PAINWeek Journal Vol 6, Q4 by PAINWeek

vol. 6 q 4 2018

benzodiazepines and z drugs for pain patients: the problem of protracted withdrawal symptoms (pws) p.16 ketamine: it’s not just for horses p.26 to the lighthouse: navigating the complexities of sexual pain terminology, evaluation, and management p.32 does understanding equal analgesia? pain education for patients using modern science frameworks p.40

THe PeNDULUM SWiNGS iN BOTH DiReCTiONS.

eDUCaTiON GOeS FORWaRD.

eXeCUTiVe eDiTOR KEViN L. ZACHAROFF md, facpe, facip, faap

eeK

PUBLiSHeR PAINW

ART DiReCTOR DARRYL FOSSA

eDiTORiAL DiReCTOR DeBRA WeiNeR eDiTOR HOLLY CASTeR

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 Paul Arnstein rn, phd, acns-bc, fnp-c, faan Clinical Nurse Specialist for Pain Relief Massachusetts General Hospital Boston, ma Said R. Beydoun md, faan Professor of Neurology Director of the Neuromuscular Program Keck Medical Center of University of Southern California Los Angeles, ca Jennifer Bolen jd Founder Legal Side of Pain Knoxville, tn 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 Vice Chair, Clinical Affairs Johns Hopkins University School of Medicine Department of Psychiatry and Behavioral Sciences Director, Pain Treatment Programs Johns Hopkins Medical Institutions Department of Psychiatry and Behavioral Sciences Baltimore, md Geralyn Datz phd Affiliate University of Southern Mississippi Department of Psychology Clinical Director Southern Behavioral Medicine Associates Hattiesburg, ms

eDiTORiAL BOARD

Peter A. Foreman dds, daapm Consultant Rotorua Hospital and Private Practice Rotorua, New Zealand Gary W. Jay md, faapm, facfei Clinical Professor Department of Neurology Division: Headache University of North Carolina Chapel Hill, nc Mary Lynn McPherson pharmd, bcps, cpe, faspe Professor and Vice Chair University of Maryland School of Pharmacy Department of Pharmacy Practice and Science Hospice Consultant Pharmacist Baltimore, md 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 Bruce D. Nicholson md Clinical Associate Professor Department of Anesthesia Penn State College of Medicine Hershey Medical Center Hershey, pa Director of Pain Specialists Lehigh Valley Health Network Department of Anesthesiology Allentown, pa

Marco Pappagallo md Director of Medical Intelligence Grünenthal usa Bedminster, nj Director Pain Management & Medical Mentoring New Medical Home for Chronic Pain New York, ny Steven D. Passik phd VP, Scientific Affairs, Education, and Policy Collegium Pharmaceuticals, Inc. Canton, ma Joseph V. Pergolizzi md Chief Operating Officer nema Research Inc. Naples, fl Robert W. Rothrock pa-c, mpa University of Pennsylvania Department of Anesthesiology and Critical Care Pain Medicine Division Philadelphia, pa 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 Sanford M. Silverman md, pa CEO and Medical Director Comprehensive Pain Medicine Pompano Beach, fl Thomas B. Strouse md Medical Director Stewart and Lynda Resnick Neuropsychiatric Hospital at ucla Los Angeles, ca

Copyright © 2018, PAINWeek, a division of Tarsus Medical Group. The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff. PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises. All rights are reserved by PAINWeek to accept, reject, or modify any advertisement submitted for publication. It is the policy of PAINWeek to not endorse products. Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

vol. 6 q 4 2018

16 26 32 40 48 49 50 51 52 54 10

key topic

benzodiazepines and z drugs for pain patients: the problem of protracted withdrawal symptoms (pws)

by robert b. raffa joseph v. pergolizzi jr. steven wright

pharmacology

ketamine: it’s not just for horses

by jessica geiger-hayes

sex & pain

to the lighthouse: navigating the complexities of sexual pain terminology, evaluation, and management

by georgine lamvu

physical therapy

does understanding equal analgesia? pain education for patients using modern science frameworks

by kate schopmeyer

book review

by kevin zacharoff

pw next generation

with alexandra mcpherson

clinical pearls

by douglas gourlay

pain by numbers one-minute clinician

with donald abrams, stephen ziegler, thomas ward, kevin zacharoff, bert vargas

pundit profile

with mary lynn mcpherson

PWJ | www.painweek.org

Q 4 | 2018

The national conference on pain for frontline practitioners.

2019

SePTeMBeR 3â&#x20AC;&#x201D;7

Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 36.0 AMA PRA Category 1 Credit(s)â&#x201E;˘. This activity will be approved for continuing pharmacy, psychology, nurse practitioner, nursing, and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.

A special addition to this issue is a Book Review of the newly published text Prewhen you intend to use a different plan if the first one fails. One of my key thoughts scription Drug Diversion and Pain: History, Kevin L. Zacharoff about regulatory reactivity to the “opioid Policy, and Treatment written by a number epidemic,” resulting in the recommendation of expert authors, and edited by Drs. John F. for limiting the use of opioid analgesics for the management of chronic Peppin, John. J. Coleman, Kelly K. Dineen, and Adam Ruggles. pain, is that there may be lack of clarity about just what a good “plan B” may be. It makes sense from a society-protective standpoint, but from a This issue’s Pundit Profile spotlights a good friend and colleague, Mary clinical point of view, telling clinicians what not to do is not the same as Lynn McPherson. When I think of the interprofessional intersection of clintelling them what to do. Read on, and see how you think this issue of pwj ical pharmacists with other healthcare providers, the image in my mind’s may be relevant to your clinical practice in that context. eye is Dr. McPherson. From demystifying opioid analgesic conversions to managing chronic pain and palliative care, she is literally the go-to person, I find the first article in this issue, by Dr. Jessica Geiger-Hayes, to be particu- and has more passion for what she does than anyone else I’ve ever met. larly interesting. For many years, ketamine was considered purely as a med- Have a look at what drives the consummate healthcare professional and ication used by anesthesiologists for humans and animals. I never imagined pain educator that she is. She is truly one of a kind and you should know ketamine, even with its unique mechanism of action, excellent safety profile, more about her. and dissociative anesthetic pharmacologic properties, would find its way into mainstream discussions about managing pain. This article, providing a valu- Alexandra McPherson (yes, related to our Pundit above) is the focus of this able historical perspective, makes a case for the potential clinical relevance issue’s Next Generation. Following in her mother’s footsteps as a clinical for ketamine as another possible component of a multimodal pain treatment pharmacist, she will surely become one of the “usual suspects” of clinicians plan. In these “opioid sparing”-minded times, this article is on target. and educators devoted to improving the quality of care for patients with pain, along with the education. It’s always nice to see what drives the next It may seem as if opioid analgesics are the only medications that cause wave of thought leaders and there is no question she will be one of them. withdrawal, but that is not the case. The next article in this issue by Drs. Enjoy reading about her drive, how she ended up where she is, and what Robert B. Raffa, Joseph V. Pergolizzi, Jr, and Steven Wright highlights her goals and aspirations are. the history, pharmacology, use of and possible adverse effects related to benzodiazepines and “Z” drugs (commonly used to treat insomnia). One Over the past 20 years, we have seen much written about the dangers of highlighted possible longer-lasting adverse effect is prolonged withdrawal chronic nonsteroidal anti-inflammatory drug (nsaid) and acetaminophen after discontinuation. The authors make a case for considering these fac- use. It wasn’t long ago we were told that as many as 100,000 people died of tors in the risk/benefit analysis when prescribed, as well as considering nsaid-related complications each year, and that the single most common abuse and misuse of these medications. The overarching question posed cause of hepatic failure in our country was acetaminophen toxicity. Opioid is whether or not it may be necessary for regulatory agencies to create analgesics were considered to be a good “plan B.” The “pendulum” has guidelines for prescribing medications like these similar to the ones devel- swung in both directions regarding certain interventional and first-line oped for opioids. Read, digest, and see what you think. pharmacologic treatments for chronic pain. This issue has provided much for us to think about, including what a good alternative plan might include, Dr. Georgine Lamvu provides us with a different kind of plan B to help pharmacologically, interventionally, diagnostically, and narratively. us to develop a rational differential diagnosis for sexual pain in women. Healthcare providers often don’t receive much education about pain and its treatment, let alone sexual pain. The article gives us an in-depth view Kevin L. Zacharoff MD, FACIP, FACPE, FAAP of different causes of sexual pain, and I guarantee that you will have more clarity about the terminology, pathophysiology, and treatment of sexual Kevin L. Zacharoff is Pain Educator and Consultant and Faculty, Clinical Instructor at pain in women than you did before. Dr. Kate Schopmeyer makes a good case for using simple terms when discussing the neurologic scientific basis of pain with patients. Instead of traditional biomedical explanations, there is a sound rationale for using metaphors, analogies, and even visual aids for patient education purposes. The intention of this approach is to better communicate with patients on an effective level, ultimately bypassing potentially negative precognitive thoughts and misconceptions they may bring with them before the conversation ever begins. Illustrative examples of analogies are given that could be quite valuable in clinical practice and tailored to individual patients regardless of their literacy level. It is undisputed that patient education is a key ingredient of any pain treatment plan, and this article provides some practical ways to do it well.

PWJ | www.painweek.org

suny Stony Brook School of Medicine, Department of Preventive Medicine, in Stony Brook, New York.

Q 4 | 2018

Jessica Geiger-Hayes PharmD, BCPS, CPE

p.26

Jessica Geiger-Hayes works at OhioHealth Riverside Methodist Hospital where she is a member of the palliative care team and plays an active role in caring for patients with complex pain. She is also involved in providing education to pharmacy students and residents, as well as medical students, residents, and fellows. She has presented on pain management at conferences on both the national and state levels.

Georgine Lamvu MD, MPH

p.32

Georgine Lamvu is a Gynecologic Surgeon and Pelvic Pain Specialist, and the Director of the Fellowship in Minimally Invasive Gynecology at the Orlando VA Medical Center, Division of Surgery, Gynecologic Section, in Orlando, Florida. She is also a Professor of Obstetrics and Gynecology at the University of Central Florida, College of Medicine, in Orlando.

Robert B. Raffa PhD

p.16

Robert Raffa is Adjunct Professor, University of Arizona College of Pharmacy, Tucson, and Professor Emeritus, Temple University School of Pharmacy, Philadelphia, Pennsylvania. He is Chief Scientific Officer at Neumentum Inc in Palo Alto, California. Joseph Pergolizzi Jr, md, is Director of Research at NEMA Research Inc in Naples, Florida; Senior Partner, Naples Anesthesia and Pain Associates, Naples; Executive Chairman and Cofounder, Neumentum. Steven Wright, md, is a consultant in medical pain management, addiction, and benzodiazepine best practices in Littleton, Colorado.

Kathryn A. Schopmeyer PT, DPT, CPE

p.40

Kate Schopmeyer is a Physical Therapy Program Coordinator in Pain Management at the San Francisco va Healthcare System in California.

PWJ | www.painweek.org

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key topic

Despite the severity and notoriety of the opioid crisis, which began to receive national attention at least as early as the late 1990s, the Centers for Disease Control and Prevention (CDC) did not produce a guideline for opioid prescription until March 2016. History might be repeating itself: the CDC has yet to produce prescription guidelines for benzodiazepines and â&#x20AC;&#x2DC;Zâ&#x20AC;&#x2122; drugs, despite a strong signal of excessive prescription of these drugs and the difficulties identifying and treating the protracted withdrawal symptoms (PWS) that sometimes follow cessation of use.

key topic

Just as BZDs were an advance over barbiturates in the trajectory of treatment (for example, generally more selective for anxiety with fewer or less severe side effects), nonbenzodiazepine BZD-R agonists represent an advance over BZDs, for the same reasons.

A drug is properly classified as a benzodiazepine (BZD) based on its chemical structure, meaning a specific arrangement of a heterocyclic ring linked to a benzene ring. Individual benzodiazepines result from substituents on the core structure. Following the discovery of the molecular basis of action of BZDs, drugs that have the same mechanism of action and pharmacologic effects—but different chemical structures—were discovered.1 Because of the similarities in mechanism and effects, they are sometimes called (improperly) BZDs. Equally unfortunate, because the earliest of such drugs had generic names that began with the letter Z (such as zolpidem and zaleplon, and the more recent zopiclone), they have become known colloquially as the ‘Z’ drugs. This terminology is particularly unhelpful for several reasons, including the fact that subsequent such drugs have names that do not start with the letter Z (eszopiclone, the active stereoisomer of zopiclone). The proper designation for this pharmacologic class is no longer benzodiazepines, because there are now nonbenzodiazepines that act in the same way, nor is Z drugs appropriate, since this is an artefact of the naming of specific drugs. The proper designation of the class is based on the shared pharmacologic mechanism of action2: benzodiazepine receptor (BZD-R) agonist. A drug can be a benzodiazepine BZD-R agonist or a nonbenzodiazepine BZD-R agonist (such as the Z drugs). In either case it will produce the same pharmacologic effects (originally described for BZDs). We will herein use the terminology that best makes the particular point.

