PAINWeek Journal Vol 8, Q2 by PAINWeek

vol. 8 q 2 2020

putting the “fun” in dysfunctional part 2: pain management options in hepatic dysfunction p.20 a trauma informed approach to pain management with ptsd p.30 fresh eyes on the role of anticonvulsants for low back pain p. 40 telehealth strategies: improving access to care p .48

A well-tolerated gabapentin, taken

ONCE DAILY FOR PHN PAIN RELIEF ¹ UNIQUE FORMULATION1,2 • Delivers a gradual release of gabapentin over time • Available in 300 mg and 600 mg tablets

WELL TOLERATED UP TO 1800 MG/DAY1,3 Pooled analysis from PHN placebo-controlled clinical trials*: • Drop-out rate due to AEs during the 2-week titration period was 3.6% for GRALISE vs 3.0% for placebo • Overall rates of discontinuation due to AEs were 9.7% (n=359) for GRALISE vs 6.9% (n=364) for placebo

Learn more about the Mechanism of Delivery at GRALISE-once-daily.com

*This was an analysis of data pooled from two Phase III, 11-week, randomized, placebo-controlled studies involving 723 patients (GRALISE 1800 mg, n=359; placebo, n=364). REFERENCES: 1. GRALISE [prescribing information]. Morristown, NJ: Almatica Pharma LLC; April 2020. 2. Argoff CE, Chen C, Cowles VE. Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview. Expert Opin Drug Deliv. 2012;9(9):1147-1160. 3. Irving GA, Sweeney M. Tolerability and safety of gastroretentive once-daily gabapentin for the treatment of postherpetic neuralgia. J Pain Res. 2012;5:203-208.

Please see additional Important Safety Information and the Brief Summary of full Prescribing Information on adjacent pages.

INDICATIONS AND USAGE GRALISE® (gabapentin) is indicated for the management of postherpetic neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS GRALISE is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. WARNINGS AND PRECAUTIONS The safety and efficacy of GRALISE in patients with epilepsy have not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Respiratory Depression Gabapentin has been associated with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or when there is an underlying respiratory impairment. When the decision is made to co-prescribe GRALISE with another CNS depressant, particularly an opioid, or to prescribe GRALISE to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating GRALISE at a low dose. Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. If such signs or symptoms are present, the patient should be evaluated immediately.

ADVERSE REACTIONS In clinical trials, the most common adverse reactions were dizziness (10.9%) and somnolence (4.5%). Across all GRALISE clinical trials, the other most common adverse reactions (≥2%) were headache, peripheral edema, diarrhea, dry mouth, and nasopharyngitis. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. DRUG INTERACTIONS An increase in gabapentin AUC values has been reported when administered with hydrocodone or morphine. It is recommended that GRALISE be taken at least 2 hours following antacid administration. USE IN SPECIFIC POPULATIONS Pregnancy Category C: GRALISE should be used during pregnancy or in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age have not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. Hepatic Impairment Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment. Renal Impairment Dosage adjustment of GRALISE is necessary in patients with impaired renal function. GRALISE should not be administered in patients with creatinine clearance <30 mL/min or in patients undergoing hemodialysis. Reductions in GRALISE dose should be made in patients with age-related compromised renal function. OVERDOSAGE Acute oral overdoses of gabapentin have been reported. Symptoms include double-vision, tremor, slurred speech, drowsiness, altered mental status, dizziness, lethargy, and diarrhea. Fatal respiratory depression has been reported with gabapentin overdose, alone and in combination with other CNS depressants.

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

GRALISE® (gabapentin) tablets Rx Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use GRALISE safely and effectively. See full Prescribing Information for GRALISE. INDICATIONS AND USAGE GRALISE is indicated for the management of postherpetic neuralgia. GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. DOSAGE AND ADMINISTRATION • GRALISE should be titrated to an 1800 mg dose taken orally, once-daily, with the evening meal. GRALISE tablets should be swallowed whole. Do not crush, split, or chew the tablets. For recommended titration schedule, see DOSAGE AND ADMINISTRATION in full Prescribing Information. • If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). • Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 or in patients on hemodialysis. CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. WARNINGS AND PRECAUTIONS GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Table 1: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in GRALISE) in the Pooled Analysis Placebo Patients with Events Per 1000 Patients

Drug Patients with Events Per 1000 Patients

Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients

Risk Difference: Additional Drug Patients with Events Per 1000 Patients

Epilepsy

1.0

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1.0

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

Indication

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that GRALISE contains gabapentin which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Respiratory Depression There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administrated with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe GRALISE with another CNS depressant, particularly an opioid, or to prescribe GRALISE to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating GRALISE at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including GRALISE). Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Increased seizure frequency may occur in patients with seizure disorders if GRALISE is rapidly discontinued. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and pre-existing tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established. 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 practice. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness.

Table 2: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group) GRALISE N = 359 %

Placebo N = 364 %

Ear and Labyrinth Disorders Vertigo

1.4

0.5

Gastrointestinal Disorders Diarrhea Dry mouth Constipation Dyspepsia

3.3 2.8 1.4 1.4

2.7 1.4 0.3 0.8

General Disorders Peripheral edema Pain

3.9 1.1

0.3 0.5

Infections and Infestations Nasopharyngitis Urinary tract infection

2.5 1.7

2.2 0.5

Investigations Weight increased

1.9

0.5

Musculoskeletal and Connective Tissue Disorders Pain in extremity Back pain

1.9 1.7

0.5 1.1

Nervous System Disorders Dizziness Somnolence Headache Lethargy

10.9 4.5 4.2 1.1

2.2 2.7 4.1 0.3

Body System – Preferred Term

The following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, bullous pemphigoid, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating. There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other central nervous system (CNS) depressants, or in the setting of underlying respiratory impairment. DRUG INTERACTIONS In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the Cmax at 3600 mg/day).

Hydrocodone Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of the interaction at other doses is not known. Morphine When a single dose (60 mg) of controlled-release morphine capsule was administered 2 hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin AUC values increased by 44% compared to gabapentin immediate release administered without morphine. The pharmacokinetics of morphine were not affected by administration of gabapentin immediate release 2 hours after morphine. The magnitude of this interaction at other doses is not known. Antacid (containing aluminum hydroxide and magnesium hydroxide) An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5% when gabapentin immediate release was taken 2 hours after the antacid. It is recommended that GRALISE be taken at least 2 hours following the antacid (containing aluminum hydroxide and magnesium hydroxide) administration. Drug/Laboratory Test Interactions False positive readings were reported with the Ames-N-Multistix SG® dipstick test for urine protein when gabapentin was added to other antiepileptic drugs; therefore, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Gabapentin is secreted into human milk following oral administration. Because the effect on the nursing infant is unknown, GRALISE should be used in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. Reductions in GRALISE dose should be made in patients with age-related compromised renal function. Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCL between 15 and 30 or in patients undergoing hemodialysis. [see Dosage and Administration in full Prescribing Information]. DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies. OVERDOSAGE Acute oral overdoses of gabapentin have been reported. Symptoms include double-vision, tremor, slurred speech, drowsiness, altered mental status, dizziness, lethargy, and diarrhea. Fatal respiratory depression has been reported with gabapentin overdose, alone and in combination with other central nervous system (CNS) depressants. Gabapentin can be removed by hemodialysis. Hemodialysis has been performed in overdose cases reported, and it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Live. Digital. Print. 365 days a year.

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

Editorial Board

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

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

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

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

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

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

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

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

Copyright © 2020, PAINWeek, a division of Tarsus Medical Group. The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff. PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises. All rights are reserved by PAINWeek to accept, reject, or modify any advertisement submitted for publication. It is the policy of PAINWeek to not endorse products. Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

DUE TO COVID-19

SEPT. 11–13 2020

75 CE/CME

CREDIT HOURS OFFERED

vol.8 q2 2020

20 30 40 48 56 62

pharmacotherapy

putting the “fun” in dysfunctional part 2: pain management options in hepatic dysfunction

by abigail t. brooks courtney m. kominek

behavioral

a trauma informed approach to pain management with ptsd

by brian e. kaufman

regional pain syndromes

fresh eyes on the role of anticonvulsants for low back pain

by derek chung mayank gupta

key topic

telehealth strategies: improving access to care

by james fricton ginevra liptan

op-ed

healing chronic pain: beyond pills and procedures

by wayne jonas

pain basics

pathophysiology: mechanism of normal pain

by kevin l. zacharoff

pw next generation

with meryl j. alappattu

68 69 70

clinical pearls

by david cosio

one-minute clinician

with garry j. bridges, timothy j. atkinson, jorge f. carrillo, meredith barad, mayank gupta

72 75

pundit profile

with david m. glick

puzzled?

by wendy caster

pain by numbers

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

for the past 35 years has allowed me to see dramatic shifts towards virtual assesspeople right now are feelment and treatment paradigms dictated Kevin L. Zacharoff ing the way virtually all patients with by a variety of reasons, including efficiency, safety, and better utilization/management chronic pain feel all the time: functionality is low, social interactions are minimal, and there is a pervasive fear of not of resources. In their timely article, Drs. James Fricton and Ginevra Liptan knowing what the coming days will bring. We are trying to make sense describe how telehealth can provide a solution to the broader challenge of the facts, trying to challenge the lack of evidence-based science, and healthcare systems are facing today as a result of the COVID-19 pandemic: hoping that better days, better treatments, and better solutions will be delivery of quality care in the face of distancing. The mission statement of ahead. When it comes to chronic pain and how it impacts people, empathy quality healthcare delivery has not changed, but how we live up to it based is something that often comes to mind. As clinicians, we try to demon- on our current situation has, possibly for the foreseeable future. Keep this strate empathic behavior by “putting ourselves in the pain patient’s shoes,” article handy for reference for sure. to think about the experience of pain and suffering given the individual contextual circumstances. In actuality, as we see with the global pandemic This issue’s Pundit Profile spotlights someone I am proud to call my friend, we face, it’s pretty much impossible to know how much others experience, Dr. David Glick. There are few people I know in pain medicine who are but one thing is for sure: we cannot lose hope. While the pain we face may more passionate in their mission for the search for knowledge, the care of be long-lasting, we must carry on together as advocates. Let’s have a look patients, and the education of other healthcare professionals. Professionat the articles in this issue of PWJ to see what might help fulfill that mission. alism truly defines this individual, along with a burning desire to always be better at what he does and making a positive difference for patients with In their 2nd article devoted to the intimate relationship between phys- pain. You will learn more about him in this profile, but it only scratches the iologic function and pharmacology, Drs. Courtney Kominek and Abigail surface of this dedicated pain expert. Brooks focus on hepatic function. Exploring how doses of common medications, ranging from over-the-counter drugs to opioids, may need modi- Dr. Meryl J. Alappattu is the focus of this issue’s Next Generation. As somefication based on hepatic function, the authors also do an excellent job of one looking to bridge the gap between research and real-world clinical providing a valuable go-to reference to help guide us with drug selection care, Meryl desires to make one of the most valuable contributions to pain and treatment planning for patients with compromised hepatic function. management over the course of her career: to help define the intersection With the high likelihood of comorbid medical conditions in patients with and relevance of evidence-based research. As a part of the next generation, chronic pain, this and their previous article (in the last issue of PWJ) should she is intent on harnessing technology and social media as tools to reach that goal. I hope you enjoy learning more about her, and how she will help be kept handy for reference. shape our future as a leader in pain care. The relationship between physical trauma and pain is well established, simple, and easily understood: injury causes pain. Dr. Brian Kaufman pro- Also, of worthy of mention in this issue of PWJ is the third installment of vides us with a detailed look at the much more complex relationship of the recurring segment Back to the Basics for people seeking foundational psychological trauma and pain. Considering a variety of traumatic events pain education, and an Op-Ed from Dr. Wayne Jonas underscoring a comranging from physical abuse in childhood to surviving a terrorist attack, a pelling argument about how our healthcare system needs to foster a more case is strongly made that it is important to query for PTSD resulting from integrative approach to managing chronic pain in a manner far beyond these experiences as a possible contributor or cause of pain. A strategy is pills and procedures. laid out for how a treatment plan can be developed that is “informed” by the traumatic event through ways that are deeply meaningful to compre- During these trying times, I hope you read this issue in good health and hensive treatment. Once again, this article underscores the importance of the comfort of your loved ones. I hope that we come back from where we are now to a place that is stronger, more secure, and vibrant. Nowhere in contextual, individualized pain care. my memory has our world relied more on healthcare providers than today, A recurring theme in my training in anesthesiology and pain medicine was including patients in pain who need us now more than ever. the need to consider that every potential treatment intervention carries with it some level of risk, and that the comparative risks between treatKevin L. Zacharoff MD, FACIP, FACPE, FAAP ment options be factored into ultimate decision-making. Derek Chung and Dr. Mayank Gupta provide us with an in-depth review of the role of anticonvulsants in the treatment of low back pain. The authors very capably Kevin L. Zacharoff is Faculty and Clinical Instructor at suny Stony Brook School point out that during this time of opioid-reducing pain management strat- of Medicine in New York, and is Ethics Committee Chair at St Catherine of Siena egies, we still have to arrive at the most educated decisions possible about Medical Center in Smithtown, New York. how anticonvulsants are used regarding both safety and efficacy, with the understanding that potential harms exist with these medications as well. From a “front row seat” in my hospital, I have been watching the face of healthcare delivery change. Being a member of the Credentials Committee

PWE Regional Conference Series

20 20

PAIN MANAGEMENT FOR THE MAIN STREET PRACTITIONER

visit www.painweekend.org for more information.

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Abigail T. Brooks PharmD, BCPS

Abigail Brooks is a Clinical Pharmacy Specialist at the West Palm Beach VA Medical Center in Florida. She coauthored her article with Courtney M. Kominek, a Clinical Pharmacy Specialist—Pain Management at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri. Abigail and Courtney completed their PGY2 Pain Management and Palliative Care Pharmacy Residency together at the West Palm Beach VA Medical Center.

p.48

James Fricton DDS, MS

James Fricton is Professor Emeritus at the University of Minnesota, Minnesota Head & Neck Pain Clinic, and President of the International Myopain Society. He coauthored his article with Ginevra Liptan, md, who is the Medical Director of the Frida Center for Fibromyalgia, on the Board of Directors at the International Myopain Society, and author of The FibroManual: A Complete Fibromyalgia Treatment Guide for You and Your Doctor.

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Mayank Gupta MD

Mayank Gupta is CEO-President of the Kansas Society of Interventional Pain Physicians and founder of Neuroscience Research Center. He coauthored his article with Derek S. Chung, a DO student Class of 2021 at the Kansas City University of Medicine and Biosciences in Missouri.

Brian E. Kaufman DO, FASAM, FACOI, FACP

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Brian Kaufman practices pain management and addiction medicine in New Hampshire and Maine. His practice emphasizes trauma informed patient-centered principles and advocates for greater patient resources. Dr. Kaufman incorporates hypnosis as well as interventional and osteopathic procedures and principles. He contributes to articles, textbook chapters, and teaches medical students, interns, and residents.

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!

Putting the " FUN" in

pain management options in hepatic dysfunction

pt. 2

, CPE

inek PharmD, BCPS

Courtney M. Kom

pharmacotherapy

As pharmacists, we get asked all kinds of questions about medications, and renal and hepatic dysfunction dose adjustments are right up there as some of the most common concerns. This is part 2 of our article (see PWJ 2020 Q1 for part 1); we will examine why certain drugs require dose adjustments in patients with hepatic dysfunction.

D, BCPS By Abigail T. Brooks Pharm PS, CPE BC D, rm inek Pha Courtney M. Kom

â&#x20AC;&#x160;â&#x20AC;Ś a higher Child-Pugh score or MELD score means that a lower dose should be used at a more extended dosing interval, at least when starting therapy.

