX3 (1-866-724-5393).

INDICATIONS AND USAGE ZTLIDO contains lidocaine, an amide local anesthetic, and is indicated for relief of pain associated with post-herpetic neuralgia (PHN).

DOSAGE AND ADMINISTRATION Apply up to three topical systems only once for up to 12 hours in a 24-hour period.

CONTRAINDICATIONS Contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product.

WARNINGS AND PRECAUTIONS Accidental Exposure Even a used ZTLIDO topical system contains residual lidocaine after use. A small child or pet may suffer serious effects from chewing or ingesting a new or used ZTLIDO. It is important for patients to store and dispose of ZTLIDO properly and keep out of the reach of children, pets, and others.

Excessive Dosing/Overexposure The following may contribute to higher blood concentration of lidocaine, leading to adverse effects: longer duration of application; application of more than the recommended number of ZTLIDO; smaller patients; hepatically impaired patients; use on non-intact skin; or applying heat sources to ZTLIDO. Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Signs may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Discontinue ZTLIDO and any other oxidizing agents.

Application Site Reactions During or immediately after treatment with ZTLIDO, application site reactions may develop including blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. Inform patients that severe skin irritation may occur with ZTLIDO if applied for a longer period than recommended.

Hypersensitivity Reactions Cross sensitivity to ZTLIDO in patients with a history of drug sensitivity to para-aminobenzoic acid (PABA) derivatives is possible.

Eye Exposure Immediately wash out the eye with water or saline and protect the eye until sensation returns.

ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail elsewhere in the labeling: • Methemoglobinemia • Application Site Reactions • Hypersensitivity Reactions

The following adverse reactions from voluntary reports or clinical studies have been reported with lidocaine. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissues: blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erosions, erythema, exfoliation, flushing, irritation, papules, petechia, pruritus, vesicles, and abnormal sensation.

Immune system: angioedema, bronchospasm, dermatitis, dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria.

Central Nervous System: lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, somnolence, respiratory depression and arrest.

Cardiovascular: bradycardia, hypotension, and cardiovascular collapse leading to arrest.

Other: asthenia, disorientation, headache, hyperesthesia, hypoesthesia, metallic taste, nausea, pain exacerbated, paresthesia, taste alteration, and vomiting.

DRUG INTERACTIONS Drugs That May Cause Methemoglobinemia When Used with ZTLIDO Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drug classes: nitrates/nitrites; local anesthetics; antineoplastic agents; antibiotics; antimalarials; anticonvulsants; other drugs (e.g., acetaminophen, metoclopramide, quinine).

Antiarrhythmic Drugs When ZTLIDO is used in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine), the toxic effects are additive and potentially synergistic. Consider risk/benefit during concomitant use.

Local Anesthetics When ZTLIDO is used concomitantly with other products containing local anesthetic agents, the effects are additive. Consider the amount of drug absorbed from all formulations when local anesthetic agents are administered concomitantly.

OVERDOSAGE Lidocaine overdose from cutaneous absorption is rare but could occur. If there is any suspicion of lidocaine overdose, check drug blood concentration. The management of overdose includes close monitoring, supportive care, and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdose with lidocaine.

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

“Meetings

come to an end, but learning never stops.

PWJ keeps you going all year long.”

—Michael R. Clark md, mph, mba

movement. Adeptly underscoring the benefits of physical activity in the context of pain on a neurological level, the I reflect on this year, I see Kevin L. Zacharoff distinct parallels between the panauthors make a solid evidence-based demic and the chronic pain experience. case for applying the beneficial princiArguably, both are things we cannot see, have difficulty measur- ples of exercise to help people suffering with painful diabetic periphing, need to better understand, and are a part of the human con- eral neuropathy. This article is a must-read if you have such patients dition. If I were to create a summary word cloud, it would likely in your practice. include fatigued, saddened, lost, depressed, isolated, stigmatized, sickened, hopeless, and hurt. Those words also describe the lives The Pundit Profile spotlights someone I have known for many of millions of people negotiating their pain and suffering every years, Dr. Robert Sproul. The first thing that comes to mind when single day. We must continue, maybe not at “warp speed,” but I think of him is passion. Additionally “honor” defines Dr. Sproul: steadily and methodically to educate ourselves, combat biases his colorful life, his talent, dedication to patient care, and love for and stigmatization, and look for safe and effective treatment for life. We wish our world had more people in healthcare like him. It people with pain. That is our mission. is a privilege to obtain this look behind the curtain.

In their article about new frontiers to better treat refractory chronic pain, Drs. Jennifer Hah and Nitin Prabhakar share the history, mechanism of action, and clinical rationale behind peripheral nerve stimulation (PNS) to treat conditions ranging from chronic daily headache to peripheral neuropathies. Commendably, the authors underscore the importance of managing expectations when PNS is considered for patients found to be refractory to more conventional, conservative pain treatments. I believe technology has a significant role in the future of pain management, and this article is a promising example of how that future may be here sooner than we think.

As soon as someone mentions “opioids,” a certain set of preconceived thoughts may be triggered, regardless of the compound and properties of an individual opioid. All opioid analgesics are not the same, which is the subject of Dr. Lynn Webster’s article about atypical opioids and their potential utility in the management of chronic pain in patients for whom other treatments are not effective. The piece details the most concerning adverse phenomenon of opioid-induced respiratory depression, along with the pharmacology of tramadol, tapentadol, and buprenorphine. As we try to ensure that patients who are appropriate candidates for opioid analgesic therapy aren’t denied access to needed pain medications, we should understand how atypical opioids might be the best choice.

Virtually all of us have navigated the over-the-counter (OTC) analgesic aisle in our local pharmacy. Dr. Laura Meyer-Junco takes us on an in-depth journey down that aisle, not only discussing the “3 main players” but also other products and formulations that line the drugstore shelves. I often say that patients are most likely to attempt to treat themselves for a pain-related problem before they seek medical attention, and it is critical for us to know as much as we can about OTC analgesics and to educate patients about the benefits, and the possible risks. This is an article to keep handy to remind us of that educational role.

Our Next Generation’s Dr. Sean Li spends his days performing procedures and giving injections, and his dedication to alleviating suffering is in his core. I believe, with leaders like Dr. Li, we have reason to hope for a better tomorrow for patients in pain. Enjoy this glimpse and the opportunity to know him better.

Dr. Mark Garofoli shares the pain expert’s perspective of an experience with acute renal colic in the time of covid-19. Nothing helps us better understand what patients with pain experience more than becoming one. Additionally worthy of mention in this issue is the fifth installment of Back to the Basics, for people seeking foundational pain education.

One of my “go to” phrases about healthcare is that if we don’t distill every discussion and debate to what benefits patients most, then we are likely off target. As we globally share the clinical/physical/ emotional challenges that the pandemic brings, we are all being forced to negotiate pain and suffering. May we weather this storm, not lose sight of the patients who need us now more than ever, and unify successfully to reach the other side. Stay safe.

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.

Coping skills are essential for patients learning how to live with chronic pain. The article by Courtney Brennaman and Dr. Beth Dinoff discusses changing the paradigm of avoiding movement in patients with painful diabetic neuropathy to one that encourages

16

p.50

Beth L. Dinoff PhD

Beth Dinoff is a Pain Psychologist and Clinical Associate Professor in the Department of Anesthesia at the Pain Management Clinic, University of Iowa Hospitals and Clinics in Iowa City. She coauthored her article with Courtney E. Brennaman, MS, CRC, a 4th year doctoral candidate at the University of Iowa. Ms. Brennaman has completed clinical work with individuals living with chronic pain as well as a research assistantship focusing on neuropathic pain research.

p.20

Jennifer M. Hah MD, MS

Jennifer Hah is an Assistant Professor in the Division of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine at Stanford University in California. She is an anesthesiologist, pain, and addiction medicine specialist. She is NIH-funded researcher focusing on interventions to limit the development of persistent post-surgical pain and opioid use after surgery. She is the Director of the Stanford Pelvic Pain Program and a Director of the World Academy of Pain Medicine United. Dr. Hah coauthored her article with Nitin K. Prabhakar, MD, who is in the Division of Physical Medicine and Rehabilitation, Department of Orthopedic Surgery, at Stanford University in California.

Laura Meyer-Junco PharmD, BCPS, CPE

p.36

Laura Meyer-Junco is a Clinical Assistant Professor at the University of Illinois at Chicago College of Pharmacy, Rockford Campus. She is also the Clinical Pharmacist with the palliative care and hospice team at Mercyhealth System and Hospice Care of America in Rockford, Illinois. She completed a PGY2 Geriatric Pharmacy residency in 2012 and has since built a teaching and pharmacy practice focused on the safe and effective use of medications in older adults, including the optimal management of pain.

Lynn R. Webster MD, FACPM, FASAM

p.28

Lynn Webster is the Vice President of PRA Health Sciences in Salt Lake City, Utah. He is board certified in anesthesiology, pain medicine, and addiction. In addition to practicing medicine for 30 years, he has conducted hundreds of clinical trials in CNS, pain, and addiction, among other areas. Human abuse potential studies and drug-induced respiratory depression have been a major research focus of his during the past decade.

18

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

new

frontiers

peripheral

nerve

stimulation:

exploring

the

renaissance

By

Jennifer

M.

Hah

MD,

MS

/

Nitin

in

K.

Prabhakar

MD

illustration: paris fossĂ

interventional pain management

Electrostimulation for analgesia has its roots in ancient civilizations. Peripheral nerve stimulation (PNS) initially involved lead placement via a surgical incision, increasing the invasiveness of the procedure and potential complications. Recent technologic advances in PNS have resulted in a resurgence of this pain treatment modality due to percutaneous needle insertion techniques and ultrasound image guidance. In this review, we briefly discuss the history of PNS, technical considerations for lead placement, indications, and adverse effects. As indications for PNS continue to expand, it is likely to become an important consideration in the interdisciplinary management of multiple acute and chronic pain conditions.

22

istory

In the 1st century AD, a Roman physician named Scribonius Largus used the electrical discharges produced by the torpedo fish to treat headaches, arthritis, and gout. The use of the electric Nile catfish for analgesia is depicted in 5,000 year old Egyptian tomb murals.1 The Narcine bancroftii, an electric ray and species of numbfish, gets its name from a derivation of the Greek “narke,” meaning numbness, and in reference to its ability to produce an electric shock; “narke” is also a root of the word “narcotic.”2 The invention of the Leyden jar allowed for storage of an electric charge and jumpstarted the study of electrostatics in the 18th century, leading to the development of electrostatic generators. In the mid-19th century, Julius Althaus was the first physician to apply electricity directly to a peripheral nerve to alleviate surgical pain in an extremity.3 In the early 20th century, an electrical stimulation device called “Electreat” (from “electricity” and “magnet”), a dielectric material that has a quasi-permanent electric charge or dipole polarization, was developed and marketed as a supposed treatment for a wide variety of ailments, including constipation, asthma, pain, and curing paralysis.3,4 These devices were further refined to involve surface metal electrodes placed over peripheral nerves proximal to painful areas, and ultimately became the basis of the modern transcutaneous electrical nerve stimulation

23

(TENS) unit. Ronald Melzack and Patrick Wall revolutionized the concept of pain modulation in 1965, proposing that the activation of non-noxious afferent nerve fibers (Aβ- fibers) could help modulate Aδ and C- fiber mediated nociceptive transmission in the spinal cord, and subsequently provided the rationale for the analgesic effect of electric stimulation.5 Patrick Wall and William Sweet performed a dramatic experiment in 1967 when they inserted electrodes into their own infraorbital foramina prior to clinically assessing eight patients in a trial of percutaneous nerve stimulation for pain relief.6 In all eight patients, infraorbital nerve stimulation by a percutaneous needle led to hypoesthesia and pain relief distal to the stimulation. This effect was demonstrated repeatedly in other case series.7,8 During this initial period, all electrode implantations were carried out via an open surgical incision.

In 1999, Weiner and Reed described a percutaneous technique of PNS by stimulating the greater occipital nerve for the treatment of occipital neuralgia in 15 patients, which demonstrated good, long-lasting pain relief.9 PNS generally refers to the stimulation of a peripheral nerve via direct placement of a lead, either with an open surgery or a percutaneous technique. Reports by others have renewed interest in percutaneous PNS, which offers a minimally invasive method that can be used in the treatment of peripheral nerve pain.1,3,7,10

How Does It Work?

The peripheral nervous system allows the body to communicate with the environment. Various afferent pathways that transmit touch, temperature, position in space, and pain are routed to the spinal cord and up to the brain, where efferent impulses fire and help guide appropriate responses. Persistent nociception can result in pathologic peripheral nerve dysfunction, ectopic firing of impulses, and changes in chemical mediators in the peripheral ganglia, spinal cord, and the brain. Hyperalgesia and allodynia, which are hyperresponsive sensory signals in response to noxious or non-noxious stimuli, respectively, can lead to chronic pain syndromes and functional disability. It is estimated that up to 10% of patients impacted by chronic pain may have a pain origin related to peripheral nerve pathology.

Patients will often have pain consistent with the sensory distribution of a single peripheral nerve.10 PNS involves the placement of a stimulating electrode or electrodes over a named peripheral nerve to elicit paresthesias along the innervated territory.3,10 Based on Melzack and Wall’s gate control theory, focal stimulation of the peripheral nerve is believed to produce analgesia—non-nociceptive electrical stimulation activates large-diameter sensory fibers that close the “gates” to nociceptive input.5 PNS may thus alter pathological nerve impulses in chronic pain syndromes leading to decreased pain perception.

Recent advances in PNS technology have evolved this treatment modality into its current modern application resulting in a resurgence of interest in PNS for neuromodulation. Previously, PNS involved off-label surgical placement of multiple stimulator electrodes near the target peripheral nerve, and lead removal often required an additional operation due to fibrous capsule formation as a reaction to non-inert lead materials.11 Given the invasiveness of the surgical approach and removal, PNS had been reserved more for chronic pain applications. With the advent of smaller leads that enable percutaneous needle insertion and use of portable ultrasound image guidance techniques, PNS is now being considered for the treatment of acute pain. At present, one particular percutaneous PNS lead and pulse generator system is FDA cleared for the treatment of acute pain.11 This particular device involves a flexible lead placed through a preloaded 20-gauge introducer

needle. With the assistance of real-time ultrasound image guidance, the introducer needle can be withdrawn, and the flexible lead stays in place due to a small anchor at the distal end. This lead can be applied for up to 60 days.11 Research is actively exploring the application of temporary PNS placement after a variety of operations including total knee arthroplasty, bunion removal, and rotator cuff repair.

Although this research is still preliminary, PNS may provide the bridge between the acute and subacute postoperative phases for pain control to ultimately prevent the development of persistent postsurgical pain.11 The development of miniature implantable pulse generators of less than 1.5 cm3 volume adds to the ease of implantation of PNS devices over the entire body ranging from superficial to deeper targets. The availability of tined and untined PNS leads allows for consideration of lead placement location and the likelihood of migration. For example, deep lead placement to target the pudendal nerve is subject to migration given the change in lead tension from hip flexion and extension.8 Thus, tined leads can be considered in anatomic locations at high risk for regular lead migration. Device capabilities traditionally associated with spinal cord stimulation are now becoming available for PNS, including current steering, low vs high frequency stimulation, and pulse dosing. Given the multitude of therapy options, research is needed to determine optimal therapy parameters for any given diagnosis.

As the research behind PNS evolves, the traditional treatment pathway for mononeuropathic pain is also likely to evolve. Conventionally, once a mononeuropathy is identified through diagnostic nerve blocks, imaging, and electrodiagnostic studies, the treatment pathway spans lesser to more invasive options: radiofrequency ablation, peripheral nerve surgery, spinal cord stimulation, and intrathecal drug therapy. PNS may appear earlier in treatment algorithms over time, and may even be considered a firstline treatment once a mononeuropathy is diagnosed.

24

Lead placement

Ultrasound or fluoroscopy can be used for target peripheral nerve localization and image guidance during PNS lead placement. With fluoroscopic guidance, bony landmarks in the proximity of the target are visualized, and the introducer and lead can be advanced under intermittent fluoroscopy. One advantage of this procedure is the documentation of final PNS lead placement and the surrounding field of view. This affords easy comparison with future X-rays if a concern for lead migration arises.

Fluoroscopic approaches have been described for PNS placement to target the supra- and infraorbital nerves and occipital nerves.10 For certain locations, a combination of image guidance techniques may allow the greatest precision. For instance, fluoroscopic guidance may be used to identify a target level for PNS of a lumbar medial branch.

…focal stimulation of the peripheral nerve is believed to produce analgesia— non-nociceptive electrical stimulation activates largediameter sensory fibers that close the ‘gates’ to nociceptive input. PNS may thus alter pathological nerve impulses in chronic pain syndromes leading to decreased pain perception.

Real-time ultrasound guidance may then be used for lead placement because of the additional visualization of vascular structures and the nerve itself.

Ultrasound guidance offers real-time visualization of the nerve and surrounding structures, and, with the advent of increasingly portable machines, is likely to play a greater role in PNS lead placement. Use of color Doppler modes help to identify vascular structures that often travel adjacent to the target nerves. For example, identification of the femoral artery and vein in relation to the saphenous nerve is critical to avoid vascular puncture during PNS placement. Because the introducer needle can be placed parallel to the target nerve under ultrasound guidance, the capabilities of the PNS system can be maximized as the leads are placed parallel to the nerve.10 If lead migration occurs, there is more likely a chance that adequate PNS continues given that multiple contacts lie in proximity to the target nerve in a parallel orientation.

25

Ultimately, successful PNS lead placement rests on the patient’s response to nerve stimulation after lead placement. A higher milliampere output required to produce a paresthesia with nerve stimulation indicates that either the stimulating probe or PNS lead is further from the intended target. PNS lead placement should be targeted to a region of the nerve that is functionally intact, typically corresponding to a region of hyperalgesia that surrounds an area of skin allodynia.10 In addition to sensory stimulation, corresponding motor stimulation is an important consideration for optimal lead placement. For instance, PNS of the medial branches of the dorsal rami nerves should result in selective activation of the lumbar multifidus muscles. Given that the patient’s sensation of the nerve stimulation in the painful area is key to successful PNS lead placement, sedation should be minimized, and the lead placement can occur under a combination of local anesthesia and conscious sedation.