Prior to the discovery of the BZDs, most of the conditions for which they are currently used were treated with barbiturates. The barbiturates (chemical derivatives of barbituric acid) represented a significant medical advance at the time. But they are nonselective central nervous system (CNS) depressants, and they are associated with a host of negative effects. The BZDs are far more selective in action and, in general, produce fewer (or less severe) side effects—alertness, sleep patterns, respiration, metabolism, drug interactions, etc—than do barbiturates.3 They thus represented a tremendous advance along a trajectory of improved therapy. So much so, in fact, that without the historical context, modern eyes view barbiturates (with some exceptions) with something akin to disdain. Just as BZDs were an advance over barbiturates in the trajectory of treatment (for example, generally more selective for anxiety with fewer or less severe side effects),4 the nonbenzodiazepine BZD-R agonists represent an advance over the BZDs, for the same reasons. We thus do not minimize the tremendous contributions made by the BZDs and Z drugs. However, we do not shy away from close scrutiny of their problems.

The molecular mechanism of BZD antianxiety (anxiolytic) action is known in detail. BZDs bind to a specific site on the large GABAA receptor complex. The BZD binding site is distinct from that to which GABA (γ-aminobutyric acid) itself binds, so it is designated as the benzodiazepine receptor, based on satisfying the pharmacologic requirements for characterization as a receptor. The binding of a BZD to its receptor (BZD-R) does not, by itself, produce an effect. Instead, binding enhances the action of GABA at the GABAA receptor. It does so allosterically, at a distance from the GABA binding site. Because the binding of GABA to the GABAA receptor results in an increase in influx of Cl- ions, the binding of BZDs to the BZD-R magnifies GABA-induced Cl- influx.5 Influx of extracellular Cl- into a neuron increases the magnitude of the already negative transmembrane potential difference (ie, hyperpolarizes the neuron) and raises the threshold for firing an action potential. This means that the neurons will still respond to stimulation, but will be less hypersensitive. Clinically, this translates into an anxiolytic effect. 20 PWJ | www.painweek.org

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The Z drugs, although not BZDs, act in the same way. They bind to BZD receptors and allosterically enhance GABA-induced influx of Cl-. Hence, the proper pharmacologic designation of BZDs and Z drugs is the same: BZD-R agonists.6

BZD-R agonists (both benzodiazepine and nonbenzodiazepine) are used as therapy for treating anxiety, certain seizures, procedure amnesia, alcohol withdrawal, movement disorders, insomnia, and muscle relaxation among others.3 The prevalence of prescribing these drugs is surprisingly high. Estimates of prevalence in the US are about 6%, in Canada about 4%, and in the EU about 4% to 16%.7-15 According to the National Institute of Health, between 1996 and 2013, the number of adults who filled a benzodiazepine prescription increased by 67%.8 Factors that are associated with greater prescribing of these drugs16 include: anxiety, insomnia, pain, a chronic medical condition; or being a smoker, in poor health, elderly, or female, Caucasian,retired, or having a low income. In addition, there is greater prevalence associated with having more than one prescriber and utilizing online prescribing.17

For most people, the most common adverse effects experienced when taking a BZD-R agonist are drowsiness, fatigue, muscle weakness, or ataxia.18 And most of these, in most people, most of the time, are rather mild. However, the complete list of adverse effects is quite extensive (see Table 1),18 and can be severe for some people.

Table 1. Diversity of adverse effects reported with the use of benzodiazepines and Z drugs (Z drugs have fewer than BZDs)

Q 4 | 2018

Organ or System

Symptom(s)

Most common

Drowsiness, fatigue, muscle weakness, ataxia

Central nervous system

Confusion, depression, headache, dysarthria, slurred speech, tremor, vertigo

Gastrointestinal

Constipation, nausea, GI disturbances

Special senses

Blurred vision, diplopia, dizziness

Cardiovascular

Hypotension

Urogenital

Incontinence, urinary retention, changes in libido

Skin & appendages

Skin reactions

Laboratories

Elevated transaminases, elevated alkaline phosphatase

Psychiatric & paradoxical

Stimulation, restlessness; acute hyperexcited states such as anxiety, agitation, aggressiveness, irritability, rage; hallucinations, psychoses, delusions, increased muscle spasticity; sleep disturbances such as insomnia, nightmares

Other

Changes in salivation: dry mouth, hypersalivation; antegrade amnesia, isolated reports of neutropenia, jaundice

www.painweek.org | PWJ

key topic

BZDs were originally thought to be among the safest of drugs, with therapeutic indexes said to be in the thousands. This was once a touted marketing advantage for the drugs. Combined with good efficacy, the safety in short-term use catapulted diazepam to one of the best-selling drugs from 1968 to 1981. However, with increasing (excess) number of prescriptions, and for longer (excessive) durations of use, there was inevitable correspondingly more instances of concomitant use with other drugs, including CNS drugs. The combinations can be less than safe. For example, BZDs and opioid analgesics are commonly co-prescribed in pain patients. The prevalence of such co-prescribing with opioids nearly doubled from 2001 to 2013,19 corresponding with a doubling of hospital emergency department admissions, and complicit in as much as a third or more of opioid-prescription deaths.19,20 The negative outcomes of such combinations prompted the FDA to mandate a black box warning on package labeling that BZDs and opioids (or other CNS depressants) can be fatal if taken together.

When properly prescribed and used, BZD-R agonists such as the BZDs and Z drugs are usually safe and effective therapy for most patients when used for a short period of time…

Another early misperception about BZDs was that they have low abuse potential, based partly on the data suggestive of low or slow onset of tolerance and physical dependence. Again, this was based on the assumption that these drugs would be prescribed appropriately, and only for a short time. But with widespread and long-term prescribing came widespread availability and thus more abuse, either as a result of the inherent properties of the drugs, or the greater exposure to persons who have a greater predisposition for a substance abuse disorder.21 It is important to note that nonmedical use is not equivalent to “addiction.” Addiction to BZDs by themselves is rare. However, BZDs are often used to amplify the euphoria or soften the intensity of other drug use experience. Nonmedical users may also employ BZDs to self-medicate symptoms that may occur due to withdrawal from other substances.

Use of BZDs leads to some degree of tolerance development and physical dependence, which by themselves are normal and not a concern. Both of these phenomena are the normal physiological adaptations to almost any drug, and therefore not an independent indication of abuse potential. However, upon cessation of intake of the drug, or interdose intervals for short-acting drugs, physical dependence is manifested as withdrawal symptoms. This can be problematic for some patients no matter how short a duration of exposure to the drug, but it is an ever increasing problem the longer the duration of drug exposure. So although the overwhelming majority of BZD users are not abusers, and tolerance and physical dependence are normal and not problematic per se, the 2 phenomena can contribute to a physiological feedback loop of cues that can make it difficult to stop taking BZDs. Normally, withdrawal symptoms reveal the now unopposed compensatory mechanism, and therefore are generally opposite to the drug-induced effects. So it is to be expected, for example, that anxiety is a withdrawal symptom associated with anxiolytic drugs. However, withdrawal from BZDs can give rise to a bewildering array of symptoms (see Table 2), many of which are difficult to reconcile with BZD-induced effects. Furthermore, some of these symptoms persist a perplexingly long time, long after the drug has seemingly been eliminated from the body. Thus, they appear to be unusually protracted withdrawal symptoms, as opposed to adverse effects. And the duration of symptoms is not always correlated to dose or to duration of use. There is currently no good understanding or mechanistic explanation for the protracted withdrawal symptoms that can be a consequence of cessation of BZD use, particularly since a spectrum of symptoms is displayed, and not everyone experiences the same symptoms. Some possibilities are long-term alterations in receptor number (an up- or

22 PWJ | www.painweek.org

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Table 2. Diversity of withdrawal symptoms (immediate or delayed and protracted) reported with the use of benzodiazepines and Z drugs (Z drugs have fewer than BZDs) Anxiety/panic attacks

Tremors

Tinnitus

Insomnia

Headaches

Paresthesia

Constant flu symptoms

Unusual fatigue, weakness

Sweating

Nausea

Loss of appetite

Pain in neck and shoulders

Restless legs

Hair loss

Sensory fog

Depersonalization

Muscle pain

Hallucinations

Delirium

Vertigo

Muscle spasms

Anhedonia

Agoraphobia

Intrusive thoughts

Hypersensory sensitivity

GI: constipation, diarrhea

downregulation, or an effect on promoters of BZD-R protein synthesis or degradation), alterations in ADME (absorption, distribution, metabolism, or elimination), or a change in GABAA receptor function or subtype distribution, or possibly some involvement of peripheral BZD binding sites.22 Each of these hypotheses need to be thoroughly explored.

When properly prescribed and used, BZD-R agonists such as the BZDs and Z drugs are usually safe and effective therapy for most patients when used for a short period of time, such as 2 to 4 weeks. However, a subset of patients experiences a lack of efficacy, severe adverse effects, or protracted withdrawal symptoms (the 2 latter phenomena can be independent of dose and of the duration of use). The possible outcomes are shown in Table 3. Unfortunately, there is currently no good data on the percentage of people in each category, and no reliable way to predict outcome prior to treatment.

The first benzodiazepine anxiolytic (chlordiazepoxide, brand name=Librium®)23,24 was discovered in 1957 and was marketed in 1960. Benzodiazepine

Table 3. Possible outcomes of treatment with benzodiazepines or Z drugs prescribed for either a short term (≤arbitrary 8 weeks) or long term (>arbitrary 8 weeks). Therapeutic effectiveness (efficacy) can be poor or good; with no (0) or mild adverse effects (AEs), or poor quality of life (qol). Upon treatment cessation, a patient might have no or only mild withdrawal symptoms, or can experience serious protracted withdrawal symptoms Short Term

Long Term

Good

0 → mild

Poor

0 → mild

Poor

Poor qol

Good

0 → mild

Poor

0 → mild

Good

0 → mild

Good

Poor qol

0 → mild

Good

0 → mild

Good

0 → mild

Problems

Good

0 → mild

Poor

0 → mild

Problems

Good

0 → mild

Good

Poor qol

Problems

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0 → mild

Good

0 → mild

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key topic

Table 4. Appraisal of the current status of benzodiazepine and Z drugs ▸▸ Not recommended as first-line medications in several applications in which they are commonly prescribed ▸▸ Should be prescribed only at the lowest effective dose for the shortest duration necessary ▸▸ Not recommended for >4 weeks ▸▸ Can become ineffective after 4 to 6 weeks of use ▸▸ Physical dependence common after 4 to 6 weeks of use ▸▸ Guided withdrawal (taper plus support) process is usually needed after physical dependency is established ▸▸ Reconsideration of the labeling seems appropriate to better reflect accumulated experience with adverse effects and the phenomenon of protracted withdrawal

7. Olfson M, King M, Schoenbaum M. Benzodiazepine use in the United States. JAMA Psychiatry. 2015;72(2):136–142. 8. Bachhuber MA, Hennessy S, Cunningham CO, et al. Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996–2013. Am J Public Health. 2016;106(4):686–688. 9. Neutel CI. The epidemiology of long-term benzodiazepine use. Int Rev Psychiatry. 2005;17(3):189–197. 10. Ashton H, Golding JF. Tranquillisers: prevalence, predictors and possible consequences. Data from a large United Kingdom survey. Br J Addict. 1989;84(5):541–546. 11. Magrini N, Vaccheri A, Parma E, et al. Use of benzodiazepines in the Italian general population: prevalence, pattern of use and risk factors for use. Eur J Clin Pharmacol. 1996;50(1–2):19–25. 12. Manthey L, Giltay EJ, van Veen T, et al. Determinants of initiated and continued benzodiazepine use in the Netherlands study of depression and anxiety. J Clin Psychopharmacol. 2011;31(6):774–779. 13. Petitjean S, Ladewig D, Meier CR, et al. Benzodiazepine prescribing to the Swiss adult population: results from a national survey of community pharmacies. Int Clin Psychopharmacol. 2007;22(5):292–298.

withdrawal symptoms were described only 1 year after marketing.25 The distinct advantages of BZDs over barbiturates rightfully catapulted the BZDs to commercial success, but legitimate and circumspect prescribing soon transitioned into good intentioned, but ever expanding (over)use for unproven applications, and for durations that greatly exceeded clinical trial experience, product labeling, and proof of efficacy and/or safety. Furthermore, long-term use was naïvely assumed to have the same safety as acute use. But in retrospect, this was an unfortunate assumption, underscored by the recent black box warning about co-medication with opioids and other CNS depressants. Now other problems are coming to the fore, long known to patients but underrecognized by healthcare providers. Among them is the experience of mechanistically perplexing protracted withdrawal symptoms. Although the exact explanation of this phenomenon needs to be elucidated, it is mechanistically plausible, and should be acknowledged and taken seriously by clinicians (Table 4). There is now also a sufficient warning signal to prompt regulatory agencies to create, or re-evaluate, guidelines and labeling of this class of drugs. References 1. Lloyd KG, Depoortere H, Manoury P, et al. Non-benzodiazepine anxiolytics: potential activity of phenylpiperazines without 3H-diazepam displacing action. Clin Neuropharmacol. 1984;7:896–897. 2. Campo-Soria C, Chang Y, Weiss DS. Mechanism of action of benzodiazepines on GABAA receptors. Br J Pharmacol. 2006;148(7):984–990. 3. Griffin CE 3rd, Kaye AM, Bueno FR, et al. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13(2):214–223.

