PAINWeek Journal, Vol 3, Q1

vol. 3 q 1 2015

VULVODYNIA: A PREVALENT YET UNDERDIAGNOSED CHRONIC PAIN SYNDROMEP.14 PAIN CATASTROPHIZING! BIOPSYCHOSOCIAL ASPECTSP.22 CHART REVIEW: THE IMPORTANCE OF DOCUMENTATION FOR THE CHRONIC PAIN PATIENTP.34 PAIN & OPIOID USE DISORDERS: THE PRESENT AND FUTURE OF RISK ASSESSMENT AND MITIGATIONP.40

June 13–20, 2015

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EXECUTIVE EDITOR KEVIN PUBLISHER Aventine

L. ZACHAROFF MD, FACPE, FACIP, FAAP

Co. 6 Erie Street, Montclair, NJ 07042

ART DIRECTOR DARRYL

FOSSA

EDITORIAL DIRECTOR DEBRA EDITOR HOLLY

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

WEINER

CASTER

EDITORIAL BOARD

Peter A. Foreman DDS, DAAPM Consultant Rotorua Hospital and Private Practice Rotorua, New Zealand Gary W. Jay MD, FAAPM , DAAPM Medical Director DNA Center Daytona Beach, FL 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

Geralyn Datz PhD Affiliate University of Southern Mississippi Department of Psychology Clinical Director Southern Behavioral Medicine Associates Hattiesburg, MS

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 Director of Clinical Addiction Research and Education Millennium Laboratories San Diego, CA John F. Peppin DO, FACP Head of Global Medical Affairs, Pharmaceuticals Mallinckrodt Pharmaceuticals St. Louis, MO Joseph V. Pergolizzi MD Adjunct Assistant Professor Johns Hopkins University School of Medicine Department of Medicine Baltimore, MD Senior Partner Naples Anesthesia and Pain Medicine 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 Executive Director Foundation for Ethics in Pain Care Bellevue, WA 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

PWJ is published by Aventine Co. Copyright © 2015, Aventine Co.

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

Aventine Co. does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. Aventine Co. 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 Aventine Co. to accept, reject, or modify any advertisement submitted for publication. It is the policy of Aventine Co. to not endorse products.

Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

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/ PWJ / Q1 / 2015 10 | EXECUTIVE EDITOR’S LETTER by kevin l. Zacharoff

FEATURES

PAIN &OPIOID USE DISORDERS: the present and future of risk assessment and mitigation by martin d. Cheatle

14 | REGIONAL PAIN SYNDROMES

VULVODYNIA: a prevalent yet underdiagnosed chronic pain syndrome by georgine Lamvu / kenneth

40 | KEY TOPIC

Barron

22 | BEHAVIORAL

PAIN CATASTROPHIZING! biopsychosocial aspects by robert r. Edwards

SHORT CUTS

33 | ONE-MINUTE CLINICIAN

with debra k. Weiner , kathryn a. Walker , paul j. Christo ,

sean Mackey , ilene Robeck , michael Saenger

48 | PUNDIT PROFILE with michael e. Schatman

34 | FRONTLINE FOCUS

CHART REVIEW: the importance of documentation for the chronic pain patient by brett b. Snodgrass

6 | PWJ | www.painweek.org

Q1 | 2015

NOW APPROVED FOR THE TREATMENT OF OPIOID-INDUCED CONSTIPATION IN ADULT PATIENTS WITH CHRONIC NON-CANCER PAIN. In a clinical study of patients with chronic non-cancer pain who suffered from opioid-induced constipation: 6 out of 10 RELISTOR® (methylnaltrexone bromide) patients had at least 3 SBMs* per week1

33% of patients taking RELISTOR experienced an SBM* within 4 hours of their first dose1

• RELISTOR targets the underlying cause of opioid-induced constipation without affecting analgesia2 • RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction2 • In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain (21%), nausea (9%), diarrhea (6%), hyperhidrosis (6%), hot flush (3%), tremor (1%), and chills (1%). * Spontaneous Bowel Movement occurring without the use of rescue laxatives.

Indication RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

Important Safety Information about RELISTOR RELISTOR (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation. ®

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

Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.

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

common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.

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

In clinical studies in adult patients with opioid-induced constipation and advanced illness, the most common adverse reactions (≥ 5%) were abdominal pain, flatulence, nausea, dizziness, and diarrhea.

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

RELISTOR may precipitate opioid withdrawal in a fetus and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most

Please see Brief Summary of complete Prescribing Information for RELISTOR on the adjacent page.