Who is it for?

As PNS has evolved as a treatment modality, the number of treatment targets has also expanded.

PNS has been applied to a variety of chronic pain conditions, including chronic migraine/headache disorders, postherpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, postamputation pain, and isolated peripheral neuropathies. At present, research has reported favorable improvements in pain when delivering PNS to patients with upper extremity mononeuropathy, chronic intractable migraine, postamputation pain, chronic hemiplegic shoulder pain, chronic neuropathic pain, and postoperative pain after total knee arthroplasty.10 Common nerve targets for shoulder pain include the suprascapular and axillary nerves. Arm pain can be targeted with PNS of the radial, ulnar, or median nerves.

A number of lower extremity targets include the femoral, sciatic, saphenous, lateral femoral cutaneous, common peroneal, and tibial nerves. Pain in the thoracoabdominal and pelvic regions can be treated through targeted PNS of the intercostal, ilioinguinal or iliohypogastric nerves.

PNS has been recommended when a patient’s symptoms are refractory to conservative treatments, including physical therapy, oral medications, and other interventional treatments. Prior to considering PNS, correctable pathologies such as nerve entrapment should be excluded with diagnostic and imaging studies.4 In some cases, it may be appropriate to trial a diagnostic local anesthetic block if there is some question of the appropriate pain generator.10 However, it is unclear whether response to a diagnostic nerve block resulting in nerve conduction block is an appropriate proxy for pain relief from PNS, which rather activates motor and sensory fibers. In other words, local anesthetic blocks are an important aspect of the diagnostic workup for mononeuropathies, but the resulting pain relief is not necessarily an established prognostic factor for a positive response to PNS.10 PNS trials can be performed for up to 30 to 60 days, depending on the device used, which allows for monitoring of pain relief, functional improvements, sleep quality, mood, and supplemental pain medication use.10 Appropriate patient expectations regarding pain modulation and risks of the procedure are crucial for success. The most common complications are wound infection, electrode migration, and skin erosion.3 Rarely, lead fracture can occur while the PNS system is implanted or during explant. MRI has been safely performed in patients with retained lead fragments up to 12.7 cm in length using a 1.5 Tesla strength magnet.11 Absolute contraindications to PNS include patients with a deep brain stimulation system, pacemaker or defibrillator, or another type of neurostimulator if the current path overlaps with the PNS system.11 Relative contraindications include coagulopathies, use of anticoagulation medication, severe adhesive allergies, and infection in the region of the lead insertion.

26

Conclusions

With technologic advances among PNS devices on the market, invasiveness of implantation has decreased while safety and efficacy has improved. PNS implantation no longer involves a surgical incision and can be completed through a percutaneous approach with the use of local anesthesia and minimal intravenous sedation. Miniaturization of the implantable pulse generator increases the feasibility of application to both superficial and deep targets. Research to determine the efficacy of PNS for specific target nerves and diagnoses is needed. A better understanding of proper patient selection will optimize outcomes, and research to determine ideal stimulation parameters is likely to increase the efficacy of this therapy.

Further areas for research include addressing lead orientation, whether parallel or perpendicular to the nerve, and whether the lead tip is pointing proximal or distal on the target nerve. There is great potential for peripheral neuromodulation to be a staple minimally invasive treatment for peripheral neuropathic pain and represents a promising tool in the multimodal approach to chronic pain treatment.

References 1. Henderson JM. Peripheral nerve stimulation for chronic pain. Curr Pain Headache Rep. 2008;12(1):28–31.

2.

Driggers III WB, Carlson J. Narcine bancroftii. The IUCN Red List of Threatened Species. 2019. Available at: dx.doi.org/10.2305/IUCN.UK.2019–2.RLTS. T63142A3121523.en.

3. Corriveau M, Lake W, Hanna A. Nerve stimulation for pain. Neurosurg Clin N Am. 2019;30(2):257–264.

4. McRoberts P, Cairns KD, Deer T. Stimulation of the peripheral nervous system for the painful extremity. Prog Neurol Surg. 2011;24:156–170.

5. Melzack R, Wall PD. Pain mechanisms: a new theory. Science.

1965;150(3699):971–979.

6. Wall PD, Sweet WH. Temporary abolition of pain in man. Science.

1967;155(3758):108–109.

7. Petersen EA, Slavin KV. Peripheral nerve/field stimulation for chronic pain.

Neurosurg Clin N Am. 2014;25(4):789–797.

8. Gregory NS, Terkawi AS, Prabhakar NK, et al. Peripheral nerve stimulation for pudendal neuralgia: a technical note. Pain Med. 2020;21(suppl 1):S51-S55.

9. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation. 1999;2(3):217–221.

10. Deer TR, Naidu R, Strand N, et al. A review of the bioelectronic implications of stimulation of the peripheral nervous system for chronic pain conditions. Bioelectron Med. 2020;6:9.

11. Ilfeld BM, Finneran JJ. Cryoneurolysis and percutaneous peripheral nerve stimulation to treat acute pain. Anesthesiology. 2020;133(5):1127-1149.

…it is vital to find ways to treat pain safely. atypical opioids may have a role in safely treating patients whose pain exceeds the limits of more conservative treatment.

By Lynn R. Webster MD, FACPM, FASAM

pharmacotherapy

Opioids are important tools in treating pain, yet

risks related to misuse, abuse, and overdose deaths cause many to question their use. The issue is global, with approximately 118,000 of 450,000 drug-related deaths being opioid-related.1 That highest statistic was from the United States, where deaths related to prescription and illicit opioids reached 450,000 between 1999 and 2018.2 With chronic pain an ongoing health crisis suffered by 1 in 5 US adults,3 it is vital to find ways to treat pain safely. Atypical opioids may have a role in safely treating patients whose pain exceeds the limits of more conservative treatment.

Atypical opioids include tramadol, tapentadol, and buprenorphine. These are opioids whose mechanisms of action differs from the Âľ-opioid receptor agonism found in morphine, oxycodone, fentanyl, and other conventional opioids. Clinical and experimental evidence describing the action of atypical opioids suggests they may induce less opioid-induced respiratory depression (OIRD).

This article briefly examines atypical opioids and discusses evidence in relation to respiratory depression, with a goal to understanding how atypical opioids differ from full Âľ-agonists in pharmacology and safety related to OIRD. 30

Opioid-Induced Respiratory Depression

The ultimate purpose of respiration is to maintain the optimal tissue concentrations of CO₂, O₂, and H+.

The body’s respiratory activity responds quickly to any changes in these substances. Changes are modulated through conscious inputs from the brain’s cortex and through chemoreceptors (centrally and peripherally) that sense and respond to fluctuations in the chemical constituents of blood.

There is no standard definition of respiratory depression, but it is generally considered to be when ventilation fails to adequately respond to hypercapnia or hypoxia that causes CO₂ to rise and O₂ to drop in blood levels.4 Parameters commonly measured at various thresholds, alone or in combination, include respiratory rate, O₂ saturation, CO₂ partial pressure during expiration, minute ventilation (MV), arterial blood gases, hypercapnic ventilatory response, and hypoxic ventilatory response.4-6 A 40% cutoff of MV has been suggested as an indicator of unsafe level of respiratory depression.7 The mechanisms of OIRD8-10 typically play out clinically as an inhibition of the hypercapnia feedback response. Depression of ventilation in respiratory rate and tidal volume leads to impaired gas exchange resulting in hypercapnia, hypoxemia, and respiratory acidosis. In a vicious cycle, opioids also inhibit the body’s normal response to hypercapnia by interfering with signals from

31

the medulla oblongata to the medullary respiratory signals, thereby decreasing efferent impulses to respiratory muscles, which would normally respond.8 Depression of the arousal response and pharyngeal muscle function, along with an irregular breathing pattern, are also characteristics of OIRD. Seen clinically, the course of OIRD that could lead to organ failure, coma, and death is dependent on underlying disease, concomitant medications, inspired O₂ concentration, genetics, gender, BMI, age, and the opioid administered (including physicochemical properties, dose, route of administration, and speed of concentration at the action site).8,10 It is established that conventional opioids decrease respiratory drive. Respiratory depressant effects with full µ-opioid receptor agonists, including morphine and oxycodone,11-13 have been demonstrated in surgical patients. There is also well-known experimental evidence of respiratory depression in healthy subjects with opioids that include morphine, oxycodone, and fentanyl.14-16 These effects are dose dependent.

Pharmacology of Atypical Opioids

Different opioids vary in specific properties with implications for analgesia and adverse events profiles. Despite some differences among them, conventional

Table. Mechanisms of Action and Metabolism of Atypical Opioids Tramadol

Tapentadol

Buprenorphine

µ-opioid receptor

Agonist

Agonist

Partial agonist

κ-opioid receptor

N/A

N/A

Antagonist

δ-opioid receptor

N/A

N/A

Antagonist

Nociceptin opioid receptor (ORL1)

N/A

N/A

Agonist

Noradrenaline reuptake inhibitor

Yes

Yes

N/A

Serotonin reuptake inhibitor

Yes

N/A

N/A

Metabolism

CYP2D6 (O-demethylation)

Glucuronidation

CYP3A4 (N-dealkylation, glucuronidation)

Abbreviations: CYP2D6 = cytochrome P450 2D6; CYP3A4 = cytochrome P450 3A4; N/A = not applicable; ORL1 = opioid receptor like-1 (now known as the nociceptin opioid receptor)

opioids are united in their primary action of µ-opioid receptor agonism, which is responsible for analgesia and adverse effects.17,18 In contrast, the atypical opioids tramadol, tapentadol, and buprenorphine each have unique mechanisms of action that may insert separation between the desired effect of analgesia and unwanted adverse events (Table).17-19 The primary adverse event of interest is respiratory depression, the major cause of opioid-related overdose death.

Tramadol

Tramadol is a Schedule IV drug available for pain treatment in immediate-release (IR) and extended-release (ER) formulations. Tramadol is a full µ-opioid receptor agonist, a noradrenaline reuptake inhibitor and serotonin reuptake inhibitor.20 Importantly, its metabolism in the liver by the cytochrome P450 2D6 (CYP2D6) enzyme system, which has great polymorphism, may affect its clinical usefulness. It is notable that poor and intermediate CYP2D6 metabolizers make up 7% to 22% of patients, and ultrarapid metabolizers make up 4% to 11% of patients.21 Therefore, clinical evidence of respiratory depression in a case series of 71 patients who overdosed on tramadol22 should be considered in relation to the possibility patients were ultrarapid CYP2D6 metabolizers.23,24 There is also a report of a patient treated with tramadol with impaired renal function experiencing respiratory depression.25

32

Clinical trials have shown that tramadol did not cause respiratory depression when given vs morphine for postoperative pain26 and when given vs placebo in children.27 One clinical trial comparing tramadol at approximately 1.5 times the equipotent dose with morphine found tramadol transiently depressed respiratory rate but had no effect on end-tidal carbon dioxide.28 An experimental study showed oxycodone but not tramadol decreased respiratory rate (P<0.05) and increased inspiration-expiration O2 difference (P<0.05) compared with placebo.12 This double-blind study in patients undergoing minor surgery found that tramadol’s effects on respiratory rate, inspiratory-expiratory O₂, end-tidal CO₂, and MV were similar to placebo. In an experimental study in healthy volunteers, tramadol (given as a 150 mg bolus and a subsequent 3-hour steady infusion of 250 mg [83.3 mg/hr]) was compared with meperidine (given as a bolus dose of 112.5 mg plus 187.5 mg in a 3-hour steady infusion [62.5 mg/hr]).29 No clinically significant effects on respiration, breathing pattern, or hemodynamics were found with tramadol. In contrast, meperidine bolus decreased tidal volume (P<0.05, difference from baseline) and pulse oxygen saturation (from 97% to 94%, P<0.05), but respiratory parameters returned to baseline during subsequent infusion.

Clinically, tramadol may have less respiratory depression and abuse potential30 than conventional opioids, although special cautions should be taken with CYPD26 ultrarapid metabolizers and in renal failure. Drug interactions may occur, including serotonin syndrome

when combined with other serotonergic drugs, and seizure risk should be considered.30,31 Of note, tramadol’s efficacy may be limited by the 400 mg maximum daily recommended dose.

Tapentadol

Tapentadol is a Schedule II drug, available in IR or ER tablets. Tapentadol’s mechanisms of action encompass a pure µ-opioid receptor agonist combined with a noradrenaline reuptake inhibitor.20 Its affinity for the µ-opioid receptor is approximately 10 to 20 times lower than is seen with morphine or oxycodone, but tapentadol is only 2 to 3 times less potent.32 Unlike tramadol, tapentadol does not have a serotonergic effect or metabolites that contribute to analgesia, and it is metabolized primarily by glucuronidation rather than CYP450.32 Therefore, tapentadol is clinically comparable in efficacy to oxycodone but with a more favorable tolerability profile.20 A systematic review identified few deaths from single-drug tapentadol overdose worldwide over 9 years.33 In addition, abuse potential may be less with tapentadol than with other Schedule II opioids.34 However, the effect of tapentadol on respiratory depression has not been well investigated, and pharmacovigilance data and poison control center reports bear watching.

Buprenorphine

Originally approved as an injectable drug, buprenorphine (a Schedule III drug) is available in transdermal and buccal film formulations. Its multiple mechanisms of action contribute to analgesia in unique ways. As a partial agonist, buprenorphine has a high affinity at the µ-opioid receptor, lower affinity at the opioid receptor-like 1, or ORL1, also known as the nociceptin opioid receptor, and is an antagonist at κ-opioid and δ-opioid receptors.35 Buprenorphine’s action at the µ-opioid receptor limits phosphorylation and β-arrestin recruitment (which has also been correlated with respiratory depression, constipation, and abuse liability). Buprenorphine is able to generate sufficient G-protein action while limiting β-arrestin signaling. The mechanisms of action preserve buprenorphine’s potent analgesia while limiting opioid-related adverse effects, including respiratory depression, to which buprenorphine exhibits a dose ceiling effect. In addition, antagonist action at κ-opioid and δ-opioid receptors limits potential for constipation, dysphoria, depression, and abuse potential.35 It is important to note that even partial activation of the µ-opioid receptor means buprenorphine could cause respiratory depression. However, comparison of respiratory effects of intravenous fentanyl and buprenorphine demonstrated a respiratory depression

33

ceiling effect with buprenorphine but not fentanyl.16 In a double-blind, placebo-controlled study in healthy volunteers (n=48), opioids were intravenously infused over 90 seconds. Investigators measured MV at a fixed end-tidal partial pressure of CO₂ of 52.5 mmHg. Buprenorphine doses in 20 subjects were 0.7, 1.4, 4.3, and 8.6 μg/ kg, and fentanyl doses in 21 subjects were 1.1, 2.1, 2.9, 4.3, and 7.1 μg/kg. Seven subjects received placebo. Fentanyl depressed MV dose-dependently with apnea at a dosage of 2.9 μg/kg or greater, whereas buprenorphine’s effect of MV depression leveled off at 3.0 μg/kg or greater to about 50% of baseline.16 Buprenorphine’s ceiling effect with respect to respiratory depression was further demonstrated36 experimentally at 2 weight-adjusted doses (intravenous 0.2 mg per 70 kg and 0.4 mg per 70 kg. Peak of steady-state inspired MV depression (at a fixed end-tidal partial pressure of CO₂ of 7 kilopascal) was dose independent while buprenorphine’s analgesic effect on experimentally-induced pain increased significantly at the higher dose (0.4 vs 0.2 mg, P<0.01).

A more recent study reported on the effect of buprenorphine buccal film and oxycodone on respiratory drive by using ventilatory response to hypercapnia (VRH), which is a stress test for the respiratory system.37 Investigators administered hypercapnic gas (7% CO₂, 21% O₂, 72% N₂) to subjects then subsequently evaluated respiratory drive as the maximum decrease in MV (Emax).

Compared with placebo, only oxycodone 60 mg (but not 30 mg) significantly reduced MV at Emax while no doses of buprenorphine (300, 600, and 900 µg) did so. Respiratory drive assessed via VRH was measured at screening, predose, and at 0.5, 1, 2, 3, and 4 hours after dosing. Each of the 15 subjects, who were recreational drug users not physically dependent on opioids, received each of the treatments (placebo, oral oxycodone, and placebo) once.

Misconceptions around the use of buprenorphine clinically for pain include that it does not provide sufficient analgesia compared to full μ-agonists and that it will exert antagonism on conventional opioids if combined. In fact, no analgesic ceiling with buprenorphine has been observed in humans, and it can be combined clinically with other μ-opioids for added efficacy when necessary.35,38,39 The lower dose of buprenorphine given for chronic pain than in treatment for substance use disorder does not translate to less effective analgesia nor does its categorization as a Schedule III drug, which is based on abuse potential, not analgesia.38 In other benefits, no waiver is required to prescribe buprenorphine for pain (rather than opioid use disorder [OUD]) and access barriers, including refills, are eased compared with Schedule II opioids.38 Of note, buprenorphine is recognized by several organizations, experts, and consensus panels as having unique mechanism of action, favorable pharmacologic properties and safety profile, and effective

Atypical opioids may be safer than conventional µ-agonists in relation to their effect on respiratory drive, although more investigation is required. ” analgesia.19,38-42 The Department of Health and Human Services (HHS) Pain Management Best Practices InterAgency Task Force recommends improved access to buprenorphine for chronic pain treatment, citing potential for improved safety over full μ-agonists.40 The HHS Task Force encourages primary use of buprenorphine, if clinically indicated, rather than solely after failure of standard μ-opioid agonists. Patients with concurrent OUD and pain may do better with buprenorphine as a first-line agent for chronic pain. In addition, the HHS Task Force recommends considering transitioning to buprenorphine in patients on high opioid doses who are unable to taper despite worsening pain and/or function in patients who may not meet the criteria for OUD.40 Finally, because buprenorphine exclusively undergoes Phase II metabolism, it may be more appropriate for phenotypic outliers in producing CYP450 enzymes that induce or inhibit CYP2D6.38 In contrast, codeine and tramadol may pose toxicity risk to ultrarapid CYP2D6 metabolizers and limited analgesia to poor CYP2D6 metabolizers.38

34

Conclusions

Atypical opioids may be safer than conventional µ-agonists in relation to their effect on respiratory drive, although more investigation is required. Tramadol is a Schedule IV drug with less abuse potential than conventional opioids but that affects respiratory drive according to CYP2D6 metabolizer status. Some respiratory depression has been reported with tapentadol, although less than with oxycodone. Among the atypical opioids, buprenorphine is a partial opioid agonist that can treat pain as well as OUD and has demonstrated a ceiling effect on respiratory depression in healthy subjects (a finding that bears closer investigation as the population with chronic pain may differ in important ways). Overall, review of the current literature suggests that atypical opioids produce less respiratory depression than conventional opioids, with the buccal film formulation of buprenorphine having the most impactful data. Because most opioid-related overdoses result from respiratory depression, atypical opioids may be considered first line when an opioid is indicated.