14. Rosman S, Le Vaillant M, Pelletier-Fleury N. Gaining insight into benzodiazepine prescribing in general practice in France: a data-based study. BMC Fam Pract. 2011;12:28. 15. Sonnenberg CM, Bierman EJ, Deeg DJ, et al. Ten-year trends in benzodiazepine use in the Dutch population. Soc Psychiatry Psychiatr Epidemiol. 2012;47(2):293–301. 16. Kroll DS, Nieva HR, Barsky AJ, et al. Benzodiazepines are prescribed more frequently to patients already at risk for benzodiazepine-related adverse events in primary care. J Gen Intern Med. 2016;31(9):1027–1034. 17. McGerald G, Dvorkin R, Levy D, et al. Prescriptions for schedule II opioids and benzodiazepines increase after the introduction of computer-generated prescriptions. Acad Emerg Med. 2009;16(6):508–512. 18. Gudex C. Adverse effects of benzodiazepines. Soc Sci Med. 1991;33(5):587–596. 19. Sun EC, Dixit A, Humphreys K, et al. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ. 2017;356:j760. 20. Jones CM, McAninch JK. Emergency department visits and overdose deaths from combined use of opioids and benzodiazepines. Am J Prev Med. 2015;49(4):493–501. 21. Becker WC, Fiellin DA, Desai RA. Non-medical use, abuse and dependence on sedatives and tranquilizers among U.S. adults: psychiatric and socio-demographic correlates. Drug Alcohol Depend. 2007;90(2–3):280–287. 22. McEnery MW, Snowman AM, Trifiletti RR, et al. Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A. 1992;89(8):3170–3174. 23. Sternbach LH. The discovery of librium. Agents Actions. 1972;2(4):193–196. 24. Wick JY. The history of benzodiazepines. Consult Pharm. 2013;28(9):538–548. 25. Hollister LE, Motzenbecker FP, Degan RO. Withdrawal reactions from chlordiazepoxide (“Librium”). Psychopharmacologia. 1961;2:63–68.

4. Lopez-Munoz F, Ucha-Udabe R, Alamo C. The history of barbiturates a century after their clinical introduction. Neuropsychiatr Dis Treat. 2005;1(4):329–343. 5. Gielen MC, Lumb MJ, Smart TG. Benzodiazepines modulate GABAA receptors by regulating the preactivation step after GABA binding. J Neurosci. 2012;32(17):5707–5715. 6. Sanger DJ. The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004;18(suppl 1):9–15; discussion 41, 43–15.

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Q 4 | 2018

By Jessica Geiger-Hayes PharmD, BCPS, CPE

pharmacology

David knew he had a terminal illness and wanted to stop coming to the hospital. He wanted to spend time with his wife and 2 children. The problem was that his pain was terribly unmanaged and the only thing that kept it at a tolerable level was a continuous infusion of hydromorphone. He was tied to an IV pole and could not get out of bed without excruciating pain. He describes his pain as sharp and shooting down both legs into his feet. Multiple dose increases of the hydromorphone have not been effective and have resulted in increased sedation. Abstract: Ketamine is a dissociative anesthetic that exudes action by binding to the

phencyclidine site of the N-methyl-D-aspartate (NMDA) receptor channel when they are open and in the activated state.1 Binding causes the NMDA channel to close and subsequently decreases re-opening time. NMDA antagonism affects pain signaling in the following ways: it decreases “wind-up”; acts on descending pain modulation pathways, anti-inflammatory properties, glutamate transmission, noradrenergic and serotonergic reuptake inhibition; and interacts with calcium and sodium channels.2,3

Ketamine was synthesized in 1962, but the

story of how the medication came to be starts in the late 1950s at the Parke-Davis and Company laboratory. Scientists were searching for an anesthetic agent that also had analgesic properties and they discovered phencyclidine, or what we know today as PCP. Fast forward a few years to human trials where it was discovered that PCP was not effective as an anesthetic due to extended excitation and psychotic reactions after administration. This led Calvin Stevens, an American chemist, down a path that would lead to synthesis of ketamine. Human trials for ketamine happened in 1964 and data was published on the effectiveness in 1965. Ketamine was initially used as an animal tranquilizer and was not approved for human use by the United States Food and Drug Administration (FDA) until 1970. A common use for ketamine after FDA approval was as a field anesthetic during the Vietnam War. It was later discovered that at subanesthetic doses, ketamine was quite effective as an analgesic.4

The pharmacokinetic profile of ketamine is unique in regard to metabolism and solubility. It is hepatically 28 PWJ | www.painweek.org

converted into norketamine, an active metabolite that has analgesic properties. The peak analgesic effect of ketamine is based on the levels of norketamine. The medication is also both lipid and water soluble, which allows for multiple routes of administration. A summary of the kinetic profile of ketamine/norketamine can be seen in Table 1. Ketamine can be beneficial for treating pain in 2 major ways. The first has to do with NMDA receptor activity. This receptor plays a role in neuropathic pain and central sensitization. Decreasing the nerve signaling, by closing the NMDA channel, can decrease the pain and thus provide relief to the patient. The second is that addition of ketamine can decrease opioid requirements by essentially “re-setting” the NMDA receptors. Researchers found that, in addition to interacting with the mu receptor, opioids can open NMDA receptors which can lead to increased pain and potentially hyperalgesia.6 Giving a dose of ketamine closes the open NMDA receptors to decrease pain and can assist in resolving opioid induced hyperalgesia. Q 4 | 2018

Table 1. Pharmacokinetic Properties of Ketamine5 Pharmacokinetic Property Half-life (t₁/₂)

Comments 1–3 hours (ketamine) ~12 hours (norketamine)

Time to maximum serum concentration (Tmax)

Oral: 30–60 minutes Subcutaneous: 15–30 minutes Intravenous: ≤15 minutes

Metabolism

Hepatic to active metabolite, norketamine

Solubility

Lipid and water soluble

Patient Selection

Consider ketamine in the following circumstances: ○○ Pain refractory to opioid therapy ○○ Refractory neuropathic pain ○○ In patients who are highly opioid tolerant with escalating doses and associated side effects ○○ Opioid induced neurotoxicity Documented hypersensitivity to ketamine and acute intermittent porphyria are absolute contraindications to using the medication. Relative contraindications include severe uncontrolled hypertension, increased intracranial pressure, and history of psychotic illness.6,7 The dose of ketamine does not need to be adjusted in renal impairment, but a dose reduction and extended interval dosing may need to occur if a patient has hepatic impairment.3

David had high opioid requirements and was experiencing a neuropathic component to his pain. He did not have uncontrolled hypertension or any other medical condition that would preclude the use of the medication. He was a good candidate for a trial of ketamine to improve his pain control and decrease his opioid requirement. Q 4 | 2018

Dosing

Due to its unique solubility properties (both lipid and water soluble), ketamine can be given via oral, sublingual, rectal, intravenous, intramuscular, subcutaneous, intranasal, epidural, or topical routes.7 The preferred route of administration for pain relief is oral. Studies suggest that oral dosing of ketamine provides more potent analgesia due to the higher levels of the norketamine metabolite which is also an effective analgesic.8 The parenteral formulation of ketamine can be mixed with juice and administered orally as there is no commercially available oral formulation. Recommended starting doses

Table 2. Recommended Ketamine Starting Doses8-11 Oral/Sublingual

2–25 mg every 6–8 hours or 0.5 mg/kg

Intravenous

2.5–25 mg every 6–8 hours

Subcutaneous

2.5–25 mg every 6–8 hours

can be seen in Table 2. There is a wide range of starting doses depending on the reference used, but a good principle to use would be to start with the low end and titrate to affect. An initial test dose can be administered to evaluate patient tolerability and effect on pain. Vital signs and pain level should be monitored at 30 minutes and 60 minutes postdose. If effective this dose can be continued as the scheduled dose. If ineffective, the dose can be repeated and then the cumulative dose becomes the scheduled dose. www.painweek.org | PWJ

pharmacology

David was given an oral dose of 5 mg administered using the IV solution. The dose was mixed in grape juice to mask its bitter taste. He was monitored at 30 minutes and 60 minutes postdose. After 60 minutes, David reported a pain decrease from 9/10 to 7/10. The 5 mg dose was repeated and pain decreased to 4/10 after an hour. No side effects were experienced. The scheduled dose will now become ketamine 10 mg by mouth every 6–8 hours.

Table 3. Ketamine Side Effects1,3,7 ▸▸Increased blood pressure ▸▸Increased intraocular pressure ▸▸Psychomimetic reactions ▸▸Anxiety ▸▸Delirium

Side Effects and Side Effect Management

As with any other medication, ketamine has side effects, some of which have the potential to be bothersome to the patient. Common side effects include vivid dreams and hallucinations as well as increased anxiety (Table 3). Lorazepam 0.5–1 mg (or another benzodiazepine at an equivalent dose) can be helpful for treating ketamine associated anxiety. Premedication is also useful if the patient is prone to anxiety and the clinician is concerned the ketamine may exacerbate the already existing condition. Haloperidol 0.5–1 mg can be used to treat hallucinations, delirium, or vivid dreams. If increased secretions occur, anticholinergic medications can be used to decrease further production. Glycopyrrolate would be the preferred agent as it does not cross the blood-brain barrier and the patient would be at a lesser risk of experiencing anticholinergic side effects.7 Side effects are less common with oral administration.

Protocol Development

Protocols should be institution specific and take state laws into account when they are being developed. Some 30 PWJ | www.painweek.org

▸▸Vivid dreams ▸▸Hallucinations ▸▸Dizziness ▸▸Increased salivary secretions

states do not allow nurse administration of ketamine. Protocol development should be a multidisciplinary process and include representatives from pharmacy, pain management, palliative care, and potentially the emergency department. Components of a protocol should include recommended starting doses, common side effects, monitoring parameters, and side effect management.

Conclusion

Ketamine can be an effective tool in pain management, and potentially decrease opioid need. Ketamine can also be considered to reverse opioid induced hyperalgesia and for treatment of refractory neuropathic pain. Q 4 | 2018

To wrap up David’s story, his opioid requirement decreased by almost 50% and after his first 2 doses of 5 mg, he was able to get out of bed and walk a lap around the room with little pain. He was discharged home the next day and maintained pain control through the end of his life.

References 1. Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;(182):313–333.

7. Prommer EE. Ketamine for pain: an update of uses in palliative care. J Palliat Med. 2012;4:474–483.

2. Iacobucci GJ, Visnjevac O, Pourafkari L, et al. Ketamine: an update on cellular and subcellular mechanisms with implications for clinical practice. Pain Physician. 2017;20:E285-E301.

8. Kannan TR, Saxena A, Bhatnagar S, et al. Oral ketamine as an adjuvant to morphine for neuropathic pain in cancer patients. J Pain Symptom Manag. 2002;23(1):60–65.

9. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacologica Sinica. 2016;37:865–872.

Craven R. Ketamine. Anaesthesia. 2007;62(1):48–53.

4. Mion G. History of anaesthesia: the ketamine story – past, present, and future. Eur J Anaesthesiol. 2017;34(9):571–575. 5. Grant IS, Nimmo WS, Clements JA. Pharmacokinetics and analgesic effects of IM and oral ketamine. Br J Anaesth.1981;53:805–810. 6. Marchetti F, Coutaux A, Bellanger A, et al. Efficacy and safety of oral ketamine for the relief of intractable chronic pain: a retrospective 5-year study of 51 patients. Eur J Pain. 2015;19:984–993.