References 1. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic nonmalignant pain: a randomized controlled study.

J Pain. 2011;12(5):554-562.

2. RELISTOR® (methylnaltrexone bromide) Prescribing Information, Salix Pharmaceuticals, Inc. www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024 ©2014 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. REL78-0914

The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

Limitation of use: Use of RELISTOR beyond four months has not been studied in the advanced illness population.

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

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

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

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

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

Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia.

This study (Study 1) included a 4-week, double-blind, placebo controlled period in which adult patients were randomized to receive RELISTOR 12 mg once daily (150 patients) or placebo (162 patients).

After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily.

Adverse reactions in adult patients with opioid-induced constipation and chronic non-cancer pain receiving RELISTOR are shown in the following table. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

Adverse Reactions* in 4-Week Double-Blind, PlaceboControlled Period of Clinical Study of RELISTOR in Adult Patients with Opioid-Induced Constipation and Chronic Non-Cancer Pain RELISTOR Placebo 12 mg once daily n = 162 n = 150 Abdominal Pain 21% 6% Nausea 9% 6% Diarrhea 6% 4% Hyperhidrosis 6% 1% Hot Flush 3% 2% Tremor 1% < 1% Chills 1% 0% * Adverse reactions occurring in ≥ 1 % of patients receiving RELISTOR 12 mg once daily and at an incidence greater than placebo.

During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature Adverse Reaction

change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR 12 mg every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 1) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%).

The safety of RELISTOR was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 2).

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

The most common (≥5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR are shown in the following table.

Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness* Adverse RELISTOR Placebo Reaction n = 165 n = 123 Abdominal Pain 29% 10% Flatulence 13% 6% Nausea 12% 5% Dizziness 7% 2% Diarrhea 6% 2% * Adverse reactions occurring in ≥ 5 % of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo.

The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1%) and placebo (2%).

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

Gastrointestinal Perforation, cramping, vomiting General Disorders and Administrative Site Disorders Diaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported.

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

Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day.

RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether RELISTOR is present in human milk.

However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions,

tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals.

Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs.

Geriatric Use In the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended.

Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault).

Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment.

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

If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

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

Administration Advise all patients to: • Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).

• Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use. • Be within close proximity to toilet facilities once RELISTOR is administered.

• Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued.

Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to: • Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days.

• Inject one dose every day.

• Inform their healthcare provider if their opioid regimen is changed, to avoid adverse reactions, such as diarrhea.

Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to: • Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

Gastrointestinal Perforation Advise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain.

Severe or Persistent Diarrhea Advise patients to discontinue RELISTOR if they experience severe or persistent diarrhea.

Opioid Withdrawal Advise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning.

Pregnancy Advise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.

Nursing Advise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024.

Manufactured for: Under License from:

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

Progenics Pharmaceuticals, Inc. Tarrytown, NY 10591

REL-RALAB56-102014

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KEVIN L.

ZACHAROFF MD, FACPE, FACIP, FAAP

T his edition of PWJ continues the tradition of bringing important and clinically pertinent information to clinicians involved in the management of people with chronic pain. As the Medical Director of PainEDU.org and serving on the Board of Directors of the American Society of Pain Educators, I am always gratified when I see literary material intending to bridge the knowledge gap for frontline practitioners of all disciplines.

I personally tend to see the parallels that abound between the management of chronic pain and other chronic medical conditions, whether education, standardization, use of best practices, tools, or documentation. I think the mission of PWJ is to paint a picture of those congruencies in a way that makes sense and provides clinical utility.

patient individuality is a function of not only their personality, but also their pain sensitivity and response. While this might sound a bit simplistic, Dr. Edwards dives in to expose the multiple factors that may be involved in this patient-level variability, specifically with respect to pain catastrophizing—a higher level of catastrophizing is associated with more severe and widespread pain, with a corresponding decrease in physical function. Even if there are adequate improvements in pain ratings, patients with pain catastrophizing may succumb to higher levels of disability and decreased social function as well. It is postulated that refinement of cognitive behavioral and other nonpharmacologic therapeutic approaches to address catastrophizing can potentially benefit the overall approach to managing chronic pain.

Family nurse practitioner Brett Snodgrass reinforces the role of chart documentation in managing patients with chronic pain, regardless of whether the practice setting is pain specialty or primary care.

The author carefully points out the inclusion of pain assessment into the clinical process as the “5th vital sign.” Clinicians now face challenges resulting from a number of fronts including unrealistic patient goal-setting and expectations, and opioid related overdoses.