Pharmacokinetic Considerations in Hepatic Dysfunction

includes serum albumin and creatinine concentrations, the international normalized ratio of prothrombin time, and the underlying cause of liver disease.2 In general, a higher Child-Pugh score or MELD score means that a lower dose should be used at a more extended dosing interval, at least when starting therapy.1,2

There are 2 phases of metabolism that take place in the liver:

Phase I: involves oxidative enzymes, including the cytochrome p450 (cyp) system Phase II: involves conjugating enzymes, including glucuronidation

Acetaminophen

It is thought that the oxidative enzymes are more significantly impacted in liver disease given the reduced oxygen levels as a result of portosystemic shunting and reduced liver perfusion. Phase II metabolism may be less impacted overall as a result of extrahepatic glucuronidation and an upregulation of uridine diphosphate-glucuronyltransferase in the remaining functional hepatocytes. Biliary excretion of drugs can also be affected in liver disease.1 Unfortunately, unlike in chronic kidney disease or end-stage renal disease, there is no accurate measure of liver disease that can be used to guide medication dose changes. Instead, liver disease has scales that measure the severity of disease from which dose adjustments can be obtained: the Child-Pugh score correlates with survival in cirrhotic patients and the model for end-stage liver disease (MELD) measures 3-month mortality. The ChildPugh score incorporates lab parameters (serum albumin, bilirubin, and prothrombin time) and clinical parameters (the presence of ascites and encephalopathy) to determine a level of mild, moderate, or severe. In contrast, the MELD

Acetaminophen, the most prescribed overthe-counter analgesic in the United States, is also the most common cause of liver failure in both the United States and Canada.3,4 The mechanism behind acetaminophen hepatotoxicity is depleted glutathione levels. Primarily, acetaminophen is metabolized via glucuronidation and the metabolite is excreted renally. A secondary pathway (<10%) involves CYP2E1 that metabolizes acetaminophen to N-acetyl-p-benzoquinone imine. With glutathione present, it is metabolized further to nontoxic metabolites, but without glutathione or low levels of glutathione, hepatotoxicity develops via oxidative damage.1,3 Aside from acute ingestion of high doses of acetaminophen, depleted glutathione levels can be found in individuals with malnutrition, chronic illness, and chronic alcoholism.1,4 Symptoms of acetaminophen toxicity progress from nausea, vomiting, and malaise initially to full-blown hepatic failure over the course of several days; treatment involves N-acetylcysteine.4 While some think that acetaminophen is contraindicated in hepatic disease or cirrhosis, that is actually not the case! Acetaminophen remains a viable treatment option in hepatic disease but does require

…oral NSAIDs should be avoided in severe hepatic dysfunction as well as cirrhosis…

dose adjustment depending on the severity of hepatic dysfunction. In fact, acetaminophen is the preferred firstline analgesic in liver disease. Short-term use (<14 days) of acetaminophen up to 4 grams/day is acceptable in most cirrhotic patients; however, for chronic use, current recommendations propose a maximum daily dose of 2 to 3 grams in cirrhosis.1,3 Patients should also be encouraged to avoid alcohol consumption with acute or chronic acetaminophen intake.3

Nonsteroidal Antiinflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs), for all their magical glory, can actually be quite dangerous in hepatic dysfunction. Most clinicians know to be cautious with using NSAIDs in renal impairment, but caution should also be used when it comes to the liver. In fact, NSAIDs account for approximately 10% of all drug-induced liver injury; hepatotoxicity is technically a class effect of NSAIDs.1,3 Given reduced albumin levels in hepatic dysfunction, some NSAIDs exhibit reduced plasma protein binding leading to significant increases in plasma free drug concentration. As a result, certain NSAIDs can then have dangerous pharmacologic effects if not dose reduced in hepatic impairment.1,2 This can also occur in chronic liver disease since NSAID drug metabolism via hepatic CYP450 enzymes can be impaired.3 The mechanism of NSAID risk in hepatic dysfunction can be quite complex. Renal impairment may co-occur in hepatic impairment, contributing to the increased risk of NSAID use in this patient population.1

Unstable renal hemodynamics can occur in those with cirrhosis but also in those with ascites, leading to increased sensitivity to the changes that NSAIDs cause by inhibiting prostaglandin synthesis which adversely impacts renal perfusion. Ascites can also be caused by NSAIDs due to reduced sodium and water excretion by the kidneys.2 On top of this, NSAIDs can reduce the effectiveness of diuretics, which are used to treat ascites.3 While it is well-known that NSAIDs increase the risk of bleeding, in those with esophageal or cardiac varices the risk of a first bleeding episode is 3 times higher in cirrhotic patients taking NSAIDs compared to cirrhotic patients who are not. In theory, the risk of acute bleeding due to esophageal varices may be lower with COX-2 selective NSAIDs, but this requires further investigation.1,2 In general, oral NSAIDs should be avoided in severe hepatic dysfunction as well as cirrhosis for the reasons discussed above. For those with mild to moderate hepatic dysfunction, NSAIDs can be used if the potential benefits are determined to outweigh the potential risks. Ibuprofen, etodolac, and diclofenac can be used at normal doses whereas naproxen, celecoxib, and sulindac can be used with a dose reduction.2 If it is thought an NSAID would be appropriate, the safest option might be a trial of a topical NSAID.

Antidepressants

Tricyclic antidepressants (TCAs) remain viable treatment options in hepatic dysfunction. As TCAs are metabolized by the hepatic CYP450 pathway, there is the possibility of drug accumulation as a result of reduced

Table 1. SNRI Considerations in Hepatic Dysfunction5-7 SNRI Medication

Hepatic Considerations

Duloxetine

▸ Metabolized by cyp2d6 and cyp1a2 ▸ Cases of hepatotoxicity particularly with pre-existing liver dysfunction ▸ Avoid in chronic liver disease or chronic alcohol use

Milnacipran

▸ Reports in elevations of alt and ast ▸ Rare cases of fulminant hepatitis ▸ Avoid in patients with significant alcohol use or chronic liver disease

Venlafaxine ER

▸ Metabolized by cyp2d6 and cyp3a4 ▸ Moderate to severe dysfunction: clearance decreases and half-life increases ▸ Dose adjustments

metabolism in liver disease. An accumulation of TCA leads to increased risk of toxicity and potential adverse effects, including but not limited to anticholinergic effects such as constipation and dry mouth. The overall recommendation, similar to chronic kidney disease, is to start low and slowly titrate TCAs in hepatic impairment as well as cirrhosis.1-3 Given the concern for constipation and the potential associated complications in patients with cirrhosis, providers may want to consider coadministration of laxatives at the start of therapy to reduce the risk for constipation-induced encephalopathy.1 Those with liver disease may require a lower maintenance dose of TCA.3 Serotonin-norepinephrine reuptake inhibitors (SNRIs) include venlafaxine, available in immediate release (IR) and extended release (ER) formulations, duloxetine, and milnacipran. Unfortunately, it depends on the particular SNRI as to whether or not it can be administered in the setting of hepatic dysfunction. (See Table 1). Let’s start with venlafaxine; since it is metabolized via the CYP450 system, the half-life and clearance of venlafaxine and its metabolite can be significantly impacted.2 Therefore, dose reduction by 50% of venlafaxine is recommended in mild (Child-Pugh of 5–6) and moderate (ChildPugh of 7–9) hepatic impairment. In severe (Child-Pugh of 10–15) hepatic impairment or cirrhosis, dose reduction of at least 50% is recommended.7 Keep in mind, the

usual target dose of venlafaxine for neuropathic pain is 225 mg/day and these dose adjustments apply to both IR and ER formulations of venlafaxine.8 Duloxetine, which carries FDA-approved indications for pain, is not recommended for those with chronic liver disease or cirrhosis. In those with “clinically evident hepatic impairment,” duloxetine metabolism and elimination is decreased. In those with cirrhosis, duloxetine’s half-life is significantly extended.5 In addition to these recommendations, duloxetine carries a hepatotoxicity warning and precaution with a recommendation to avoid use in those with substantial alcohol use.2,5 Finally, milnacipran has no dose adjustments required in those with hepatic impairment but caution with use is suggested in those with severe hepatic impairment. Similar to duloxetine, milnacipran also carries a warning and precaution about a risk for hepatotoxicity and suggestion to avoid use in those with substantial alcohol use or chronic liver disease.6

Anticonvulsants

Fortunately, what may be the most common anticonvulsants used for neuropathic pain—gabapentin and pregabalin—require no dose adjustment in hepatic impairment or liver disease! This is most likely due in part to the fact that they are minimally metabolized by the liver

Table 2. Anticonvulsant Hepatic Considerations10-19 Medication

Hepatic Considerations

Carbamazepine

▸ Metabolized by CYP3A4 ▸ Acute liver failure with DRESS (drug reaction with eosinophilia and systemic symptoms)

Gabapentin, gabapentin enacarbil, gabapentin CR

▸ Safe to use

Lamotrigine

▸ Metabolized by glucuronidation

▸ No adjustments

▸ Mild impairment: no adjustments ▸ Moderate to severe impairment w/o ascites: reduce dose 25% ▸ Moderate to severe w/ ascites: reduce dose 50% ▸ Adjust based on clinical response Levetiracetam

▸ Severe hepatic impairment, Child-Pugh Class C clearance reduced 50% ▸ No dose adjustments recommended in hepatic impairment

Oxcarbazepine

▸ Metabolized in the liver by cytosolic enzymes ▸ Cleared by kidneys ▸ Mild-moderate impairment had no impact on PK

Pregabalin, pregabalin CR

▸ Safe to use

Topiramate

▸ Plasma concentrations may increase

▸ No adjustments

▸ moa unknown ▸ No adjustments provided

and are excreted unchanged through the kidneys.1-3 However, gabapentin takes the prize in terms of being the safest choice since pregabalin has been associated with rare cases of pregabalin-induced and pregabalin-aggravated liver injury.9 Newer formulations of gabapentin—gabapentin enacarbil and gabapentin CR—and the controlled release (CR) formulation of pregabalin are also safe to use in hepatic impairment and liver disease, although exercise caution with pregabalin CR given the reports of rare liver injury with pregabalin IR use.10-12 (See Table 2). Carbamazepine is not recommended for use in those with cirrhosis due to risk for hepatoxicity or acute liver failure as part of the drug reaction with eosinophilia and systemic symptoms (DRESS) as well as the risk of bone marrow suppression.1,9 Other sources suggest avoiding carbamazepine altogether in any type of chronic

liver disease.2,3 Oxcarbazepine, an alternative to carbamazepine, can also be associated with DRESS. However, dose adjustment is not recommended in mild to moderate hepatic impairment.15 Lamotrigine, also a potential cause of DRESS, requires no adjustment in mild hepatic impairment. For moderate to severe hepatic impairment without ascites, a 25% reduction in the initial, escalation, and maintenance doses is recommended whereas in those with moderate to severe hepatic impairment with ascites, a 50% reduction is recommended.16 No dose adjustments or recommendations are made for topiramate in hepatic impairment, although this drug can be associated with hepatic failure and hepatitis.17 Finally, levetiracetam does not require any dose adjustments in hepatic impairment. Similar to topiramate, hepatic failure and hepatitis can occur with levetiracetam use.18

Skeletal Muscle Relaxants

Typically, for most indications, skeletal muscle relaxants are recommended to be used at the lowest effective dose for the shortest duration possible.20 Baclofen requires no dose adjustment in hepatic impairment.21 Methocarbamol has no specific dose recommendations provided but caution is suggested in cirrhosis due to reduced clearance.22 In keeping with this theme, diazepam also has no specific dose adjustment recommendations but instead it is suggested to modify the dose based on clinical response and level of impairment.23 Orphenadrine provides no specific dose recommendations for use in hepatic impairment but caution is advised since it is metabolized via the liver.24 While carisoprodol is generally not recommended for use given its abuse potential, as it is metabolized via CYP2C19 the dose should be reduced in hepatic failure due to increased concentrations of parent drug.25 Chlorzoxazone should be avoided in those with hepatic impairment and has also been known to cause hepatotoxicity.26 Cyclobenzaprine can be used in mild hepatic impairment; the suggestion is to start at 5 mg/dose and titrate slowly. The patient with hepatic impairment will likely require less frequent dosing. Due to pharmacokinetic changes, cyclobenzaprine is not recommended in moderate to severe hepatic impairment.27 On the contrary, metaxalone should be administered with great care in those with pre-existing liver impairment or liver disease and it is suggested to monitor serial liver function tests; use is contraindicated in significant hepatic impairment.28 Finally, tizanidine has been known to cause hepatotoxicity. For this reason, and the fact that it is metabolized via CYP1A2 to inactive metabolites, it should be used with caution in any type of hepatic impairment. If a higher dose is needed, consider increasing the dose rather than the dosing frequency.29 (See Table 3).

Opioids

Opioids can have an increased risk of toxicity in hepatic impairment, especially in those with cirrhosis. It has been postulated that in hepatic impairment endogenous opioids are upregulated and increase sensitivity to exogenous opioids. For this reason, IR opioid formulations are generally recommended over ER/long acting (ER/LA) opioid formulations due to the risk of drug accumulation. Once tolerability of a particular opioid is established, only then should ER/LA opioid formulation be considered, if clinically appropriate. In addition, similar to TCAs, coprescribing of an effective bowel regimen is suggested to avoid the complications that can come with constipation in cirrhosis. As always, opioids should be utilized only when the potential benefits outweigh the potential risks and nonopioid pharmacological modalities have failed or are contraindicated.1,2,9

Literature suggests that, in theory, the “best” opioids to recommend in liver dysfunction are likely hydromorphone, oxymorphone, and tapentadol given minimal metabolism via CYP450.3 Hydromorphone is metabolized via glucuronidation, as is morphine, but it does not require metabolism to an active analgesic metabolite. While some parameters of hydromorphone are impacted in liver disease, it does not appear to impact the elimination of hydromorphone.9 Hydromorphone, since it can be used in renal impairment, may be an appropriate choice in hepatorenal syndrome as well; although some sources recommend caution with use in renal impairment given the potential for accumulation of the neurotoxic metabolite hydromorphone-3-glucuronide (H3G).2 Tapentadol is metabolized via conjugation to tapentadol-O-glucuronide, and tapentadol sulphate and CYP enzymes are then responsible for another 15% of the metabolism of tapentadol. Higher serum concentrations have been observed in those with mild and moderate liver disease along with an increase in area under the curve (AUC) and half-life. Therefore, no dose adjustment is recommended in mild hepatic impairment (ChildPugh 5–6) but in moderate impairment (Child-Pugh 7–9), tapentadol should be initiated at the lowest possible dose (50 mg) with an increased dosing interval (every 8 hours). There have been no studies done in severe hepatic disease (Child-Pugh 10–15), and its use is not recommended in this population.2,30 Morphine, which seems to be incorrectly assumed to not be appropriate for use in hepatic impairment, still remains a viable treatment option for most hepatic patients but needs to be used in a more cautious manner. Specifically, in severe hepatic impairment or cirrhosis, since morphine’s half-life and oral bioavailability is significantly increased due to impaired metabolism, it is suggested that the initial morphine dose be reduced. It would likely be prudent for the provider to also extend the dosing interval, at least initially.1,2 Given the fact that morphine’s metabolites are renally cleared and accumulation of the morphine-3-glucuronide (M3G) metabolite can precipitate seizures, it is recommended to avoid morphine in those with hepatorenal syndrome.9 Of note, some sources recommend avoiding morphine all together in cirrhosis or trialing other opioids before considering morphine.3 Codeine, since it is converted via CYP2D6 to morphine, can result in decreased analgesia or lack of effectiveness in hepatic impairment. For this reason, it is not typically the recommended analgesic for those with liver disease.1,2 Hydrocodone and oxycodone are both metabolized via CYP2D6 and CYP3A4 to hydromorphone and oxymorphone, respectively. If drug metabolism is adversely impacted in liver disease, serum levels could be variable and analgesic response could be unpredictable or diminished.1,9,31 It is recommended that oxycodone be used

Table 3. Skeletal Muscle Relaxant Hepatic Considerations21-29 Medication

Hepatic Considerations

Baclofen

No dose adjustment needed

Carisoprodol *AVOID IN GENERAL Chlorzoxazone

▸ Metabolized by cyp2c19 ▸ Reduce dose in hepatic failure due to increased concentrations of parent drug ▸ Metabolized by cyp2e1 ▸ Avoid in those with hepatic impairment ▸ Reports of rare, severe, idiosyncratic hepatoxicity

Cyclobenzaprine

▸ Not recommended in moderate to severe hepatic impairment ▸ Mild impairment: 5 mg dose and titrate slowly and require less frequent dosing ▸ auc, peak levels doubled in hepatic impairment

Diazepam

▸ Metabolized by cyp2c19, cyp3a4 ▸ Modify dose based on clinical response and level of impairment ▸ No specific dosage adjustments provided

Orphenadrine

▸ Metabolized in liver via unmentioned route ▸ Caution is recommended ▸ No specific recommendations provided

Metaxalone

▸ Administer with great care in those with pre-existing liver impairment/disease ▸ Monitor serial liver function tests ▸ Contraindicated in significant hepatic impairment

Methocarbamol

▸ No specific dosage adjustments provided ▸ Use caution in cirrhosis since clearance is reduced

Tizanidine

▸ Potential hepatoxicity ▸ Metabolized by cyp1a2 to inactive metabolites ▸ Use with caution with any level of hepatic impairment ▸ If higher dose needed, increase dose but not frequency

at lower doses or at extended dosing intervals in those with hepatic impairment.2 Given that both hydrocodone and oxycodone are available in combination products with acetaminophen, the total daily dose of acetaminophen should also be taken into consideration for those with hepatic impairment and could be a rate-limiting step for increasing the dose of either combination opioid.