References 1. World Health Organization. Information sheet on opioid overdose: key facts.

August 2018. Available at: www.who.int/substance_abuse/information-sheet/en/.

22. Ryan NM, Isbister GK. Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely. Clin Toxicol (Phila). 2015;53(6):545–550.

2. Centers for Disease Control and Prevention. Understanding the epidemic.

Available at: www.cdc.gov/drugoverdose/epidemic/index.html.

23. Orliaguet G, Hamza J, Couloigner V, et al. A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics.

2015;135(3):e753–755.

3. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of chronic pain and high-impact chronic pain among adults - United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001–1006.

4. Ko S, Goldstein DH, VanDenKerkhof EG. Definitions of “respiratory depression” with intrathecal morphine postoperative analgesia: a review of the literature.

Can J Anaesth. 2003;50(7):679–688.

5. Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology. 2010;112(1):226–238.

6. Practice Guidelines for the Prevention, Detection, and Management of Respiratory Depression Associated with Neuraxial Opioid Administration: An Updated Report by the American Society of Anesthesiologists Task Force on Neuraxial Opioids and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology.

2016;124(3):535–552.

7. Voscopoulos CJ, MacNabb CM, Freeman J, et al. Continuous noninvasive respiratory volume monitoring for the identification of patients at risk for opioid-induced respiratory depression and obstructive breathing patterns. J Trauma Acute Care Surg.

2014;77(3 suppl 2):S208–215.

8. Pattinson KT. Opioids and the control of respiration. Br J Anaesth.

2008;100(6):747–758.

9. Pattinson KT, Governo RJ, MacIntosh BJ, et al. Opioids depress cortical centers responsible for the volitional control of respiration. J Neurosci. 2009;29(25):8177–8186.

10. 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.

11. Chang SH, Maney KM, Phillips JP, et al. A comparison of the respiratory effects of oxycodone versus morphine: a randomised, double-blind, placebo-controlled investigation. Anaesthesia. 2010;65(10):1007–1012.

12. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth. 1997;9(7):582–585.

13. Tantucci C, Paoletti F, Bruni B, et al. Acute respiratory effects of sublingual buprenorphine: comparison with intramuscular morphine. Int J Clin Pharmacol Ther Toxicol. 1992;30(6):202–207.

14. Modalen AO, Quiding H, Frey J, et al. A novel molecule with peripheral opioid properties: the effects on hypercarbic and hypoxic ventilation at steady-state compared with morphine and placebo. Anesth Analg. 2006;102(1):104–109.

15. Leino K, Mildh L, Lertola K, et al. Time course of changes in breathing pattern in morphine- and oxycodone-induced respiratory depression. Anaesthesia. 1999;54(9):835–840.

16. Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth.

2005;94(6):825–834.

17. Pergolizzi JV Jr, LeQuang JA, Taylor R Jr, et al. Designing safer analgesics: a focus on μ-opioid receptor pathways. Expert Opin Drug Discov. 2018;13(10):965–972.

18. Boom M, Niesters M, Sarton E, et al. Non-analgesic effects of opioids: opioid-induced respiratory depression. Curr Pharm Des. 2012;18(37):5994–6004.

19. Pergolizzi JV Jr, Coluzzi F, Taylor R Jr. Transdermal buprenorphine for moderate chronic noncancer pain syndromes. Expert Rev Neurother. 2018;18(5):359–369.

20. Raffa RB, Elling C, Tzschentke TM. Does ‘strong analgesic’ equal ‘strong opioid’?

Tapentadol and the concept of ‘µ-load’. Adv Ther. 2018;35(10):1471–1484.

21. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95(4):376–382.

24. Stamer UM, Stüber F, Muders T, et al. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg.

2008;107(3):926–929.

25. Barnung SK, Treschow M, Borgbjerg FM. Respiratory depression following oral tramadol in a patient with impaired renal function. Pain. 1997;71(1):111–112.

26. Houmes RJ, Voets MA, Verkaaik A, et al. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg. 1992;74(4):510–514.

27. Payne KA, Roelofse JA. Tramadol drops in children: analgesic efficacy, lack of respiratory effects, and normal recovery times. Anesth Prog. 1999;46(3):91–96.

28. Vickers MD, O’Flaherty D, Szekely SM, et al. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia. 1992;47(4):291–296.

29. Mildh LH, Leino KA, Kirvelä OA. Effects of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamics. J Clin Anesth.

1999;11(4):310–316.

30. Tsutaoka BT, Ho RY, Fung SM, et al. Comparative toxicity of tapentadol and tramadol utilizing data reported to the National Poison Data System.

Ann Pharmacother. 2015;49(12):1311–1316.

31. Miotto K, Cho AK, Khalil MA, et al. Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg. 2017;124(1):44–51.

32. Raffa RB, Buschmann H, Christoph T, et al. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother.

2012;13(10):1437–1449.

33. Channell JS, Schug S. Toxicity of tapentadol: a systematic review. Pain Manag.

2018;8(5):327–339.

34. Fudin J. Tapentadol: a real-world look at misuse, abuse, and diversion.

Pract Pain Manag. 2019;19(7).

35. Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. Pain Ther. 2020;9(1):41–54.

36. Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in analgesia. Br J Anaesth. 2006;96(5):627–632.

37. Webster L, Hansen E, Cater J, et al. A phase 1 placebo-controlled trial comparing the effect of buprenorphine buccal film and oral oxycodone hydrochloride on respiratory drive. In preparation.

38. Webster L, Gudin J, Raffa RB, et al. Understanding buprenorphine for use in chronic pain: expert opinion. Pain Med. 2020;21(4):714–723.

39. Khanna IK, Pillarisetti S. Buprenorphine - an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859–870.

40. U.S. Department of Health and Human Services. Pain Management Best Practices Inter-Agency Task Force Report: Updates, Gaps, Inconsistencies, and Recommendations (Final Report). May 9, 2019. Available at: www.hhs.gov/ash/ advisory-committees/pain/index.html./index.html.

41. Kjaer K, Lee C, Barrett J. Opioid patient safety tool kit. Weill Cornell Medicine Quality & Patient Safety. 2018.

42. O’Brien T, Ahn JS, Chye R, et al. Understanding transdermal buprenorphine and a practical guide to its use for chronic cancer and non-cancer pain management.

J Opioid Manag. 2019;15(2):147–158.

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Over-the-counter (OTC) shelves contain a bewildering array of analgesic products…

Over-the-counter (OTC) shelves contain a bewildering array of analgesic products (acetaminophen, NSAIDs, aspirin, caffeineâ&#x20AC;&#x201D;alone or in combination) and formulations (effervescent tablets, powders, liquidfilled capsules, standard tablets, fastacting tablets, and more galore!). As clinicians, we have to be prepared to help our patients navigate this OTC jungle. As much as one-third of adults use OTC analgesics regularly for management of both acute and chronic pain.1 In fact, between 2015 and 2018, internal and external analgesics were the second most commonly sold OTC products after cough and cold products.2 With cutbacks on opioids by providers, and growing patient hesitance with opioids, one can only imagine that OTC analgesic use may be on the rise.

38

key topic

the frequency of OTC product use and the failure of many patients to share their OTC use with us, we should be speaking with our patients regularly about OTC analgesic use.3,4 We should be cognizant that our patients are susceptible to the OTC brand extension trap, and may be using products that neither you nor your patient were aware of. For instance, there are 3 ExcedrinÂŽ products: Excedrin Extra Strength and Excedrin Migraine, which contain the same active ingredients (aspirin, acetaminophen, caffeine) but with different instructions, and Excedrin Tension Headache does not contain aspirin at all.5 Speaking with patients about active ingredients (generic names) instead of brand names will improve communication, particularly when discussing OTC combination analgesic products.

39

Table 1. Acetaminophen Single Entity: Adult otc Formulations12-20 Formulation Product Oral, immediaterelease

Brand Name

Mg per Unit Time to Peak

Regular strength Tylenol (tablet, caplet, liquid gel)

325 mg

Extra strength Tylenol (tablet, caplet, capsule, solution)

500 mg

Duration

Comments

∙ 45 min, fasted, 4 hrs pill formulations

∙ 6 mg of sodium per 15 mL of solution

∙ 30 min, fasted, oral solution

∙ Capsules can be opened and granules poured into spoon of liquid or soft food

4 hrs

Oral

Gelcap

Tylenol

500 mg

45 min, fasted

4 hrs

Dissolves 37 sec slower than standard tablets

Oral, extendedrelease

Bilayer caplet

Tylenol 8 Hr 650 mg Arthritis Pain

1–2 hrs, fasted

6–8 hrs

∙ Outer layer of 325 mg immediaterelease dose ∙ Inner layer of 325 mg with delayed dissolution

Rectal

Suppository

FeverAll®

325 mg 650 mg

2–4 hrs

8–9 hrs

∙ Adult formulations less commonly stocked in stores ∙ Rectal bioavailability: 50%–60%

*Acetaminophen dosing: 325–1000 mg every 4–6 hours as needed

Due to symptom marketing, unintentional overuse of an OTC analgesic (for instance, acetaminophen or aspirin) from a variety of products is also possible.6 Therefore, patients should be encouraged to turn products around and read the back label. Fortunately, the FDA regulates nonprescription labels, which must contain the following standardized content: active ingredient, purpose, uses, warnings, directions, other information (such as storage temperatures), and inactive ingredients.7,8 Through the use of online resources such as those available from getreliefresponsibly.com and knowyourdose.org, clinicians can help patients better understand product labeling, including warnings.8-10

OTC systemic analgesics: the major players

• Acetaminophen Acetaminophen is an analgesic and antipyretic indicated for mild to moderate pain and fever, with generally weaker analgesic activity than NSAIDs. Owing to its central inhibition of prostaglandin synthesis and only weak activity on cyclooxygenase (COX) in peripheral tissues, acetaminophen lacks anti-inflammatory activity and is not associated with platelet inhibition or gastric side effects.11 Due to concerns of hepatoxicity with doses >4 g/day, particularly with chronic use and with fasting and chronic alcoholism, the FDA requires all OTC

acetaminophen products to contain the “Liver Warning”12 against concurrent chronic alcohol use and avoiding use of acetaminophen from more than one product.13 The FDA has also advised OTC acetaminophen manufacturers to voluntarily lower the maximum daily dose. The manufacturer of Tylenol® heeded this suggestion and lowered the dose of all its Tylenol products: from 4 g/day to 3250 mg/day for regular strength products (325 mg); 3 g/day for Tylenol Extra Strength (500 mg); and 3900 mg/day for Tylenol 8 Hr (650 mg).13 Although some generic manufacturers made similar changes, not all followed suit. A variety of single-entity acetaminophen products can be found in the OTC analgesic aisle with formulations ranging from standard tablets to “rapid-release” gelcaps as shown in Table 1.12-20 Due to the importance of drug formulation and speed of absorption on efficacy of analgesics for acute pain (see Speed Matters Side Bar), OTC manufacturers frequently produce multiple drug formulations including those marketed as rapid-release or “fast-release.”21-23 As shown in Table 1, some claims fall short and fail to demonstrate faster gastric dissolution than regular tablets, such as the rapid-release gelatin coated acetaminophen gelcaps from 5 large US companies.17 In contrast, solubilized ibuprofen products and ibuprofen sodium products have shown a shorter time to maximal blood concentrations (known as “time to peak”) than standard ibuprofen tablets (Table 2).24-30

40

Table 2. Ibuprofen Single Entity: Adult OTC Formulations13,24-31 Formulation Product

Brand Name

Mg Time to Peak* Duration Comments per Unit

Ibuprofen

Coated tablets, caplets

Advil, Motrin

200 mg

Solubilized ibuprofen

Liquid gels, soft gels

Advil Migraine, Advil Liqui-Gels, Motrin Liquid Gels

Ibuprofen sodium

Film coated tablet Advil FilmCoated Tablets

200 mg

200 mg

1.25–2 hrs, fasted

6–8 hrs

30–40 min, fasted

6–8 hrs

30–35 min, fasted

6–8 hrs

∙ Advil Tmax < Motrin Tmax ∙ Not an enteric coating ∙ Advil Tmax = Motrin Tmax ∙ Advil “Minis” available in smaller liquid gel

∙ Available as brand only ∙ Not an enteric coating

Ibuprofen, chewable

Chew tablet

100 mg Children’s Advil, Children’s Motrin, Advil Junior Strength, Motrin Junior

1 hr

6–8 hrs

Marketed as children’s products

Ibuprofen, suspension

100 mg/5 mL suspension

Children’s Advil, Children’s Motrin

45 min

6–8 hrs

∙ Marketed for children

100– 300 mg

∙ Shake well before use ∙ Dosing cup with product ∙ 2 mg of sodium per 5 mL

Tmax: time to maximal concentrations (time to peak) *Anti-inflammatory time to peak is 2–3 weeks Ibuprofen OTC dosing: 200–400 mg q 4–6 as needed (OTC max: 1200 mg/day; prescription max: 3200 mg/day)

• NSAIDs Two broad categories of NSAIDs are available OTC: the nonselective NSAIDs and the salicylates. OTC nonselective NSAIDs include ibuprofen and naproxen. Ketoprofen is another FDA-approved nonprescription NSAID; however, it is not found in any current commercially available OTC product.13 OTC salicylates include acetylsalicylic acid (aspirin) and the nonacetylated salicylates. In the OTC analgesic aisle, nonacetylated salicylates include magnesium salicylate tetrahydrate (available as brand name products Doan’s® and Percogesic®) and sodium salicylate in the combination product, Cystex®, which is marketed as a urinary analgesic.

As highlighted in this publication’s article by Drs. Atkinson and Fudin, “He SAID, She SAID… What’s the Deal with NSAIDs?” (2018 Q2), NSAIDs achieve their therapeutic effect by inhibiting the inducible cyclooxygenase-2 (COX-2) enzyme, and their toxic effects occur by inhibition of the constitutive COX-1 enzyme responsible for the production of prostaglandins for maintenance of hemostasis, integrity of gastric mucosa, and platelet aggregation.29,30-32 In terms of OTC NSAIDs, ibuprofen is more COX-2 selective than naproxen and, therefore, is thought to possess a lower risk of gastrointestinal (GI) toxicity particularly when used in nonprescription doses (Table 3).33-36 Another factor to

41

consider when selecting an OTC NSAID is half-life. Since ibuprofen’s half-life is shorter than naproxen (2–2.5 hours vs 12–17 hours, respectively), overall NSAID exposure may be reduced with ibuprofen and could be an important consideration for patients who require an NSAID but are at greater risk for bleeding, renal insufficiency, and fluid retention. In terms of NSAID cardiovascular (CV) safety, the FDA in 2015 strengthened CV warnings on prescription NSAIDs, and updates to OTC nonaspirin NSAID labels followed in August 2016 with the “Heart Attack and Stroke Warning” that indicated increased risk with use of higher doses and for longer durations than directed.37,38 This CV warning, however, was not extended to the OTC nonacetylated salicylates such as magnesium salicylate as these products may have a safer CV profile as suggested by the American Heart Association.