The author makes the point that the responsibility for documentation falls squarely on the shoulders of healthcare providers, whether paper or electronic medical record systems are employed. This is a valuable read from a clinical, legal, and quality-of-care perspective.

Dr. Martin Cheatle provides a competent and comprehensive summary of the controversy involving the use of chronic opioid therapy in the management of chronic noncancer pain. Context is provided to enable the reader to gain an in-depth sense of the differing opinions on the rational use of chronic opioid therapy, along with a literature minireview of the efficacy and scope of aberrant drug-related behaviors in chronic pain patient populations. Most importantly to this Editor, Dr. Cheatle identifies a clear and reproducible set of components that can be employed to mitigate opioid “risk” and evaluates each of them from the perspective of utility in clinical practice. The author presents a stepwise process of what is currently considered the “standard of care” by many in the field, while waiting for other answers to be delivered by proven scientific evidence. This article is relevant to anyone involved in the treatment of chronic noncancer pain when opioid analgesic therapy is considered as a component of therapy.

Drs. Georgine Lamvu and Kenneth Barron use a case based approach along with detailed background to provide perspective on the need to include vulvodynia as part the differential spectrum of regional pain syndromes when faced with a female patient who presents com- As with past issues of PWJ, this issue successfully fulfills its mission plaining of chronic genitally related pain. Their article details the of complementing annual and regional PAINWeek and PAINWeekepidemiology and prevalence of this chronic pain condition and calls End conferences with information specifically targeted to frontline attention to the fact that, despite its common occurrence, it is rarely practitioners. I hope you enjoy reading this and, most of all, find some diagnosed in clinical practice. The authors also point out that, much things that can impact you and your patients in a positive way. like other types of chronic pain, vulvodynia’s impact on function and overall quality of life are essential drivers to make it important — KEVIN L. ZACHAROFF to consider in the appropriate patient population. Lastly, the case is made that women with vulvodynia may often suffer from a variety of other pain syndromes, as this condition rarely occurs in a vacuum.

Dr. Robert Edwards provides us with some insights into chronic pain from a behavioral perspective. The author reinforces the idea that

10 | PWJ | www.painweek.org

Q1 | 2015

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Martin D. Cheatle PhD

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Robert R. Edwards PhD, MSPH

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Georgine Lamvu MD, MPH

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Brett B. Snodgrass MSN, APRN, FNP-C

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Martin Cheatle is Clinical Assistant Professor of Psychology in Psychiatry and Director of Behavioral Medicine at the Penn Pain Medicine Center, and Director of Pain and Chemical Dependency Research at the Center for Studies of Addiction at the University of Pennsylvania Perelman School of Medicine. Dr. Cheatle has over 28 years of experience in the treatment of patients with chronic pain and concomitant addition.

Robert R. Edwards is Associate Professor at Harvard Medical School, Department of Anesthesiology, Perioperative, and Pain Medicine in Cambridge, Massachusetts. He is also Staff Psychologist at Brigham and Women’s Hospital Pain Management Center in Boston.

Georgine Lamvu is Medical Director of Gynecology and Director of Advanced Minimally Invasive Gynecology at Florida Hospital, Orlando. She is Associate Clinical Professor at the University of Central Florida and Past President of the International Pelvic Pain Society. Dr. Lamvu coauthored her article with Kenneth Barron, MD, who is a current fellow in Advanced Minimally Invasive Surgery and Gynecology.

Brett Badgley Snodgrass is a Family Nurse Practitioner specializing in pain management and palliative care at Saint Francis Bartlett Interventional Pain Clinic in Bartlett, Tennessee. She is also an award winning healthcare blogger known as The NP Mom. She speaks and teaches nationally on a wide array of healthcare topics.

12 | PWJ | www.painweek.org

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a prevalent yet underdiagnosed chronic pain syndrome

by Georgine

Lamvu MD, MPH / Kenneth Barron MD

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R GiONAL PAIN SYNDROM S

“CHRONiC PAiN CONDiTiONS OFTeN TRAVeL iN 2s AND 3s.

ONe OF THe TROUBLeSOMe AND VeRY PReVALeNT CHRONiC PAiN CONDiTiONS…iS VULVODYNiA…”

abstract: A 35-year-old mother of 2 walks into your clinic for follow-up of her irritable bowel syndrome. She seems to be in your clinic every month with various complaints: first it was burning with urination, then back and arm pain, and today she complains of 6 months of vaginal burning and pain. You’re beginning to wonder if there isn’t some common underlying element driving her various pain syndromes, including this newest complaint of vaginal symptoms.