Fentanyl is largely protein bound, mainly to albumin, and is mostly metabolized in the liver by CYP3A4. The pharmacokinetics of intravenous (IV) administration of fentanyl vs the fentanyl transdermal patch and the impact of liver dysfunction are quite different. Given its high hepatic extraction ratio (0.8), fentanyl’s clearance is mainly impacted by changes in hepatic blood flow rather

… sublingual buprenorphine has been linked to cases of hepatitis and jaundice in those being treated for opioid dependence.

than changes in enzyme activity due to liver disease. The manufacturer of the fentanyl transdermal patch found that Cmax and AUC were increased by 35% and 73%, respectively, in cirrhosis with no change in the half-life. 1,2,9,31 Fentanyl citrate for IV administration should be given with great care to in liver dysfunction; the package insert suggests to reduce the dose as needed and monitor the patient closely for adverse effects.32 Fentanyl is a recommended opioid in renal impairment and may also be a good choice in hepatorenal syndrome, but dose reduction should be considered to prevent accumulation. Reduced dosing should also be considered in hypoalbuminemia.1,2,9,31 Tramadol is also metabolized to its active metabolite, O-desmethyltramadol, via CYP2D6. So, like codeine, it is postulated that, given reduced metabolic activity in liver disease, it will be less effective. In those with cirrhosis, the AUC and half-life were increased due to reduced hepatic clearance. For these reasons, 50 mg PO Q12H is the recommended adjustment in severe hepatic impairment or cirrhosis, with extended dose frequency and decreased overall total daily dose.1,2,9,31,33 A “hot topic” in the pain management world with old and new formulations being used for chronic pain management, buprenorphine is metabolized via CYP3A4 to an active metabolite (norbuprenorphine) that requires glucuronidation and biliary excretion for elimination. For this reason, a dose reduction may need to be considered in hepatic impairment.2,9 In looking at the package insert for the buprenorphine patch, FDA-approved for pain, it is suggested that an alternative opioid with better dosing

flexibility be considered in severe hepatic impairment. For buprenorphine buccal film, also FDA-approved for pain, a reduced starting dose and reduced titration dose by 50% is recommended. Aside from this, sublingual buprenorphine has been linked to cases of hepatitis and jaundice in those being treated for opioid dependence. Therefore, it is recommended in patients with an increased risk of hepatotoxicity (history of excessive alcohol intake, IV drug abuse, or liver disease) to obtain baseline liver enzyme levels with periodic monitoring while prescribed buprenorphine.34,35

Conclusion

Hepatic impairment and how to dose adjust medications can be a clinically complex and daunting process. We hope that this overview has provided you with a better understanding as to why dose adjustments are recommended for some medications and not for others. In addition, it is also clear that certain pain medications should be avoided all together in either renal or hepatic impairment.

The views and opinions expressed in this presentation are those of the authors and do not necessarily reflect the official policy or position of any agency of the United States government, including the Department of Veterans Affairs, as well as employers, employee affiliates and/or pharmaceutical companies mentioned or specific drugs discussed.

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10. Gralise package insert. Neward, CA: Depomed, Inc; September 2015. 11.

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Horizant package insert. Atlanta, GA: Arbor Pharmaceuticals, LLC; October 2016.

12. Lyrica CR package insert. New York, NY: Pfizer; October 2017.

30. Nucynta ER package insert. Stoughton, MA: Collegium Pharmaceutical, Inc; October 2018.

13. Carbamazepine package insert. North Wales, PA: Teva Pharmaceuticals USA, Inc; October 2018.

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14. Neurontin package insert. New York, NY: Pfizer; February 2018.

32. Ultram package insert. Titusville, NJ: Janssen Pharmaceuticals Inc.

15. Oxcarbazepine package insert. Hawthorne, NY: Taro Pharmaceuticals USA, Inc; August 2014.

33. Butrans package insert. Stamford, CT: Purdue Pharma LP; October 2019.

16. Lamotrigine package insert. Baltimore, MD: Lupin Pharmaceuticals, Inc; October 2018.

34. Belbuca package insert. Raleigh, NC: Biodelivery Sciences International, Inc; October 2019.

17. Topiramate package insert. Baltimore, MD: Lupin Pharmaceuticals Inc; July 2018.

35. Fentanyl citrate injection package insert. Lake Forest, IL: Akorn, Inc; December 2016.

18. Levetiracetam package insert. Lawrenceville, GA: Exelan Pharmaceuticals, Inc; December 2018.

an facp ufm , Ka E. , facoi ian Br fasam By DO,

rauma” is derived from the Greek word for wound and is defined as a deeply distressing or disturbing experience.1 Dutch psychiatrist, author, and educator Bessel van der Kolk, an expert in posttraumatic stress, stated that “Trauma is the result of exposure to an inescapably stressful event that overwhelms a person’s coping mechanism.”2 When traumatic events occur, people can experience changes in their behavior and body that may lead to profound medical and emotional issues and can, in turn, lead to chronic pain and substance use disorders.

Adverse Childhood Events

Between 1995 and 1997, the adverse childhood events (ACEs) trial was conducted jointly by the Centers for Disease Control and Prevention (CDC) and Kaiser Permanente and enrolled >17,000 health maintenance organization members. All received physical exams and completed confidential surveys regarding their childhood experiences, current health issues, and behaviors. The results indicated that ACEs are common across all populations with almost two-thirds of study participants reporting ≥1 ACE and >20% reporting ≥3 ACEs. As the number of ACEs went up, there was a notable increase in incidence and worsening severity of substance use disorders, mental health problems, and physical maladies.3

Over the years, knowledge and awareness of trauma has increased dramatically as studies have examined its prevalence and effect on patients, and the connections between trauma and the development of posttraumatic stress disorder (PTSD), chronic pain, and other maladies. With increased recognition of trauma and its aftereffects, the principles of trauma informed care have arisen and been applied to a variety of settings. In this article, aspects of trauma and trauma informed care will be discussed as they apply to pain management.

Trauma

Surviving trauma can lead to the development of PTSD. The most common events leading to development of PTSD4 are ● Combat exposure ● Childhood physical abuse ● Sexual violence ● Physical assault ● Accidents ● Fire ● Natural disasters ● Mugging ● Robbery ● Torture ● Kidnapping ● Terrorist attacks PTSD has even been reported after hearing about something horrific or receiving a diagnosis of a life-threatening illness. While most symptoms develop within 3 months of the trauma, sometimes symptoms appear much later. The severity of symptoms is related to the individual’s coping mechanisms, and ability to process the events, along with individual personalities and experiences.4 For instance, having an inherently negative view of the world or a history of traumas may cause a new trauma to escalate the severity. Additionally, ready access to social support for both mental and emotional processing may help to alleviate the severity of the trauma’s effects.5

behavioral

Patients with PTSD may avoid anything that reminds them of the traumatic event, including people, places, activities, objects, and situations. Patients may resist talking about the events or their feelings about the events and may dislike visits to the doctor because it reminds them of their traumatic event.â&#x20AC;? PTSD

PTSD is a clinical syndrome characterized by 3 major characteristics: 1) intrusive thoughts, 2) avoidance, and 3) negative beliefs/feelings, all of which can manifest as repeated involuntary memories, distressing dreams, and flashbacks of the traumatic event. Patients with PTSD may avoid anything that reminds them of the traumatic event, including people, places, activities, objects, and situations. Patients may resist talking about the events or their feelings about the events and may dislike visits to the doctor because it reminds them of their traumatic event. These feelings can manifest as hostility towards health professionals or a generally negative perception of themselves or the healthcare environment.6 Patients with PTSD have higher rates of somatic symptoms and substance use disorder and may engage in self-soothing behaviors, such as medication misuse or substance use, which can complicate interactions with healthcare professionals.7-9 Healthcare professionals may disbelieve pain complaints or feel they are exaggerated and ascribe them to mental health issues or secondary gain, such as obtaining opiate medications to sell. Socioeconomic factors may lead to a lack of resources, resulting in some patients being disenfranchised or complaints being dismissed, with little recourse for the patient.5

Neuroanatomy and Physiology

Changes in neuroanatomy and physiology have been demonstrated in trauma exposed individuals. Exposure to traumatic experiences causes dysregulation of the hypothalamic-pituitary-adrenal axis activity.10 Studies examining changes in neurohumoral response with trauma show decreased levels of gamma-aminobutyric acid (GABA),11 which can lead to increased anxiety and agitation, decreased endogenous opiate levels (leading to greater pain), and other alterations of neurotransmitters, which increases dysphoria.12,13

Brain structure remodeling in trauma exposed adults has been demonstrated by MRI studies that show smaller hippocampi, amygdala, and anterior cingulate cortex volumes in patients with PTSD compared to healthy controls.14 Pediatric samples exhibited smaller corpus callosum15 and frontal lobe volumes in traumatized children.16-19 PTSD patients often experience hypervigilance (increased threat surveillance), increased startle response, and decreased emotional regulation along with inhibition of frontal cortex activity, all of which lead to behavioral changes. Patients might react strongly to seemingly innocuous statements. PTSD patients may demonstrate sensitivity to sound, light, smells, and tactile stimulation and may present wearing sunglasses in the office or eschew touch. If medical settings trigger them, patients may avoid office visits and have a high no-show rate, despite a genuine desire for help.4,20,21

Reward Behavior

Reward behavior is the seeking of soothing stimulus, which is perceived to ease physical or mental/ emotional pain. It is an attempt to self-regulate the inner experience.22 Over time, symptoms of chronic pain can lead to maladaptive reward circuitry function. Pain is considered an aversive stimulus, and analgesia appears to act as a rewarding stimulus.23-25 The reward circuit involves brain structures including the nucleus accumbens, ventral tegmental area, amygdala, and periaquaductal grey as well as cortical areas such as the prefrontal cortex.26 These structures work in concert to identify actions that produce relief, and avoid pain, often searching for ways to achieve quick/immediate relief of the symptoms. Chronic pain is postulated to produce lasting changes on the aversion-reward circuit similar to addiction.27 Unfortunately, although self-protective behaviors may achieve transient relief, over time these same actions

can lead to worsening function and behavior escalation. One example is the overuse of immediate release opiates, which may alleviate the symptoms of pain for a short while but leads to increased tolerance with worsening efficacy and resultant worsening pain and dysphoria. Another example is the tendency to lie down when pain is present or worsening. Patients may experience short-term pain improvement, but increased reliance on remaining sedentary leads to muscle atrophy, kinesiophobia (fear of moving), worsening symptoms, and debility.28-30 In contrast, the frontal cortex identifies and plans how to achieve long term-goals; it is our executive function but can be inhibited with increased limbic activation.31 This inhibition may lower the patient’s ability to find solutions and leads to increased impulsivity and reliance on short-term relief strategies.31 When patients have chronic limbic activation, there is a shift in the physiologic set point, known as allostasis. Allostatic load is the term for the total of stressors on the individual, and with greater allostatic load there is an increase in health issues.32 For a child, an increased allostatic load can lead to all sorts of disruptive behavior. They may struggle in school and at home with social issues and tasks. The child may be labeled as difficult or a troublemaker or as having limited intelligence, or misidentified as having ADHD or autism-spectrum disorder due to overlapping symptoms. When these children become adults, they may present to our office with these same problems along with chronic pain, addictions, and complicated health issues.33-38

Polyvagal Theory

There are 2 distinct vagal nerve centers that serve very different functions. The ventral vagus is newer, from an evolutionary perspective, and responsible for carrying out general functional activities when we are “socially engaged” and not hyper- or hypoaroused. We also have a system far older on the evolutionary scale, labeled the dorsal vagus. It is an ancient protective mechanism that engages when we perceive a life threat. This is the “play dead” mechanism or the reason someone might faint in response to an emotional event. While providing a mechanism to avoid the terror of an inescapable situation that is perceived as life-threatening, this same mechanism can produce a persistent state of hypoarousal that results in worsening function when chronic, such as in PTSD.39,40 A patient with PTSD may exhibit threat hypervigilance and, upon perceiving a threat, as might happen with a medical procedure, self-protective behaviors may be triggered. The patient may shift from a ventral vagal state (an ideal state of social engagement when there is no danger) to a hypersympathetic state (the readying for action to a perceived threat). From a hyperarousal (or sympathetic) state the patient may shift to a dorsal vagal state, or one of

hypoarousal. This may manifest as halting conversation or speaking in truncated sentences, avoiding eye contact, and an inability to see solutions for their problems. If the underlying pathology is not understood by a practitioner, it is possible to mistake this patient presentation as being unconcerned or not comprehending whatever is being discussed. Therefore, it is important for health professionals to understand that these behaviors are not conscious decisions and are being driven by trauma pathology. Health professionals who observe these behaviors should recognize them as a warning that the individual’s psyche has moved to extreme dysregulation and is in a state of perceived life threat. The individual is in what is termed “dorsal vagal collapse” and has lost the ability to self-regulate.39,40

Neuroception

Neuroception describes the ability of the subconscious mind to perceive threat with greater and faster discrimination than the conscious mind. It is responsible for “gut intuition” of danger. But patients with PTSD respond at times to threats from internal sources, and these may not reflect external or observable events. This may lead to exaggerated or inappropriate responses that may appear to have no context but in fact are being triggered by encountering subtle vocal or facial inflections.39,40

Prosody

Humans evolved in the presence of environmental dangers and certain stimuli can trigger a perception of danger. The growling of wild animals or the sound of someone’s voice when angry tend to be low pitched. Therefore, hearing deep resonant sounds may trigger a sense of danger and cause limbic activation. Speech normally has an inherent musicality, termed “prosody.” Anger is associated with a loss of prosody. Therefore, clinicians should avoid monotonal speech, maintain melodic tone, and avoid lower frequencies. Also, clinicians need to be aware of their own physical and emotional state, because if they are irritable or tired, the patient can pick up those subliminal messages and become triggered.41

Chronic Pain

Chronic pain can be a debilitating condition and is associated with a decreased life expectancy and quality of life.42 Chronic pain is a common reason for adults to seek medical care. In 2016 the CDC estimated that 20.4% (50 million) of US adults had chronic pain, and 8.0% (19.6 million) of that total had high-impact chronic pain, defined as lasting ≥3 months and accompanied by ≥1 major activity restriction, such as being unable to work outside the home, go to school, or do household chores.

The office visit may be one of the few times that the patient gets treated with kindness and respect.â&#x20AC;?

Chronic pain contributes to an estimated $560 billion each year in direct medical costs, lost productivity, and disability programs. Chronic pain is also a major cause of suicide, with a high comorbidity of depression in patients.43-45

Chronic Pain and PTSD

The chronic pain population has a PTSD prevalence of 35%, compared to 3.5% in the general population. In a study of patients with chronic low back pain, 51% of the patients experienced significant PTSD symptoms.46 In either case, this is a disproportionate representation in chronic pain patients. There is also a positive correlation of PTSD severity with pain severity.47 Patients with PTSD are at increased risk for many health problems ranging from cardiovascular disease, respiratory disease, and many types of somatic complaints, to having a higher incidence of autoimmune disease than the general population.48,49 The incidence of mental health comorbidity, substance use disorder, and overall economic burden is increased as well.50-52 Patients with PTSD experience a sensory profile typical for a high pain tolerance to normal stimulus levels but with increased pain severity to suprathreshold stimuli.53 Patients with chronic pain and PTSD may have different clinical features and behaviors than those without PTSD. They are more likely to present in a state of hyperarousal and, as such, might be resistant to treatments or changes that may cause temporary pain increases, even if they are likely to produce improvement over time.54 PTSD patients may appear hostile, distrustful, or may perceive motivations not present in the provider. Patients who have progressed to hypoarousal, or a predominant dorsal vagal state, may be noncommunicative, withdrawn, and/or unable to muster enthusiasm for changes. They can appear emotionally blunted, profoundly depressed, and it may be difficult to have an intellectual discussion with them. These patients may tend to run late and have higher than average no-show rates possibly due to avoidance behavior.39,40,55

Central Sensitization Syndrome

Patients with PTSD are more likely to present with features of central sensitization syndrome (CSS).56 CSS has been defined as a condition of the nervous system associated with the development and maintenance of chronic pain with 2 distinct characteristics: allodynia and hyperalgesia. Allodynia is experiencing pain with a typically nonpainful stimulus. Hyperalgesia is when a painful stimulus is perceived in greater severity for a patient than it would be compared to controls.57,58 Some common examples of diagnoses consistent with CSS are fibromyalgia, irritable bowel syndrome, migraine, myofascial pain syndrome, and interstitial cystitis. While these diagnoses do not correlate 100% with trauma, PTSD has a high prevalence in these patients.59 Central sensitization is also associated with cognitive deficits, such as poor concentration and poor short-term memory and corresponds with increased levels of emotional distress, particularly anxiety.60-63

Trauma Informed Care

Trauma informed care is an approach that acknowledges the hallmarks of PTSD and provides a framework for treatment of these patients. It is based on 6 key principles64: 1. Safety 2. Trustworthiness and transparency 3. Peer support 4. Collaboration and mutuality 5. Empowerment and choice 6. Knowledge of cultural, historical, and gender issues Opportunities to improve the patient experience and effectiveness of visits can improve as these principles are applied. Patient interactions can either improve or worsen clinician-patient relationships; therefore, in working with patients with known PTSD, it behooves clinicians to become familiarized with these concepts.