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10. Zgaia AO, Irimie A, Sandesc D, et. al. The role of ketamine in the treatment of chronic cancer pain. Clujul Med. 2015;8(4):457–461. 11. Kurdi MS, Theerth KA, Deva RS. Ketamine: current applications in anesthesia, pain and critical care. Anesth Essays Res. 2014;8(3):283–290.

www.painweek.org | PWJ

navigating the complexities of sexual pain terminology, evaluation, and management By Georgine Lamvu MD, MPH

sex & pain

You are talking with a patient who has been seen previously by several healthcare providers. As you review her chart, you notice that the chief complaint is “pain with intercourse” and her medical problem record lists several related diagnoses including: “dyspareunia, vaginismus, and vulvodynia.” You wonder, “What do these diagnoses mean? How are they different? Should I treat them separately?” If you’ve ever asked these questions, you’re not alone. Sexual pain terminology can be confusing, redundant, and often misused. In my clinical practice, fellows and students often ask me to differentiate the 3 terms and I find that it is not an easy task. This article will clarify sexual pain terminology and provide a brief overview of evaluation and treatment.

is the term used to describe recurrent or persistent genital pain associated with sexual intercourse.1 It is estimated that dyspareunia affects 12% to 21% of adult women in the United States and 8% to 21% of women worldwide.2 The term dyspareunia should be used to describe pain that is present only just before, during, or immediately following intercourse. It may be superficial or deep.3 Typically, dyspareunia is a symptom of an underlying condition rather than a diagnosis in and of itself. For example, deep dyspareunia—if the pain is experienced during deep vaginal penetration—can result from pelvic conditions such as endometriosis, fibroids, or pelvic infections; superficial dyspareunia, where the pain is localized to the vaginal entrance (vulvar vestibule or vaginal introitus), may be associated with superficial conditions such as vaginal dermatoses, atrophic vaginitis, and vulvovaginitis. Regardless of the cause, dyspareunia is a term that should be limited to describe pain that occurs only when provoked by intercourse. Generally, dyspareunia is not thought of as a chronic pain syndrome, although many women report having had dyspareunia for years before they seek care. 34 PWJ | www.painweek.org

Q 4 | 2018

is currently defined by the International Society for the Study of Vulvovaginal Diseases (ISSVD) as chronic vulvar pain occurring for at least 3 months, without clear identifiable cause, which may have potential associated factors.4 It is estimated that approximately 16% of women in the US experience chronic vulvar pain.5 Research shows that women with vulvodynia suffer significant distress and poor quality of life. More than 50% experience pain with intercourse and more than 80% fear intercourse or report debilitating sexual dysfunction.6 In contrast to dyspareunia, which is usually provoked by intercourse, vulvodynia can be provoked by contact or can occur spontaneously. Vulvodynia is further characterized by location, generalized or localized to the vaginal entrance or clitoris, and by whether the pain is persistent or intermittent. Provoked localized vulvodynia, also known as provoked vestibulodynia or vestibulitis, is essentially the same as superficial dyspareunia, in that both definitions are used to describe pain that occurs on contact with the vaginal entrance. Although vulvodynia was originally defined as pain without obvious etiology, 2015 diagnostic criteria for vulvodynia acknowledge that chronic vulvar pain can also be caused by specific disorders such as vaginal infections, neoplasms, or neurologic disorders. The new ISSVD definition of vulvodynia recognizes that in some cases this type of chronic pain can coexist with other disorders such as pelvic floor muscle dysfunction, specific skin disorders such as lichen sclerosus, or other comorbid pain syndromes such as painful bladder syndrome (PBS), or irritable bowel syndrome (IBS).4 The broadening of the vulvodynia definition was in part intended to better represent the wide ranging phenotypic presentation of patients with genital pain; however, it is important to note that healthcare providers (including myself) often have difficulty differentiating primary etiologic causes from associated comorbidities. In clinical and research settings, there is significant overlap between vulvodynia and other chronic pain conditions such as IBS, PBS, fibromyalgia, chronic fatigue syndrome, migraines, and temporomandibular joint disorders, such that approximately 20% of patients with vulvodynia also report being diagnosed with one or more of these disorders.6 Q 4 | 2018

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sex & pain

is a term that is also commonly used to describe sexual pain; however, it is often misused. In the early 2000s, vaginismus was defined by the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-4) as a recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with intercourse, causes marked distress or interpersonal difficulty, is not explained by another disorder (eg, somatization), and is not directly due to the direct physiological effects of a general medical condition.7 As such, this term was intended to describe patients who experienced severe vaginal muscle spasm accompanied by an intense fear of touch or intercourse. Although patients with dyspareunia and vulvodynia may also present with vaginal muscle pain and fear of intercourse, Lahaie and colleagues demonstrated that these 2 characteristics are significantly more pronounced in vaginismus, to the point that vaginismus patients often cannot undergo examination or even light touch.8 By 2013, vaginismus was newly re-defined in DSM-5 as genito-pelvic pain/penetration disorder (GPPPD).9 The revised definition merges female sexual dysfunction, dyspareunia, and vaginismus such that GPPPD is now characterized by at least one of the following recurrent symptoms: Difficulty with vaginal penetration during intercourse Genital or pelvic pain during vaginal intercourse or penetration attempts Fear or anxiety associated with genito-pelvic pain or vaginal penetration Tightness of the pelvic floor muscles during attempted vaginal penetration Symptoms must cause significant distress and be present for at least 6 months.9 Although severe fear of touch and extreme muscle spasm may be more consistent with vaginismus, the merger of these terms under a new classification was due to overlap in clinical presentation and difficulties in distinguishing dyspareunia from vaginismus and vulvodynia. Under this new diagnostic criterion, the prevalence of GPPPD has not yet been ascertained. Nonetheless, the newer definition of GPPPD may be more useful in clinical settings because it takes into account many of the biopsychosocial variables that influence sexual pain as well as the overlap between each of these diagnoses. On the other hand, GPPPD does not have the specific pain descriptors that refer to location of pain and

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differentiate superficial/introitus pain from deep pain, or generalized from localized pain, or provoked from spontaneous pain. These independent pain characteristics may still be important to identify during evaluation because they may influence treatment selection. For example, research indicates that provoked localized vestibular pain may be pathophysiologically distinct from generalized vulvar pain. Although both types of patients can present with pain during penetration, fear of intercourse, and musculoskeletal dysfunction, vestibulectomy—a procedure where the vaginal vestibule is surgically removed—is only recommended for patients with localized provoked vestibulodynia, and generally contraindicated in patients with generalized vulvodynia.10 Therefore, even if GPPPD is used to define sexual pain, it is still important to carefully characterize the location (localized to a particular genital structure or generalized) and timing (spontaneous or provoked onset) of the pain.

Although the diagnostic terminology for sexual pain can be confusing and patients may present with a variety of symptoms, the evaluation is similar, regardless of whether the pain is classified as dyspareunia, vaginismus, vulvodynia, or GPPPD. A detailed pain history should be undertaken to assess severity of symptoms and associated dysfunction.10,11 The use of patient reported pain diaries and quality of life questionnaires to assess onset, timing, location, intensity, duration, quality of pain, and physical and psychological impact of pain is highly recommended, both in the initial evaluation and in the assessment of treatment response.11 Q 4 | 2018

The presence of sexual pain should be viewed in the context of sexual dysfunction and providers must ensure patient comfort before embarking on this type of evaluation. Several visits may be needed before trust is established and the patient is able to disclose what is often considered very private and intimate information. Since pain comorbidities (such as IBS, PBS, migraines), psychiatric comorbidities (such as depression and anxiety), and trauma (physical or sexual) are more common in this patient population than in patients who do not have pain, providers must also remember to screen patients with sexual pain for these comorbidities because they can influence pain severity, sexual dysfunction, and response to treatment.11,12 Surgical and obstetric trauma can also be a potential cause of sexual pain; thus, a detailed surgical and obstetric history is necessary. An extensive medical history can identify other factors associated with sexual pain, such as estrogen deficiency in postmenopausal women and gynecologic disorders, such as endometriosis. Lastly, it is necessary to rule out worrisome symptoms such as abnormal bleeding, foul vaginal discharge, or pelvic pain which may indicate infectious or neoplastic pathology.11,12 The physical examination should include a psychological assessment and an abdominal and back musculoskeletal evaluation before proceeding to an external vaginal exam. The external exam should include examination of external sensory dermatomes and pain sensitivity, internal palpation of the vaginal muscles, bi-manual palpation of the pelvis, and internal speculum examination—performed only if the patient was able to tolerate single digit palpation. Pelvic examination can be anxiety provoking and traumatizing to patients with sexual pain. Before examination it is essential to inquire about previous experience with pelvic examinations, obtain the patient’s consent, and have a female chaperone present. Patients should be given full control and given the option to slow down or terminate the examination at any point.12 The speculum examination may be delayed if the patient does not report any abnormal bleeding or vaginal discharge and there are no other physical findings such as a pelvic or abdominal mass.

It is rare that sexual pain is caused by one factor alone: organic, musculoskeletal, and psychological causes for pain must all be considered in the evaluation and treatment. An individualized multidisciplinary treatment approach is often required. The multidisciplinary treatment team may involve experts in gynecology, physical therapy, pain management, sexual therapy, and mental health working together to treat all aspects of the patient’s pain experience. In fact, for vulvodynia, many single pharmacologic interventions have already been shown to be mostly ineffective.13 Thus, it is imperative to educate patients on the need for multiple, sometimes prolonged, interventions. Validation of the patient’s pain experience, along with education about expectations for a “cure,” discussion about sexual anatomy, physiology, and behavior Q 4 | 2018

are considered key components of therapy. Instructions on vulvar care (avoiding irritants, using lubrication) and addressing sexual myths—such as “some pain during intercourse is normal” or “the bigger the better” or “the more sex the better”— is also important.11,12 Pharmacotherapy, such as hormonal replacement in women with dyspareunia resulting from postmenopausal vaginal atrophy,14 or topical steroids for pain resulting from vulvar dermatoses, may be helpful in patients with specific causes of pain.11 Lubricants and topical analgesics can provide temporary relief during intercourse but are rarely effective in the long term. Tricyclic antidepressants, serotonin norepinephrine re-uptake inhibitors and anticonvulsants such as gabapentin have not been confirmed in randomized trials (RCTs) to significantly impact pain, however, they may be helpful to control other important pain modulators such as depression, anxiety, and insomnia.10-12 Pelvic floor muscle dysfunction is commonly found in women with sexual pain. In a report from the National Vulvodynia Registry more than 90% of women had abnormal vaginal muscle findings.15 In general, dyspareunia, vulvodynia, and vaginismus are associated with pelvic floor muscle overactivity, increased resting tone, and impaired voluntary relaxation. When these changes become chronic they are thought to lead to muscle hypoxia and neurogenic inflammation that can manifest as vaginal itching, burning, tingling, or sharp shooting pain in the vulvar and/or vaginal areas.16 Primary changes in pelvic and vaginal musculature can result from a variety of events such as acute infection, vaginal birth, abdominal and pelvic surgery, or pelvic trauma. In other cases, the muscular dysfunction can be a secondary process resulting from being in chronic pain.17,18 Physical therapy is useful in patients who have an abnormal musculoskeletal (external or internal) findings. The goal of physical therapy is to decrease muscle tone and tension, which should lead to decreased pain and improved muscle function. Physical therapists may use different strategies, internal and external, to improve muscle function, including manual therapy techniques, vaginal dilators, ultrasound, electrical stimulation, biofeedback, home exercises, and education. A 2017 systematic review by Morin and colleagues concluded that although physical therapy modalities used in women with localized provoked vestibulodynia varied, physical therapy is consistently effective for decreasing pain and improving sexual function.19 Pain related psychological distress is linked to sexual dysfunction; pain and distress can lead to fear and avoidance of intercourse affecting intimacy and the ability to maintain a healthy relationship.20 Pain, anxiety, and fear of experiencing pain can also lead to pelvic floor muscle hypertonicity and spasm, which in turn contributes to a cycle of worsening pain and sexual dysfunction.12 Cognitive behavioral therapy (CBT) using techniques www.painweek.org | PWJ

sex & pain

which generally focus on behavior that decreases genital pain, reduces anticipatory fear of pain, and improves sexual function has been studied in women with vulvodynia. RCTs show that CBT is an effective modality of improving pain, satisfaction with treatment and improved sexual function.21 Based on current evidence, CBT and physical therapy are the only two treatments that can be routinely recommended for all patients with sexual pain that is not due to acute treatable infectious, inflammatory, or neoplastic conditions.

associations with comorbidities and quality of life. Obstet Gynecol. 2006;107(3):617–624. 7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: 2000. 8. Lahaie MA, Amsel R, Khalife S, et al. Can fear, pain, and muscle tension discriminate vaginismus from dyspareunia/provoked vestibulodynia? Implications for the new DSM-5 diagnosis of genito-pelvic pain/penetration disorder. Arch Sex Behav. 2015;44(6):1537–1550. 9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: 2013. 10. Goldstein AT, Pukall CF, Brown C, et al. Vulvodynia: assessment and treatment. J Sex Med. 2016;13(4):572–590.