In their 2007 scientific statement on NSAIDs, the American Heart Association indicated that nonacetylated NSAIDs were preferred to nonselective and COX-2 selective NSAIDs in patient with CV disease or CV risk factors.39 • Salicylates,

More Specifically…

The chemical name of aspirin is acetylsalicylic acid, and it functions by adding an acetyl group to COX-1 and COX-2 enzymes resulting in irreversible inhibition

Table 3. Naproxen Single Entity: Adult OTC Formulations13,34-36 Formulation

Product

Brand Name Mg per Unit

Tablets, Naproxen Aleve sodium, caplets regular-release Liquid-filled Aleve capsules, liqui-gels, gelcaps

Time to Peak*

Duration

Comments

220 mg

1–2 hrs, fasted

Up to 12 hrs

220 mg

1.5 hrs, fasted

Up to 12 hrs

∙ Naproxen base (prescription only) time to peak is 2–4 hrs ∙ Enteric coated naproxen base (prescription only) time to peak is 4–6 hrs

*Anti-inflammatory time to peak is 2–3 weeks Naproxen OTC dosing: 220 mg q 8–12 hours as needed (OTC max: 660 mg/day; prescription max: 1500–1650 mg/day)

of COX activity. The duration of the effect of aspirin is therefore related to the turnover rate of COX activity in tissues with effects on platelet aggregation lasting for the life of the platelet (7–10 days).40 Aspirin effects are dose-dependent with low doses (<300 mg/day) inhibiting COX-1 resulting in antiplatelet effects. Intermediate doses (300–4000 mg/ day) inhibit both COX-1 and COX-2 enzymes for analgesic and antipyretic effects. High doses (4000–8000 mg/day) of aspirin are generally required for effective anti-inflammatory activity, but use is limited by toxicity with 4 g/day being the maximum daily OTC dose.40,41 Clinicians should be familiar with single entity and combination OTC aspirin products, particularly the high aspirin-containing powders marketed for headache, back pain, and arthritis due to the potential for unintentional overdose (Table 4).13,40-51 These include BC® powders (845–1000 mg of aspirin per dose) and Goody’s® (500–520 mg of aspirin per dose).49-50 Use of Goody’s and BC powder is prevalent in southern states, and, between 2006 and 2015, the human exposure cases from these aspirin powders increased by 208% according to data from the Virginia Poison Center.52-54 As shown in Table 4, a variety of aspirin products are available over-the-counter including enteric coated (EC) tablets (which contain a polymer coating to prevent dissolution in the stomach) and buffered tablets (which contain buffering agents that help neutralize stomach acid) as well as effervescent tablets (which are pressed powder discs containing a buffering agent) for ready dissolution in water. The rationale for these formulations is to reduce topical toxicity, at least in theory.55 When aspirin is taken on an empty stomach (gastric pH 1–2), a higher percentage remains un-ionized and is therefore capable of permeating into gastric mucosa. Once inside the gastric mucosa where the intracellular pH is 7.4, aspirin becomes ionized and temporarily trapped, causing damage to the gastric epithelium. This is referred to as the “ion trapping phenomenon,” and the lower the pKa (acid dissociation constant) of the NSAID, the greater propensity for topical toxicity to occur (aspirin pKa 3.5, naproxen pKa 4.15, ibuprofen pKa 5.2).56,57 By raising the gastric pH to 3–4 through the use of acid suppressive medications or to a

42

pH of 6 with food, the percentage of un-ionized aspirin is reduced and less ion trapping occurs.58 The use of alkaline buffering agents (aluminum hydroxide; magnesium carbonate, hydroxide, or oxide; calcium carbonate; sodium bicarbonate) in buffered tablets (such as Bufferin®) or effervescent aspirin solutions (Alka-Seltzer® Original or Extra Strength) serves to increase gastric pH and decrease the percentage of un-ionized aspirin. Another effect of these products is increased aspirin solubility and faster time to onset.59 The use of gastric resistant polymers in EC aspirin prevents disintegration in the stomach and allows for absorption in the alkaline pH of the small intestine.55,56 However, taking EC aspirin with acid suppressive drugs (eg, proton pump inhibitors) or with food (which increases gastric pH) causes premature dissolution in the stomach, negating the benefit of enteric coating on reducing topical toxicity.13,60 Enteric coating also results in erratic absorption of aspirin with peak salicylate levels delayed >6 hours after a single dose.42,43 For this reason (as noted on the label for Bayer® Safety Coated aspirin), EC aspirin is inappropriate for rapid pain relief in acute pain.44 The effectiveness of these strategies for reducing topical gastric irritation has been evaluated in endoscopic studies with mixed results.55 In endoscopic studies of healthy, younger adults, patients who used EC aspirin 300 mg for 5 days had less evidence of gastric injury compared to patients using plain aspirin.61 However, in older, long-term users of EC aspirin, endoscopic evidence of benefit from the coating was not demonstrated, potentially due to hypochlorhydria—where the production of hydrochloric acid in gastric secretions of the stomach and other digestive organs is absent or low—in older adults.55,62 For buffered aspirin tablets and effervescent aspirin solutions, early studies demonstrated reduced GI side effects and mucosal injury when high doses (aspirin 650 mg TID) were used by healthy volunteers and compared to plain aspirin.63,64 However, the benefit did not hold true for lower doses.65,66 It is the convention to recommend taking aspirin and NSAIDs with food; however, whether this confers actual protection to the gastric mucosa has never been systematically studied, and data are lacking.57,67 However,

Table 4. Aspirin Single Entity: Adult OTC Formulations13,40-51 Formulation Product

Brand Name Mg per Unit Time to Peak Duration

Aspirin, chewable

Bayer, St. Joseph

Aspirin, enteric coated (aka “safety coated”)

Low dose tablet

Regular strength Bayer, (tablet, caplet) Ecotrin®

Aspirin, Regular strength Bayer immediate- (tablet, caplet) release

Extra strength (tablet, caplet)

Bayer

Comments

81 mg

Platelet inhibition within 1 hr

Low dose is not for Effects last analgesia 7–12 days after stopping aspirin

325 mg

8–14 hrs, erratically absorbed

Variable

45–120 min

4–6 hrs

325 mg

∙ Inappropriate for rapid pain relief ∙ Enteric coated aspirin products are delayed-release ∙ Thin coating is not enteric coating ∙ Dosage: 325–650 mg q 4 hrs as needed or 975 mg q 6 hrs as needed (max: 3,900 mg/day)

500 mg

45–100 min

4–6 hrs

∙ Thin coating is not enteric coating ∙ Dosage: 500–1000 mg q 4–6 hrs as needed (max: 4,000 mg/day)

Aspirin, buffered

Buffered tablet

Bufferin

325 mg

20 min

4–6 hrs

∙ Contains 3 buffering agents (calcium carbonate, magnesium carbonate, and magnesium oxide) ∙ Dosage: 650 mg q 4 hrs as needed (max 3,900 mg/day)

Effervescent solution

Alka-Seltzer 325 mg (original) 500 mg (extra strength)

15 min

4–6 hrs

∙ Contains anhydrous citric acid 1000 mg (antacid) and sodium bicarbonate 1916 mg (buffering agent) ∙ Each tablet contains 567 mg of sodium ∙ Dosage: dissolve 650–1000 mg (2 tablets) in 4 oz of water q 4 hrs as needed (max: 2600–2300 mg/ day; >60 yo: 1300–1500 mg/day)

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Speed Matters When selecting an OTC analgesic for acute pain, formulation matters…because speed matters.

• Speedier absorption provides more rapid relief but also better overall pain relief.21-22,27 • Earlier pain reduction has been associated with longer pain relief and less use of additional analgesics (meaning less risk for adverse effects!).21-22 • Fast-acting formulations perform well in studies of acute pain (see Table 5).21,75 • Taking with food delays absorption and time to peak, decreases maximum blood concentrations, and may reduce the effectiveness of oral analgesics for acute pain.21,23,57 Evaluating the time to peak for OTC formulations may help facilitate analgesic selection for acute pain (see Tables 1–4).

food may delay absorption of NSAIDs and onset of analgesia (Speed Matters).

Regardless of the formulation of aspirin administered, no difference in the risk for major GI ulceration and bleeding has been identified. This is largely because systemic inhibition of prostaglandins and impaired platelet aggregation may have more to do with significant GI toxicity than local irritation.13 For instance, a study investigating plain, EC, and buffered aspirin demonstrated no substantial difference in risk of major upper GI bleed based on formulation used.68 This study did demonstrate, however, that higher dose use (>325 mg/day) and regular use (at least every other day for 1 week) of both higher and lower doses (<325 mg/day) were associated with increased risk of gastric and duodenal bleeding. Fortunately, a large systematic review found that proton pump inhibitors and double dose H2-receptor antagonists (≥ranitidine 300 mg BID) significantly reduced the risk of both gastric and duodenal ulcers from chronic NSAID use. However, standard dose H2-receptor antagonists (ie, the doses marketed for OTC use) were only effective in reducing duodenal but not gastric ulcers.69 In contrast to aspirin, the nonacetylated salicylates lack an acetyl group and are weak, reversible COX inhibitors with limited effect on prostaglandin synthesis.40 As a result, the OTC nonacetylated salicylates (which include magnesium salicylate tetrahydrate and sodium salicylate) do not clinically inhibit platelet aggregation and have a low incidence of GI side effects.70,71 Nonacetylated salicylates (prescription or OTC) may be preferable when COX inhibition should be avoided, such as in patients with bleeding risk factors, asthma, or potentially those with renal impairment but only under medical supervision.11 Due to magnesium content (40–50 mg per OTC tablet) and risk for hypermagnesemia, magnesium salicylate should be used with caution in patients with renal impairment and avoided in patients with severe kidney disease.70 In addition, salicylates—aspirin and nonacetylated salicylates—in doses of 1–2 g/day can interfere with renal tubular excretion of uric acid and should be avoided in patients with gout.13,70 Although sometimes touted as less effective than aspirin for analgesia and inflammation, nonacetylated salicylates are equipotent to aspirin at the same daily dose of 3–4 g/day, according to well controlled studies.71,72 Given weak COX inhibition with nonacetylated salicylates, the

mechanism for analgesia and anti-inflammatory effect may be nonprostaglandin mediated.73 Despite the lower risk of serious GI effects with magnesium salicylate and sodium salicylate, all OTC NSAIDS—including the nonacetylated salicylates—contain the “Stomach Bleeding Warning” on their package labeling. In 2010, the FDA approved the OTC label warning which states that this product contains an NSAID and may cause severe stomach bleeding.74 Risk factors increasing the risk for GI bleeding are also listed on the label: age ≥60, history of GI ulcers or bleeding, concurrent use of an anticoagulant or steroid, use of other NSAIDs (including aspirin), consuming ≥3 alcoholic drinks/day, and taking more or for longer than directed.

The Side Kick: Caffeine

Caffeine is a common component of OTC analgesic combination products with the caffeine content typically ranging from 32–65 mg per dosage form. For reference, a cup of coffee contains on average 100 to 150 mg of caffeine; a cup of tea 75 mg of caffeine; and a can of pop/soda 40 mg of caffeine.75 The mechanism by which caffeine enhances analgesia is not clearly understood. It may be that caffeine speeds up drug absorption by increasing gastric blood flow and thereby shortening the time it takes to achieve maximal blood levels of the primary analgesic; onset of acute pain relief with caffeine combination analgesics may occur as early as 15 minutes.75,76 Or perhaps, caffeine has a direct analgesic effect mediated through blockade of adenosine receptors or via alteration of mood, impacting the perception of pain.75,77 Caffeine can be found in combination with aspirin such as in these OTC products: Bayer Back & Body (aspirin 500 mg and caffeine 32.5 mg/caplet; 2 caplets/ dose), Anacin® (aspirin 400 mg and caffeine 32 mg/tablet; 2 tablets/dose), BC Original (aspirin 845 mg and caffeine 65 mg/powder; 1 powder/dose), and BC Arthritis (aspirin 1000 mg and caffeine 65 mg; 1 powder/dose).44,48,49 Caffeine is also combined with acetaminophen in Excedrin Tension Headache (acetaminophen 500 mg and caffeine 65 mg/ caplet; 2 caplets/dose). Caffeine can be found with dual analgesics in these OTC products: Excedrin Extra Strength and Excedrin Migraine (acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg/caplet; 2 tablets/dose); Goody’s Extra Strength (acetaminophen 260 mg, aspirin 520 mg, and caffeine 32.5 mg/powder; 1 powder/dose) and Goody’s Cool Orange or Mixed Fruit Blast (acetaminophen 325 mg, aspirin 500 mg, and caffeine 65 mg/powder; 1 powder/ dose). All these products, except Bayer Back & Body, contain a caffeine warning on the OTC label to alert the consumer of the caffeine content of roughly a cup of coffee per dose.

In a systematic review of 25 comparisons of OTC simple analgesics (aspirin, acetaminophen, ibuprofen, and aspirin plus acetaminophen) at standard doses with

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Table 5. Indirect Comparisons of Nonprescription Analgesics for Acute Pain21 Studied Drug

Associated Product

Dose (mg)

Ibuprofen + acetaminophen

Regular-release 200 mg ibuprofen and Tylenol extra strength 500 mg tablet/caplets

400 + 1000 1.5 (1.4 – 1.7)

Ibuprofen + acetaminophen Ibuprofen fast-acting*

Advil liquid gels Advil Migraine (solubilized ibuprofen)

Ibuprofen fast-acting*

NNT (95% confidence interval)

200 + 500

1.6 (1.5 – 1.8)

400

2.1 (1.9 – 2.3)

200

2.1 (1.9 – 2.4)

Ibuprofen + caffeine

Combination product not available in US

200 + 100

2.1 (1.9 – 3.1)

Ibuprofen

Advil 400 mg tablet/caplet

400

2.5 (2.4 – 2.6)

Naproxen

Aleve liquid gels, tablet/caplets

440

2.7 (2.2 – 3.5)

Ibuprofen

Advil 200 mg tablet

200

2.9 (2.7 – 3.2)

Naproxen

Aleve liquid gels, tablet/caplets

220

3.4 (2.4 – 5.8)

Acetaminophen

Tylenol extra strength 500 mg tablet/caplets

500

3.5 (2.7 – 4.8)

Acetaminophen

500 mg or 325 mg (regular strength) tablet/caplets

975–1000

3.6 (3.2 – 4.1)

Aspirin

Regular strength 325 mg tablet and enteric coated

650

4.2 (3.8 – 4.6)

Aspirin

Bayer Extra Strength 500 mg coated caplets

1000

4.2 (3.8 – 4.6)

Acetaminophen

Tylenol Arthritis/8 Hr (extended-release)

650

4.6 (3.9 – 5.5)

Aspirin

Bayer Extra Strength 500 mg coated caplets

500

Not better than placebo

*Note: Only solubilized ibuprofen was available for study. Potentially faster-acting ibuprofen sodium, film-coated tablets (Advil Film-Coated Tablets) were not included in this review as the product was not commercially available until August 2013.2

or without caffeine, the addition of caffeine in doses of 100–200 mg resulted in a small but significant increase in the percentage of patients who, over 4 to 6 hours, achieved 50% of maximum pain relief, which is considered an indicator of effective pain relief.75,78 Patients with acute pain were included in this review with the most common painful conditions being postoperative/postpartum pain; headache, and dysmenorrhea.

Although combination simple analgesic and caffeine products are available OTC, caffeine need not be in a tablet or powder form to be used as an adjuvant agent for pain. Combining a simple analgesic with a caffeinated beverage may just do the trick!21

published that analyzed all Cochrane reviews of randomized controlled trials for single dose nonprescription oral analgesics for acute postoperative pain—dental pain, inpatient surgery, and day surgery—in fasted adult patients.21 Although headache, migraine, and dysmenorrhea were excluded, postoperative pain was selected to represent moderate to severe acute pain. The majority of studies that were included evaluated dental pain after third molar extraction, which is frequently used as a model for studying acute pain.

The primary outcome of the included studies was the number of patients experiencing at least 50% pain relief compared to placebo over 4 to 6 hours. In Table 5, the number needed to treat (NNT) for each analgesic or analgesic combination is presented. NNT refers to the number of patients who need to be treated with the study drug for one person to achieve good pain relief. Lower numbers are better, and a NNT of 1 is ideal, meaning that everyone treated achieves a 50% reduction in pain.78 As shown in Table 5, combination ibuprofen and acetaminophen products performed particularly well with the lowest

Efficacy of OTC Systemic Analgesics in Acute Pain

As OTC analgesics are FDA approved for no more than 10 days unless directed by a clinician, the efficacy of nonprescription analgesics for acute pain will be reviewed here.13 In 2015, a systematic review was

45

Due to symptom marketing, unintentional overuse of an OTC analgesic (for instance, acetaminophen or aspirin) from a variety of products is also possible.

Therefore, patients should be encouraged to turn products around and read the back label.

or best NNT at 1.5 for ibuprofen 400 mg plus acetaminophen 1000 mg, and a similar NNT of 1.6 at half the dose.

This was followed by fast-acting, solubilized ibuprofen 200–400 mg and ibuprofen 200 mg plus caffeine 100 mg, all with an NNT of 2.1. Important to note: Use of combination products and fast-acting ibuprofen allows for use of lower analgesic doses without compromising analgesia.

For instance, fast-acting, solubilized ibuprofen 200 mg performed just as well as solubilized ibuprofen 400 mg (NNT 2.1) and better than ibuprofen 400 mg tablets (NNT 2.5). Lower dose ibuprofen 200 mg in combination with caffeine also performed better than higher dose standard ibuprofen 400 mg tablet (NNT 2.1 vs 2.5, respectively).

Aspirin 500 mg was not better than placebo, and although aspirin 650 mg and 1000 mg were better than placebo, the NNT was 4.2 for both doses. Only aspirin 1000 mg and ibuprofen 200 mg plus caffeine 100 mg (although barely) had adverse event rates that differed from placebo. The number needed to harm was 7.5 and 19, respectively.

Looking at the indirect comparisons of various acetaminophen doses and products vs placebo, a few interesting findings emerge from this review.21 One,

acetaminophen 650 mg in the 8 hour formulation had an NNT (4.6) below that of all other analgesics, except aspirin 500 mg, which was not effective. If speed matters for acute pain (which appears to hold true in this review), an extended-release acetaminophen product with a lag time to peak of 2 hours, fasted, would be expected to have lower efficacy for acute pain. After multiple doses or with regular use in chronic pain, the speed of drug onset is of minimal benefit once steady state blood levels have been achieved. However, for patients with chronic pain using OTC analgesics intermittently on an as needed basis, speed may matter.

Another interesting finding: higher doses of acetaminophen regular strength 975–1000 mg had a similar or slightly worse NNT than lower doses of 500 mg (NNT of 3.6 vs 3.5, respectively). This finding goes against the convention that higher or “full” doses of acetaminophen provide greater pain relief than lower doses. However, a meta-analysis of direct comparison studies in which 2 doses of acetaminophen were directly compared does suggest a statistically significant benefit of 1000 mg of acetaminophen over 500–650 mg (NNT 9).79,80 Headto-head comparisons also demonstrate a dose response

46

for prescription doses of ibuprofen (800 mg) over OTC doses (400 mg) with a NNT of 10 and aspirin 1000 mg over 500–600 mg with NNT of 16.79,80 It is important to recognize, however, that the dose response for doubling doses of these simple analgesics may not be linear. In the meta-analysis discussed above, doubling of the dose led to roughly an absolute increase of 10% more patients achieving good pain relief (NNT 10), while studies suggest that doubling an opioid dose results in a 30% absolute increase in responders for a NNT of 3.79 Therefore, when considering use of nonopioid analgesics, particularly NSAIDs, lower doses in the OTC range may provide acceptable pain relief with lower risk for adverse effects.