The Examination

The Office Experience

For a PTSD patient, the physical surroundings of an office can create a sense of calm or chaos. Wall color, reading choices, and art affect the overall impression. Blue on office walls has been shown to promote a calming effect and to increase patient perception that their interaction is positive and professional.65,66 Negative self-criticism may worsen for a patient confronted by waiting room magazines highlighting glamour and unrealistic physical and lifestyle goals.67 An office TV may be used to highlight medical information or distract from wait times; however, it can also raise the ambient level of sound and increase the sense of chaos and anxiety around medical visits, triggering those with PTSD. Therefore, paying attention to the overall sound/volume of the office environment can work to create a sense of calm for those who might be triggered.68 Hanging diplomas and important official notices can seem educational but may serve to illustrate that patients are in a medical environment and may produce memories of ED visits, hospitalizations, or other medical visits. Many patients with PTSD have reported negative experiences with the medical profession and it is possible that these diplomas or notices can lead to a negative perception of the visit.69,70 Some studies indicate a role for “fragrancing” in enhancing the office interaction. Fragrances may positively affect patients’ mood and mental clarity.71 However, be aware that some patients have negative associations with smells or have hypersensitivities. The office visit may be one of the few times that the patient gets treated with kindness and respect. They may present in a pain flare; have life stressors; or may be dealing with nonpain health issues as well as underlying anxiety and wariness in medical settings. Presenting this way can create challenges to the staff-patient and clinician-patient, interaction. For this reason, staff involvement and training are crucial to implementing changes to maximize the success of the visit and avoid negative interactions. The staff have important roles in creating safety and openness, treating patients respectfully, and letting them know their conversations and concerns are heard. If patients are interrupted while talking, if staff members have an edgy demeanor, or do not pay attention while engaging with patients, the medical encounter can be sabotaged.72 Lastly, although this section has focused on staff interactions, the same principles can apply to the clinician interaction.73-75

Given the high prevalence of PTSD in chronic pain patients, clinicians should take a trauma history to assess for the presence and severity of symptoms. In approaching this subject, it may help to elicit whether trauma occurred, without having the patient provide specifics, keeping in mind that we don’t want to re-traumatize the patient by their recollection. Patients with PTSD may not recognize their own traumatic experiences due to normalization of those events and consequently may not report significant events. The clinician may need to ask pointed questions about alcoholism, divorce, depression, suicide, fighting, any military service, and other potential causes of trauma.4,76 Perform a mental health history to ascertain any depression, anxiety, ADHD, or hypervigilance. Ask for a medical history, including substance misuse/abuse, but be clear that a history of trauma does not mean the patient is not entitled to pain management. Look for diagnoses that are consistent with central sensitization syndrome, as it may guide treatment.77 Patients with PTSD may associate touch with trauma and can have increased kinesthetic sensitivity. Many pain complaints occur in the low back and pelvis; therefore, it is advisable on initial visits to avoid any physical examination requiring touch. When examining for pain generators to determine a precise diagnosis, start by asking the patient if he/she has any issues with touch, or if there are areas that should be avoided. Explain what/where you are planning to examine and why it is necessary. Always consider using a chaperone for any sensitive examinations or those that involve disrobing but include the patient in the discussion of who they feel safe with. It is advised that you limit the examination to minimize contact. The initial consultation is not the time to do your full physical, and any sensitive areas are best avoided until you have established a good rapport with the patient.78 The clinician should also evaluate for physiological arousal—tremor, sweating, agitation, etc—or signs of previous traumatic injury and head injury as part of a PTSD evaluation.78,79 Prosody is associated with safety and social engagement. It has already been noted that loud, deep resonant sounds can trigger PTSD symptoms and are to be avoided. When clinicians are stressed, irritated, or angry (regardless of the source or direction of the anger), prosody decreases along with increased volume and/or deeper vocalizations. By maintaining awareness, clinicians can monitor themselves and should avoid using potentially threatening tones that might trigger the patient and deteriorate the clinical relationship. Maintain good eye contact but avoid a confrontational demeanor. Clinicians can try to think pleasant thoughts/ideas that will then be reflected in both facial muscles and voice.80,81

Eye Movement Desensitization and Reprocessing

Exercise

Exercise has been shown to have many health benefits in a variety of disease states. It improves stress capacity, has an overall positive effect on mood, and can produce analgesia.82 Many studies have demonstrated increased activation of descending pain pathways and increased serotonin levels, and other neuroendocrine effects that result in less pain. Although the full extent of the mechanisms responsible are not clear, the consensus is that therapeutic exercise is usually a safe and effective way to improve pain scores in patients.82 In PTSD, exercise has demonstrated improved active coping and resumption of activities with a shift of patient focus on abilities, creating a positive affective experience, improved quality of life, increased determination, a sense of accomplishment, and improved social well-being.83 It should be noted that some studies have shown fibromyalgia patients reporting more pain with exercise, but studies conflict and some show positive benefits.84-87 Clinicians should provide consistent encouragement along with tailored exercise prescriptions to patients. It is recommended that patients start slowly and increase gradually. Consistency and goal setting are emphasized.88,89

Behavioral Interventions

Many behavioral interventions have demonstrated improvement in the mental health of patients with PTSD and chronic pain; some have lowered pain scores and raised quality of life scores. Behavioral interventions include cognitive behavioral therapy (CBT), acceptance and commitment therapy (ACT), and mindfulness-based treatment. Meta-analysis and other studies, however, present conflicting results.90-92 Despite conflicting studies, a plethora of anecdotal data and enough clinical studies support the use of these interventions, which can be invaluable to help the patient learn to regulate, thereby improving pain scores. In clinical medicine, chronic pain patients often report having “already done counseling” and deny that it helped their pain. It is useful to explore what form of counseling they did and emphasize that other evidence-based treatments can produce different results. Also discuss the possibility that, as their lives enter different stages, patients might achieve different results and that it may still be beneficial to explore interventions.93,94

Eye movement desensitization and reprocessing (EMDR) has been used to treat trauma symptoms and PTSD for many years with good evidence for both safety and effectiveness, although the mechanism is not fully understood. The use of EMDR for treatment of symptoms of chronic pain is newer, but studies show efficacy. The mechanism of action is largely unknown, but it is both safe and effective.95-97

Emotional Freedom Technique

The emotional freedom technique, which involves tapping near energy meridians to reduce tension and increase the mind-body connection, has been used to treat anxiety, PTSD, and pain. Small trials have demonstrated clinical improvement in patients, but the mechanism is not well established.98-100

Hypnosis

Hypnosis is used to treat many conditions, inclusive of chronic pain, PTSD, insomnia, anxiety, and smoking cessation. Although clinical trials tend towards smaller studies, evidence demonstrates clinical efficacy and safety. Given the long-standing use of hypnosis and its known safety, it can be a powerful adjunct to a comprehensive treatment plan.101-104

Osteopathic Manipulation Therapy

Osteopathic manipulation along with other physical medicine modalities can be effective tools for change. There are several possible mechanisms to explain how physical manipulation: ● Acts to decrease mechanical dysfunctions ● Releases articular and soft tissue restrictions ● Improves range of motion ● Improves blood flow ● Increased lymphatic drainage All the above result in a decrease in allostatic load, in turn reducing the overall nociceptive input from the musculoskeletal system to the central nervous system and can improve outcomes. There can be both local body regional improvement along with global improvement in functioning. Improved outcomes have been demonstrated in many different pain syndromes, from cervical dysfunction to pelvic pain and of course low back pain, and can decrease the need for medications.105-111

Cigarette Smoking and Pain

There is a high co-occurrence rate of smoking and mental health issues, but it is not known whether this is causation or correlation. It is known that cigarette smoking affects pain and mood. Cigarette smoking is involved in the transition from acute to chronic pain, and chronic pain in smokers is significantly worse compared to matched nonsmokers.112 Additionally, greater functional impairments are present in smokers compared with nonsmokers.113,114 Due to the short half-life of nicotine, smokers can experience withdrawal characterized by increased anxiety and negative affect. They may attribute the relief of these symptoms to smoking, which can stimulate reward pathways.115 Also, many chronic pain patients utilize smoking as a coping strategy, which is reinforced with continued use.116 Smoking cessation has been demonstrated to improve pain and depressive symptoms, improve mood and overall health. It is important to address cessation with patients. By using techniques of motivational interviewing and the principles of trauma informed care, clinicians can partner with patients to work on change behavior by emphasizing pain reduction.64,117-119

Conclusion

Trauma is caused by unpleasant inescapable events that overwhelm an individual emotionally and leads to an altered perception of themselves, others, and the world. PTSD manifests behavioral and health changes, with a high prevalence of chronic pain. Chronic pain can be a debilitating condition and is associated with decreased life expectancy and quality of life. Trauma informed care is a set of principles designed to better suit patients with PTSD. Because medical visits and procedures can be triggering for patients with PTSD, clinicians who utilize these principles may transform the medical office experience and decrease avoidance and negative associations with the visit. These principles promote clinician-patient trust, foster effective communication, and potentially decrease the no show rate of these patients. Many interventions are effective tools for positive patient change (exercise, mental health interventions, physical interventions, smoking cessation); however, these are only effective when there is patient engagement and â&#x20AC;&#x153;buy-in.â&#x20AC;? By partnering with patients and sharing decision making, clinicians have an opportunity to affect meaningful change.â&#x20AC;&#x201A; Go to https://pain.sh/KaufmanPWJ for the reference list.

By Derek Chung MS / Mayank Gupta MD

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providers navigate the treatment of acute and chronic low back pain amongst the societal and regulatory efforts to reduce the burden of opioids, many are turning to anticonvulsant medications like gabapentin and pregabalin as safe and effective alternatives. These agents are approved only for the treatment of certain neuropathic pain conditions and fibromyalgia. Evidence to support their off-label use in low back pain remains minimal. Further, their growing popularity, coupled with adverse effects, warrants discussion.

The IQVIA Institute for Human Data Science released its annual report Medicine Use and Spending in the U.S. in May 2019 which showed gabapentin as the 6th most prescribed medication in 2018 at 67 million dispensed prescriptions, up from 64 million in 2017.1 Shockingly it is estimated that 95% of gabapentin is being prescribed off-label for conditions such as depression, anxiety disorders, migraines, and low back pain.2 Likewise, Lyrica (pregabalin) was ranked the 6th highest prescription drug in nondiscounted spending in the US in 2018 at 5.2 billion dollars.1 Although information for the use of off-label pregabalin is limited, we can assume that, with the recent FDA approval of the generic, we will likely see 42

an increase in off-label use as it becomes more accessible. An Australian study investigated the prescribing behaviors of general practitioners treating spinal pain, including back pain with or without radiculopathy and excluding serious pathologies like fractures or infections. Prescribing patterns from 9,100 general practitioners over a 10-year span were analyzed. In the unadjusted data from 2004 to 2005, 12 per 1,000 spinal pain problems were treated with neuropathic pain medications. Between 2013 and 2014, that number rose to 76 per 1,000. After accounting for patient and general practitioner data, researchers found a yearly relative increase of 19% in the use of neuropathic pain medications during this period.3

EVIDENCE FOR OTHER AGENTS The CDC Guideline for Prescribing Opioids for Chronic Pain released in 2016 recommends initiating nonpharmacologic and nonopioid pharmacologic therapy as preferred modalities, and included anticonvulsants as an example.4 In the guidelineâ&#x20AC;&#x2122;s contextual evidence review section, the authors note that multiple guidelines recommend NSAIDs as first-line treatment for low back pain, and anticonvulsants, tricyclic antidepressants, and serotonin norepinephrine reuptake inhibitors as first- and second-line drugs for neuropathic pain.4 A vital issue in this discussion is the extrapolation of anticonvulsant use in diabetic and postherpetic neuropathies to radiculopathies in the literature. The fact that anticonvulsants helped in diabetic neuropathic pain does not necessarily mean they will help in radicular pain; the conditions have different etiologies and pathophysiologies. There are no significant clinical data showing efficacy. A systematic review looked at the efficacy of pharmacologic interventions on painful diabetic neuropathy. Investigators included 16 studies with direct comparisons of anticonvulsant medications to placebo. The analysis found a statistically significant decrease in pain within 3 months with a standardized mean difference (SMD) of -0.67 on a continuous pain scale.5 The study of analgesic effects >3 months still showed a statistically significant reduction of pain, although to a lesser degree and with a smaller pool of data.5 A systematic review looked at the efficacy of drug therapies for the treatment of postherpetic neuralgia (PHN). It included 12 randomized controlled trials, 2 for gabapentin, and 3 for pregabalin. Investigators measured the difference in the percent of pain reduction compared to placebo and found gabapentin and pregabalin provided a 21.9% and 22.4% reduction in pain, respectively.6 This review also found divalproex sodium to offer a 38.7% reduction in pain, although the data originated from only one included study.6 A similar meta-analysis focused on the efficacy of gabapentin for PHN, which included 9 additional randomized controlled trials and found parallel results of significant reduction of pain when compared to placebo.7 With significant findings showing efficacy in treating these neuropathic conditions, it is understandable why clinicians would consider anticonvulsants for low back pain, reflecting its commonly mixed features. Neuropathic pain is a sharp, shooting pain down the leg possibly due to neural compression (ie, stenosis from disc bulge), vascular compromise, or localized inflammation. Nociceptive pain is a deep ache that can be poorly localized, perhaps attributed to facet arthropathy or internal disc disruption. Additionally, when systematic reviews like a 2015 publication in Lancet Neurology provide 43

pharmacotherapy data and recommendations for neuropathic pain in aggregate, it can be easy to infer anticonvulsants as viable options for low back pain.8 This systematic review included 229 trials, with 55% of those conducted in diabetic polyneuropathy or PHN.8 Investigators also included radiculopathy as long as the primary outcomes measured were related to neuropathic pain.8 Analysis showed a NNT (number needed to treat) for varying degrees of pain reduction of 8 for pregabalin, 7 for gabapentin, and 9 for the extended release forms of gabapentin/enacarbil.8 These NNT values are of particular clinical significance and ultimately contribute to the designation of these drugs as first-line agents for neuropathic pain.