Sexual pain is a heterogeneous symptom that may result from a complex interplay of musculoskeletal, psychological and environmental factors. An extensive history and careful examination are key to making the correct diagnosis. Terminology describing genital pain disorders overlaps significantly. Clinically genito-pelvic pain/penetration disorder may be the term that allows the most flexibility in describing patient symptoms; however, specific physiologic differences between dyspareunia, vulvodynia, and vaginismus may still need to be considered in treatment selection. References

11. Oshinowo A, Ionescu A, Anim T, et al. Dyspareunia and vulvodynia. In: Valovska AT, ed. Pelvic Pain Management. New York, NY: Oxford University Press; 2016:44–57. 12. Sorensen J, Bautista KE, Lamvu G, et al. Evaluation and treatment of female sexual pain: a clinical review. Curēus. 2018;10(3):e2379. 13. Goldstein AT, Marinoff SC, Haefner HK. Vulvodynia: strategies for treatment. Clin Obstet Gynecol. 2005;48(4):769–785. 14. Kelley C. Estrogen and its effect on vaginal atrophy in post-menopausal women. Urol Nurs. 2007;27(1):40–45. 15. Lamvu G, Nguyen RH, Burrows LJ, et al. The EVA (Evidence-Based Vulvodynia Assessment) Project: a national registry for the study of vulvodynia. J Reprod Med. 2015;60(5–6):223–235. 16. Pukall CF, Goldstein AT, Bergeron S, et al. Vulvodynia: definition, prevalence, impact, and pathophysiological factors. J Sex Med. 2016;13(3):291–304.

1. Amato P. Categories of female sexual dysfunction. Obstet Gynecol Clin North Am. 2006;33(4):527–534.

17. Reissing ED, Binik YM, Khalife S, et al. Etiological correlates of vaginismus: sexual and physical abuse, sexual knowledge, sexual self-schema, and relationship adjustment. J Sex Marital Ther. 2003;29(1):47–59.

2. Latthe P, Latthe M, Say L, et al. WHO systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health. 2006;6:177.

18. Reissing ED, Brown C, Lord MJ, et al. Pelvic floor muscle functioning in women with vulvar vestibulitis syndrome. J Psychosom Obstet Gynaecol. 2005;26(2):107–113.

MacNeill C. Dyspareunia. Obstet Gynecol Clin North Am. 2006;33(4):565–577, viii.

4. Bornstein J, Goldstein AT, Stockdale CK, et al. 2015 ISSVD, ISSWSH, and IPPS consensus terminology and classification of persistent vulvar pain and vulvodynia. J Sex Med. 2016;13(4):607–612. 5. Harlow BL, Stewart EG. A population-based assessment of chronic unexplained vulvar pain: have we underestimated the prevalence of vulvodynia? J Am Med Womens Assoc. 2003;58(2):82–88. 6.

Arnold LD, Bachmann GA, Rosen R, et al. Vulvodynia: characteristics and

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19. Morin M, Carroll MS, Bergeron S. Systematic review of the effectiveness of physical therapy modalities in women with provoked vestibulodynia. Sex Med Rev. 2017;5(3):295–322. 20. Dunkley CR, Brotto LA. Psychological treatments for provoked vestibulodynia: integration of mindfulness-based and cognitive behavioral therapies. J Clin Psychol. 2016;72(7):637–650. 21. Masheb RM, Kerns RD, Lozano C, et al. A randomized clinical trial for women with vulvodynia: cognitive-behavioral therapy vs. supportive psychotherapy. Pain. 2009;141(1–2):31-40.

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Pain Education for Patients Using Modern Science Frameworks By Kate Schopmeyer PT, DPT, CPE

physical therapy

Prominent clinicians and researchers in the field of pain care are calling for a dramatic shift in how we as a healthcare community conceptualize pain, which will change treatment options.1 The physical therapy profession is undergoing a groundswell of change. As a group, we have embraced a shift in conceptual framework for pain and begun explaining to our patients the neurophysiology and neuroimmune factors that influence pain as part of a standard course of care. There is mounting evidence to support the use of this type of education, which goes by many names, including pain neuroscience education (PNE), in clinical practice, particularly for people who live with persistent pain.2,3

Any human seeking treatment or medical investigation to address a pain problem wants to know4-6

○○ Why do I have pain? ○○ How long will it take for the pain to go away? ○○ What can I (the patient) do to stop the pain? ○○ What can you (the provider) do to stop the pain? After ruling out sinister causes, clinicians often attempt to explain pain to their patients using various biomechanical models. In cases where injury is evident, and the injured body part is also painful, teaching people about tissue health and healing timelines is appropriate, and may even be beneficial.7,8 When pain persists beyond normal expected timeframes, or when pain cannot be connected to any known injury or illness, biomedical explanations are not only inadequate and ineffective, but may actually increase fear and erode function.9,10 Wood et al summarized the concept of pain neuroscience education: “PNE differs from traditional pain education by aiming to desensitise the neural system by focusing on the neurophysiology, neurobiology, representation of pain and meaning of pain, in place of using a traditional anatomical and biomedical model.”11 PNE for chronic musculoskeletal conditions benefits patients in varied ways, including reducing pain, improving patient knowledge of pain, improving function, lowering disability, enhancing movement (reducing unhelpful protective guarding), and minimizing healthcare utilization.12-16 Though many have made this shift in framework, more clinicians hesitate to adopt this approach or shy away from it after a

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few failed attempts. If you have ever sat across from a person in pain who looked back with skepticism and disappointment as she remarked, “So you think this pain is all in my head?” then you know what it means to fail at teaching. One reason for PNE failures is that patients need first to be “un-educated” about inaccurate health information before they can be re-educated using an updated framework.17,18 This type of un-educating could include discussing the multidimensional and individual nature of, and how, thoughts about pain, beliefs, emotions, and behavior habits (movement and lifestyle) can reinforce a vicious pain/disability cycle.

One salient example of how thoughts and emotions influence our physiology is the human experience of embarrassment. When we get embarrassed, our body shows it. We flush, may feel warm, might sweat, and our body posture changes involuntarily. The same relationship between thoughts or emotions and our other protective systems exists. Researchers have been able to show that just looking at someone bending over to pick up a piece of luggage can make your back hurt.20 In other words, thoughts like “it’s dangerous to lift with a rounded back” can cause low back pain, even when the human having the thoughts is lying still in an fMRI scanner. As easily as a negative thought about back health can result in a pain experience, a positive one can reduce distress and alter pain related behavior. Changing the language included in medical imaging reports can improve Q 4 | 2018

When pain persists beyond normal expected timeframes, or when pain cannot be connected to any known injury or illness, biomedical explanations are not only inadequate and ineffective, but may actually increase fear and erode function.

health outcomes in people with pain,21,22 for example, supplying common radiographic findings for asymptomatic people along with an individual medical imaging study report. More specifically, when the percentage of people with no back pain who also have evidence of bulging discs, degenerative disc disease, or spinal stenosis was included on the bottom of a medical imaging report, patients treated for back pain were prescribed fewer narcotics in the course of their care than those whose MRI reports did not include these data.22

Have you ever believed your glass contained milk and were shocked to taste orange juice instead? Feelings of disgust would normally not accompany a swig of OJ, but when we expect one thing and experience something different, our protective systems respond and can completely alter a taste experience. Someone with longstanding back pain is often frightened to Q 4 | 2018

move, believing that the pain felt with certain movements means his/her back is being reinjured. This type of catastrophic belief can lead to greater disability over time.23 Health beliefs are engendered and reinforced by medical providers, and can be extremely difficult to unlearn. Compassionately reassuring patients that movement is safe and healthy, even if it is painful, combined with strategically placed PNE can have a profound impact on function for people with persisting pain.24,25

For clinicians, it is important to have a basic list of items to use in the clinic: use prepared metaphors and examples to shift thinking frameworks, and include illustrations like hand drawings or other visual aids.26,27 Some pertinent concepts that www.painweek.org | PWJ

physical therapy

…to effectively teach about pain, it is imperative that a clinician has a deep understanding of the biological principles and complex neurobiological processes underpinning pain mechanisms and painful states.

underpin pain mechanisms and should be integrated into our clinical reasoning with each patient case are these:

○○ Persistent pain is not just about “tissue issues” ○○ The central nervous system plays a big role in all pain states ○○ Pain is an output of the brain, which influences inputs ○○ Pain is modulated by meaning, context, beliefs, expectations, and experience ○○ Nociception is neither sufficient nor necessary for pain production ○○ Sensitization is a natural adaptive feature of the nervous system and can be unhelpful ○○ Neuroplasticity or bioplasticity principles are used to reverse some unhelpful adaptations in the nervous system This list could be sample language for practitioners discussing patients with practitioners, or the phrases can be used with patients. Contrary to common belief, both patients and clinicians can understand higher level pain terminology.28 For those seeking simpler ways to talk to the patient about his or her pain condition, metaphors have proven effective.2,26,29 Below are a few examples of how to distill your language for patients.

Have you ever removed the batteries from your smoke detector? Why did you do that? We’ve all experienced a smoke detector that was too sensitive and triggered by something as simple as burnt toast. Pain is one part of our body’s alarm system. Pain is usually useful,

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because it’s designed to protect us. But sometimes the pain alarm can go off when there is no actual danger to our body tissues. Sometimes our body’s alarm system becomes too sensitive, like a smoke alarm alerting you about the toast or when a single candle is lit.

Think about your pain problem like a guitar with an amplifier attached. If the sound coming from a guitar is off, it’s logical to try and repair the strings, look for imbalances, or “fix” what’s broken. Science now tells us that many persistent pain conditions are like a guitar that is intact and working well, but its amplifier is dialed up too high, causing a screech. Treatments for amplifiers are different than treatments for guitar parts. Phrases to reassure patients in a short visit:

○○ Pain is complex and individual ○○ When you have persistent pain, it means there is a problem in your body AND a problem in your nervous system ○○ The nervous system is wonderfully adaptable ○○ Find the threshold of your body’s alarm and go to it, not through it ○○ It’s safe for you to move [presuming that a thorough assessment and physical examination was conducted with no sinister findings or medical precautions] ○○ You can be sore, but safe ○○ Movement is the best medicine and if it hurts to move, we need to find the right dose Q 4 | 2018

For the eager clinician hoping to launch into a new realm of pain treatment after reading this article, it is important to note that PNE should not be considered a stand-alone intervention. Teaching about pain from a neurobiology perspective works best in combination and can enhance the effectiveness of many other traditional treatments including manual therapy,30-32 trigger point dry needling,33 aerobic exercise including circuit training,34 stabilization exercise/motor control,30,34-36 aquatic exercise,37 movement and general exercise,16,38 and graded exposure/pacing strategies for daily tasks.38-41 Graded exposure to exercise, movement, and activity is fundamental to any physical therapy treatment plan, and inserting PNE to address beliefs, fear, and modify inputs (including mechanical loads, sensory information, and cognitive associations) at key moments can yield enhanced treatment results.2

Scholarly Articles ●● Louw A, Zimney K, O’Hotto C, et al. The clinical application of teaching people about pain. Physiother Theory Pr. 2016;32(5):385–395. ●● Moseley GL, Butler DS. Fifteen years of explaining pain: the past, present, and future. J Pain. 2015;16(9):807–813. ●● Nijs J, Van Wilgen CP, Van Oosterwijck J, et al. How to explain central sensitization to patients with ‘unexplained’ chronic musculoskeletal pain: practice guidelines. Man Ther. 2011;16(5):413–418. Books for the Ambitious Adult Learner ●● Butler DS, Moseley GL. Explain Pain. Adelaide, Australia: Noigroup Publications; 2013. ●● Louw A, Puentedura E. Therapeutic Neuroscience Education: Teaching Patients About Pain. A Guide for Clinicians. 1st ed. (OPTP ed.) Louisville, Kentucky: International Spine and Pain Institute; 2013. ●● Mosley GL, Butler DS. Explain Pain Supercharged. Adelaide, Australia: NOI Group; 2017. References