OTC Topical Analgesics

Topical analgesics act locally in the skin and underlying tissues, and under ordinary circumstances do not achieve appreciable concentrations in the bloodstream. This offers many advantages including lower risk for systemic side effects and drug-drug interactions.81 A variety of OTC topical products exist in a wide range of formulations, including creams, sprays, gel sticks, and patches, and may be important treatment options for patients with localized symptoms. For more information on the clinical role of topical analgesics, check out Drs. Atkinson and Crumb’s article on this topic in the Q3 2018 issue of PWJ.82

Herbal Products for Osteoarthritis

Two herbal products may be of interest to osteoarthritis patients.83,84 The first is arnica gel (frequently sold as Arnicare® Gel); when applied twice daily for 3 weeks, it was found to reduce stiffness and pain compared to baseline.85 In another study, arnica gel applied 3 times daily for 3 weeks was found to be as effective as ibuprofen 5% gel for hand osteoarthritis with a similar degree of adverse effects.86 Arnica inhibits COX-1 and COX-2 and is thought to have anti-inflammatory activity.83 Turmeric extract (or curcumin) taken orally 3–4 times daily for 4–6 weeks was found comparable to oral ibuprofen 400 mg 2–3 times daily for reducing knee pain in arthritis with minimal difference in side effects.87 The most common side effects in both groups were dyspepsia, dizziness, nausea, and vomiting. Turmeric is thought to have an anti-inflammatory effect, but the exact mechanism is not certain. However, it is postulated that inhibition of cyclooxygenase and other substances in the inflammatory pathway may be involved.87 Due to potential antiplatelet effect of turmeric, there may be an increased risk of bleeding especially in patients taking antithrombotic agents.88 In addition to screening for use of OTC simple analgesics during patient visits, it is imperative to also screen for potential use of herbal products such as those discussed above, particularly if COX inhibition should be avoided.

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Conclusion

By increasing familiarity with available OTC analgesic products and formulations, clinicians will be better prepared to educate patients on the risks of OTC polypharmacy and on the importance of reading and understanding labels. With brand extensions and risk for double dipping of active ingredient, OTC products should be reconciled with patients frequently. Although on demand, easy to use OTCs are the cornerstone of self-care, clinician assisted self-care should be the norm for patients with regular use of OTC analgesics or with multiple, complex comorbidities. For acute pain, oral formulation matters with greater pain relief when combining analgesics (eg, ibuprofen and acetaminophen) and with faster acting analgesics, such as ibuprofen sodium, solubilized ibuprofen, or the addition of caffeine to simple analgesics. For prevention of major NSAID-induced GI toxicity, oral formulation (enteric coating, buffered or effervescent tablets) is less important. Drug, dose, duration, and patient risk factors are more important considerations.

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33. Clinical Resource, Managing NSAID Risks. Pharmacist’s Letter/Prescriber’s Letter.

July 2018.

34. Naproxen. Clinical Pharmacology powered by Clinical Key. Elsevier. Available at: www-clinicalkey-com.proxy.cc.uic.edu/pharmacology/.

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55. Dulin W. Oral targeted drug delivery systems: enteric coating. In: Wen H, Park K, eds. Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice.

Hoboken, New Jersey: John Wiley &Sons, Inc; 2010.

56. Biarnason I, Scarpignato C, Holmgren E, et al. Mechanism of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs. Gastroenterology.

2018;154(3):500–514.

57. Rainsford KD, Biarnason I. NSAIDs: take with food or after fasting? J Pharm Pharmacol. 2012;64(4):465–469.

78. Teater D. National Safety Council. Evidence for the safety of pain medications.

Available at: safety.nsc.org/painmedevidence.

58. Daneshmend TK, Stein AG, Bhaskar NH, et al. Abolition by omeprazole of aspirin induced gastric mucosal injury in man. Gut. 1990;31(5):514–517.

79. McQuay HJ, Moore RA. Dose-response in direct comparisons of different doses of aspirin, ibuprofen and paracetamol (acetaminophen) in analgesic studies. Br J Clin Pharmacol. 2007;63(3):271–278.

59. Vigano G, Garagiola U, Gaspari F. Pharmacokinetic study of a new oral buffered acetylsalicylic acid (ASA) formulation in comparison with plain ASA in healthy volunteers. Int J Clin Pharmacol Res. 1991;3(11):129–135.

80. McQuay HJ, Derry S, Eccleston C, et al. Evidence for analgesic effect in acute pain—50 years on. Pain. 2012;153(7):1364–1367.

60. Nefesoglu FZ, Ayanoglu-Dulger G, Ulusoy NB, et al. Interaction of omeprazole with enteric-coated salicylate tablets. Int J Clin Pharmacol Ther. 1998;36(10):549–553.

81. Olenak J. Musculoskeletal injuries and disorders. In: Handbook of Nonprescription Drugs. 19th ed. Krinsky DL, Ferreri SP, Hemstreet BA, et al, eds. Washington, DC: American Pharmacists Association; 2018.

61. Cole AT, Hudson N, Liew LC, et al. Protection of human gastric mucosa against aspirin-enteric coating or dose reduction. Aliment Pharmacol Ther. 1999;13(2):187–193.

82. Atkinson T, Crumb M. Everybody’s greasing up, but should you rub it in? PWJ— PAINWeek Journal. 2019;7(Q3):42–51.

62. Walker J, Robinson J, Stewart J, et al. Does enteric-coated aspirin result in a lower incidence of gastrointestinal complications compared to normal aspirin?

Interact Cardiovasc Thorac Surg. 2007;6(4):519–522.

83. Cameron M, Chrubasik S. Topical herbal therapies for treating osteoarthritis.

Cochrane Database Syst Rev. 2013;5:CD010538

63. Murray FE, Hudson N, Atherton JC, et al. Comparison of effects of calcium carbasalate and aspirin on gastroduodenal mucosal damage in human volunteers.

Gut. 1996;38(1):11–14.

84. Cameron M, Chrubasik S. Oral herbal therapies for treating osteoarthritis.

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85. Knuesel O, Weber M, Suter A. Arnica montana gel in osteoarthritis of the knee: an open, multicenter clinical trial. Adv Ther. 2002;19(5):209–218.

64. du Pre BC, van Laake LW. Buffered aspirin: what is your gut feeling? Neth Heart.

2014;22(3):105–106

86. Widrig R, Suter A, Saller R, et al. Choosing between NSAID and arnica for topical treatment of hand osteoarthritis in a randomized, double-blind study. Rheumatol Int. 2007;27(6):585–591.

65. Jaspers Focks J, Tielemans MM, van Rossum LG, et al. Gastrointestinal symptoms in low-dose aspirin users: a comparison between plain and buffered aspirin.

Neth Heart J. 2014;22(3):107–112.

87. Kuptniratsaikul V, Thanakhumtorn S, Chinswangwatanakul P, et al. Efficacy and safety of curuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med. 2009;15(8):891–897.

66. van Ojjen MG, Dieleman JP, Lahejj RJ, et al. Peptic ulcerations are related to systemic rather than local effects of low-dose aspirin. Clin Gastroenterol Hepatol.

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88. Turmeric. Professional. Natural Medicine Database. Available at: naturalmedicines-therapeuticresearch-com.proxy.cc.uic.edu/.

67. Biarnason I. Gastrointestinal safety of NSAIDs and over-the-counter analgesics.

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69. Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev. 2002;4:CD002296.

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Comparing acetylated salicylates, nonacetylated salicylates, and nonacetylated nonsteroidal anti-inflammatory drugs. Arthritis Rheum. 1994;37(1):1–9.

72. Preston SJ, Arnold MH, Beller EM, et al. Comparative analgesic and antiinflammatory properties of sodium salicylate and acetylsalicylic acid (aspirin) in rheumatoid arthritis. Br J Clin Pharmacol. 1989;27(5):607–611.

73. The Multicenter Salsalate/Aspirin Comparison Study Group. Does the acetyl group of aspirin contribute to the anti-inflammatory efficacy of salicylic acid in the treatment of rheumatoid arthritis? J Rhematol. 1989;16(3):321–327.

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75. Derry CJ, Derry S, Moore RA. Caffeine as an analgesic adjuvant for acute pain in adults. Cochrane Database Syst Rev. 2014;12:CD009281.

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By Courtney E. Brennaman MS, CRC / Beth L. Dinoff PhD

By Courtney E. Brennaman MS, CRC / Beth L. Dinoff PhD

behavioral pain management

understanding that movement is beneficial for coping with pain is especially important for people who experience chronic pain, such as via the phenotype of diabetic neuropathy.

For many years, people experiencing diabetic neuropathy have been advised NOT to keep moving, with the goal of preventing falls, injury, ulcers, and amputations. In this article, we review the new science that explores the benefits of safely remaining physically active to maintain and improve functioning in the context of diabetic neuropathy.

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benefits of physical activity have been well documented for healthy adults.1-3 The external physical benefits of activity, such as weight loss and tonal definition, may be easier to see initially; however, the impact of physical activity is more than skin deep. Studies have shown that physical activity can influence our bodies on cellular levels, improve mental health, and reduce the onset and/or progression of disease.1 The health behavior of physical activity encompasses any kind of movement that increases energy use, and the term exercise is used to identify planned or structured physical activity.4 Physical activity includes taking the stairs at work or watering the flower garden, whereas exercise includes going to the gym to use the elliptical machine or meeting a friend for a 60-minute walk twice a week.

on psychological and functional well-being that cannot be fully related though simple verbal descriptions. Pain remains the most commonly reported medical symptom amongst individuals in the United States and across the globe.6 In 2014, at least 100 million American adults were living with chronic pain. This number represents more than 40% of the US adult population.7 In the US alone, the economic costs exceed $635 billion annually.6

Peripheral Neuropathy and Neuropathic Pain

The International Association for the Study of Pain (isap) has announced a new definition of pain, which indicates that pain is â&#x20AC;&#x153;an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.â&#x20AC;?5 The IASP website indicates that pain is always a very personal event influenced by biopsychosocial factors, including emotions, memories, and individual life experiences.

Furthermore, the IASP definition includes the contextual understanding that pain frequently has detrimental effects

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Peripheral neuropathies represent a group of more than 100 conditions that can negatively impact the peripheral nervous system. The peripheral nervous system is responsible for communication between the central nervous system (ie, brain and spinal cord) and the rest of the body. This communication system is bidirectional, meaning that the peripheral nerves send signals to the brain via the spinal cord; in turn, the brain transmits signals back through the spinal cord to peripheral nerves in the rest of the body. The central nervous system and the peripheral nervous system are in constant communication to recognize and respond to potential dangers to the body, help muscles contract to facilitate movement, and keep our cardiovascular system automatically functioning effectively. At times, this vast communication system can be disrupted by dysfunction within the peripheral nervous system, and this can lead to the development of peripheral neuropathy in some individuals.

Peripheral neuropathy is usually a chronic medical condition commonly associated with persistent, progressive, and debilitating pain. Peripheral neuropathies include dysfunctions or damage within components of the peripheral nervous system: motor, sensory, or autonomic nerves: ● When motor nerves are impaired, activities such as picking up a cell phone or taking a walk may be impacted. ● Motor symptoms of peripheral neuropathy include weakness, muscle twitching, loss of coordination, and falling. ● Sensory nerve damage can lead to experiencing allodynia—pain from even the gentle stroke of a feather or a piece of clothing. ● Sensory symptoms of peripheral neuropathy include numbness, tingling, burning sensations, heightened sensitivity to touch, impaired ability to feel cold and hot temperatures, and severe pain. ● Autonomic nerve damage can cause significant problems with systems that automatically—without conscious awareness— regulate physical processes, such as cardiac, respiratory, and digestive functions. ● Autonomic symptoms of peripheral neuropathy include problems with orthostatic hypotension, dizziness, fainting, vomiting, urination, and constipation.

a serious chronic medical condition and a major cause of morbidity, diabetes is associated with numerous complications impacting multiple areas of the body, including severe damage to the eyes, heart, and kidneys.11 Diabetic neuropathy leads to peripheral damage in many important nerves in the body, causing many deficits in functioning, including impaired vision, stroke, and/or urinary retention.

And, diabetic neuropathy can have a devastating impact on an individual’s quality of life by leading to extensive physical complications such as muscle weakness, ataxia, incoordination, development of ulcers, gastroparesis, and chronic pain.14 In fact, diabetic neuropathy is noted to cause more hospitalizations than other diabetes symptoms and is responsible for 50% to 75% of nontraumatic amputations.14

National Institutes of Health report that more than 20 million Americans experience at least one kind of peripheral neuropathy.8 Common causes of peripheral neuropathy include physical injury or trauma, alcohol use, exposure to environmental toxins, and taking certain medications (ie, chemotherapies and antibiotics). In addition, peripheral neuropathy may be caused by metabolic and/or cardiovascular microvessel changes linked to exposure to glycemic abnormalities.9 Diabetes mellitus is the most common cause of peripheral neuropathy related to glycemic abnormalities, and 90% of people with diabetes have type 2 diabetes.10

Diabetes and Diabetic Neuropathy

Diabetes is a chronic disease of the endocrine system, which is a delicate system of glands that releases hormones into the circulatory system. Diabetes is defined as “a group of metabolic conditions characterized by hyperglycemia which results from defects in insulin secretion, insulin action, or both.”11 Globally, about 9% of adults have diabetes, making diabetes a significant public health issue worldwide.12 The prevalence of diabetes worldwide has reached sweeping proportions with almost 630 million people projected to have diabetes by 2045.13 Known to be

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At least 50% of people with diabetes will develop diabetic neuropathy, and approximately 25% of people with diabetic neuropathy will develop a painful phenotype of diabetic neuropathy. Maintaining tight glycemic control of blood sugars through diet and careful monitoring may lead to slowing the progression of diabetic neuropathy. Unfortunately, the management of diabetes and maintaining tight glycemic control of diabetes does not necessarily mitigate the progression of peripheral neuropathy into the painful phenotype of diabetic neuropathy. For many individuals, neuropathic pain is viewed as the most distressing symptom experienced with diabetic neuropathy. People often report that painful diabetic neuropathy causes sensations of intense burning, electrical, and shooting pains while simultaneously experiencing numbness and tingling. Compared to individuals with painless diabetic neuropathy, individuals with the painful phenotype of diabetic neuropathy report a vastly negative impact on overall physical health and quality of life.15,16 Most people with painful diabetic neuropathy experience bilateral sensory dysfunction in the glove (hand) or stocking (feet) distributions that may be invoked or spontaneous.17 Painful diabetic neuropathy substantially interferes with daily functioning from sleep disruption through nocturnal symptom exacerbations, decreased physical activity, and insensitivity to physical trauma due to loss of sensation and may lead to psychological symptoms. Two systematic reviews found that anxiety, depression, poor sleep quality, and reduced quality of life were associated with having painful diabetic neuropathy.18,19 Furthermore, painful diabetic neuropathy is notoriously challenging to manage with available treatment regimens. And significantly increased long-term healthcare costs are associated with painful diabetic neuropathy as compared to having painless diabetic neuropathy.20 Kiyani et al reviewed the records of 360,559 US patients with diabetes; researchers found that the 5-year costs for healthcare were approximately 20% to 31% higher for people with painful diabetic neuropathy when compared with diabetic controls having no symptoms of neuropathy.21 The risk of amputation was

One type of behavior change that may restore sensorimotor functioning in people with painful diabetic neuropathy is engaging in physical activity.

16% higher in patients with painful diabetic neuropathy, almost 90% more patients with painful diabetic neuropathy were treated for lower extremity infections, and twice as many patients with painful diabetic neuropathy experienced falls with injuries, as compared to controls with diabetes. Also, compared with diabetic controls, people with painful diabetic neuropathy were 200% more likely to use opioid pain medications.

Etiology of Painful Diabetic Neuropathy

The etiology of painful diabetic neuropathy has been explored; however, the natural history of progression from diabetic neuropathy to painful diabetic neuropathy remains unclear. Although risk factors are well known for diabetic neuropathy, such as poor glycemic control, duration of diabetes, obesity, physical inactivity, and smoking, similar risk factors are not yet known for painful diabetic neuropathy. Painful diabetic neuropathy is notoriously challenging to manage with available medication and treatment regimens. Because no efficacious strategies for restoring functioning have been identified, prevention of

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painful diabetic neuropathy is vitally important. Researchers are diligently working to provide answers to how to prevent painful diabetic neuropathy; however, the current state of the science exposes vast gaps in knowledge related to prevention of painful diabetic neuropathy.

A new research finding of great concern is the fact that many people develop symptoms of painful diabetic neuropathy while being overweight or obese even before diabetes has been diagnosed. Whether the problem stems from insulin resistance secondary to weight gain, reduced activity due to living a sedentary lifestyle, decline in muscle strength, or some other unidentified risk factor, health behavior change appears to be the only modifiable risk factor showing promise in preventing or reversing effects of painful diabetic neuropathy. One type of behavior change that may restore sensorimotor functioning in people with painful diabetic neuropathy is engaging in physical activity. Physical activity is recognized as critical for maintaining optimal weight as well as assisting in healthy blood glucose control in people with diabetes. For years, out of an abundance of caution in trying to prevent falls, injuries, and amputations, concerned healthcare

providers were hesitant to recommend physical activity to people experiencing painful diabetic neuropathy. Until recently, patients were advised to refrain from weight-bearing exercise to mitigate the risk of lower extremity injury.22 Currently, we are indeed hopeful that the tide may have changed regarding recommending physical activity for people coping with painful diabetic neuropathy. In 2016, the American Diabetes Association released a comprehensive new position statement on physical activity/exercise and diabetes.4 Although this position paper provides insight into the adoption and maintenance of physical activity for people with diabetes, we believe that this information will broadly apply to people at risk for diabetes as well as people experiencing painful diabetic neuropathy.

After our summary of the position paper, we will introduce the limited specific research findings that have been identified for physical activity options when an individual has painful diabetic neuropathy.

Exercise and Diabetes

Aerobic exercise, resistance/strength training, and flexibility/balance activities all have a role to play in prevention of diabetes and delaying the progression of the severe consequences of having diabetes. For people with diabetes, the benefits of aerobic exercise include improved insulin sensitivity, lung capacity, cardiac output, and immune system functioning. Regular exercise training reduces triglycerides, A1c, hypertension, and insulin resistance in people with type 2 diabetes. In the diabetic population, strength or resistance training can lead to better psychological well-being, increased muscle mass, improvements in strength and functioning, and enhanced cardiovascular health.4 Flexibility and balance exercises improve gait and reduce falls even when someone has a diagnosis of diabetic neuropathy. Physical activity recommendations include: a) reducing sedentary behavior, b) interrupting prolonged sitting with bursts of light activity every 30 minutes to maximize blood glucose benefits, and c) committing to both increased structured exercise and increased routine activity levels. Recommendations for adults with type 2 diabetes include participation in daily physical activity that includes aerobic and resistance exercises for a minimum of 150 minutes weekly. We recommend that all adults seeking to introduce a new physical activity regimen or increase their current level of exercise should consult with their healthcare provider; however, the new American Diabetes Association position paper indicates that the exercise-related risk of injury is minimal for people with diabetes who wish to engage in low or moderate intensity physical activities or formal exercise.