If you’ve ever come across a patient like this you are not alone. Clinicians and researchers alike often notice common features of multiple chronic pain syndromes in the same patient. In fact, chronic pain conditions often travel in 2s and 3s. One of the troublesome and very prevalent chronic pain conditions that should be included in this group (but rarely is) is vulvodynia, currently defined as chronic vulvar pain lasting 3 months or longer and characterized by burning, stinging, irritation, or rawness of the female genitalia.1 The association between interstitial cystitis and vulvodynia was first noted in 1990.2 Since then many more studies have shown that vulvodynia can coexist with other pain disorders.3 Vulvodynia affects nearly 14 million American women, the majority of whom suffer for years. In spite of its high prevalence and association with poor quality of life, vulvodynia is diagnosed in less than 2% of women who have it.4 This article focuses on the role that healthcare providers can play in screening and identifying patients with this disorder in order to promote earlier evaluation and treatment.

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www.painweek.org | PWJ | 15

REGIONAL PAIN SYNDROMES

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PiD MiOLOGY to 7%, vulvodynia’s economic burden in the US has been Vulvodynia, first noted in 1880,5 has carried such names estimated at $31 to $72 billion annually—a sum greater as vulvitis, chronic vulvovaginitis, vulvar vestibulitis syn- than individual estimates for interstitial cystitis, fibromydrome, vestibulodynia, essential vulvodynia, dysesthetic algia, and endometriosis alone.14 vulvodynia, and vulvar dysesthesias. Once thought to be caused by excess oxalate intake, HPV infection, prior sexual Despite the burden of disease and personal distress, studabuse, or somatization, vulvodynia is now conceptualized as ies report that 30% to 48% of patients with vulvodynia a heterogeneous disorder characterized by varying degrees never seek care.10 Harlow et al reported in 2003 that 60% of pain and disability resulting from a convergence of a of patients who seek treatment see more than 3 doctors and variety of physiologic mechanisms modulated by psycho- 29% see 5 or more doctors before receiving a diagnosis.7 As logical traits.6 When considered as a singular diagnosis, a testament to the increasing familiarity with vulvodynia, approximately 14 million women suffer with chronic vulvar those numbers were smaller in a 2014 study by the same or vaginal pain at any given time,7 and there are poten- group showing 41% and 18%, respectively.10 Despite the tially a million new cases of vulvodynia each year.8 This decrease in specialist visits, the average patient suffered for corresponds to a prevalence of 8% in the general female 5 years without a definitive diagnosis and only 50% received population,9,10 with a median age of onset of 30 years.9 The an actual diagnosis.10 Less than 3% of those seeking care incidence is approximately 4.2 cases per 100 person years,11 actually received an appropriate diagnosis of vulvodynia.9 with the average patient suffering for 8 to 12 years with symptoms.9 Demographics that have been associated with Multiple studies have reported that women with chronic vulvodynia incidence include age, ethnicity, sleep function, pain suffer distress as a result of dismissive invalidating and psychological characteristics.11 Hispanic women have behavior by others.15 Phrases such as “There is nothing been shown in multiple studies to have a higher incidence of wrong with you” and “It’s all in your head” are commonly vulvodynia and African American women have consistently heard by our patients before being referred to our clinic.

Vulvodynia patients are at risk for feeling isolated and abanhad a lower incidence.9,10 doned and this might have an impact on seeking care or help The burden of disease can be devastating for the woman, her from social support networks. Data from a survey adminpartner, and her family, in addition to utilizing significant istered by the National Vulvodynia Association found an medical resources. Women suffer significant distress from increase in sentiment that other people did not believe they symptomatic disease leading to poor quality of life, psy- were in pain (invalidation) from a baseline of 9% in women chological distress, and sexual dysfunction. In a mail based without current vulvar pain to 12%, 14%, and 22% with 1, 2, survey of clinically proven vulvodynia patients, Arnold et al or 3 comorbid pain conditions,15 including chronic fatigue reported that 56% of patients stopped having intercourse syndrome, endometriosis, fibromyalgia, interstitial cystitis, due to pain, 87% reported a moderate to disabling impact and irritable bowel syndrome. Similar results were found of pain on their sex life, 42% felt out of control of their lives, for feelings of isolation with a baseline of 14% up to 25% and 60% felt out of control of their bodies.12 A population with increasing number of comorbid conditions. Similarly, based survey of clinically unconfirmed patients showed the longer a patient has vulvar pain the less likely they are similar results.13 Based on a conservative prevalence of 3% to discuss it with family or partners.16