Most challenging for the clinician will be to “un-learn” the way we teach about pain. Educating patients in a manner consistent with modern pain science does not have to be lengthy or complicated. However, in order to effectively teach about pain, it is imperative that a clinician has a deep understanding of the biological principles and complex neurobiological processes underpinning pain mechanisms and painful states. Ideally, clinicians also have a sophisticated perspective on all factors within the biopsychosocial framework that drive persistent pain experiences. An abundance of resources is now available to clinicians (and patients) to facilitate a shift in persistent pain conceptualization. It is up to each practitioner to recognize and reject outdated knowledge of pain mechanisms. Understanding neuroplasticity, appreciating the neuroimmune underpinnings of pain processing and remaining in awe of the complexity of pain is the duty of all healthcare providers. Armed with a solid foundation of knowledge and a little practice, a clinician can be an effective teacher during a brief clinical interaction. We are on the verge of a sea change in pain care with a significant cultural transformation on the rise. With enough humbleness to risk being misunderstood at first, and the willingness to persist and improve communication about pain, we can hope to more effectively treat persistent pain and prevent disability for our patients. Online Resources ●● aptei.ca

●● ispinstitute.com

●● bettermovement.org

●● lifeisnow.ca

●● bodyinmind.org

●● noigroup.com

●● gradedmotorimagery.com

●● painscience.com

●● greglehman.ca (free e-book for pain education and recovery strategies)

●● retrainpain.org

●● healthskills.wordpress.com

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●● tamethebeast.org

1. Lewis J, O’Sullivan P. Is it time to reframe how we care for people with non-traumatic musculoskeletal pain? Br J Sports Med. 2018;June 25. [ePub ahead of print] 2. Louw A, Zimney K, O’Hotto C, et al. The clinical application of teaching people about pain. Physiother Theory Pr. 2016;32(5):385–395. 3. Moseley GL, Butler DS. Fifteen years of explaining pain: the past, present, and future. J Pain. 2015;16(9):807–813. 4. Verbeek J, Sengers MJ, Riemens L, et al. Patient expectations of treatment for back pain: a systematic review of qualitative and quantitative studies. Spine (Phila Pa 1976). 2004;29(20):2309–2318. 5. McPhillips-Tangum CA, Cherkin DC, Rhodes LA, et al. Reasons for repeated medical visits among patients with chronic back pain. J Gen Intern Med. 1998;13(5):289–295. 6. Gifford L. Pain, the tissues and the nervous system: a conceptual model. Physiotherapy. 1998;84(1):27–36. 7. Louw A BD. Chronic Pain. In: Clinical Orthopaedic Rehabilitation. 3rd ed. Philadelphia, Pennsylvania: Elsevier Ltd; 2011. 8.

Gifford L. Aches and Pains. Falmouth, UK: CNS Press; 2014.

9. Stewart M, Loftus S. Sticks and stones: the impact of language in musculoskeletal rehabilitation. J Orthop Sport Phys Ther. 2018;48(7):519–522. 10. Zimney K, Louw A, Puentedura EJ. Use of therapeutic neuroscience education to address psychosocial factors associated with acute low back pain: a case report. Physiother Theory Pract. 2014;30(3):202–209. 11. Wood L, Hendrick P, Quraishi N. A systematic review of pain and disability outcomes of pain neuroscience education (PNE) in the management of chronic low back pain. Spine J Podium Presentations. 2016:S51. 12. Louw A, Zimney K, Puentedura EJ, et al. The efficacy of pain neuroscience education on musculoskeletal pain: a systematic review of the literature. Physiother Theory Pract. 2016;32(5):332–355. 13. Louw A, Puentedura EL, Diener I, et al. Preoperative therapeutic neuroscience education for lumbar radiculopathy: a single-case fMRI report. Physiother Theory Pract. 2015;31(7):496–508. 14. Louw A, Butler DS, Diener I, et al. Development of a preoperative neuroscience educational program for patients with lumbar radiculopathy. Am J Phys Med Rehabil. 2013;92(5):446–452. 15. Louw A, Diener I, Fernández-de-Las-Peñas C, et al. Sham surgery in orthopedics: a systematic review of the literature. Pain Med. 2017;18(4):736–750.

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16. Bodes Pardo G, Lluch Girbés E, Roussel NA, et al. Pain neurophysiology education and therapeutic exercise for patients with chronic low back pain: a single-blind randomized controlled trial. Arch Phys Med Rehabil. 2018;99(2):338–347. 17. O’Sullivan PB, Caneiro JP, O’Keeffe M, et al. Cognitive functional therapy: an integrated behavioral approach for the targeted management of disabling low back pain. Phys Ther. 2018;98(5):408–423. 18. Louw A, Zimney K, Johnson EA, et al. De-educate to re-educate: aging and low back pain. Aging Clin Exp Res. 2017;29(6):1261–1269. 19. Butler DS, Moseley GL. Explain Pain. Adelaide, Australia: Noigroup Publications; 2013. 20. Shimo K, Ueno T, Younger J, et al. Visualization of painful experiences believed to trigger the activation of affective and emotional brain regions in subjects with low back pain. PLoS One. 2011;6(11):e26681. 21. Bossen JKJ, Hageman MGJS, King JD, et al. Does rewording MRI reports improve patient understanding and emotional response to a clinical report? Clin Orthop Relat Res. 2013;471(11):3637–3644. 22. McCullough BJ, Johnson GR, Martin BI, et al. Lumbar MR imaging and reporting epidemiology: do epidemiologic data in reports affect clinical management? Radiology. 2012;262(3):941–946.

36. Dolphens M, Nijs J, Cagnie B, et al. Efficacy of a modern neuroscience approach versus usual care evidence-based physiotherapy on pain, disability and brain characteristics in chronic spinal pain patients: protocol of a randomized clinical trial. BMC Musculoskelet Disord. 2014;15:149. 37. Pires D, Cruz EB, Caeiro C. Aquatic exercise and pain neurophysiology education versus aquatic exercise alone for patients with chronic low back pain: a randomized controlled trial. Clin Rehabil. 2015;29(6):538–547. 38. Vibe Fersum K, O’Sullivan P, Skouen JS, et al. Efficacy of classification-based cognitive functional therapy in patients with non-specific chronic low back pain: a randomized controlled trial. Eur J Pain (United Kingdom). 2013;17(6):916–928. 39. Nijs J, Meeus M, Cagnie B, et al. A modern neuroscience approach to chronic spinal pain: combining pain neuroscience education with cognition-targeted motor control training. Phys Ther. 2014;94(5):730–738. 40. Van Oosterwijck J, Nijs J, Meeus M, et al. Pain neurophysiology education improves cognitions, pain thresholds, and movement performance in people with chronic whiplash: a pilot study. J Rehabil Res Dev. 2011;48(1):43–58. 41. Meeus M, Nijs J, Van Oosterwijck J, et al. Pain physiology education improves pain beliefs in patients with chronic fatigue syndrome compared with pacing and self-management education: a double-blind randomized controlled trial. Arch Phys Med Rehabil. 2010;91(8):1153-1159.

23. Turner JA, Jensen MP, Romano JM. Do beliefs, coping, and catastrophizing independently predict functioning in patients with chronic pain? Pain. 2000;85(1–2):115–125. 24. O’Sullivan K, Dankaerts W, O’Sullivan L, et al. Cognitive functional therapy for disabling nonspecific chronic low back pain: multiple case-cohort study. Phys Ther. 2015;95(11):1478–1488. 25. Meziat Filho N. Changing beliefs for changing movement and pain: classification-based cognitive functional therapy (CB-CFT) for chronic non-specific low back pain. Man Ther. 2016;21:303–306. 26. Gallagher L, McAuley J, Moseley GL. A randomized-controlled trial of using a book of metaphors to reconceptualize pain and decrease catastrophizing in people with chronic pain. Clin J Pain. 2012;29(1):20–25. 27. Louw A, Puentedura E. Therapeutic Neuroscience Education: Teaching Patients About Pain. A Guide for Clinicians. 1st ed. (OPTP ed.). International Spine and Pain Institute; 2013. 28. Moseley L. Unraveling the barriers to reconceptualization of the problem in chronic pain: the actual and perceived ability of patients and health professionals to understand the neurophysiology. J Pain. 2003;4(4):184–189. 29. Loftus S. Pain and its metaphors: a dialogical approach. J Med Humanit. 2011;32(3):213–230. 30. Moseley L. Combined physiotherapy and education is efficacious for chronic low back pain. Aust J Physiother. 2002;48(4):297–302. 31. Moseley G. A pain neuromatrix approach to patients with chronic pain. Man Ther. 2003;8(3):130–140. 32. Puentedura EL, Flynn T. Combining manual therapy with pain neuroscience education in the treatment of chronic low back pain: a narrative review of the literature. Physiother Theory Pract. 2016;32(5):408–414. 33. Tellez-Garcia M, de-la-Llave-Rincon AI, Salom-Moreno J, et al. Neuroscience education in addition to trigger point dry needling for the management of patients with mechanical chronic low back pain: a preliminary clinical trial. J Bodyw Mov Ther. 2015;19(3):464–472. 34. Ryan CG, Gray HG, Newton M, et al. Pain biology education and exercise classes compared to pain biology education alone for individuals with chronic low back pain: a pilot randomised controlled trial. Man Ther. 2010;15(4):382–387. 35. Beltran-Alacreu H, López-de-Uralde-Villanueva I, Fernández-Carnero J, et al. Manual therapy, therapeutic patient education, and therapeutic exercise, an effective multimodal treatment of nonspecific chronic neck pain. Am J Phys Med Rehabil. 2015;94(10 suppl 1):887–897.

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

Prescription Drug Diversion and Pain:

History Policy, and Treatment

Edited by John F. Peppin, John J. Coleman, Kelly K. Dineen, and Adam J. Ruggles Oxford University Press 2018

This book was written to inform healthcare professionals about some of the key components of pain treatment, with particular focus on long-term use of opioid analgesic therapy. Authored by a number of different experts in the field, perspectives are given from people involved in law enforcement, medicine, regulatory and public policy, pharmacy, drug treatment, academia, along with general public opinion. One of the strongest qualities about this text is the authors’ capability in making the subject matter presented both clinically and ethically relevant. Admittedly, much has changed and will change regarding the role of long-term opioid therapy in the treatment of chronic pain. By giving a good contextual history and current controversies surrounding this subject, the authors do a very good job in detailing the past and present landscape. This book provides a strong emphasis on legal and policy perspectives, which are likely to be quite valuable to both healthcare professionals and others who are interested in grappling with the ethical questions at hand—prescribing opioids to people in valid medical need vs potential abusers, misusers, people who may become addicted, and diverters.

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Many questions are posed to the reader throughout and handily answered regarding important events that have helped shape today’s pain management environment, including the outcome of the of the Decade of Pain Control and Research, the role of pharmaceutical manufacturers in today’s “opioid epidemic,” and how regulatory agencies have become more and more integrally involved in the clinical terrain of managing chronic pain. About two thirds of the way through the text, the authors focus on the “nuts and bolts” of managing pain in clinical practice. A subject not often covered in similar books is the intimate relationship between medical and biopsychosocial approaches in the treatment of chronic pain. Concluding with a comprehensive examination of substance abuse and risk assessment, a strong emphasis is placed on how clinicians can practically approach these complex situations without losing focus of the mission of managing pain. I think this book has a valuable place in every frontline practitioner’s library for both knowledge acquisition and reference purposes. Further, I think this could be an excellent educational resource for students in every healthcare discipline that is or will likely be involved with managing chronic pain in the near and distant future. With so little education taking place in those settings today for our clinicians of tomorrow, this text could certainly go a long way to bridge that educational gap. Q 4 | 2018

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Alexandra McPherson pharmd, mph

Adjunct Professor Philadelphia College of Pharmacy Clinical Pharmacist Einstein Medical Center, Intensive Care Unit, Satellite Pharmacy, Philadelphia

alexandra MCPHeRSON GPS Washington, DC Typical Day There really is no “typical” day. Often, the day begins with sit-down rounds to provide

pertinent clinical updates, assign responsibility for new consults and follow up visits, and bounce ideas off our colleagues regarding complex cases. The rest of the day is spent seeing patients at the bedside, facilitating family meetings, and presenting/participating in didactic lectures, workshops, and journal clubs with the team, fellows, and other learners. When I wrap up for the day, I head home to walk my two dogs, work out, and make dinner with my husband. (Side note: if you don’t have an Instant Pot, you need one!) Persona I firmly believe that if you’re the smartest person in the room, you’re in the wrong room. Throughout my training, I’ve been fortunate to be surrounded by influential and innovative thought leaders who have helped pave the way for future leaders such as myself. As I embark upon my first “real” job, I believe it is my resiliency, persistence, belief in the team approach, and genuine desire to advance the practices of pain management and palliative care that will position me to be a key opinion leader of the next generation. Contribution When done correctly, palliative care is an example of how all medicine should be conducted. Individualized, patient centered, quality care that honors the values, beliefs, and experiences which have led the patient to this point in their life. I’m most proud when I’m able to make recommendations that alleviate a patient’s symptoms and improve their quality of life for whatever quantity remains. People I’m sure it will come as no surprise when I say the person I most admire is my mother, Dr. Mary Lynn McPherson. She is, without question, the hardest working person I know and she truly embodies the concept of lifelong learning. This, coupled with the fact that she’s an undeniably dynamic speaker, has allowed her to develop a cult-like following. I can only hope that all those years of her driving me to field hockey practice while performing methadone calculations on speakerphone osmosed into my brain! A close runner up is my PGY-2 Residency Program Director turned mentor, colleague, and friend, Dr. Kathryn Walker, who serves as the MedStar Health System Senior Clinical Director for Palliative Care. She makes the impossible possible and is always one step ahead, strategizing ideas to help those in her network. Words Having just completed two years of residency, I’m looking forward to having the free time to read things besides guidelines and peer-reviewed journal articles. In my time off over the summer, I read the Kevin Kwan trilogy (great beach reads!). Other favorites are Tuesdays with Morrie, The Help, Tiny Beautiful Things, and anything by Brené Brown. Popcorn My favorite movie is Father of the Bride. I know (and will recite) every single word, Franck accent and all. Another favorite is Bridesmaids, which never fails to make me laugh, and in the spirit of Halloween, Hocus Pocus is an oldie but a goodie. Favorite Podcasts: The Curbsiders, GeriPal, Dear Sugars, Rise, 10% Happier P iNWeek PAINWeek provides an unparalleled opportunity to expand the breadth and depth of your knowledge base across all areas of pain management. It’s also a great place to reconnect with old colleagues, meet new people, and build your network.