A full position paper is available for more detailed information about how to minimize the risks of exercise-related negative events, such as hypoglycemia, hyperglycemia, medication effects, possible heat-related illnesses, and overuse or orthopedic injuries.4

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As noted above, exercise has been found to significantly reduce complications from diabetes including improving physical function in people with diabetic neuropathy.23 Researchers at the University of Kansas Medical Center enrolled 30 participants in a 10-week aerobic and strengthening exercise program to determine whether an exercise intervention could improve symptoms of neuropathy, nerve function, and cutaneous innervation. Seventeen participants (9 females and 8 males with a mean age of 58.4) completed at least 75% of the intervention. All the participants were identified as obese; and no reduction in body mass index or waist circumference was noted after the exercise program was completed. Hemoglobin A1c, a measure of glycemic control of the previous 3 months, was improved by more than 7% following the intervention. Ratings of worst pain experienced during the previous month were significantly reduced; resting heart rate, neuropathic symptoms, and cutaneous nerve fiber branching were improved at the end of the exercise program. One of the most compelling findings of this feasibility study is the reduction in worst pain ratings, as people with painful diabetic neuropathy frequently avoid physical activity due to anticipatory fear of experiencing increased pain levels.23

Physical Activity and Painful Diabetic Neuropathy

We identified one study specifically about physical activity in people with painful diabetic neuropathy. Yoo and colleagues, also at University of Kansas Medical Center, conducted a pilot study on the role of exercise therapy on pain with people experiencing painful diabetic neuropathy.24 Researchers enrolled 14 sedentary individuals having painful diabetic neuropathy (mean age 57) in a 16 week supervised exercise program. The exercise intervention included supervised exercise 3 times weekly.

Duration of exercise sessions progressed from 30 to 50 minutes over the course of the study. Exercise intensity was tailored specifically to the individual based upon preliminary heart rate data. Heart rate was monitored by using pulse oximetry before, after, and continuously during exercise. Exercise sessions included stretching, a brief warm-up, aerobic exercise, and a cool-down period.

Pain intensity was measured across 4 domains: worst in the last 24 hours, least in the last 24 hours, average pain, and current pain on a 0 to 10 scale (0 = “no pain”; 10 = “pain as bad as you can imagine”). Pain interference was measured across the 7 domains of quality of life: general activity, mood, sleep, walking ability, normal work, interpersonal relationships, and enjoyment of life in the past 24 hours. Body mass index, level of aerobic fitness, blood pressure, and glycemic control (A1c) were captured as secondary outcomes. At the end of the study, body mass index, glycemic control (A1c), and blood pressure did not change substantially. Aerobic fitness did achieve statistically significant improvement. Researchers reported no

significant reductions in pain intensity; yet, pain interference was reduced in more than half of the domains measured, including walking ability, normal work, interpersonal relationships, and sleep. In addition, the median level of pain interference was significantly reduced from 4.29/10 to 2.36/10.24

Conclusion

Results from the pilot study above are encouraging in that pain interference was reduced and aerobic fitness was increased through a brief supervised exercise program in a sample of participants with painful diabetic neuropathy. Even with these promising results, many more studies need to be conducted. More data are needed to identify which exercises are most effective for which symptoms in which individuals. Clearly, the benefits of physical activity and exercise for people experiencing painful diabetic neuropathy warrant further exploration, particularly through large randomized controlled trials.

References

9. Spallone V, Greco C. Painful and painless diabetic neuropathy: one disease or two.

Curr Diabetes Rep. 2013;13(4):533–549.

10. Shen H, Zhao J, Liu Y, et al. Interactions between and shared molecular mechanisms of diabetic peripheral neuropathy and obstructive sleep apnea in type 2 diabetes patients. J Diabetes Res. 2018;15:1–15.

11. Falvo DR. Diabetes and other conditions of the endocrine system. Medical and Psychosocial Aspects of Chronic Illness and Disability. 5th ed. Burlington, MA: Jones & Bartlett Learning; 2014;chapter 23.

12. Alexander J Jr, Edwards RA, Brodsky M, et al. Using time series analysis approaches for improved prediction of pain outcomes in subgroups of patients with painful diabetic peripheral neuropathy. PLOS ONE. 2018;13(12):1–20.

13. Shillo P, Sloan G, Greig M, et al. Painful and painless diabetic neuropathies: What is the difference? Curr Diabetes Rep. 2019;32(19):1–13.

14. Vinik AI, Nevoret M-L, Casellini C, et al. Diabetic neuropathy. Endocrinol Metabol Clin North Am. 2013;42:747–787.

15. Van Acker K, Bouhassira D, De Bacquer D, et al. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatient clinics. Diabetes Metab. 2009;35:206–213.

16. Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. Brit Med J. 2014;348:g1799.

17. Tesfaye S. Assessment and management of painful diabetic peripheral neuropathy. Diabetic Neuropathy. Tesfaye S, Boulton A, eds. Oxford University Press, Oxford; 2009.

1. Hills AP, Street SJ, Byrne NM. Physical activity and health: “What is old is new again.” Adv Food Nutr Res. 2015;75:77–95.

18. Kioskli K, Scott W, Winkley K, et al. Psychosocial factors in painful diabetic neuropathy: a systematic review of treatment trials and survey studies. Pain Med. 2019;20(9):1756–1773.

2. Blair SN, Morris JN. Healthy hearts -- and the universal benefits of being physically active: Physical activity and health. Ann Epidemiol. 2009;19(4):253–256.

3. NIH Consensus Development Panel. Physical activity and cardiovascular health.

J Am Med Assoc. 1996;276(3):241–246.

19. Naranjo C, Del Reguero L, Moratalla G, et al. Anxiety, depression and sleep disorders in patients with diabetic neuropathic pain: a systemic review. Exp Rev Neurother. 2019;19(12):1201–1209.

4. Colberg SR, Sigal RJ, Yardley JE, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diab Care.

2016;39:2065–2079.

20. daCosta DiBonaventura M, Capperelli JC, Joshi AV. A longitudinal assessment of painful diabetic peripheral neuropathy on health status, productivity, and health care utilization and cost. Pain Med. 2011;12(1);118–126.

5. International Association for the Study of Pain. IASP announces revised definition of pain. Available at: https://www.iasp-pain.org/PublicationsNews/ NewsDetail.aspx?ItemNumber=10475.

21. Kiyani M, Yang Z, Charlambous LT, et al. Painful diabetic peripheral neuropathy: health care costs and complications from 2010 to 2015. Neurol Clin Pract.

2019;10(1);47–57.

6. Gatchel RJ, Peng YB, Peters ML, et al. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull. 2007;133(4):581–624.

22. Kluding PM, Bareiss SK, Hastings M, et al. Physical training and activity in people with diabetic peripheral neuropathy: paradigm shift. Phys Ther. 2017;97(1):31–43.

7. Foreman J. A Nation in Pain: Healing Our Biggest Health Problem. Oxford: University Press; 2014.

23. Kluding PM, Pasnoor M, Singh R, et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J Diabetes Complications. 2012;26(5):424–429.

8. National Institute for Neurological Disorders and Strokes through the National Institutes of Health. Office of Communications and Public Liaison. Peripheral Neuropathy Fact Sheet. 2020. Available at: https://www.ninds.nih.gov/Disorders/ Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet.

24. Yoo M, D’Silva L, Martin K, et al. Pilot study of exercise therapy on painful diabetic peripheral neuropathy. Pain Med. 2015;16(8):1482-1489.

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By p Ma r ha k Ga rmd ro fol , mba i , bccp , cpe

I am Mark Garofoli, an Assistant Clinical Professor at the University of West Virginia School of Pharmacy in Morgantown. I’m a frequent presenter at PAINWeek and PAINWeekEnd conferences, as well as PW PREMIERE webinars. PWJ asked me to share my kidney stone story in hopes of offering some clinical pearls and shining a light on a firstperson point of view of pain management.

I was a “pain guy” in pain.

Here’s my story…

…I’m holding back no detail.

You’re welcome.

I’m sorry.

Like father like son

On a beautiful April morning in 1996, my Dad passed a kidney stone in the middle of a river. Despite his pain, the thought of skipping the opening day of trout fishing season simply never crossed his mind. The show must go on, and the fish were not going to catch themselves.

Almost a quarter of a century later I was visited by the wonders of kidney stones personally. The pain from a kidney stone is a profound example of acute pain.

However, due to the COVID pandemic putting a halt to nonemergency surgeries, I unfortunately joined 50 million Americans1 suffering from chronic pain. When my acute pain shifted to a drawn-out adventure, it then qualified as chronic pain: it took longer to heal than expected and hit the common qualifier of 3 months.

It was just an average night with the Garofoli family making pizza until yours truly had to stop, thanks to a sharp, intense, throbbing pain on my right backside just below the ribs. I thought it was one of two culprits: pancreas issues or kidney stones. Either way, an hour later, on Friday the 13th during a pandemic no less, my wife and 3-year-old son dropped me off at the ER where no visitors were allowed.

First, the vitals

My typical blood pressure reads about 118/68, yet on this adventurous evening, the automatic sphygmomanometer beeped incessantly at 148/98. Next up was the infamous and controversial assessment of the debatable vital sign of pain: “Sir, could you rate your pain from 1 to 10?”

I channeled my inner Brian Reagan [see pain.sh/ff3a2 at 4:17], and sputtered “8.5!” conceding a half-point each to broken femurs, childbirth, and bear maulings. I considered an answer of 30, since my blood pressure was universally up 30, but alas the subjective multiple choice only went up to 10. Although I was currently a patient, I believe “Never Stop Teaching.” I mentioned the DVPRS2

as the one pain scale that I utilize and recommend (and, after saying the acronym 20 times, just rolls right off your tongue!). The DVPRS—Defense & Veterans Pain Rating Scale—basically combines all your favorite approaches to common pain scales including color, emotional faces, and of course numbers. However, and here’s the part that can really improve one’s patient care, it also includes 4 powerful questions assessing a patient’s activity, sleep, mood, and stress.

Back to my all-inclusive stay in the emergency room with the usual IV electrolytes, urine dip, CBC with Diff, and eventually a CT scan, which in itself proved intriguing as the contrast injection resulted in a pelvic burning sensation. I appreciated the levity and enlightenment provided by my gurney neighbor, Jason (which gave me pause, as it was Friday the 13th), having an acute schizophrenic exacerbation, reminding me that things can always be worse. The CT results came back conclusive for a 7 mm rifle bullet, I mean kidney stone. I officially was suffering from nephrolithiasis.

Pharmacologic options

I was immediately injected with ketorolac, my new favorite urologic pain medication. Although no opioid risk screening was conducted on me, I was prescribed acetaminophen/codeine 300 mg/30 mg, otherwise known as Tylenol #3 or T3, along with ondansetron 4 mg and tamsulosin 0.4 mg. Now as you read this, you maybe be thinking, “Was he just whining about his pain” and only needed a Tylenol 3 with a morphine milligram equivalent (MME) factor of 0.15? PAINWeek faculty spend countless hours conducting dynamic and engaging conference presentations, many featuring MME, every year in Las Vegas and during regional PAINWeekEnd meetings (which I personally invite you to attend, as there’s simply no better when it comes to pain management education, including MMEs).

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2016 CDC Opioid Guidelines3

The guidelines

The 2016 CDC Opioid Guideline provided us with the most widely—yet still not universally—accepted listing of MME factors, which are far from perfect, yet we are often left without other acceptable options. This listing states that a daily MME level ≥50 should only be used with caution, and a daily MME level ≥90 should be avoided unless a clinician can carefully justify the titration.3 Considering that the approximate adjusted hazard ratio (or relative likelihood of overdose) for a patient receiving ≥100 MME of any opioid medication per day is 11,4 one can easily realize the importance of healthcare professionals being familiar with the concept of MMEs. If a healthcare professional simply memorizes that morphine and hydrocodone each have an MME factor of 1, while oxycodone has an MME factor of 1.5, one can multiply that factor by the respective opioid daily dose to calculate the MME/day (MEDD) for the vast majority of utilized prescription opioid medications in our country.

When contemplating relative “potency” of opioids, please remember to account for both the MME factor and the opioid’s respective actual dose. For instance, if an opioid is dosed in hundreds of milligrams, with a relatively low MME factor, it still may yield a high-risk opioid dosage and vice-versa for high MME factor opioids with microscopic doses. I find it prudent to provide a summarized listing of the 2016 CDC MME factors herein (see next column).

Type of Opioid

mme Factor

Buprenorphine (tablet/film)

30 (for mg doses)

Buprenorphine (transdermal)

12.6 (then divide by days)

Codeine

0.15

Dihydrocodeine

0.25

Fentanyl (transdermal)

7.2 (then divide by days)

Hydrocodone

1

Hydromorphone

4

Levorphanol

11

Meperidine

0.1

Methadone

4 (0–20 mg) 8 (21–40 mg) 10 (41–60 mg) 12 (>60 mg)

Morphine

1

Oxycodone

1.5

Oxymorphone

3

Pentazocine

0.37

Tapentadol

0.4

Tramadol

0.1

I departed that pharmacy reminding myself that the vast majority of my fellow pharmacists provide amazing patient care and go well above and beyond the expectations of the Omnibus Budget Reconciliation Act of 1990 (OBRA ’90). What a great opportunity that pharmacist missed, at midnight on a weekend, to discuss with a patient the importance of medication storage—all medications, not just controlled substances—or even mention some expected side effects such as constipation, or even jot down the 1 (800) 222–1222 poison center phone number for me just in case. I’ll be inviting that pharmacist to our next PAINWeek!

Patient counseling

Onward, I ventured from the ER to a local 24-hour corporate community pharmacy. I’m sure anyone would have been as puzzled as I upon receiving 14 medium sized tamsulosin capsules and 21 tiny ondansetron pills in two 40-dram vials, when an 8 dram would’ve been reasonable. It was sort of like buying a quart of milk in a gallon jug. What really got my blood flowing, however, was my fellow professionals merely asking me to “Please sign here” to waive any consultation requirement.

Then I received a text message from my pharmacy benefits manager (PBM) asking if I’d like to save money by switching my new “maintenance” tamsulosin medication to their mail-order pharmacy, even though it obviously was a 24-day supply of medication. Although I know letters with these offerings are sent out daily across our country, the text message avenue was a whole new ballgame to me.

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Surgery plans

peripheral acting mu-opioid receptor antagonist (PAMORAs, including alvimopan, methylnaltrexone, naldemedine, and naloxegol) if the constipation resulted from opioid therapy.

It is invaluable to also consider that any patient has most likely attempted anticonstipation OTC self-care options before finally resorting to talking with a healthcare professional, given the sensitive nature of talking about GI issues.

Six days after my ER visit, my urology physician’s assistant explained that I needed a ureteroscopy (invasive) to safely remove my kidney stone as opposed to the less invasive lithotripsy. A lithotripsy utilizes external ultrasound to break up a kidney stone, whereas a ureteroscopy basically involves putting a tube, laser, and minibucket through the urethra, and past the bladder, to reach the kidney. At that moment I realized that I shouldn’t buy any lottery tickets, as my luck had clearly run out. Three days later my nonelective surgery was cancelled due to COVID concerns, and I was instructed to go to the ER for emergency surgery if I experienced an intense breakthrough pain episode. Of note, hospital beds in my entire state of West Virginia remained majorly unoccupied for the entire duration of elective surgery cancellations.5

The big day arrived

Opioid utilization

Over the course of 3 months, I had 3 incredible breakthrough pain episodes, generally resolved with the use of acetaminophen/codeine 300 mg/30 mg. One truly must consider both the dose and the MME factor in every prescription opioid utilization, as codeine’s MME factor is a meager 0.15, yet once multiplied by the respective 30 mg dose, the yield MME is 4.5 mg. Ironically, almost matching that of low-dose hydrocodone/APAP, a prescription opioid observed to be diverted much more often, while also providing a higher probability of opioid induced constipation (OIC). In fact, codeine is the most likely opioid to produce OIC. Many PAINWeek OIC presentations will “push” a clinician to more successfully help patients with this “classified” situation. In the meantime, healthcare professionals should encourage patients to utilize a diet with adequate fiber and fluid intake, and engage a stepwise approach including docusate ± senna, followed by polyethylene glycol-3350.

Next steps should involve a healthcare professional providing either a chloride channel activator (ie, lubiprostone) if the constipation was present prior to opioid therapy, or a

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Eleven weeks after my initial ER visit, I eventually arrived at the hospital at 5:30a donning an N95 mask and goggles. (While gently spring cleaning our garage during the pandemic, I found an N95 mask purchased years earlier to use while scrubbing my shower with pungent cleaning solution. It felt like finding buried treasure!)

Within the hospital, I was accosted by stares for simply being extra cautious with my COVID attire. I thought to myself, “So this is what stigma feels like?”

After a urine dip and a few failed intravenous line insertions, I pestered my anesthesiologist regarding the sedatives on my menu. He recognized me as a patient of his younger brother, also an anesthesiologist, when I had a septoplasty 2 years earlier, when adjunctive ketamine was utilized with fentanyl. I shared his brother’s reaction to my chosen words at that time, “You’re giving me Special K?” which had brought long silent seconds of universal “deer in the headlights” stares from the rounding team before I explained that I had been impressed by international studies on its adjuvant utilization to lower an opioid load. My new anesthesiologist and I chuckled, and I fell asleep in the operating room moments later.