FALLING SHORT: Reviewing the Evidence Alas, there is moderate to high quality evidence that anticonvulsants are ineffective for the treatment of low back pain and radicular pain, as reported in a systematic review.9 In contrast to previous reviews on this topic, this study included only randomized trials that compared medication (gabapentin, pregabalin, and topiramate) to placebo. It also excluded trials that compared the efficacy of 2 active drugs (ie, tricyclic antidepressants vs pregabalin) in hopes of more accurately isolating a signal of efficacy if only one is present. Investigators found 9 eligible trials looking at the outcomes of pain and disability, one of which included a 2017 study not incorporated into the analysis of preceding systematic reviews.10 Two trials included in this systematic review compared topiramate to placebo. The first clinical trial compared topiramate to the active placebo diphenhydramine for lumbar radicular pain. Although this study found a mean reduction of leg pain by 19%, because of a high dropout rate the study authors advised against the use of topiramate unless future studies provided a better therapeutic ratio.11 Reviewers determined there was no treatment effect favoring topiramate for pain or disability.5 The second trial comparing topiramate to placebo also reported significant pain relief for which reviewers determined that treatment effect favored topiramate for pain in the short term.8,12 Interestingly, this topiramate study also measured the bodyweight of the 48 participants in the treatment group before and after the 10-week trial, weight loss being a known side effect of topiramate. Investigators reported an average weight loss of 6.5 kg (14.3 lbs), which may have been responsible for some of the reported improvement in pain.12 Commonly reported adverse effects in the topiramate trials included paresthesias,

As our knowledge of the risk of anticonvulsant drugs evolves, we must stay vigilant to the trends of these interventions… sedation, and diarrhea. Notably, case reports show acute angle closure glaucoma as a serious but rare occurrence.13 Further, topiramate has known carbonic anhydrase properties, which can lead to kidney stone formation.14 Of the 7 trials investigating gabapentinoids, 3 looked at the reduction of pain and disability in patients with chronic low back pain with or without radiating leg pain. Analysis of the pooled data showed no effect on pain in the short (2 weeks to 3 months) or intermediate term (3 months to 1 year) and no effect on disability in the short term.9 The remaining 4 trials investigated gabapentinoids in patients with lumbar radicular pain specifically. Similarly, analysis of the pooled data showed no effect on pain in the intermediate or long term (>1 year), with analysis showing no effect on disability at all time points.9 Along with data from the topiramate studies, the results from the aggregated 859 unique participants revealed a lack of treatment efficacy of anticonvulsants accompanied by an increased risk of adverse events from the use of gabapentinoids for which the level of evidence is high.9 For example, looking at the Atkinson et al study published in 2016, 55 participants were in the gabapentin group and 53 were in the placebo. The following

are the number of gabapentin group participants reporting notable side effects vs placebo15: ● Fatigue (27/15) ● Orthostatic dizziness (24/14) ● Concentration difficulties (21/6) ● Accommodation disturbance (19/3) ● Loss of balance (18/2) The Mathieson et al study published in 2017 had 106 patients in the pregabalin group and 101 in the placebo.10 Again, the following are the number of pregabalin group participants reporting notable side effects vs placebo: ● Dizziness (42/13) ● Confusion (2/0) ● Somnolence (5/2) ● Peripheral edema (5/2) ● Vision changes (2/0) Overall, the most common adverse events reported by participants taking gabapentinoids in aggregate were drowsiness or somnolence, dizziness, and nausea.9,10

ROUNDING OUT THE PICTURE Additionally, published case studies endorse the adverse effect profiles of these drugs and can give context to the discussion of risk. A 2009 publication involved a 38-year-old physician who experienced toxic delirium when taking higher doses of gabapentin than prescribed, along with buspirone and bupropion for depression and anxiety. The authors also described a prolonged post-withdrawal confusion state akin to benzodiazepine withdrawal.16 Another case report, published in 2012, involved a 44-year-old woman being treated with pregabalin for lumbar radiculopathy. This patient started at 150 mg per day, and received a dose increase to 300 mg after 1 week of no pain relief. On the third day of treatment with 300 mg, the patient developed visual hallucinations, psychosis, irritability, and what was described as an “acute confused state.” 24 hours after discontinuing the medication her symptoms resolved.17 Common adverse effects may be innocuous on their own, but with many patients being prescribed multiple prescriptions from different providers, the combined central nervous system effects merit proper stewardship. Further, there are concerns regarding the abuse potential of these drugs. A case series published in 2019 reviewed 104 cases in which the decedents tested positive for gabapentin postmortem. Investigators reported that in 47.1% of these cases, gabapentin was directly involved in deaths, with most having other intoxicants present, such as opioids, anxiolytics, and antidepressants.18 Of those who died of gabapentin-related drug deaths, 91.4% obtained gabapentin legitimately, with 84.2% having a history of abuse of prescription medications.10 Similarly, a population-based cohort study in Sweden published in 2019 found an increased risk of suicidal behavior, unintentional overdoses, head/body injuries, and traffic incidents in those who filled a gabapentinoid prescription within the 7-year data window.19 This study found that pregabalin was associated with a higher risk of these outcomes compared to gabapentin.19 Although these epidemiologic studies are compelling, we must temper our understanding with the reality of the nascency of the research.

CONCLUSION

low back pain. But when keeping in mind the lack of efficacy, we as providers should more strongly voice the potential harms of medications. In the CDC Guideline, it is recommended that clinicians consider the risk of falls when prescribing potentially sedating medication like tricyclic antidepressants, anticonvulsants, or opioids.4 Further, they also strongly caution the combination of benzodiazepines and opioids for obvious reasons.4 In light of recent evidence, we believe a strong word of caution should be attached to anticonvulsants as well. The ubiquity of low back pain causes pain management to fall on the shoulders (or more appropriately backs) of providers in various specialties, and the need for evidence-based medicine is particularly pronounced. We hope this article echoes the sentiments of Dr. Christopher Goodman and Dr. Allen Brett who voiced in New England Journal of Medicine in 2017 that patients may benefit from a therapeutic trial of gabapentin or pregabalin for off-label indications but that we should not accept that they work for all pain syndromes or are always appropriate substitutes for opioids.20

References 1. Medicine Use and Spending in the U.S. IQVIA – A review of 2018 and outlook to 2023. May 2019. Available at: www.iqvia.com/insights/the-iqvia-institute/reports/ medicine-use-and-spending-in-the-us-a-review-of-2018-and-outlook-to-2023. 2. Peckham AM, Evoy KE, Ochs L, et al. Gabapentin for off-label use: evidence-based or cause for concern? Subst Abuse. 2018;12:117822181880131. 3. Mathieson S, Valenti L, Maher CG, et al. Worsening trends in analgesics recommended for spinal pain in primary care. Eur Spine J. 2017;27(5):1136–1145. 4. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. JAMA. 2016;315(15):1624–1645. 5. Griebeler ML, Morey-Vargas OL, Brito JP, et al. Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med. 2014;161:639–649. 6. Edelsberg JS, Lord C, Oster G. Systematic review and meta-analysis of efficacy, safety, and tolerability data from randomized controlled trials of drugs used to treat postherpetic neuralgia. Ann Pharmacother. 2011;45(12):1483–1490. 7. Zhang M, Gao C-X, Ma K-T, et al. A meta-analysis of therapeutic efficacy and safety of gabapentin in the treatment of postherpetic neuralgia from randomized controlled trials. BioMed Res Int. 2018;2018:1–10. 8. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173. 9. Enke O, New HA, New CH, et al. Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis. CMAJ. 2018;190(26):E786-E793.

As our knowledge of the risk of anticonvul-

sant drugs evolves, we must stay vigilant to the trends of these interventions, especially with the widely accepted use of gabapentinoids. In the wake of the opioid epidemic, it may seem trivial to pursue criticism of one of the few drug alternatives that may provide relief to patients with

10. Mathieson S, Maher CG, McLachlan AJ, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med. 2017;376:1111–1120. 11. Khoromi S, Patsalides A, Parada S, et al. Topiramate in chronic lumbar radicular pain. J Pain. 2005;6(12):829–836. 12. Muehlbacher M, Nickel MK, Kettler C, et al. Topiramate in treatment of patients with chronic low back pain. Clin J Pain. 2006;22(6):526–531.

13. Craig JE, Ong TJ, Louis DL, et al. Mechanism of topiramate-induced acute-onset myopia and angle closure glaucoma. Am J Ophthalmol. 2004;137(1):193–195. 14. Daudon M, Frochot V, Bazin D, et al. Drug-induced kidney stones and crystalline nephropathy: pathophysiology, prevention and treatment. Drugs. 2017;78(2):163–201. 15. Atkinson JH, Slater MA, Capparelli EV, et al. A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component. Pain. 2016;157(7):1499–1507. 16. Kruszewski SP, Paczynski RP, Kahn DA. Gabapentin-induced delirium and dependence. J Psychiatr Pract. 2009;15(4):314–319. 17. Pedroso JL, Nakama GY, Filho MC, et al. Delirium, psychosis, and visual hallucinations induced by pregabalin. Arq Neuropsiquiatr. 2012;70(12): 960–961. 18. Tharp AM, Hobron K, Wright T. Gabapentin‐related deaths: patterns of abuse and postmortem levels. J Forensic Sci. 2019;64(4):1105–1111. 19. Molero Y, Larsson H, D’Onofrio BM, et al. Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden. BMJ. 2019;365(2147). 20. Goodman CW, Brett AS. Gabapentin and pregabalin for pain— is increased prescribing a cause for concern? N Engl J Med. 2017;377(5):411-414.

Education is the best analgesic. www.painweek.org

By James Fricton DDS, MS/Ginevra Liptan MD

key topic

infection with COVID-19 has forced a rapid transition into telehealth for many healthcare providers, including those treating pain conditions. Although the technology to provide remote healthcare is not new, it had not been widely adopted due to barriers with insurance reimbursement, privacy concerns, logistical challenges with how to involve staff in appointments, and plain old provider stubbornness. But the need for physical distancing during the pandemic has forced the hand of insurers and reluctant providers, and we are all now doing a deep dive into telehealth. Particularly for providers treating chronic pain, the ability to treat patients remotely is vital during this time of increased stress and anxiety. We know that stress causes an increase in the severity of pain conditions, and by continuing to care for our patients remotely we can help them avoid going to emergency rooms or other health professionals to deal with their pain. We also know that patient engagement and training to support self-care for pain conditions improves outcomes and reduces healthcare utilization. Whether you were an early adopter of telehealth services or have been recently forced to start, there are important strategies and services you can use to provide the best possible teleheath care for your pain patients. You may find that you like it so much you continue to offer these services even after the necessity has been lifted. Although a virtual physical exam will never be the same as an in-person exam, video visits can give a unique window into a patient’s home life, their joys (“Hello, curious feline friend!”), and their stressors that can help you provide better and more holistic care.

Telehealth Services Telehealth is defined as the utilization of electronic information and telecommunications technology to support and promote long-distance clinical healthcare, patient and professional health education, public health, and health administration.1-8 The World Health Organization (WHO) defines telemedicine as the remote delivery of healthcare through the use of telecommunications technology and information technologies to provide remote clinical services to patients including digital imaging, video consultations, patient education, and remote monitoring. Common types of telemedicine include:

1 Interactive telemedicine: patients and physicians can communicate in real-time while maintaining HIPAA (Health Insurance Portability and Accountability Act) compliance 2 Telehealth care programs: providers can support self-care training and coaching of patients to extend care into the daily lives of patients

3 Remote patient monitoring: providers can monitor patients who reside at home by using mobile medical devices and assessments to collect data on sleep habits, pain, blood sugar, blood pressure, etc Telemedicine consists of not only audio communication, but also video, which allows the healthcare provider to closely match in-person health professional and patient encounters including virtual examinations. As stated, modes of communication used by healthcare providers to interact with patients need to comply with HIPAA regulations and allow for verification of an individual’s transmitting and receiving information. With use of telehealth technologies, it is important to implement the policies and procedures that will safeguard privacy, integrity, and quality of the care provided to patients, as described below. It is also important that telehealth providers supply information prior to the visit and then get feedback from their patients regarding what they expect during these encounters and the aspects of telehealth in which they wish to participate.

Telehealth Benefits Providers and Patients Health professionals are using telemedicine to improve access to care, improve efficiency of care, monitor patients in real-time, and provide self-care support. Ultimately, this leads to better long-term patient outcomes. Providers also have increased revenue with telehealth through reimbursement for telehealth visits, telehealth care programs, risk assessment, and telehealth coaching without the need to hire more staff or increase office space. Telemedicine can also benefit patients by improving their access to healthcare services without having to leave their home. The spread of infections, such as COVID-19, is reduced because patients with contagious diseases can’t expose others in crowded waiting rooms. With telemedicine consultations, patients can avoid spending money on gas or wasting time in traffic. They can schedule a consultation during a work break or after work hours and minimize any difficulty finding childcare for an in-person visit.

Health Plan Coverage for Telehealth Many health plans have expanded coverage of telehealth services to respond to the current public health emergency. These services enlarge the current telehealth covered services, to help patients have access from more places (including the patient’s home), with a wider range of communication tools (including smartphones), to interact with a range of providers, such as doctors, nurse

practitioners, clinical psychologists, telehealth coaches, and licensed clinical social workers. Healthcare payers also benefit: patients with pain and substance abuse disorders can be managed effectively with telehealth strategies. The use of these self-care strategies plus telehealth coaching can help the patient implement self-management, instead of relying solely on in-clinic costly treatments. Patients can manage pain flare-ups easier. The cost per treatment of telehealth is cheaper overall and offers cost savings across the board.

Interactive Telemedicine Policies and Procedures Each health professional needs to follow the Federation of State Medical Boards guidelines for the practice of telemedicine to ensure that it meets standards consistent with the current practice of healthcare. The telehealth visit needs to follow standards consistent with an in-person visit as regulated by all state licensures. These include the following guidelines. Informed consent, disclosures, and functionality of online services. State requirements for obtaining informed consent to practice telemedicine vary. All health professionals should obtain informed consent for using telemedicine technologies, such as videoconferencing, e-visits, or text-messaging. Establishment of the health professional and patient relationship. This relationship is a keystone of care and is more challenging with a telemedicine visit; it’s the basis for treatment plans, enhancing self-care and treatment compliance, encouraging patient activation, supporting shared decision making, and encouraging long-term healing. Evaluation and treatment. The standard of care for practicing telemedicine is the same as that of traditional healthcare. All evaluations, consultation, and prescribed treatment are thoroughly documented in the patient’s electronic health record. The following are steps to help our patients gain access to care for pain conditions. ● Continuity of care. Follow-up care should be readily available to patients, either from the health professional conducting telemedicine or a provider designated by the health professional such as a telehealth coach or treatment coordinator. If the patient and health professional encounters are done exclusively using telemedicine, then all documentation must be accessible to the patient consistent with in-person visits. Patients may also request that the information be provided to their other healthcare providers. ● Self-care support. With pain conditions, reducing risk factors such as repetitive strain, tensing posture, stressors, and emotion issues can be helpful and reinforced via telemedicine visit. The use of

telehealth-based coaching with a patient engagement platform such as www.pactforpain.com can be helpful to support robust self-management care. ● Referrals for emergency services. An emergency plan should be implemented when the information obtained (via telemedicine) indicates that the patient requires referral. The health professional will provide the patient with an emergency plan and include a formal, written protocol in the electronic medical records that is appropriate to the services being rendered via telemedicine. ● Medical record documentation. The medical records for telemedicine are consistent with standards required for documentation in traditional in-person care. Medical records for telemedicine include copies of all patient related electronic communications, laboratory tests and results, evaluations and consultations, prescriptions, records of past care, and any instructions produced in connection with telemedicine. ● Privacy and security in exchange of information. All applicable federal and state legal requirements for the privacy and security of medical records and health information exchange need to be met or exceeded. This includes compliance with HIPAA, HITECH (Health Information Technology for Economic and Clinical Health), and state privacy, security, confidentiality, and medical record retention rules and laws. All data transmitted by healthcare providers electronically (audio, video, written, etc) should be sent via use of encryption that meets current standards. Devices used to transmit protected health information should have up-to-date security software to guard against cyber attacks. ● Prescribing medications. When prescribing via telemedicine, we take all precautions needed to ensure patient safety in the absence of a traditional physical examination including informed, accurate, and error prevention practices. Medications prescribed using telemedicine technologies include only those the patient is currently on or that are considered safe to prescribe by the medical or dental board. In addition, any medications prescribed are done at the discretion of the health professional. Medications that require close monitoring or may lead to side effects in a patient’s condition are not recommended, particularly if the patient is not near a health facility or healthcare provider.

and ChironHealth. The patients who have participated in telemedicine visits in the authors’ clinics have found most telemedicine platform easy to use. They have been very appreciative for the continued care for their pain condition. Staff have also found the process to be easy to use. These secure audio-video platforms are designed for telemedicine visits and include at the least the following components: ● Automated emails to patients with links to the platform ● Pre-call testing of audio and video ● A virtual waiting room for the patient until the health provider connects. This should include the ability for the practitioner to triage patients ● Sharing of screens for handouts ● Meeting history ● A simple to use (for both staff and patients) help center and secure messaging ● Documentation of consent and billing in electronic health records

Telehealth Care Programs Providers can also use telehealth to support self-care training and telehealth coaching to extend care into the daily lives of patients. Telehealth services can employ a patient engagement platform (PEP) to provide care programs that include an array of telehealth services including: ● Pain, health, and risk assessment ● Patient training to reduce risk factors that contribute to a pain condition, such as repetitive and postural strain, through 5 to 10 minute online microlessons ● Telehealth coaching with audio-video platforms ● Remote telehealth monitoring with tracking outcomes ● Patient-centered dashboard to monitor patient engagement and outcomes ● Chronic care management

Interactive Telemedicine Platforms With both new patient consultations and established patients, telemedicine visits require the use of a secure audio-video platform such as Doxy.me, eVisit,