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By Doug Gourlay md, msc, frcpc, fasam

Patient centered care does not mean “Give the patient whatever they want, as long as they know the risks.” When talking to patients, it’s important to offer choices with similar risk. Certainly, if Choice A, B, and C are all roughly equal, the patient should be encouraged to make the final choice. But if Choice A and B are roughly equal, and Choice C is simply wrong, the patient centered options are A or B, NOT C. A classic example is the patient who dismisses the risks of high dose opioids: “I don’t care if I get addicted” or “I don’t care if they (opioids) shorten my life— I absolve you of all responsibility.” The group known as “next-of-kin” will not be nearly so forgiving!

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Use of polyethylene (XLPE) for hip implant components substantially decreased incidence of revision surgery following total hip replacement. A study analyzed

240,000

arthroplasty procedures between 1999 and 2016.

Conventional polyethylene (CPE) surfaces were used in

41,000 implants;

251

A study followed

In patients who did not take opioids prior to their surgery, a

An assessment of patients <55 years at 7 years’ postprocedure found the advantage associated with XLPE to be about 5x.1

Younger patients who filled a prescription for opioids when undergoing wisdom tooth extraction were 2.7x more likely to fill ≥2 more prescriptions in the following year.

Some

3.5 million extraction procedures are performed

in the US yearly, and opioids are routinely prescribed for postsurgical pain.

56,686 patients who were opioid naïve prior to their wisdom tooth extraction and who filled an opioid prescription, 1.3% progressed to “persistent” opioid use, as compared to 0.5% repeat users in

14,256 patients who did not receive opioids at the time of their surgery.2

people, had chronic pain; or

helped almost

to wean off their opioids.

Almost

US adults, or

Transitional Pain Program

During the study interval, usage of XLPE increased from ~9% to 97%. At 9 years postprocedure, patients with CPE implants were 3x more likely to require revision surgery compared to XLPE patients.

20.6 % 50million 8.0% 19.6 million

estimated

surgical patients at risk for developing chronic postsurgical pain.

XLPE were used in

199,000.

Using 2016

National Health Interview Survey data, the CDC concluded that an

had high-impact chronic pain.

The survey authors cite

major strengths

of patients who were taking opioids before surgery were also successful in weaning completely. Among the techniques used for weaning: regular communications via phone call and follow-up meetings for up to 6 months postprocedure.3

of the current work, including use of a large, nationally representative population group.5

A study examined health records from 1998 to 2017

8,879

patients with fibromyalgia.

138

The group included

34 96

known attempts at suicide and

adults

who had no prior experience with naloxone were shown a

cases of suicidal thoughts.

-minute video demonstrating correct administration via 1 of 3 methods:

substantially reduce the incidence of attempted suicide among patients with fibromyalgia:

2 nasal sprays 1 intramuscular involving

and

Single-step nasal spray delivery of naloxone proved to be the

easiest and most successful route of administration for members of the general community.4

Regular physician visits can

patients who did NOT attempt suicide spent an average of

50 hours

per year with their doctor, as compared to

<1 hour

annually by fibromyalgia sufferers who attempted self-harm.6

1. https://bit.ly/2puYwRn 2. https://bit.ly/2MUZCiZ 3. https://bit.ly/2Nt24SX 4. https://bit.ly/2QPrqbC 5. https://bit.ly/2PTaeRi 6. https://bit.ly/2QOqBjd

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Cannabis and the Endocannabinoid System Donald Abrams MD

The endocannabinoid 1 receptor is the single most densely populated G-protein coupled 7 transmembrane domain receptor in the human brain. So why do we and all animal species, down through sponges, have this system of cannabinoid receptors? Because just like with endorphins, we also make our own endogenous cannabinoids: the so-called endocannabinoids. It’s been postulated that the reason we have cannabinoid receptors and endocannabinoids is to help us forget pain. Cannabis was removed from the US pharmacopoeia in 1942. Most of today’s physicians have been trained during the era of cannabis prohibition where not only did we not learn about the endocannabinoid system and cannabinoid receptors, but we don’t learn anything about cannabis as medicine. But I believe that PCPs need to learn about what cannabis is and what it does and what its potential medical utility is in therapeutic settings. The knowledge base is still not as complete as we’d like it to be largely due to cannabis being considered a schedule 1 substance with a high potential for abuse; this makes it quite difficult to study. So the research looking at potential benefits of the plant itself is not really there, but there is enough that we are able to say that cannabinoids and cannabis may be useful for pain, for chemotherapy induced nausea and vomiting, and for spasticity associated with multiple sclerosis. Some states that are approving medicinal cannabis are now requiring a certain amount of education for PCPs, and I would urge people to take advantage of those offerings and learn what cannabis is and what it isn’t. It’s going to be hard for the cart to catch up to the horse, if you will, because patients have been telling us that this stuff works for a number of different conditions, but physicians want randomized placebo controlled double blind clinical trials, and they’re just not there yet.

Prescribing Guidelines —Prescribers, Patients, and Pain Care Stephen Ziegler PhD, JD

The terms prescribing guidelines and prescribing rules are often used interchangeably although they really have separate meanings. Guidelines, by their nature, are voluntary recommendations. Whereas rules are mandatory. It’s important for prescribers to be aware of what exactly the rules or the guidelines are in their state.

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The recent history of prescribing guidelines started in Washington State. A pilot educational project ended up being a rule: when a chronic noncancer patient receives 120 mg morphine equivalent dose or more per day it will trigger the necessity for the prescriber to secure a pain consultation unless exempted from the rules. And so, this approach heavily emphasizes dosage thresholds as a key part of policy, and has essentially spread across the United States in various forms—some states 60, some 120, some 100. Prescribing guidelines were originally created to aid the practitioner and be combined with their knowledge and experience to provide an additional point of information. Unfortunately, states and other entities such as insurance companies are now using the guidelines for things other than clinical purposes. Oftentimes prescribers, being risk adverse, will reduce their prescribing and/or not want to take on chronic noncancer pain patients. And although the CDC may recommend nonpharmacologic approaches to treating pain, the reality is there may not be other modalities that are as effective as opioids or are covered by insurance. Denial of coverage is denial of care. And so, you have these lost souls—people in pain with limited ways to go. A recent study found that only 12% of state medical boards had a plan in place about what to do if patients were to lose prescribers who can prescribe opioids to treat chronic pain. There is also reason for concern about the impact of current guidelines on the patient/ provider relationship. What has happened is that there are other people at the party, so to speak, and those are regulators. And so, it brings up certain ethical concerns about privacy and what’s in the best interest of the patient. Pain treatment by its very nature is individualized and states that implement guidelines in the interest of reducing harm associated with opioids, whether legitimate or illicit, need to realize that one size does not fit all and a primary focus on dosage alone is problematic for a variety of reasons.

Treating Chronic Migraine: Remember the Fundamentals

Thomas Ward MD

Headache, by itself, is just a symptom. It’s like saying someone has arm pain: there are many causes of arm pain. There are over 300 different causes of headache. Some of them are threatening, secondary headaches. Some are not threatening but problematic: those are primary headaches. Once you know that your patient has a primary headache, then you want to find out, with as much specificity as possible, what kind of a headache is it. Is it in fact a migraine? If so, is it episodic migraine, meaning less than half the month, or chronic migraine meaning 15 or more days a month. When you’re choosing an acute treatment for a patient with headache, you really need to know the characteristics of the patient’s attack—does it wake them up at night full blown so there’s really little time to treat? Do they have nausea or vomiting, which suggests that giving a pill isn’t a great plan? Those patients could use a nasal spray or an injection or maybe a suppository. The person whose headache comes on leisurely over several hours during the day might use an oral medication if they can catch the headache fast enough. Some patients need more than one option. The Migraine Treatment Optimization Questionnaire is a set of YES/NO questions that you ask a patient: Is their treatment reliable? Can they count on it? Does it work quickly? Can they plan their life? Each answer should be a YES. The questionnaire addresses

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unmet needs. So if your patient answers NO, “I can’t count on my acute treatment to relieve an attack,” that’s an unmet need that needs to be addressed. Or “I can’t make plans for my weekend family event because I don’t know if I’m going to be able to control my headaches,” or does their medication, the formulation, work only some of the time. Any NO answers mean there is an unmet treatment need.

Naloxone: Silver Bullet or Tool in the Shed?

Kevin Zacharoff, MD, FACIP, FACPE, FAAP

Is naloxone the silver bullet? Well maybe the silver bullet du jour. I think the biggest challenges with respect to naloxone are educational hurdles because, unlike the EpiPen, naloxone is intended to be administered by someone else, not the patient. So that means the burden of determining an appropriate candidate for administration, determining the fact that naloxone needs to be administered, has to be done by someone who is not the patient and the question in my mind is, how does that education take place? How does it take place on a wide enough spectrum to enable somebody to administer it in the correct setting at the right time in the right place? It’s a big challenge and I don’t see a lot taking place with respect to education about the administration of the medication, let alone what the potential risks are giving it to someone who is physiologically dependent on an opioid medication. The administration of naloxone could precipitate withdrawal instantaneously and somebody needs to know how to deal with the consequences of that. It’s important to remember that reversing respiratory depression does not equal reversing overdose. Prince, for example, experienced a respiratory arrest on a plane and naloxone was administered to him. He got to a hospital, where presumably he was on naloxone infusion, and then he checked himself out of the hospital a day and a half later and overdosed. Naloxone can be a component of a broader risk management strategy due to what I call “the new math of risk benefit analysis” that says we need to consider the societal impact of the prescription. And when you think about the societal impact, that could mean bringing up naloxone when you’re writing the opioid prescription and talking about keeping it in the household in the event that someone suffers unintended consequences. So it’s a component, but it’s only a component in the context of a much, much broader initiative.

ask a patient what they want, the overwhelming response is going to be that they want to be pain free. And, we know that that is just not possible in certain populations. There’s a lot of neurobiochemical reasons why that may occur; changes that make someone a little bit more prone to having pain for an indefinite period. Those are the people where you really need to focus on functionality, where maybe the goal is not going to be “pain freedom” but to be able to learn how to function and cope with the pain they experience daily. Now that CGRP medications and monoclonal antibody therapies are coming out, there will be a very large new armamentarium that we’ll have available to treat headache patients. It seems like early studies on those medications are very promising, that not only are they efficacious, but they’re also very well tolerated. It seems like they’re going to be appropriate medications for populations of people that perhaps other medications that we use frequently are not appropriate for. The issue, of course, is going to be cost and what is that going to mean for the accessibility of these medications. Beyond medications we have other things that studies indicate are effective, and are becoming more popular, including single-pulse transcranial magnetic stimulation, noninvasive vagal nerve stimulation, and peripheral stimulation through devices that stimulate supraorbital nerves, or even implanted devices that can stimulate greater occipital nerves. When choosing among treatment options, we look for comorbid conditions and for other issues resulting from their chronic pain, such as cardiovascular risk factors or cerebrovascular risk factors, depression, anxiety, GI issues. We pick medications that may not only work for treating chronic migraine issue, but also may treat some other comorbid conditions. We can frequently titrate antiepileptic medications, antidepressant medications, antihypertensives to get more than one treatment effect out of them.