Postsurgery

I woke up in the recovery room with extreme 13-out-of-10 kidney pain and urethra burning, which I decided to

reasonably describe as a 7-out-of-10 when asked. My compassionate nurse kept my anesthesiologist near to make treatment calls. Fentanyl already on board, and my blood pressure eventually normalizing, I was provided an oxycodone/APAP 5/325 mg oral tablet, which failed after 20 minutes, causing me to ramp up and admit I was 8-out-of-10. On came the “Vitamin D” push you may know as hydromorphone, to no avail. To clarify, fentanyl, oxycodone, AND hydromorphone did nothing for my pain. Time to listen to the pharmacist on the gurney and the caring nurse with a concurring therapeutic opinion: ketorolac. Ten minutes later, I was laying back enjoying what seemed to be an amazing glass of orange juice and talking with the nurse about her niece recently graduating our School of Pharmacy, and her own son beginning at a regional School of Pharmacy in a few months.

75% stated that their first regular opioid was a prescription opioid.7 Yet as with countless headlines across our country, the respective acquisition source of said prescription opioids is not only omitted, but presumed to be in the legal healthcare supply chain. Conversely, a 2017 DEA report included a study showing that approximately two-thirds of illicit misused prescription opioids were obtained outside of the healthcare system.8,9

Treatment protocols

My post-op urine gradually transitioned from ketchuplike on the gurney to diluted red Kool-Aid within a few days.

I was entirely more concerned with the 4 days of continued piercing, throbbing, stabbing, absolutely incredible kidney/ ureter/bladder stent pain upon urination. The only comfort I found was the placement of a Dammit Doll between my teeth for clenching and any as-needed audible inflections of pain, which is something no adult wants their gracious visiting mother-in-law to witness, let alone one’s toddler, nor spouse. After messaging my surgeon asking if this level of pain was expected, we deduced that I had not yet been prescribed oxybutynin to calm things down a bit, so it was immediately sent to my pharmacy. The oxybutynin (in combination with tamsulosin and hydration) eased my urethral discomfort within the day, although the overall pain was another story. Treatment protocols really do matter. My pain decreased to only needing OTC acetaminophen 500 mg, but I started feeling a more intense urethra burning upon urination, so I messaged my surgeon on Friday. The following Monday, phenazopyridine 200 mg was provided, which immediately improved my urination discomfort, while turning my urine a deep orange color. Once acclimated to the kaleidoscope of urine colors exiting my body, I no longer needed any pain medication. Since our 3-year-old was splashing around in our new portable pool with a foot of water, I ended up joining the fun and experiencing the nonpharmacological thermodynamic effects of ice-cold water numbing one’s body. Never skip the nonpharm!

Limitations are not a panacea

Perhaps with respect to our opioid crisis, my doctors provided me with a mere 32-hour (8-tablet) supply of oxycodone/APAP 5/325 mg. West Virginia state law dictates up to a 7-day supply being appropriate and allowed by the WV Opioid Reduction Act, and let’s not even mention the lack of an opioid risk assessment yet again.

I proactively mentioned a probable need to rely on my leftover acetaminophen/codeine 300 mg/30 mg from the ER more than 2 months prior, and all agreed. Undoubtedly, my care team was aware of the study showing that the day supply of initial opioid prescribing for opioid-naïve patients has shown an association with a higher likelihood of long-term opioid medication utilization.6 Of note, that refers to chronic opioid use, not opioid use disorder (addiction), but should propel healthcare professionals to consider supplying no more than a couple of days’ supply of any initial opioid medication, especially when a patient has been screened as being higher risk. Undoubtedly, my healthcare team was also aware of the study showing that, of those who began their opioid abuse in the 2000s,

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Best of times, worst of times

Three long months after my ER visit, I returned to the hospital for my stent removal. To quote Charles Dickens, “It was the best of times, it was the worst of times…”

Walking into the hospital alone (still no visitors or loved ones allowed), I was greeted at the front door for a COVID check by one of our student pharmacists. I was taken to the same-day surgery urology room, and seated in seat 2 of 3 in a row, as directed. The RN chose to change things up for a fun Friday, and placed the gentleman scheduled ahead of me in seat 3 instead of seat 1. My surgeon soon entered the room, stood in front of me and asked, “Have you been catheterizing yourself?” We stared at each other until I cracked a smile seconds later thinking he must be joking, but the smile was not returned. My nurse practitioner graciously informed my surgeon of the RN’s Friday chair switch, and redirected my surgeon to the gentleman in seat 3. Once they left the room, I asked the nurse practitioner, “What do I need to do in life to never be asked that question again?” and we enjoyed a laugh.

The surgery room radio played the The (formerly Dixie) Chicks “Wide Open Spaces” followed by Garth Brooks “Friends in Low Places” and apparently I was the only one finding the irony. The prep included ice-cold betadine followed by a urethra injection of lidocaine as a local anesthetic. My psychological horrors continued with the urethral insertion of a large snake-like device to pull out my stent in “only” 30 seconds—the longest 30 seconds of this man’s life! My surgeon immediately showed me the 8-inch stent, to which I said “Too soon!” Shortly thereafter, I was discharged and drove myself home, choosing to not have the radio on; I already had enough of fate’s song selection. When I arrived home, another PBM letter offered to convert my (no longer needed) oxybutynin prescription from a 14-day supply to a 90-day supply. For 24-hours post-stent removal, I was psychologically drained, with constant flashbacks to the procedure—perhaps an unorthodox acute PTSD—particularly when trying to fall asleep. The next day, I felt human

again for the first time in 3 long months. Perhaps most importantly, my wife happily returned to having only one human in our house (our 3-year-old) always talking about urination.

What’s in a stone?

My kidney stone analysis stated 90% oxalate 10% phosphate, meaning that I had the most common type of kidney stone: calcium oxalate. Oxalates are a natural substance in many foods that bind to calcium during digestion in the stomach/intestines and leave the body in stool. Typically, a 24-hour urine collection will assist in deciding on the need for dietary oxalate changes. A fundamental issue for oxalate kidney stones is a high salt (sodium) diet.10 An average daily diet includes approximately 200 to 300 mg of oxalate, with a limited diet aiming for less than 100 mg of oxalate.11 So it is “Adios salty potatoes and Reese’s Cups…and spinach?” As food and beverage oxalate-level resources are extremely inconsistent,12 I have compiled a Table. (Popeye must have had a high pain tolerance.)

Conclusion

I hope you enjoyed this article and are better able to provide high quality care to any patient experiencing the agonizing pain of nephrolithiasis. May you never be afflicted by the pain of kidney stones! However, when providing patient care to someone who has, please, please proceed with compassion and the clinical expertise discussed herein and continually dispensed through PAINWeek. Not even COVID stopped PAINWeek! The show must go on.

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Table of Food and Beverage Oxalate Levels7,13 Oxalate Level

Foods

Low

Popcorn, apples, bananas, pears, peaches, cucumbers/pickles, cauliflower, broccoli, cheeses, meat, fish, crackers, pudding, Jell-O, olive oil, milk, coffee, wine, water

15 mg to 20 mg

Carrots (1/2 cup), kidney/refried beans (1/2 cup), couscous (1 cup), peanut butter (1 tbsp), kiwi (1 fruit), Brussels sprouts (1/2 cup), all-purpose flour (1 cup), pasta (2 cups cooked), tomato sauce (1/2 cup), pumpkin seeds (1 cup), muesli (2/3 cup), olives (10), avocado, celery raw (1/2 cup)

21 mg to 30 mg

Soy milk (1 cup), potato chips (1 oz), pancakes (4), brown rice (1 cup), dried figs (5), dates (1), prunes (1), chili with beans (1 cup), peanuts (1 oz), sweet potato (1 cup), wheat flour (1 cup), orange (1), mashed potatoes (1 cup), dried pineapple (1/2 cup)

31 mg to 40 mg

Brownie (1 oz), walnuts (7 nuts), wheat bran (1 cup), bamboo shoots (1 cup), chocolate syrup (2 oz), mixed nuts (1 oz), bagel, yam (1/2 cup), veggie burgers (1)

41 mg to 60 mg

Natural Stevia, soy beans (1/2 cup), raspberries (1 cup), grapefruit (1), cashews (1 oz), okra (1/2 cup), French fries (4 oz)

61 mg to 70 mg

Cornmeal (1 cup), brown rice flour (1 cup), hot chocolate (1 cup), cocoa powder (4 tsp)

71 mg to 100 mg

Beets (1/2 cup), navy beans (1/2 cup), bulgur (1 cup), baked potato with skin (1), corn grits (1 cup)

101 mg to 130 mg

Miso soup (1 cup), almonds (1 oz), buckwheat (1 cup)

~300 mg

Rice bran (1 cup)

~500 mg

Rhubarb (1/2 cup)

~650 mg to 750 mg

Spinach (1 cup raw or ½ cup cooked)

References

8. United States Drug Enforcement Administration. DEA releases 2017 National Drug Threat Assessment. Available at: www.dea.gov/press-releases/2017/10/23/ dea-releases-2017-national-drug-threat-assessment.

1. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults—United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67:1001–1006.

9. Daniulaityte R, Falck R, Carlson RG. Sources of pharmaceutical opioids for non-medical use among young adults. J Psychoactive Drugs. 2014;46(3):198–207.

2. Defense and Veterans Pain Rating Scale. Available at: www.va.gov/PAINMANAGEMENT/docs/DVPRS_2slides_and_references.pdf.

10. Harris J. How to eat a low oxalate diet. The University of Chicago. Available at: kidneystones.uchicago.edu/how-to-eat-a-low-oxalate-diet/.

3. Centers for Disease Control and Prevention. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. MMWR. 2016;65. March 18.

11. Harvard T.H. Chan School of Public Health Nutrition Department’s File Download Site. Directory Listing of /health/Oxalate/files. Available at: regepi.bwh.harvard.edu/ health/Oxalate/files.

4. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Int Med. 2010;152(2):85–92.

12. Attalla K, De S, Monga M. Oxalate content of food: a tangled web. Urology.

2014;84(3):555–560.

5. West Virginia Department of Health & Human Resources. Coronavirus disease 2019 (COVID-19). Available at: dhhr.wv.gov/COVID-19/Pages/default.aspx.

13. Harris J. Kidney Stone Diet. Oxalate food list. Available at: kidneystonediet.com/ oxalate-list.

6. Shah A, Hayes CJ, Martin BC. Characteristics of initial prescription episodes and likelihood of long-term opioid use – United States, 2006–2015. MMWR Morb Mortal Wkly Rep. 2017;66:265–269.

7. TJ Cicero, Ellis MS, Surratt HL, et al. The changing face of heroin use in the United States. JAMA Psychiatry. 2014;71(7):821–826.

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EDUCATION IS THE BEST ANALGESIC

pain assessment part 1

pain assessment part 1

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

Regardless of whether pain is thought to be nociceptive, neuropathic, or idiopathic, it is also usually broadly categorized as either acute or chronic.

Additionally, pain is categorized based on other characteristics, such as its intensity, location, quality, and factors that alleviate or worsen it.

Chronic pain ○ Persistent (generally ≥3 months duration or longer), often undetermined onset ○ Usually the result of some chronic disease, condition, or situation ○ May have no obvious cause ○ Prolonged functional impairment → Physical → Psychological ○ May or may not be associated with characteristic behavior, such as insomnia, anorexia, irritability, and depression ○ Often more difficult to manage than acute pain

Some simple distinguishing characteristics of acute and chronic pain include the following: Acute pain ○ Generally sudden onset, certainly recent onset ○ Usually has an obvious identifiable cause → Injury → Disease → Iatrogenic (eg, surgery) ○ Short duration (<1 month) ○ Intensity generally variable and indicative of severity of underlying condition or situation → Characteristic behavior, such as rubbing, moaning, crying

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Basic Terminology

Acute pain is the result of an injury or illness that is time limited and of recent onset. Low back pain after an injury, acute headache, and postoperative pain are examples of acute pain. Acute pain is generally thought to have the biologic function of alerting the individual to harm and preparing for the “fight-or-flight” response to danger. It is an important part of the vital, protective sentry system that permits us to live in an environment filled with potential dangers. Diagnosing and treating the underlying cause of pain, in addition to treating the symptomatic pain, are the critical elements of pain management. Subacute pain is pain that usually lasts ≤3 months.

Baseline pain is generally constant in nature and lasts at least half of the day.

Breakthrough pain increases over baseline pain to a significantly higher degree of intensity. Incident pain is a type of breakthrough pain that increases with activity or movement.

Central pain is initiated or caused by a primary lesion or dysfunction in the central nervous system.

Pain Categorized by Source and Related Nociceptors

Cutaneous pain is caused by injury to skin or superficial tissues. Cutaneous nociceptors terminate just below the skin and have a high concentration of nerve endings, producing well-localized pain.

Somatic pain originates from somatic nociceptors, located in structures such as ligaments, bones, and blood vessels.

The low concentration of nerve endings results in a dull, poorly localized pain sensation that is usually of longer duration than cutaneous pain.

Visceral pain originates from organ-level nociceptors located within the organs themselves or visceral cavities.

Visceral nociceptors exist in even lower concentrations than somatic or cutaneous nociceptors, resulting in more elusive qualities with respect to localization. The quality of visceral pain is typically more of a diffuse aching pain of longer duration.

Assessment

Chronic pain has usually been defined arbitrarily as pain that persists for 3 to 6 months or longer, or beyond the period of expected/apparent healing. Ongoing or progressive tissue damage may be present in some types of chronic pain, including progressive neuropathic pain and rheumatologic conditions. In other cases, chronic pain may be present when tissue damage is stable or undetectable. Chronic pain persists and does not resolve spontaneously.

Neuralgia is pain along the distribution of a nerve or nerves.

Neurogenic pain is initiated or caused by a primary lesion, dysfunction, or transitory irritation in the peripheral or central nervous system.

Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system. Peripheral neuropathic pain occurs when the lesion or dysfunction affects the peripheral nervous system. Central neuropathic pain may be also referred to as central pain when the lesion or dysfunction affects the central nervous system.

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To begin an assessment, all patients should be asked about the presence of current pain or of pain over the past several months. Clinicians often ask, “How can I know how much pain my patient is feeling?”

Unfortunately, there are no objective tests that can indicate the precise quality and intensity of pain and tease out the patient’s affective and behavioral reactions to it. Because of the multiple dimensions of pain, it is considered to be a purely subjective experience.

There are, however, standardized measures and clinical questions that can be used to assess pain and associated symptoms, such as sleep disturbance and functional status.

These measures rely primarily on the patient’s self-report, which, despite limitations, remains the single most reliable indicator of the existence and intensity of pain. In this section, several commonly used measures of pain intensity are reviewed, as are clinical interview questions that form part of the pain assessment. Important points of assessment in the physical examination and thorough diagnostic testing also are included.

Careful and accurate assessment of pain is critical for successful diagnosis and treatment. Some important first steps include identifying key points with respect to the patient’s pain: ○ The description of painful symptoms (eg, burning, throbbing) ○ The location of the pain ○ The temporal nature of the pain → Acute vs chronic → Time of occurrence and duration ○ The severity of the pain → Functional impact on activities of daily living → Psychological impact → Social impact ○ Exacerbating (eg, bending) and/or alleviating (eg, ice) factors ○ Steps taken before presenting for management → Reduction in activity → Medication use before visit

Patients should be informed of the need for regular pain assessment and told that a pain rating above a predetermined level will be therapeutically addressed as expeditiously as possible.

Patient History

Much of the information the clinician gleans about the patient’s pain complaint is gained in a comprehensive history and physical examination. The following sample questions should be included as part of a thorough clinical history evaluation: ○ What is the location, quality, and frequency of pain? ○ In addition to pointing to the location of the pain and providing a verbal description, the patient can draw the location of their pain on a body diagram. ○ Primary and secondary sites should be elicited because patients often experience more than one location of pain. In addition, the patient can be asked to assign the percentage of pain in each area relative to the overall pain experienced. ○ Diagnostic information can be obtained by asking about the quality of pain. For example, neuropathic pain is often described as “tingling, burning, or shooting,” whereas visceral pain is often described as “dull, aching, or squeezing.” ○ The frequency of pain can be constant, intermittent, or cyclic, with exacerbations that occur over and above a consistent level of pain.

It is also important to consider that pain assessment is not a one-time phenomenon. According to the Joint Commission Standards, since 2001, pain is considered to be the fifth vital sign and should be assessed initially and reassessed on a scheduled and regular basis.1 The National Comprehensive Cancer Network2 set these guidelines for assessment of patients receiving opioid analgesics for the treatment of severe cancer pain in 2010: ○ Patients receiving intravenously administered short-acting opioids should be assessed every 15 minutes for rapid titration. ○ Patients receiving intramuscularly administered short-acting opioids should be assessed every 60 minutes. ○ Patients receiving long-acting opioids by any route should be reassessed at least every dosing cycle.

References 1. Hadjistavropoulos HD, Clark J. Using outcome evaluations to assess interdisciplinary acute and chronic pain programs. Jt Comm J Qual Improv. 2001;27(7):335–348.

2. 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.

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short cuts

Sean Li MD Regional Medical Director/Partner Premier Pain Centers, LLC, Shrewsbury, NJ; Attending Pain Physician Riverview Medical Center, Red Bank, NJ

II focus focus on on offering offering my my patients patients the the best, best, most most innovative, innovative, evidenceevidencebased based treatment treatment to to help help alleviate alleviate their their chronic chronic pain. pain.