Personalized Activated Care and Training (PACT™) at www.pactforpain.com is a PEP that was developed and tested to support health professionals in implementing patient-centered training for telehealth services in preventing chronic pain and addiction and help address the opioid crisis.9-11 PACT is a service that is typically reimbursed by health plans to prevent chronic pain and addiction by engaging patients in self-management. PACT extends the healthcare professionals’ treatments into the patient’s daily life to shift to a more transformative solution where patient engagement is paramount and self-management training is smoothly integrated with treatment to improve

“Telemedicine…allows the healthcare provider to closely match in-person, health professional and patient encounters including virtual examinations.”

long-term outcomes of pain conditions. PEP is accessible by any online device and includes integration with preventive medicine counseling with the patient’s health professional and a family and friend support network. It addresses the whole person, engaging animated characters, interactive content, simple but powerful action plans, outcomes and engagement dashboard, reminders, and written handouts. PACT supports coordinated, patient-focused, long-term outcomes that will ● Relieve patient’s pain condition by self-management training to supplement treatments and reduce the causes of pain ● Offer preventive self-care and wellness oriented strategies ● Expand access to risk assessment, reduction training, telehealth coaching, and remote monitoring through technology and telemedicine ● Reduce or eliminate unnecessary diagnostic testing, ongoing medications, higher risk interventions, and emergency room visits ● Generate additional significant revenue because it is reimbursed by most health plans to prevent chronic pain and address the opioid crisis ● Provide reimbursable services including pain and risk assessment, risk reduction training, preventive medicine counseling, and remote monitoring of patient outcomes

Telehealth coaching. Telehealth coaching is a relationship-centered, client-driven process designed to facilitate and empower a client to achieve self-determined goals related to health and overall well-being. While client goals may be informed or suggested by others, such as an individual’s physician or other health provider, the selection of the goal and exploration of where one is in relation to the goal is up to the client. Telehealth coaching is an integral part of PACT; coaches are nationally certified health professionals who are well-trained to review risk assessments and provide training to patients with pain conditions to facilitate their knowledge and skills necessary for self-management. The process incorporates the needs, goals, and life experiences of the patients and is guided by evidence-based interventions for the target condition. Systematic reviews of social support and health coaching show they improve functional recovery from chronic pain.12,13 Steps for providing a telehealth visit. Patients can receive a specific set of services through telehealth including evaluation and management visits (common office visits), mental health counseling, preventive medicine counseling, and screenings. These sources will help ensure that patients are able to visit with their doctor from their home, without having to go to a doctor’s office or hospital, which puts them and others at risk of exposure to COVID-19. Here are the steps for providers to conduct and bill for a telehealth visit that have been used in our clinics.14

Scheduling. Front desk staff schedules new patients or converts existing appointments to a telehealth visit due to the COVID-19 crisis. The staff tells all patients that, although we would like to see them in person, all visits will be done through a telemedicine platform until the “emergency only” order is lifted. Emergencies that require an in-clinic assessment will be determined and at the discretion of the treating provider after a telemedicine visit. Prior to visit. Staff will email patients the morning of the visit to confirm and consent to the visit and send them the link to the telemedicine platform waiting room. This email can include any forms to be reviewed at the time of visit, including diagrams, diagnosis, and a treatment planning form previously sent out as part of PACT orientation. A half hour before the visit, the staff will complete check-ins and intake with the patients. Clinicians can then review the intake prior to the visit. Visit with patient. At the time of the visit, the clinician clicks “start” to begin the visit with the patient from the virtual waiting room of the telemedicine platform being used. ● The provider completes a history and conducts a provider assisted self-examination via telemedicine platform. ● Ask the patients to review symptoms and any changes. Ask about self-care and treatment efficacy. Ask about barriers to recovery and reasons for improvement (what works?) or flare-ups (what made it worse?). ● The clinician can then review the tentative diagnoses, treatment plan, risk assessment, and immediate self-care. ● Enroll them in the telehealth self-care program at www.pactforpain.com if the patient is interested and willing. Forms are available online. ● If they need medications short term, a prescription can be sent electronically if the clinician is comfortable doing so.

● Bill using appropriately timed office visit with a 95 modifier for telehealth. ● If telehealth preventive medicine counseling with self-care support (CPT 99401 to 99404) is provided in addition to the office visit, document the same diagnosis codes from previous visits for the office visit and include ICD-code Z13.9 (Screening for Disorders) for use with the preventive medicine CPT codes. When using 2 CPT codes during same visit, a 25 modifier is required.

Summary The practice of telemedicine to improve access to care needs to be consistent with the current standards that exist for traditional healthcare. Telehealth visits are intended to improve the accessibility and delivery of healthcare but, based on inherent limitations, is not expected to replace in-person visits. However, during crises such as COVID-19, health professionals need to make every effort to provide telehealth visits that will follow these quality principles: ● Practices implemented should ensure patient safety ● Communication methods utilized should be secure and effective ● Treatment options recommended should be appropriate, practical, and safe ● Self-care strategies and identification of emergency or urgent care needs should be supported ● Mechanisms that allow for patient feedback should be established ● Strategies should be in place to ensure patient satisfaction

Next steps. All prior authorization for imaging or treatment will be started after the visit. Patients should be scheduled for telemedicine visits with other providers—in physical therapy, health psychology, or medicine/ dentistry—as needed. To our knowledge, each can be reimbursed for telemedicine visits. Documentation and billing. All visits will be documented as usual with the beginning of the note stating that this was a telemedicine visit with patient consent and use of a secure HIPAA compliant audio-video platform. ● Document changes to the chart: history of present illness, review of systems and physical examination findings, assessment, and treatment plan. Templates or macros can be set up for a telehealth document in the electronic health record to facilitate medical documentation.

References: 1. Federation of State Medical Boards. Model Policy for the Appropriate Use of Telemedicine Technologies in the Practice of Medicine. Report of the State Medical Boards’ Appropriate Regulation of Telemedicine (SMART) Workgroup. Available at: www.fsmb.org/Media/Default/PDF/FSMB/Advocacy/FSMB_Telemedicine_Policy.pdf 2. World Health Organization. Global Health Observatory (GHO) data. Analysis of third global survey on eHealth based on the reported data by countries, 2016. Available at: www.who.int/gho/goe/telehealth/en/. 3. American Telemedicine Association. About telemedicine. Available at: legacy. americantelemed.org/main/about/about-telemedicine. 4. American Telemedicine Association. Core Operational Guidelines for Telehealth Services Involving Provider-Patient Interactions. Available at: www.uwyo.edu/wind/_ files/docs/wytn-doc/toolkit-docs/ata_core_provider.pdf. 5. American Telemedicine Association. State Telemedicine Gaps Analysis. Health professional Practice Standards & Licensure. May 2015. Available at: utn.org/ resources/downloads/50-state-telemedicine-gaps-analysis-physician-practice-standards-licensure.pdf.

6. Center for Connected Heath Policy. The National Telehealth Resource Center. State Telehealth Laws and Medicaid Program Policies. A comprehensive scan of the 50 states and district of columbia. March 2016. Available at: www.cchpca. org/telehealth-policy/statetelehealth-laws-and-reimbursement-policies-report. 7. Telehealth Resource Centers. Resource available at: www.telehealthresourcecenter.org/. 8. Center for Connected Health Policy. Resource available at: www.cchpca.org/. 9. Fricton JR, Gupta A, Weisberg MB, et al. Can we prevent chronic pain? Pract Pain Manag. 2015;15(10):1-9. 10. Fricton, J, Clavel A, Weisberg M. Transformative care for chronic pain. PWJâ&#x20AC;&#x201D;PAINWeek Journal. 2016;4(3):44-57. 11. Fricton J, Whitebird R, Vazquez-Benitez G, et al. Transformative self-management for chronic pain utilizing online training and telehealth coaching. Health Care Systems Research Conference; Apr 11, 2018; Minneapolis. 12. Kamper SJ, Apeldoorn AT, Chiarotto A, et al. Multidisciplinary biopsychosocial rehabilitation for chronic low back pain: Cochrane systematic review and meta-analysis. BMJ. 2015;350:h444.

13. Holden J, Davidson M, Oâ&#x20AC;&#x2122;Halloran PD. Health coaching for low back pain: a systematic review of the literature. Int J Clin Pract. 2014 ;68(8):950-962. 14. Minnesota Head and Neck Pain Clinic. Resource available at: mhnpc.com/pain-relief/ telemedicine-expands-healthcare-access/.

By Wayne Jonas MD

a family physician practicing at a military hospital in northern Virginia. I have had the fortunate opportunity to investigate nondrug approaches for pain at the National Institutes of Health and the Uniformed Services University and in my practice while I was in the military. I have learned that by integrating evidencebased complementary approaches and methods to support patients in their own self-care and behavior change, their ability to heal is markedly improved. 58

Every day, we are bombarded

with headlines about “the opioid crisis.” And make no mistake, with opioid-related deaths approaching 50,000 a year in America1 and an estimated 11.5 million people misusing opioids at least once within the past year,2 we indeed face a public health calamity. But I believe, based on my many years of treating chronic pain, that the emphasis on controlling and reducing opioid prescriptions, while important, misses the underlying causes and solutions for this epidemic.

practitioners can become more effective healers if we can learn to ask our patients the right questions, listen more closely to their answers, and guide them more surehandedly on a path to self-care. Let me give you an example with a patient I’ll call Sally. She was an executive with a midsize company, a very hard-charging person, and she was rushing to a meeting when she crashed her car into the vehicle in front of her. It did not appear to be a serious injury, but her back hurt. She was taken to the emergency room for testing and put on nonsteroidal anti-inflammatory drugs and then came to me. I refilled her pain medications and sent her to physical therapy. She began to get better, although not completely.

We don’t just have an opioid problem; we have a much larger problem with how our medical system mismanages the treatment of chronic pain. This is part of an even larger misfocused debate on healthcare reform where we are arguing about who will pay for all the pills and procedures while failing to address the fundamental questions of whether these treatments work for chronic disease and whether we need to concentrate more on behavioral and self-care approaches to healing.

A month later, Sally was picking up her suitcase to go on a business trip and “something popped,” she told me. Her pain was excruciating, and she was unable to stand. Taken back to the ER by ambulance, she was put on opioids. So now she was on nonsteroidals plus opioids and had to endure more physical therapy. Then she had several injections into the painful areas. She was hurting and kept coming back to see me, seeking resolution. She was not a candidate for surgery, yet she was still suffering.

Our healthcare system has failed to embrace the importance of numerous nondrug approaches to managing pain. Encouragingly, a number of major medical organizations have started to make recommendations for increasing the nonpharmaceutical treatment of pain, including the American College of Physicians, the Food and Drug Administration, and the Centers for Disease Control and Prevention.3-5 The Defense Department and the Veterans Administration are among the leaders in promoting an integrative approach to pain, including practices such as therapeutic yoga and massage, biofeedback, mind-body practices, acupuncture, and even battlefield acupuncture, which was covered in a PAINWeek course.

I sent her to a behavioral health specialist who diagnosed her with depression and put her on an additional medication. She was miserable. To top it off, we then recommended that she enter an opioid recovery program, which made her even more miserable. Her take? “Doc, I’m not crazy and I’m not addicted! My back hurts!” After various pain, anti-anxiety, and sleep medications, as well as muscle relaxants, it was clear that pills and procedures were not going to help Sally. Based on a wealth of research and more than 30 years of practice, I have learned that >80% of good health is determined by factors outside my office, including behavioral and lifestyle factors—smoking, alcohol, stress, nutrition, movement, and sleep—as well as larger social and environmental determinants of health in our society.7

Our patients have long known the value of treating pain with these complementary, alternative, and integrative approaches, but we, as healthcare practitioners, haven’t been listening to them or helping them do a better job of managing their own health. Nearly 40% of the US population already uses a variety of alternative approaches for chronic illnesses and prevention.6 From my experience, I believe that

The HOPE approach was developed by me over several years to more easily address the underlying personal determinants of health with my patients. It is now being widely adopted in practices around the country and we have produced resources to help other practitioners implement it. These tools and resources are available free at www.drwaynejonas.com/hope. If you would like to implement such an approach, send me a note through my website and my team will be in contact. Or simply download from my website. I needed to reframe the whole conversation with Sally and focus on factors beyond the walls of my office. I set up an appointment with her for what I call a HOPE visit. As physicians, we were trained to follow a diagnostic SOAP note (subjective, objective, assessment, plan), but over the years, I have developed a supplementary note to assess a patient’s healing-oriented practices and environments, or HOPE (see above). My goal is to reach a deeper understanding of the whole person and how to help that person heal. Instead of asking, “What’s the matter with you?” I am going deeper to ask, “What really matters to you?” I explore with them what factors in their own life they can use to accelerate their recovery. Most of these factors do not involve more medical treatments or changes in medications. In our HOPE visit interview, Sally talked about how she had tried to improve her health. She told me she was taking some supplements, which we hadn’t known about, and had tried yoga, but had injured herself and swore it off. Every morning, she soaked in a hot tub to try to relax. Her sleep was constantly disrupted by her pain, but her pain medications and sleep medications were not helping enough. When I asked about stress, she said, “I don’t have any stress. I used to be stressed when I was working, but now I don’t do anything. I just sit around all day.” She didn’t fully realize how her pain was causing stress and poor sleep and this further perpetuated her pain. When I asked how she was managing her troubles, she told me that she watched TV and had a couple of drinks. “My biggest problem is that I can’t work anymore. I used to be the breadwinner in this family. My husband and my kids used to joke and call me ‘Salary’ instead of ‘Sally.’ When they stopped doing that, I knew I was done.” Armed with a fuller picture of her life, we put together an integrative health team to help Sally find ways to

improve her self-care, rather than have her bounce around to different specialists for different treatments. Our pharmacologist helped her manage her supplements and drugs. Our behaviorist took on a slightly different role; he became her health coach rather than a therapist and helped her find a personal space and process for self-care. She started journaling, which helped her become more aware of how she was influencing her own health and well-being. In addition, we brought in a yoga therapist who was trained in evidence-based techniques specifically for back pain. Within 3 months Sally’s pain had dropped from 5 to 6 out of 10 to a 2 out of 10 on average. In another 3 months she started looking for a job, restoring her valued purpose in life. This is what we call integrative healthcare. On the surface, it doesn’t look much different from what we were doing before, but it is in some ways radically different. It involves a reorientation of how we practice healthcare, integrating the areas of conventional medicine, complementary approaches, and changes in lifestyle. The evidence shows that when patients are engaged in the process of self-care and managing their own healing, they end up healthier, and the cost of care is reduced. We have effective tools to reduce pain, if we look beyond pills and procedures. By reorienting how we talk and listen to our patients, we can empower them to manage their chronic pain. Rather than “delivering treatments” that may or may not help our patients in the long run, we can build a team that guides and supports patients on their self-healing journey. In fact, this is the secret to success: to elicit a meaningful response in the person who requires healing. That’s how healing works.

“In fact, this is the secret to success: to elicit a meaningful response in the person who requires healing. That’s how healing works.” References 1. CDC. Centers for Disease Control and Prevention. Opioid overdose. Drug overdose deaths. June 27, 2019. Available at: www.cdc.gov/drugoverdose/data/statedeaths.html. 2. Center for Behavioral Health Statistics and Quality. Results from the 2017 National Survey on Drug Use and Health: Detailed Tables. Rockville (MD): SAMHSA; 2018. Available at: www.samhsa.gov/data/report/2017-nsduh-detailed-tables. 3. Qaseem A, Wilt TJ, McLean RM, et al, for the Clinical Guidelines Committee of the American College of Physicians. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166:514–530. 4. Statement by FDA Commissioner Scott Gottlieb, MD, on balancing access to appropriate treatment for patients with chronic and end-of-life pain with need to take steps to stem misuse and abuse of opioids. Available at: www.fda.gov/news-events/ press-announcements/statement-fda-commissioner-scott-gottlieb-md-balancingaccess-appropriate-treatment-patients-chronic. 5. CDC Guideline for Prescribing Opioids for Chronic Pain. Washington, DC. Available at: www.cdc.gov/drugoverdose/prescribing/guideline.html. 6. National Center for Complementary and Alternative Medicine, National Institutes of Health, U.S. Dept. of Health and Human Services. The use of complementary and alternative medicine in the United States. 2008. Bethesda, MD. 7. Olson DP, Oldfield BJ, Morales Navarro S. Standardizing social determinants of health assessments. March 18, 2019. Available at: www.healthaffairs.org/do/10.1377/ hblog20190311.823116/full/.