Preventative Pharmacotherapy for Chronic Migraine —One Step at a Time

Bert Vargas MD, FAHS, FAAN

Approximately 1 billion people in the world are affected with migraine and the thought is that about 40% of them are candidates for some type of preventative therapy, and a sizable proportion doesn’t receive it. That equates to a very large burden exerted on a population who can’t function normally because they have headache of a very high frequency. We need to not only identify those people and recognize who is a candidate for therapy, but then also make sure that they’re receiving the right kind of therapy. One of the things that we look to do is set up some reasonable goals, especially when you have an individual who has headache on most days or every day. I think if you

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mary lynn

mcpherson

pharmd, ma, mde, bcps, cpe

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“It is a privilege and honor to walk with a patient on their final journey.”

Q What inspired you to become a healthcare provider?

Right after graduating with my first degree (business), I got a job as a pharmacy technician. I loved it, but decided I wanted to BE the pharmacist, not just work for one. So I went to pharmacy school and eventually accidentally (happily) ended up in academia, which allows me to indulge all my passions of clinical practice, teaching, and research.

Why did you focus on pain management?

My focus is on pain management and palliative care. When I was in pharmacy school I signed up for what I thought would be an easy rotation: Hospice. The preceptor almost worked me to death, but I fell in love that month. It may sound cheesy, but helping to care for this fragile patient population absolutely fulfills part of my personal mission statement to make a difference every day. It is a privilege and honor to walk with a patient on their final journey.

Who were your mentors?

I have had many mentors throughout my career, brilliant and gracious individuals. Throughout pharmacy school and early in my career: Dr. Gary Hollenbeck, a pharmaceutics professor at the University of Maryland School of Pharmacy. In

Q 4 | 2018

palliative care I have been very fortunate to learn from the giants: Dr. Mellar P. Davis, Dr. Eduardo Bruera, and so many others.

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

If I didn’t practice in palliative care I’d probably be a sit-down comic. Bad knees preclude me being a stand-up comic.

What is your marked characteristic?

I think I have several distinctive characteristics. I believe people should do what they feel passionately about, and with a great deal of compassion. I am rabidly passionate about meaningful education, and I have great compassion for people living with a serious illness. Of course, I also tend to enjoy living “out of the box.” My bestie has promised that somewhere on my headstone one day it will say “There’s a box?”

Q What do you consider your greatest achievement?

My daughter Alexandra (see her Next Generation interview in this issue). Alex has an incredible personality that allows her to immediately put vulnerable populations at ease—pets, small children, delirious patients, patients with

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“I also tend to enjoy living ‘out of the box.’ My bestie has promised that somewhere on my headstone one day it will say ‘There’s a box?’”

an advanced illness, and so forth. We are so proud of her decision to also become a palliative care pharmacist (sorry Jim [hubbie, an accountant], you lose!). After Alex, it would have to be the book I wrote on opioid conversion calculations, which has been astonishingly successful. Probably because most people would rather eat a bug than do drug math.

What is your favorite language?

I’m fluent actually in several different languages: English of course, drugs, profanity, and my favorite—sarcasm (specializing in the dialect of snark!). Seriously, I wish I spoke the beautiful language of French. After four years of high school French, I can tell you that Jean-Claude is at the swimming pool, but that’s about it!

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?

I wish I could tell you I’d select some erudite book like One Hundred Years of Solitude by Gabriel Garcia Marquez, but I’m going to go with the entire Eve Dallas In Death series written by JD Robb (who is really Nora Roberts in disguise). For the film, it would have to be The Princess Bride—seriously, I do palliative care for a living; there’s a HUGE difference between “mostly dead” and “all dead!”* For

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the music, I would go with Rachmaninoff/RimskyKorsakoff’s Flight of the Bumble Bee. I aspire to play it like Maksim,† but that might be a while in coming.

What would you like your legacy to be?

I hope that when I transfer to the Eternal Care Unit that I will have made a difference in people’s lives. And if I have, I hope it continues to self-perpetuate, with people paying it forward.

What is your motto?

There are so many to choose from! I frequently borrow from Mahatma Gandhi: “Live as if you were to die tomorrow. Learn as if you were to live forever.” (Have I told you about my masters in palliative care program yet?). Another favorite is “Work smarter, not harder!” But I must not be following my own advice because I’m frequently heard to say “Eh, I can sleep when I’m dead!” Mary Lynn McPherson, pharmd, MA, MDE, BCPS, CPE, is a Professor at the University of Maryland School of Pharmacy, where she is the Executive Director of Advanced Post-Graduate Education in Palliative Care, and the Program Director of the Online Master of Science and Graduate Certificates in Palliative Care. *Available on youtube: https://bit.ly/2rRHhfW

†Available on youtube: https://bit.ly/2IUkNB2

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NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) CONTRAINDICATIONS: NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extendedrelease products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a or injecting the dissolved product will result in the uncontrolled potentially fatal overdose of tapentadol. delivery of tapentadol and can result in overdose and death. Profound sedation, respiratory depression, coma, and death Opioids are sought by drug abusers and people with addiction may result from the concomitant use of NUCYNTA ER with disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, reduce these risks include prescribing the drug in the smallest muscle relaxants, general anesthetics, antipsychotics, other appropriate quantity and advising the patient on the proper opioids, alcohol). Because of these risks, reserve concomitant disposal of unused drug. Contact the local state professional prescribing of these drugs for use in patients for whom licensing board or state controlled substances authority for alternative treatment options are inadequate. information on how to prevent and detect abuse or diversion of this product.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants (continued) Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs. Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: NUCYNTA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Alternatively, consider the use of non-opioid analgesics in these patients. Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock.

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication. Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER.

The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

Risk of Use in Patients With Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy.

Please see Brief Summary, including BOXED WARNING, on the following pages.

ADVERSE REACTIONS: In clinical studies, the most common (≥10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence.

Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing NUCYNTA ER, gradually taper the dose. Do not abruptly discontinue NUCYNTA ER.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use NUCYNTA ER safely and effectively. See full Prescribing Information for NUCYNTA ER. INDICATIONS AND USAGE NUCYNTA ER (tapentadol) is indicated for the management of: • pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Usage • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations (see Warnings and Precautions), reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. • NUCYNTA ER is not indicated as an as-needed (prn) analgesic. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.3). • Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7). CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product (see Adverse Reactions). • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see Drug Interactions). WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present (see Drug Abuse and Dependence). Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death (see Overdosage). Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the

proper disposal of unused drug (see Patient Counseling Information). Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see Overdosage). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential (see Dosage and Administration). Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see Use in Specific Populations, Patient Counseling Information). Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol (see Clinical Pharmacology). Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Drug Interactions and Patient Counseling Information). Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: NUCYNTA ER treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER (see Warnings and Precautions). Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see Warnings and Precautions). Alternatively, consider the use of non-opioid analgesics in these patients. Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration (see Warnings and Precautions). Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic

antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see Drug Interactions). This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy. Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms (see Drug Interactions). When discontinuing NUCYNTA ER, gradually taper the dose (see Dosage and Administration). Do not abruptly discontinue NUCYNTA ER (see Drug Abuse and Dependence). Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication (see Patient Counseling Information). Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment (see Dosage and Administration and Clinical Pharmacology). Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known (see Clinical Pharmacology). ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see Warnings and Precautions) • Life-Threatening Respiratory Depression (see Warnings and Precautions) • Neonatal Opioid Withdrawal Syndrome (see Warnings and Precautions) • Interaction with Benzodiazepine or Other CNS Depressants (see Warnings and Precautions)

• Serotonin Syndrome (see Warnings and Precautions) • Adrenal Insufficiency (see Warnings and Precautions) • Severe Hypotension (see Warnings and Precautions) • Gastrointestinal Adverse Reactions (see Warnings and Precautions) • Seizures (see Warnings and Precautions) • Withdrawal (see Warnings and Precautions) Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The most common adverse reactions (reported by ≥10% in any NUCYNTA ER dose group) were: nausea, constipation, dizziness, headache, and somnolence. The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA ER dose group for NUCYNTA ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively. Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients. Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The most commonly reported ADRs (incidence ≥10% in NUCYNTA ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache. Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients. Postmarketing Experience The following adverse reactions have been identified during post approval use of tapentadol. Psychiatric disorders: hallucination, suicidal ideation, panic attack Serotonin syndrome: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in NUCYNTA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see Clinical Pharmacology). DRUG INTERACTIONS Clinically Significant Drug Interactions with NUCYNTA ER Alcohol Clinical Impact:

Concomitant use of alcohol with NUCYNTA ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Due to additive pharmacologic effect, the concomitant use of Impact: benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical The concomitant use of opioids with other drugs that affect Impact: the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.6]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue NUCYNTA ER if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical MAOI interactions with opioids may manifest as serotonin Impact: syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. Intervention: Do not use NUCYNTA ER in patients taking MAOIs or within 14 days of stopping such treatment Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical May reduce the analgesic effect of NUCYNTA ER and/or Impact: precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Tapentadol may enhance the neuromuscular blocking action of Impact: skeletal muscle relaxants and produce an increased degree of respiratory depression.

NUCYNTA ER (tapentadol) extended-release tablets, CII BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION (continued) Muscle Relaxants (continued) Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUCYNTA ER and/or the muscle relaxant as necessary. Diuretics Clinical Opioids can reduce the efficacy of diuretics by inducing the Impact: release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical The concomitant use of anticholinergic drugs may increase Impact: risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions). The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications. Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see Warnings and Precautions). Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor. Opioid analgesics, including NUCYNTA ER, can prolong labor. Lactation Risk Summary There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded. Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER. Clinical Considerations Monitor infants exposed to NUCYNTA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Pediatric Use The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established. Geriatric Use Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients. Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see Warnings and Precautions). Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment (ChildPugh Score 10-15) is not recommended. In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), dosage reduction of NUCYNTA ER is recommended (see Dosage and Administration). Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended. DRUG ABUSE AND DEPENDENCE Controlled Substance NUCYNTA ER contains tapentadol, a Schedule II controlled substance.

Abuse NUCYNTA ER contains tapentadol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA ER can be abused and is subject to misuse, addiction, and criminal diversion (see Warnings and Precautions). The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. NUCYNTA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of NUCYNTA ER NUCYNTA ER is for oral use only. Abuse of NUCYNTA ER poses a risk of overdose and death. The risk is increased with concurrent use of NUCYNTA ER with alcohol and other central nervous system depressants. With intravenous abuse the inactive ingredients in NUCYNTA ER can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. NUCYNTA ER should not be abruptly discontinued (see Dosage and Administration). If NUCYNTA ER is abruptly discontinued in a physicallydependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see Use in Specific Populations). OVERDOSAGE Clinical Presentation Acute overdosage with NUCYNTA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

TIME TO DUAL

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OF PAIN OF RELIEF

NUCYNTA® ER is the first and only FDA-approved long-acting opioid designed to control both nociceptive pain and the neuropathic pain associated with diabetic peripheral neuropathy (DPN).

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Not an actual patient. INDICATIONS AND USAGE NUCYNTA ER (tapentadol) is indicated for the management of: • Pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • Neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediaterelease opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain • NUCYNTA ER is not indicated as an as-needed (prn) analgesic

IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse NUCYNTA ER exposes patients and other users to the risks of opioid addiction, experts. If opioid use is required for a prolonged period in a pregnant woman, abuse, and misuse, which can lead to overdose and death. Assess each patient’s advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure risk prior to prescribing NUCYNTA ER, and monitor all patients regularly for the that appropriate treatment will be available. development of these behaviors and conditions. Interaction With Alcohol Life-threatening Respiratory Depression Instruct patients not to consume alcoholic beverages or use prescription or Serious, life-threatening, or fatal respiratory depression may occur with use of non-prescription products that contain alcohol while taking NUCYNTA ER. The coNUCYNTA ER. Monitor for respiratory depression, especially during initiation of ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol NUCYNTA ER or following a dose increase. Instruct patients to swallow NUCYNTA levels and a potentially fatal overdose of tapentadol. ER tablets whole; crushing, chewing, or dissolving NUCYNTA ER tablets can cause Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants rapid release and absorption of a potentially fatal dose of tapentadol. Concomitant use of opioids with benzodiazepines or other central nervous system Accidental Ingestion (CNS) depressants, including alcohol, may result in profound sedation, respiratory Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can depression, coma, and death. result in a fatal overdose of tapentadol. • Reserve concomitant prescribing of NUCYNTA ER and benzodiazepines or other Neonatal Opioid Withdrawal Syndrome CNS depressants for use in patients for whom alternative treatment options are inadequate. Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, • Limit dosages and durations to the minimum required. and requires management according to protocols developed by neonatology • Follow patients for signs and symptoms of respiratory depression and sedation.

Please see additional Important Safety Information, including BOXED WARNING, and Brief Summary on the following pages. Nucynta ER is a registered trademark of Depomed, Inc. © 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0001 02/18