GPS I was born in Shanghai and grew up in Canada. I am currently a privademic physician in the New Jersey division of the largest pain management practice in the country. Typical Day My clinic days typically start at 8 am where I see patients

with chronic pain and perform routine injections and procedures. On Thursdays, I am in the operating room: spinal cord stimulator implants, interspinous spacers, minimally invasive lumbar decompression, SI joint fusion, and intrathecal pumps. Persona I focus on offering my patients the best, most innovative, evidence-based treatment to help alleviate their chronic pain. My goals are excellence in clinical practice, research, and teaching. I have been fortunate to participate in some of the recent landmark studies in the field of pain and neuromodulation. If these clinical experiences and research endeavors have given me the opportunity to formulate an opinion that may help others, I am thus honored to be considered an opinion leader. Social Media Habits I occasionally use social media to stay in touch with distant relatives and friends. Other than professional outlets such as LinkedIn, I tend to be a social media novice. Contribution What I can offer to patients is not a reflection of what I learned in medical school or residency but more importantly my experiences as a human being. I would never have imagined myself growing up to be a physician and living the American Dream. My parents were both physicians who were persecuted during the Cultural Revolution and landed in America with a suitcase, $300, and the dream that their son would have the freedom to learn without censorship. My experiences of growing up in a Third World country and later as an immigrant in the New World has taught me invaluable lessons in life and human perseverance. These experiences give me a deeper understanding of poverty, racial disparity, and social injustices when treating chronic pain patients. People I value human culture as a collective. I enjoy traveling and go off the tourist grid, visiting local supermarkets, libraries, and shops to peek into everyday life. Words During long flights, I enjoy reading spiritual guides from Thich Nhat Hanh that help enrich my understanding of human suffering and compassion for one another. Popcorn Shawshank Redemption. When faced with complete hopelessness, the main character found solace in friendship and ultimately his freedom through shear grit. In life, sometimes we all must crawl through a mile of sewage to find our redemption. PAINWeek pw is not a typical medical meeting. It is a celebration of chronic pain awareness and a united nation of treating clinicians. There is a diverse fellowship of all healthcare providers who treat patients suffering from pain. pw goes beyond medicine and explores the humanity of chronic pain by recognizing its role in art, culture, and education. It is the highlight event of the year.

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short cuts

By Jennifer Bolen

jd

When a patient dies from an overdose, the prescriber has some potential liability.

Whether it’s a licensing board issue or licensing board + malpractice— or even worse, a criminal case— depends on the nature of that provider’s care.

In other words, the story that they’ve written with that patient throughout the provider-patient relationship.

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short cuts

In a study of post spine surgery patients,

A study examined potential pain management abilities of lysergic acid diethylamide (LSD).

LSD was used in the

In a study of tmjd— temporomandibular muscle and joint disorders—researchers examined CT scans of

experienced poorly controlled pain. Of

≥18 years old, for terminally ill or cancer patients.

women who received >2 treatments of botulinum toxin (Btx) over a 6-month period, and

It was given to

experienced poorly controlled pain during the first 24 hours after surgery.

healthy volunteers who were then given a cold pressor test.

Conclusions: LSD 20µg significantly ↓ pain perception and ↑ pain tolerance by about

variables associated with poor pain control were incorporated into a prediction model, including a ↑ Patient Health Questionnaire–9 depression score and surgery involving ≥3 motion segments.

The model was discriminative (C-statistic 0.74, 95% CI 0.71–0.77) and calibrated (Hosmer-Lemeshow goodness-of-fit, p = 0.99) for predicting the outcome.1

who received none.

A phase 3 clinical trial (NCT03223298) is in progress to determine new indications for Btx. The mean density of 1st and 2nd ROIs was similar between exposure groups.5

Acetaminophen is in Analgesic effects of this dosage were in effect after 1.5 and 5 hours, and might even outlast the study’s 5 hour time window.3

Yoga has more benefits

Pain impacts the patient,

then we originally thought.

and the spouse. A study of

participated in a “12 week of no yoga” period followed by 16 weeks of yoga for

medicines and, in the US, is taken each week by approximately

was explored— patients = 59% females, average age = 57.81 years; spouses: 41% females, average age = 57.32 years

of the adult population.

To test if it affects risk taking/perception, a dose of 1000 mg was given to 73 participants:

of spouses indicated a high‐to‐severe burden.

A multivariate model with spouse and patient factors accounted for 37.8% of the variance. This info may guide family interventions in the future.2

every other day.

Significant improvements were noted in symptomatic episodes of atrial fibrillation— 8, down from 15 pre yoga— and blood pressure lowering an average of 11/6 mmHg.4

of the 142 undergraduate volunteers total (76 men, 64 women, 2 nonresponses; mean age of 19.36 years), 69 were given placebo.

The acetaminophen group’s rate of risk taking shows that a better understanding of the medication is needed.6

1. pain.sh/2v6 2. pain.sh/992 3. pain.sh/18b00 4. pain.sh/asm 5. pain.sh/52bc0 6. pain.sh/gdo

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short cuts

2

How to Prevent Clinician Burnout!

Jamie Clapp PT, DPT, OCS; Heather King, PhD Self-care: ● Sleep well, eat well, socialize, exercise ● Have strong social support ● Connect with people at work with whom you feel safe and respected ● Share with a coworker; ask for assistance: “This has been such a bad day for me and I’m really struggling” ● Practicing mindfulness based stress reduction can help us be less reactive

1

On an organizational level:

Chronic Pain Treatment: An Algorithm

● Changes need to happen and be supported by leadership ● A wellness committee can be helpful ● The organization should allow for some practitioner control over when patients are seen—how many and for how long

Paul J. Christo MD, MBA

A chronic pain patient may see many doctors, from their general practitioner to a pain specialist. But what comes between those visits? Here’s what I have seen.

Usually:

3

● The patient is managed conservatively by the primary care doctor or practitioner, which may entail medication therapies or physical therapy for pain ● If it reaches the point where the patient is not improving and quality of life hasn’t changed, that’s when primary care doctors may refer to a pain specialist such as myself

Abuse Deterrent Formulation Types and Goals Mark Garofoli PharmD, MBA, BCGP, CPE

Abuse deterrent formulations (ADFs): different manners of preventing someone from transgressing to the inhalation or snorting of medications, or even intravenous use

Once a patient comes to see me: ● I do a physical examination and conduct a history ● I figure out where their primary pain is and determine what the next best course is, say, interventionally or medically ● Primary care practitioners usually try acetaminophen or nsaids, or advanced therapies like gabapentin or pregabalin ● My goal is to partner with the patient to try to determine what s/he feels comfortable trying first. It might not be an intervention; we might try another medical therapy ● We may try a combination of medication: giving the patient 6 weeks to determine if it’s effective or not, or, if it’s just partially effective, adding an intervention, such as a nerve block procedure for additional pain relief

● Aversion: if someone attempts to abuse the product it would just not feel good. For instance, if you were to crush the product and then attempt to snort it, your nose would feel very bad ● There are products that include opioid antagonists: if someone utilizes the medication as intended, fine, but if it’s abused/misused/crushed, a second medication will be activated and block the first ● Coatings: where the medicines aren’t activated in the gi tract until a specific point. pH comes into play: how acidic is the environment? If the medication is coated, it won’t be absorbed in the stomach The big idea: ● Smart goals: the intention is not to be the panacea.

Nothing is going to take care of everything ● Even with future technologies—multi-pill abuse resistance, other formulations of adfs, etc— the goal is to prevent the transgression of someone going to injection, snorting, abusing. That is one tool in the overall toolbox for risk reduction, both patient risk reduction and professional risk reduction as well

Referral timeframe? ● Probably, ballpark, there are ~3 months before a referral is made to a pain specialist ● It’s difficult: some medications require adequate trials which could be several weeks ● 3 months is a figure that primary care physicians and practitioners have said they usually give a patient with physical therapy or even trying integrated techniques like acupuncture or medication

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How Healing Works: Patients Have More Control Than They Think

Migraine in the Pediatric Population

Scott Powers PhD, ABPP, FAHS

Wayne Boice Jonas MD

Migraine is one of the largest chronic illnesses of childhood, one of the most disabling, and one of the most underrecognized diseases of childhood:

Healing—possibly up to 80%—comes from factors outside of what practitioners usually do in the clinic or hospital. Patients can combat some chronic pain and fight some genetic factors. Most people don’t realize that what they eat influences their pain. What else should patients be aware of? Patients are surprised but…

● Before puberty, 6% to 7% of boys and girls have headaches ● During adolescence into young adulthood, more females than males have migraine, but overall prevalence is somewhere around 10% ● Upwards of 1 out of 4 young women (from post high school age to early 20s) receive a diagnosis of migraine

● Health comes from your own inherent healing capacity ● You wouldn’t be alive if your body wasn’t continually repairing itself, recovering from traumas and stresses, reintegrating itself ● It’s a natural process and if we can enhance that process then that is where most of health and wellbeing come from ● Medical treatment is a supportive thing: if you have a disease that must be treated, it must be treated ● The goal is good health that comes from one’s own inherent healing capacity, which is a different journey for everyone ● There are some core common components—sleep and rest, stress management, food, movement, and the patient’s social and spiritual environment

How to diagnose? ● Kids <6: involve the parents quite a bit in the history taking ● A family history of migraine is certainly a high suspicion indicator for potentially having migraines as a young child: it is known to run in families ● We do a lot of drawings, pain drawings ● We do individualized, child-oriented type of simple questions to get at symptoms ● We might do a few more imaging studies in a young child where we aren’t quite sure of the history as we would in adolescent ● As children develop they obviously are better at self-awareness and describing their symptoms

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robert d.

sproul

pharmd

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“…treat…patients with the personalized care you would provide for your loved ones. It’s one of the most important components of the clinical, patient centric, tool kit, and often one of the most appreciated by those cared for.

Simply, when you come to care, ‘Don’t leave your heart at home!’”

Q

What inspired you to do what you do?

When I completed pharmacy school, in 2006, I was somewhat at a loss as to how I wanted to move forward as a pharmacist.

I simply was not emotionally moved by the more traditional opportunities offered in the pharmacy world. However, fate intervened!

A pharmacy residency position in pain and palliative care at Moffit Cancer Center in Tampa, Florida, would be reposted at the last minute. Little did I know the impact this residency program would have on me, to provide the inspiration of need, not only as the means to continue, but also to develop and flourish.

for help, from both the patient and the family.

Within a half-day, the adjustments made by our team were immeasurable: the patient’s pain was well-controlled, the sedation mitigated, and the patient was sitting up, speaking, and smiling with the family.

I would see this type of care with similar outcomes time and time again

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Who were your mentors?

Two providers truly impacted me, both during my residency at Moffit. Dr. D. Craig, pharmd, warmly known as David, was my residency preceptor. David is exceptionally bright, but importantly to me as an old country boy, he was down to earth, humble, and blessed with a great sense and delivery of humor. He made this learning experience robust and exciting. Late in my residency, David asked, “Robert, would you like to do a hospice rotation? I have the perfect person for you up in Baltimore.” There I met and trained with the esteemed Lynn McPherson, pharmd. What a hoot! Dr. McPherson, Lynn, whom I often reference as the “Queen of Hospice,” was perfect for me and still today calls me her Southern Boy, or “Bubba.” I loved every minute of the time spent with these two very special people!

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Q

Why did you focus on pain management?

I solely attribute this to my experiences at Moffit. What our small palliative team was able to accomplish at times was amazing. As my first exposure to such, our palliative team received a consult for a terminally ill patient who was refractory to the care offered and displaying significant symptoms with the current medication. Not only was the patient struggling with the emotional and physical aspects of the disease, but also the uncontrolled pain and significant sedation and accompanying incoherency, resulting in cries

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Q What do you consider your greatest achievement? a It was more of a soulful awakening. While at Moffit, our palliative team was treating a young, vibrant, but terminally ill patient. I was preparing to fly to DC for a pain conference and received a message that this young lady had asked to see me before my leave. She was quickly losing the battle with her disease, and as I approached her bedside, she weakly reached out to pull me close as she could only whisper her thoughts. She smiled and thanked me for my care, detailing the pain control which allowed her “to spend quality time with my husband” in her remaining days. On my return from the conference, I was stunned to find she had passed. To this day, I have much trouble speaking aloud this story. In all its sadness, which touched me deeply, I’m forever grateful to this proud, stoic young lady. In the midst of all she had to bear, she found it important to take the time to thank me for the personalized care received. This was a pivotal moment my in life, noting the difference one can make in another’s life if we will only take the time to do so. When I lecture or teach, I often share a personal perspective for treating patients with the personalized care you would provide for your loved ones. It’s one of the most important components of the clinical, patient centric, tool kit, and often one of the most appreciated by those cared for.

Simply, when you come to care, “Don’t leave your heart at home!”

pharmacy pursuit, I would, and will again, take this path. I’m preparing for this as my retirement from the VA nears. When I went back to school, I set my instruments down in favor of ongoing education and a new vocation. In this past year, I have once again begun playing these estranged instruments. As an effective measure to hone my musical skills, I’ve been performing for Veterans and staff at our VA hospital in Orlando. This a nice blend of patient care with the healing of music, and the perfect course to prepare for the inevitable transition per the sun setting on this VA career.

Q

What is or are your favorite languages?

I’m fascinated with sign language and though I did complete a couple of semesters I, unfortunately, did not stick with it. Today, Spanish has come to mind. I am particularly impressed with Argentinian guitarist/vocalist Luis Salinas. I love his guitar prowess and vocals that are always sung in his native language. It sounds so beautiful, but I cannot understand the language/meaning. As such, I have begun to “Babbel” in Spanish, and have purchased and started learning to play guitar, a language in itself. By this year’s end, my goal is to sing in Spanish while playing the guitar. I’m starting this fledging effort with one of my favorite Salinas’ ballads, Contigo en la Distancia.

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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: Ernest Hemingway’s Old Man and the Sea

Q

What is your most marked characteristic?

While “passion for” has always accompanied me, the attribute which found its way to me much later in life is unquestionably that of unbridled “determination.” Once the commitment is made, whether it’s learning to design and build large waterfalls or learning to play a new musical instrument, regardless of trials along the way, I will see the vision to its fruition.

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Movie: Black Hawk Down (2002). I found this a most unsettling, visceral depiction of routine mission—the Battle of Mogadishu (Mission: Gothic Serpent) on October 3, 1993—gone horribly awry. It reminds one of the risks, cost, and ultimate sacrifice of our many soldiers, both of our sung and unsung heroes. Never to be forgotten, our amazing men and women to be honored.

Q If you weren’t a healthcare provider, what would you be?

Robert Frost, you’re up!

Two roads diverge in a yellow wood…

Music: George Gershwin’s concerto, Rhapsody In Blue. Is there any other musical masterpiece to relish while basking in the earth’s heavens?

Because I was an entertainer and musician in my “first life,” before my doctorates of

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“Find ‘A Garden Within a Rose.’

It notes the necessity to appreciate and enjoy that which is offered, not simply to exist but to flourish.

Life is simply too short to do otherwise!”

Q

What would you like your legacy to be?

Simple: All things come to an end, most to be forgotten in time. For most, the coveted legacy is in the eye of the owner. Were you what you should have been? In life, did you present to yourself and others with honor?

Did your deeds, when appropriate, transcend that of self-gratification to include the benefit of others? How you’ll be remembered may not be detailed on a plaque, but may very well be that of your last self-assessment and I hope that to be a good one!

surroundings. It notes the necessity to appreciate and enjoy that which is offered, not simply to exist but to flourish. Life is simply too short to do otherwise!

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Robert D. Sproul, PharmD, is the Program Director, OVAMC Pain Management, and Program Manager at the Pharmacy Pain Management & Palliative Care Pain Program, Orlando VA Medical Center in Florida.

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Plans for the future?

Upon my retirement from the VA, I would like to continue to lecture and participate in national community efforts to engage the challenges of pain and opioid use disorder and management. With regards to the artist within me, I will continue to pursue my musical endeavors with the sax, drums, and guitar, of course now with a touch of Spanish flare.

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What is your motto?

Find “A Garden Within a Rose.” That is the title of my first attempt at prose, an unshared, private effort detailing my almost innate inability to recognize in simplicity the overt or seemingly hidden treasures offered in daily

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By Wendy Caster

BREAKING THE PAIN Across 1. Post-scrape wound cover 5. Zingy taste 9. Contribute, as to a 401k or IRA 14. Japanese plucked zither 15. Best selling cookie brand in US 16. Cousin to an alpaca 17. Hero 18. Deterioration 19. Quiet 2 0. Wiping item in less fancy restaurants 23. Type widths 24. Okay 25. Begets 27. Pedestals 31. Socialite Kane from “All My Children” and author Jong 35. Aries animal 36. Mediterranean currency 39. English tableware brand 4 0. Not anear 42. Monty Python’s Michael 44. Diamonds or hearts 45. Tending to a definite end, or a brand of footwear 47. Prison-related 49. Basic monetary unit of Romania 5 0. Category of drugs used to treat infections 52. Withered 54. Nets 57. Cherry or apple 5 8. Nice buddy 61. Painter with a thing for Tahiti 6 6. Red Cross supply 6 8. One way to keep out enemies 69. Gaelic 7 0. Type of phobia 71. Quintessential clown 72. Rattling sound in lungs 73. Use a zoom lens 74. Almost box 75. Kind of dog Down 1. Bypass 2. Conclusion 3. On 4. When she fell in love, she lost her head 5. Locality 6. Width times height 7. Some tides

8. A ridge in Antarctica, or Cuban rock musician Águila 9. Tools to reduce thickness, e.g., of a piece of wood 10. Beginning and end of the Three Musketeers motto 11. Where three current Supreme Court justices got their law degrees 12. Muslim leader 13. They vote against the ayes 21. Left the rat race, in brief 22. Anger 26. Partakes daintily 27. British idiots 2 8. Type of table, or character in “All’s Well That Ends Well” 29. _____ ferklempt 3 0. Like some decisions 32. “I ____ Have Danced All Night” 33. Nice farewell 34. Arrangement 37. Amber, for one

Puzzle solution: painweek.org/crossword.

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38. It has zest 41. Ready to eat 43. The one who tells the story 4 6. Singer Tracy who was talking ‘bout a revolution 4 8. In ____ of 51. Celestial altar 53. Those that trim, e.g., hedges 55. Anesthetizes 56. Type of boat 5 8. Stat!

59. Prefix to -phones or -bits 6 0. Dewrinkle 62. Huxley novel, “Eyeless in ____” 63. River through Kazakhstan 6 4. Capri, for one 65. Requirement 67. Mentalist Geller or Israeli writer and politician Avnery

Education is the best analgesic. www.painweek.org

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 Parkinsonâ&#x20AC;&#x2122;s disease.â&#x20AC;?

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.

Practical Education for Specialists and Frontline Practitioners Treating CNS Disorders

Live Virtual Conference

www.brainweek.org

Fri-Sun May 7–9 2021

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.