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

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

In the past, it was thought that a sensory input, such as a pinprick, would cause a pain â&#x20AC;&#x153;signalâ&#x20AC;? to be sent directly to the brain via a single nerve. Although still not completely understood today, the science of pain reveals a much more complex process that continues to evolve. New receptors, pathways, and hypotheses are being investigated every day. In addition to identifying new pathways, genetic variations at the receptor level further complicate the treatment process and evaluation of its efficacy. The following is a brief review of basic concepts important to understanding the physiology of pain. The pain pathway

Four steps occur along the pain pathway1: 1 Transduction 2 Transmission 3 Modulation 4 Perception

Transduction is the process by which afferent nerve endings participate in translating noxious stimuli (such as a pinprick) into nociceptive impulses. Silent nociceptors, also involved in transduction, are afferent nerves that do not respond to external stimulation unless inflammatory mediators are present. The peripheral nervous system contains primary sensory afferent neurons that have an important role in pain signaling. The axons of these afferents diverge from the cell body in the dorsal root ganglion near the spinal cord and send a short fiber centrally into the cord and a long fiber down the peripheral nerve into the tissues. Their receptors detect mechanical, thermal, proprioceptive, and chemical stimuli.

There are 3 types of primary afferents: A-beta fibers, A-delta fibers, and C-fibers. A-beta fibers are myelinated, largediameter fibers that respond primarily to light touch and moving stimuli, such as vibration. A-delta fibers (myelinated, small-diameter fibers) and unmyelinated C-fibers respond to noxious (potentially painful) stimuli. Fibers that respond maximally to noxious stimulation are classified as pain fibers, or nociceptors; these are generally A-delta fibers and C-fibers. These nociceptors respond to noxious mechanical, thermal, and chemical stimuli.2 Noxious stimulation is first carried by the faster A-delta fibers and then by the slower C-fibers. Local injury can cause nociceptors to become hypersensitive to noxious stimuli, thereby creating a condition called sensitization, mediated by algogenic (or pain generating) substances in the periphery. A sequence of events occurs after local tissue injury, including local vasodilation, edema, and spreading vasodilation (flare), which is known as the triple response of Lewis. This is accompanied by hyperalgesia (an exaggerated response to painful stimuli) in the injured area

New receptors, pathways, and hypotheses are being investigated every day.

(primary hyperalgesia) and hyperalgesia that spreads beyond the injured area (secondary hyperalgesia).3

Normal Pain Pathways at a Glance Transduction

Transmission is the process by which impulses The process by are sent to the dorsal horn of the spinal cord, which afferent nerve and then along the sensory tracts to the brain. endings participate The primary afferent neurons are active senders in translating noxious and receivers of chemical and electrical signals. stimuli into nociceptive Their axons terminate in the dorsal horn of impulses. the spinal cord, where they have connections Transmission with many spinal neurons. In turn, spinal neu- The process by which rons have inputs from many primary afferents. impulses are sent to These spinal neurons project axons to the con- the dorsal horn of the tralateral thalamus, which in turn projects to spinal cord and then the somatosensory pathway, frontal cortex, along the sensory and other areas. The somatosensory cortex is tracts to the brain. thought to be involved in the sensory aspects Modulation of pain, such as the intensity and quality of pain, The process of whereas the frontal cortex and limbic system dampening or are thought to be involved with the emotional amplifying pain-related neural signals, primarily responses to it. in the dorsal horn of

The major ascending tract is the spinothalamic the spinal cord, but also elsewhere, with tract (STT). Cell bodies of the STT are located input from ascending primarily in lamina V, but also in laminae I, VII, and descending and VIII. These neurons have axons that cross to pathways. the opposite side of the spinal cord and enter its anterolateral quadrant. The STT divides in 2 dif- Perception ferent pathways as it approaches the thalamus. The subjective experience of feeling The neospinothalamic tract, or lateral STT, is the pain that results tract that subserves the sensory/discriminative from the interaction aspects of pain perception. It synapses on the of transduction, lateral thalamus and projects to the somatosen- transmission, sory cortex. The medial STT, or paleospinotha- modulation, and lamic tract, synapses in the brain stem reticular psychological aspects formation, the medial thalamus, periaqueduc- of the individual. tal gray matter, and the hypothalamus, and has subsequent projections to the cortex and limbic system. This tract subserves the affective/motivational aspects of pain perception.3

Modulation is the process of dampening or amplifying these pain-related neural signals. Modulation takes place primarily in the dorsal horn of the spinal cord, but also elsewhere, with input from ascending and descending pathways. Rich arrays of opioid receptors (mu, kappa, and delta) are present in the dorsal horn. In addition to an ascending tract, the nociceptive system contains descending pathways that send neurons from the frontal cortex and hypothalamus to the midbrain and medulla. These neurons inhibit nociceptive neurons and interneurons in the ascending pathway.4 Important centers of this descending antinociceptive modulation system are the periventricular and periaqueductal gray matter, the dorsolateral pons, the nucleus raphe magnus, and the rostroventral medulla. Descending pathways project axons to laminae I, II, and V in the spinal cord. In addition to endogenous opioids, the biogenic amines (serotonin and norepinephrine) are neurotransmitters involved in this process. A variety of modalities can activate the descending antinociceptive pathways, including systemic or neuraxial injection of opioids, electric stimulation, stress, suggestion, and pain.3 The gate control theory is a popular model of pain modulation proposed by Melzack and Wall5 in 1965 and was later revised by Melzack and Casey6 in 1968. These investigators proposed the existence of an endogenous ability to reduce or increase the degree of perceived pain through modulation of incoming impulses at a gate located in the dorsal horn of the spinal cord. The gate acts on signals from the ascending and descending systems and weighs all the inputs. The integration of these inputs from sensory neurons, the segmental spinal cord level, and the brain determines whether the gate will be opened or closed, either increasing

or decreasing the intensity of the ascending pain signal. The importance of psychological variables in the perception of pain, including motivation to escape pain, and the role of thoughts, emotions, and stress reactions in increasing or decreasing painful sensations, is evident in the gate control theory. An example of this is when patients report more pain at night when they are isolated and less distracted from their pain than they might be during the day. The proposed gate can be opened or closed by pharmacologic manipulation, transduction, transmission, modulation, and psychological intervention. Perception refers to the subjective experience of pain that results from the interaction of transduction, transmission, modulation, and the psychological aspects of the individual.

References 1. Katz WA. Pain Management in Rheumatologic Disorders: A Guide for Clinicians. N.p.: Drugsmartz; 2000. 2. Fields HL, Basbaum AI. Central nervous system mechanisms of pain modulation. In: Wall PD, Melzack R, eds. Textbook of Pain. 6th ed. London: Elsevier; 2013:309–330. 3. Raj PP. Pain mechanisms. In: Raj PP, ed. Pain Medicine: A Comprehensive Review. 2nd ed. Missouri: Mosby-Year Book; 2003:12–23. 4. Mannion RJ, Woolf CJ. Pain mechanisms and management: a central perspective. Clin J Pain. 2000;16(suppl 3): S144-S156. 5. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150(3699): 971–979. 6. Melzack R, Casey KL. Sensory, motivational, and central control determinants of pain. A new conceptual model. In: Kenshalo DR, ed. The Skin Senses. Fort Lauderdale, FL: Bannerstone House; 1968:423–439.

next article in this series will address the mechanisma of abnormal pain.

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Meryl J. Alappattu pt, dpt, phd Research Assistant Professor Department of Physical Therapy, University of Florida

GPS Gainesville, fl Typical Day Wake up 5:30–6, take the dogs for a walk, go to the gym or a run with friends, and then

head into work. I’ll review my slides for class and figure out which discussion questions I will strategically place in the slides so that I don’t bore my students (and myself!) to death with lecture. Or I’m working on a grant submission, manuscript, collecting data for an ongoing project, or irb submission. Persona For me, role models are those willing to bridge the gap between research and clinical practice. When I was completing my training, there was a big emphasis on publishing a paper in a high impact journal and less emphasis on dissemination of this work to those in clinical practice and to patients. So, how can providers working every day with people in pain use the information we’ve published? How is this relevant to clinical practice? How can patients use this information to have a voice in their healthcare? I think, given the rise of social media, podcasts, blogs posts, etc, there are more opportunities for these groups to hear and learn from each other. Contribution I’m really proud of the work I’ve done with Girls Gone Strong, an organization aimed at improving the awareness and level of care women receive from health and fitness professionals and healthcare providers, including elevating our understanding of the unique needs of women in the ante- and postpartum stages of pregnancy. Social Media/People Dr. Jen Gunter (@DrJenGunter on Twitter, Instagram). She is confident, strong, intelligent, and uses her large social media following to address important issues in women’s health and politics. We need more voices like hers. Words Cutting for Stone by Abraham Verghese; When Breath Becomes Air by Paul Kalanithi. Popcorn One of my favorite movies is Welcome to the Dollhouse, a dark comedy about a socially awkward middle child and preteen navigating the incredibly awkward environment that is middle school. The movie takes you through her journey with friendships, crushes, and family dynamics and is funny, sad, and oddly relatable. PAINWeek PAINWeek is an innovative meeting that pushes the boundaries and generates important discussions. I really like the faculty interviews pw conducts [our Expert Opinion videos]. Watching these, you get a snapshot of a speaker’s thoughts outside of their immediate presentation and it opens another side of them. It’s a unique and insightful aspect of pw that I value.

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By David Cosio

phd, abpp

Oftentimes, it’s not that patients are “difficult.” Practitioners may be rushed and unable to spend the time necessary to work with these populations. But the time we invest brings about the best results.

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Discussed at an annual conference attended by

A newly released national study

raises some tough questions about the level of empathy amongst medical students.

A study found that opioids are prescribed to ~1/3 of older adults with “new and persistent” low back pain (lbp). The study used Medicare claims data on

with new

hematology professionals: >1/2 half of adults with sickle cell disease (SCD) develop chronic pain, which is associated with ↑ levels of opioid use, worse clinical outcomes, and ↓ quality of life. Of the patients with SCD who reported worse than average pain impact in the past 7 days, 56% had neuropathic pain and 44% did not.1

41 campuses completed a web-based survey at the end of the 2017–2018 academic year.

Findings? Empathy levels dropped when students progressed from the preclinical years (years 1 and 2) into the clinical phase (years 3 and 4) of medical school “when empathy is most needed.”3

An online survey of nearly

LBP from 2011 through 2014.

About 70% of patients were women; average age approximately 77. >1/2 half of patients (54%) made only 1 healthcare visit for LBP. Advanced imaging studies—computed tomography (CT) or magnetic resonance imaging (MRI) scans— were used in ~15% of patients overall, and 29% of those with ≥2 LBP visits. In about 1/2 of cases, CT or MRI scans were performed within 6 weeks.5

Although ethnic differences in pain perception are well documented, the underlying mechanism has not been established. The present study examined differences between

with Gulf War illness (GWI) suggests a high burden of disease almost 3 decades after the conflict. GWI affects 25% to 30% of the 693,826 military personnel who were deployed to the 1990–1991 Persian Gulf War. 485 veterans with GWI responded, grading the current severity of 37 symptoms from “none” (0) to “severe” (4). The median symptom score was 95 out of 148. Respondents reported symptoms over the past 6 months: 91% with fatigue, 90% not feeling rested after sleep, 89% with joint pain, 84% having problems falling or staying asleep, and 83% with muscle pain. Additionally, 80% reported cognitive dysfunction.2

use over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs)

to treat pain. Every year in the United States, NSAID use is attributed to approximately 100,000 hospitalizations and 17,000 deaths. Acetaminophen has no clinically relevant anti-inflammatory properties and accounts for >50% of drug overdose related liver failure and about 20% of liver transplant cases, as well as kidney disease.4

pet volumes of interest analyses revealed significantly greater [11c]-Carfentanil bpnd among nhb participants in bilateral ventral striata [(left): f1,52=16.38, p<.001; (right): f1,52=21.76, p<.001], bilateral dorsolateral prefrontal cortices [(left) f1,52=17.3, p<.001; (right): f1,52=14.17, p<.001], bilateral subgenual anterior cingulate cortex [(left): f1,52=10.4, p=.002; (right): f1,52=12.91, p=.001], and right insula (f1,52=11.0, p=.002).6

1. pain.sh/jbv 2. pain.sh/v8d 3. pain.sh/afi 4. pain.sh/op8 5. pain.sh/q6q 6. pain.sh/xjy

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NSAIDs + Opioids?

Timothy J. Atkinson PharmD, BCPS, CPE Safety concerns, warnings, and new formulations focused on harm reduction have led many providers to question NSAIDs place in therapy. NSAIDs have been a cornerstone of pain management of inflammatory, connective tissue, and autoimmune disorders for over a hundred years. Can they be used in conjunction with opioids? In most cases there’s not a problem using NSAIDs and opioids together. In fact, it’s often encouraged: ● They don’t tend to interact ● They don’t have the same metabolic pathway ● We want to make sure that we’re treating the underlying cause of the pain and not just masking it with an opioid ● If the patient has an etiology consistent with inflammatory pain, that needs to be addressed

The Who and How of Certified Nurse Anesthetists

Garry J. Brydges DNP, MBA, ACNP-BC, CRNA, FAAN Where do Certified Registered Nurse Anesthetists practice?

NSAIDs:

● Large: CRNAs are on anesthesia care teams—along with physicians, nurses, nurse anesthetists, et al— in academic practices and bigger urban centers ● Small: CRNAs provide similar services independently, predominantly in rural settings—with surgeons, circulating nurses, recovery room nurses—in critical access hospitals

● Decrease stiffness, which opioids do not ● Improve a person’s ability to move their joints and function more than opioids do ● May be opioid-sparing, if the nsaid is more potent or an iv formulation

crna and eras: What do they do?

● They are doing revolutionary things, including reducing hospital length of stay by on average 3 to 4 days ● They are implementing regional anesthesia techniques to supplement multimodal pain management strategies ● It’s a niche markets right now, with innovations supplementing enhanced recovery protocols ● We’re seeing a lot more high definition types of equipment with ultrasound ● So many types of regional anesthetics—local blocks—are being implemented; what we’re able to do with anesthetic techniques around nerve fibers is changing literally on an annual basis

Visceral vs Somatic Pain

Jorge F. Carrillo MD

Chronic pelvic pain specialists deal with visceral pain, which is very different from somatic pain because of pain pathways coming from visceral organs ● Visceral pain is poorly localized ● Visceral pain doesn’t necessarily follow the same peripheral nerves as somatic pain; it often follows autonomic nerves ● Patients may have difficulty pinpointing where the pain is ● Patient symptoms may be vague

An example:

Visceral pain is a tricky and difficult type of pain:

● It’s pretty common practice now to do knee replacement or that type of procedure in a day-surgery setting ● Patients now—if they’re not walking out of the pacu, they’re walking out of the actual operating room. That’s how revolutionary this is ● Outcomes: decreased length of hospital stay, and patients raving about new implemented techniques

● It requires a strong understanding of the pathways of bladder, uterus, and rectum pain in order to discuss and explain to the patient ● Somatic pain coming from the abdominal wall muscles or the pelvic floor muscles is a different kind of perception than with period pain, endometriosis, or bladder pain syndrome

Meredith Barad MD

Mayank Gupta MD

Migraine and Estrogen: A Clear Link

Neuromodulation: The Time Is Now

An understudied topic: sex hormones and their interaction with the central nervous system. Migraine is 2 to 3 times more common in women. Doctors would hear, “I feel like around my period, I get a headache.” Migraine is a process that the brain has to go through, but the process can be shorter, it can be less disastrous to daily life. Estrogen impacts the lifecycle and can, therefore, impact headaches.

Neuromodulation has become one of the important alternative treatment options in refractory chronic neuropathic pain syndromes. The field of neuromodulation has advanced over the years. Now you can give patients: ● Multiple frequencies up to 10,000 hertz ● Different kinds of patterns of stimulations, like burst stimulation ● Dorsal root ganglion stimulation

Practitioners need to better understand:

Then/Now

● The intersection between estrogen and stroke—there’s fear surrounding use of exogenous estrogen and its contribution to stroke risk, especially in women who have migraine with aura ● The subtypes of migraine in order to treat more efficiently and help patients plan ● If a patient is only having menstrually-related migraine, they may not need Topamax, which can be beneficial for headaches but causes side effects; estrogen treatments might contain the menstrual migraine

● Patients who had multiple back surgeries, or injections, or physical therapy were offered opioids, initially short-acting and then long-acting. Now, if a patient has had those things and the pain is not getting better, rather than subjecting that patient to a high dose of opioids, I think it’s better to offer neuromodulation therapy earlier ● If the patient was on a high dose of opioids and it was still not working, then we offered neuromodulation therapy ● With the advancement of neuromodulation therapy, and the clinical data available, and the fact that high-dose opioids in long-term chronic patients doesn’t help those patients much, I think it’s time to bring back an algorithm and offer patients neuromodulation therapy early

Patients must understand: ● The migraine brain likes schedule and routine ● Laying a foundation will help the brain run as optimally as possible and recover as rapidly as it can ● That they need to: 1) go to bed at the same time nightly 2) wake at the same time daily 3) eat regular meals—with protein, not a lot of sugar or junk food 4) exercise regularly

So, what should practitioners know? Bottom line: Offer neuromodulation therapy earlier!

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with

david m.

glick

dm, daipm, cpe, faspe

“Initially I had a fascination for the heart and thought about being a cardiac surgeon, a ‘heart doctor’…”

What inspired you to do what you do?

Initially I had a fascination for the heart and thought about being a cardiac surgeon, a “heart doctor” in the eyes of a child. In college I worked part-time as an EKG technician monitoring in cardiac stepdown units. Working in a hospital emergency department opened my eyes to the realm of treating so much more. There appeared to be something special about emergency medicine that required a diverse knowledge and skillset, and the ability to act on moment’s notice.

I would have to credit Dr. John Grostic for influencing the path of treating musculoskeletal problems in general and Dr. Andrea Trescot for broadening my awareness in the field of pain specifically. Dr. Barry Cole helped to foster the idea that education was just as important a tool as any instrument in our armamentarium. I feel like the Borg in Star Trek, thanks to the physicians with whom I have worked closely and learned from, adding their unique knowledge to my own. I also credit the American Academy of Pain Management and PAINWeek for providing the venue to engage many of the individuals I have learned from.

While I regret not following that path, my second passion was problem solving, which I now apply to musculoskeletal pain. The idea of being able to help resolve a complex pain pathology in a patient who has failed other treatments yields a remarkable level of gratification. I’ve never sought simple referrals. Send me the patient who failed to respond after neck or back surgery, or one with overlapping comorbidities that complicates treatment.

Who were your mentors?

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

My mind is always seeking to improve upon or fix something. I often use car or road analogies to describe the process of pain and the art of practicing the science of delivering healthcare. That might be related to my passion for spending time in the garage, repairing and restoring little British sports cars. So, technically that would make me a mechanic, with the car being my patient. No matter what my career choice, there would have to be a diagnostic or analytic component.

Why did you focus on pain management?

The idealist’s answer is always to help mitigate human suffering. The idea of treating the patient experiencing pain became my natural course with the training I had. I do still wrestle with the concept of pain management, though. My first rule when it comes to pain and patient care is, attempt to resolve the pain pathology. If that is not possible then, and only then, at least help to make the pain less severe and more manageable. The actual focus should be to address the underlying pathology to the best of one’s ability, which in the perfect scenario could eliminate the need for the problem to be managed. All too often, such is not possible. That never means the primary goal should be less.

What is your most marked characteristic?

Being impatient. Strangely enough, it has served me well in healthcare. My goal has always been to seek an immediate response to the treatment I provide, something observable and measurable. Viewing each individual in a highly patient-centered manner and seeking the most effective clinical means to address their unique problem is my goal.

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“I’ve always been passionate about the Henry David Thoreau quote, ‘Be not simply good; be good for something.’ Then again, there is always Rube Goldberg…” Q What do you consider your greatest achievement?

when attending the funeral for a friend of 30 years. Hundreds attended his memorial service and I was quite confident he positively impacted every single one of their lives. The lesson he left with me, which I wish I had realized before his passing, was that it’s one thing to lead, but it’s more important to inspire.

a When I look back over the things I have accomplished, and the people I have helped, I am sure that part of my story hasn’t been written yet. Then again even if I were only able to help provide relief to a single patient who was suffering, that in itself could be considered an achievement. I hope that someone whose life I have impacted would impact or save the life of another. Q

Having reached a point in my career where it is time for a change, and the ability to deliver healthcare in the manner that I find gratifying is near impossible, the future has become “now.” I truly enjoy the opportunities to teach and help share the wealth of information acquired during my career, which participating in PAINWeek and PAINWeekEnd meetings afford. There is something to be said for helping impart knowledge to others who then, in turn, make a difference helping even more individuals than I could ever impact on my own.

What is your favorite language?

Having spoken enough Spanish and French to be dangerous, Italian has always been the language I would like to learn. I guess the best way for that to happen would be for me to take on an Italian car for my next restoration project.

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?

And, who knows? Maybe there will be a small Italian sports car in my future to help necessitate finally learning Italian.

As I would find a book, film, or piece of music to be boring in short order, I would prefer a set of tools to use to create or repair something. There is nothing that I find more gratifying and comforting than working with my hands and mind. Guess it is a good thing that patient care requires the same process. But if all else failed and I had to settle on a book, it would have to have been written by, or an anthology of, Rube Goldberg.

Plans for the future?

What is your motto?

I’ve always been passionate about the Henry David Thoreau quote, “Be not simply good; be good for something.” Then again, there is always Rube Goldberg, who had the uncanny knack of finding the most complex invention to accomplish a simple task. Without a challenge, there would be no need for a result.

What would you like your legacy to be?

David M. Glick, dc, daipm, cpe, faspe, is ceo & Medical Director of HealthQ2 in Lewes, Delaware.

My legacy would be to know that, somehow, I made a difference in someone’s life. Coincidentally, I gave much thought to this question recently

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By Wendy Caster

Across

1. Vitality 6. Phooey! 9. ____PHOBIA (FEAR OF PAIN) 13. British sleep disturbance 15. Making use of 17. Chase away 18. One who hears 19. Cry of disgust 2 0. Panaches 22. Ascot or Windsor 23. Used to be 24. City ~30 miles south of Cleveland 25. To a smaller extent 26. Shack 27. Leave it alone 2 8. More than 1,000th of an inch 29. ____ deal (unique opportunity) 31. Cold summer treats 33. Portuguese wine 34. Struck 38. Soon 39. Once cyanide is removed, edible root of a tropical tree 4 0. Nastiness 42. Synagogue 43. Nickname for a ginger 44. Without 45. Cacophonous 4 6. Time period 47. PC component 4 8. Believed by some to be the final resting place of Noah’s Ark 5 0. In the least 51. Three before seven, in the United States 53. Lie atop 56. Type of lemur 57. Measure of fuel performance 5 8. _____PHOBIA (FEAR OF FEET) 59. Unlubricated 6 0. Lubricated

Down

1. Not good to some people, but good to others 2. Creatures living on the surface of a body of water 3. Demanded 4. Ain’t gonna happen 5. Oh, gosh 6. What one votes on 7. Bird-like 8. Biblical verb 9. It can be stout, pale, or amber

10. Part of a door frame 11. Rock often used as a building material, e.g., as in flooring or work surfaces 12. Shrek and Mrs. Shrek 14. _____PHOBIA (FEAR OF CHICKEN) 16. Possessive often misspelled with an apostrophe 21. A native of a particular Greek island 23. Ask not for ____ the bell tolls 24. Radiant 25. Pronounces “s” as “th” 2 8. Paltry 3 0. Marine mammals believed to be as smart as dogs 31. Sit bones 32. _____PHOBIA (FEAR OF CONFINED OR CROWDED SPACES) 35. A type of affection or medicine 36. The whole bunch 37. Art movement 4 0. Spanish neighborhood

Puzzle solution: painweek.org/crossword.

41. Mean to 42. Woefully 44. Line of cliffs 45. The pits 4 8. Do something 49. Way to go 5 0. Wine region 52. Before now 54. Prefix with system 55. Homer’s TV neighbor

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

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

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

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

– Increased fluid absorption from gut7

– Decreased fluid secretion into gut7

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

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

IMPORTANT SAFETY INFORMATION • RELISTOR tablets are contraindicated in patients with known or suspected mechanical gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. • Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom. • If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR tablets and consult their healthcare provider. • Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR tablets. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal. • Avoid concomitant use of RELISTOR tablets with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

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

REACTIVATE PERISTALTIC MOTION1,7

3 RESTRICT FLUID ABSORPTION1,7

RESTORE FLUID SECRETION1,7

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

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

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

TAKE A PROACTIVE APPROACH TO OIC AND CHOOSE RELISTOR FOR YOUR ADULT PATIENTS WHO ARE NOT RECEIVING ADEQUATE RELIEF FROM OTC LAXATIVES.1,4 LEARN MORE AT RELISTORHCP.COM IMPORTANT SAFETY INFORMATION • In a clinical study, the most common adverse reactions for RELISTOR tablets (≥ 2% of RELISTOR patients and at a greater incidence than placebo) in patients with chronic non-cancer pain were: abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%), hyperhidrosis (3%), anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%). • The use of RELISTOR tablets during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Advise pregnant women of the potential risk to a fetus. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR tablets. • A dosage reduction of RELISTOR tablets is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets is needed in patients with mild renal impairment. • A dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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

BRIEF SUMMARY OF PRESCRIBING INFORMATION This Brief Summary does not include all the information needed to use RELISTOR safely and effectively. See full prescribing information for RELISTOR. RELISTOR (methylnaltrexone bromide) 150 mg tablets, for oral use. RELISTOR (methylnaltrexone bromide) injection, for subcutaneous use. 8 mg/0.4 mL methylnaltrexone bromide in single-dose pre-filled syringe. 12 mg/0.6 mL methylnaltrexone bromide in a single-dose pre-filled syringe, or single-dose vial. Initial U.S. Approval: 2008 INDICATIONS AND USAGE Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR tablets and RELISTOR injection are indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Opioid-Induced Constipation in Adult Patients with Advanced Illness or Pain Caused by Active Cancer RELISTOR injection is indicated for the treatment of OIC in adult patients with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care. CONTRAINDICATIONS RELISTOR tablets and injection are contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Cases of gastrointestinal perforation have been reported in adult patients with OIC and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom. Severe or Persistent Diarrhea If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider. Opioid Withdrawal Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR tablets was evaluated in a double-blind, placebo-controlled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 12-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR tablets 450 mg orally (200 patients) or placebo (201 patients). After 4 weeks of double-blind treatment administered once daily, patients continued 8 weeks of double-blind treatment on an as needed basis (but not more than once daily). The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR tablets are shown in Table 4. Adverse reactions of abdominal pain, diarrhea, hyperhidrosis, anxiety, rhinorrhea, and chills may reflect symptoms of opioid withdrawal. Table 4: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Tablets in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 1) RELISTOR Tablets Placebo Adverse Reaction n = 200 n = 201 Abdominal Pain** 14% 10% Diarrhea 5% 2% Headache 4% 3% Abdominal Distention 4% 2% Vomiting 3% 2% Hyperhidrosis 3% 1% Anxiety 2% 1% Muscle Spasms 2% 1% Rhinorrhea 2% 1% Chills 2% 0%

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

The safety of RELISTOR injection was evaluated in a double-blind, placebocontrolled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 2) included a 4-week, doubleblind, placebo-controlled period in which adult patients were randomized to receive RELISTOR injection 12 mg subcutaneously once daily (150 patients) or placebo (162 patients). After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR injection 12 mg subcutaneously was administered less frequently than the recommended dosage regimen of 12 mg once daily. The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR injection are shown in Table 5. The adverse reactions in the table below may reflect symptoms of opioid withdrawal. Table 5: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Injection in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 2) RELISTOR Injection Placebo Adverse Reaction n = 150 n = 162 Abdominal Pain** 21% 7% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% <1% Chills 1% 0%

*Adverse reactions occurring in at least 1% of patients receiving RELISTOR injection 12 mg subcutaneously once daily and at an incidence greater than placebo. **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness During the 4-week double-blind period, in patients with OIC and chronic non-cancer pain that received RELISTOR every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR injection 12 mg subcutaneously every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 2) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%). The safety of RELISTOR injection was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with OIC and chronic non-cancer pain (Study 3). Patients were allowed to administer RELISTOR injection 12 mg subcutaneously less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 2. Additionally, in Study 3, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR. Opioid-Induced Constipation in Adult Patients with Advanced Illness The safety of RELISTOR injection was evaluated in two, double-blind, placebo-controlled trials in adult patients with OIC and advanced illness receiving palliative care: Study 4 included a single-dose, double-blind, placebo-controlled period, whereas Study 5 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common adverse reactions in adult patients with OIC and advanced illness receiving RELISTOR injection are shown in Table 6 below. Table 6: Adverse Reactions from All Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR Injection in Adult Patients with OIC and Advanced Illness* (Studies 4 and 5) RELISTOR Injection Placebo Adverse Reaction n = 165 n = 123 Abdominal Pain** 29% 10% Flatulence 13% 6% Nausea 12% 5% Dizziness 7% 2% Diarrhea 6% 2%

*Adverse reactions occurring in at least 5% of patients receiving all doses of RELISTOR injection (0.075, 0.15, and 0.3 mg/kg) and at an incidence greater than placebo **Includes: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort and abdominal tenderness The rates of discontinuation due to adverse reactions during the double-blind, placebo-controlled clinical trials (Study 4 and Study 5) were comparable between RELISTOR (1%) and placebo (2%). Postmarketing Experience The following adverse reactions have been identified during post-approval use of RELISTOR injection. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Perforation, cramping, vomiting. General Disorders and Administration Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported. DRUG INTERACTIONS Other Opioid Antagonists Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal. Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.3 mg/kg of RELISTOR did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. USE IN SPECIFIC POPULATIONS Pregnancy The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Advise pregnant women of the potential risk to a fetus.

Lactation Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR. In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of RELISTOR tablets and injection have not been established in pediatric patients. Geriatric Use In clinical studies of RELISTOR tablets, no overall differences in effectiveness were observed. Adverse reactions were similar; however, there was a higher incidence of diarrhea in elderly patients. In clinical studies of RELISTOR injection, no overall differences in safety or effectiveness were observed between elderly patients and younger patients. Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dosage adjustment based on age is recommended. Monitor elderly patients for adverse reactions. Renal Impairment In a study of subjects with varying degrees of renal impairment receiving RELISTOR injection subcutaneously, there was a significant increase in the exposure to methylnaltrexone in subjects with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault) compared to healthy subjects. Therefore, a dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment. No dosage adjustment of RELISTOR tablets or RELISTOR injection is needed in patients with mild renal impairment (creatinine clearance greater than 60 mL/minute as estimated by Cockcroft-Gault). Hepatic Impairment Tablets In a study of subjects with varying degrees of hepatic impairment receiving a 450 mg dose of RELISTOR tablets, there was a significant increase in systemic exposure of methylnaltrexone for subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment compared to healthy subjects with normal hepatic function. Therefore, a dosage reduction of RELISTOR tablets is recommended in patients with moderate or severe hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). Injection There was no clinically meaningful change in systemic exposure of methylnaltrexone compared to healthy subjects with normal hepatic function. No dosage adjustment of RELISTOR injection is needed for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions. OVERDOSAGE A study of healthy subjects noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate. If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. NONCLINICAL TOXICOLOGY Carcinogenesis Oral administration of methylnaltrexone bromide at doses up to 200 mg/kg/day (about 81 times the subcutaneous maximum recommended human dose (MRHD) of 12 mg/day based on body surface area) in males and 400 mg/kg/day (about 162 times the subcutaneous MRHD of 12 mg/day) in females and in Sprague Dawley rats at oral doses up to 300 mg/kg/day (about 243 times the subcutaneous MRHD of 12 mg/day) for 104 weeks did not produce tumors in mice and rats. Mutagenesis Methylnaltrexone bromide was negative in the Ames test, chromosome aberration tests in Chinese hamster ovary cells and human lymphocytes, in the mouse lymphoma cell forward mutation tests and in the in vivo mouse micronucleus test. Impairment of Fertility Methylnaltrexone bromide at subcutaneous doses up to 150 mg/kg/day (about 122 times the subcutaneous MRHD of 12 mg/day; about 3.3 times the oral MRHD of 450 mg/day) was found to have no adverse effect on fertility and reproductive performance of male and female rats. Animal Toxicology and/or Pharmacology In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone caused concentration-dependent inhibition of hERG current. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). For more information, go to www.Relistor.com or call 1-800-321-4576. Based on 9493104 11/2018 Salix Pharmaceuticals 400 Somerset Corporate Blvd. Bridgewater, NJ 08807 USA www.salix.com

Manufactured for:

Under license from:

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591 U.S. Patent Information: For Injection: U.S. Patent Numbers: 8,247,425; 8,420,663; 8,552,025; 8,822,490; 9,180,125; 9,492,445 and 9,669,096 For Tablets: U.S. Patent Numbers: 8,420,663; 8,524,276; 8,956,651; 9,180,125; 9,314,461; 9,492,445 and 9,724,343 Relistor is a trademark of Salix Pharmaceuticals or its affiliates. REL.0082.USA.19

What is the difference between transduction and transmission? Education is the best analgesic.