“PeRHAPS THe MOST DiFFiCULT ASPeCT OF CLASSiFYiNG VULVODYNiA iS iTS LABeL AS A DiAGNOSiS OF eXCLUSiON…”

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PATHOPHYSiOLOGY Vulvodynia is defined as chronic vulvar discomfort or pain, characterized by burning, stinging, irritation, or rawness of the female genitalia in which there is no infection, skin disease, or neoplasia of the vulva or vagina, or specific clinically identifiable neurologic disorder as the cause of these symptoms.1 The pain can be further differentiated as generalized (entire vulva) or localized (restricted to the clitoris, vestibule, etc); provoked by contact, unprovoked, or mixed; and as either symptoms beginning with first attempt at vaginal penetration (primary) vs after a period of normal function (secondary).

as neurogenic inflammation.6 Histologic studies of reproductive aged women with vulvodynia have identified vaginal samples containing “skip lesions” that lack estrogen receptors,25 but the role of hormones and altered estrogen receptor function in promoting neurogenic inflammation or sensory abnormalities is poorly understood. Hormonal effects on the vaginal mucosa are better understood in postmenopausal women where hypoestrogenism is a well-known cause of vaginal atrophy and pain.26 Pelvic floor muscular dysfunction is commonly found in women with vulvodynia. Most theories explain muscle dysfunction as secondary to chronic mucosal inflammation and vulvar pain.27 Women with vulvodynia have been shown to have lower pelvic muscle pressure pain thresholds along with increased resting tone, impaired voluntary relaxation, and decreased voluntary muscle contractibility.18 The presence of chronic pain is thought to lead to sensitization of C-fibers, which leads to central sensitization and muscle hyperalgesia.28 It is also plausible, however, that patients may have primary pelvic floor muscular dysfunction and then suffer mucosal injury as a result of neurogenic inflammation.24

Perhaps the most difficult aspect of classifying vulvodynia is its label as a diagnosis of exclusion, because this definition assumes that providers who are doing gynecologic exams can exclude rare neurologic and dermatologic disorders.

In reality, there are few described clinical examination tools to help subtype patients who often present with little more than vestibular allodynia and erythema of varying degrees17—symptoms that are common to many pathologic processes leading to pain. Mucosal changes, exaggerated inflammatory response, neuronal proliferation and hyperactivity, central nervous system processing dysfunction, muscular dysfunction, psychological conditions, and genetic A number of studies have shown that patients with chronic polymorphisms are all thought to play a role in the etiology pain syndromes have elevated measures of psychosocial disof vulvodynia.6,18 tress, environmental stress, catastrophizing, and somatic awareness when compared to controls. Similarly, vulvodyStudies have shown that women with vulvodynia have abnor- nia patients tend to have higher trait anxiety, depression, mal sensory thresholds and increased proliferation of nerve somatization, and catastrophizing scores.29-33 It is not clear fibers in vestibular mucosal tissue.6,19-22 It is hypothesized whether psychological symptoms promote development that mucosal allodynia can result from several neuropathic of vulvodynia, develop as a consequence of being in pain, processes including 1) increased excitability of peripheral or are bidirectional. Prospective studies have shown that vaginal nociceptors leading to lower sensory thresholds existing psychological factors predict the development of for pain (allodynia) and resultant peripheral sensitization, several other chronic pain syndromes including chronic and 2) increased excitability to pain stimuli at genital and widespread pain,34 regional musculoskeletal pain,35 and low extragenital sites consistent with sensitization of the central back pain.35-37 Khandker et al specifically evaluated this nervous system or central sensitization.23 Therefore, patients temporal relationship and found that vulvodynia was 4 times with these types of neuropathic features may present with more likely among women with antecedent mood or anxiety pain localized to the vulva or they may present with vulvar disorders in a community sample.38 Those with vulvodynia pain and comorbid pain syndromes. were also 7 times more likely to develop a new mood or anxiety disorder. We do not yet understand the relationship Periodic erythema or swelling of the vestibule is another between degree of psychological distress and severity,30,39 feature commonly reported by patients with chronic vulvar persistence,30 or response to treatment, nor do we have a firm pain. Once acute infectious etiologies have been ruled grasp on the interaction between psychological distress and out, it is thought that this periodic erythema is second- the presence of other chronic pain syndromes. ary to a neuroinflammatory response.24 An exaggerated inflammatory response is characterized by excess release Over the last decade, a multitude of data has been published of proinflammatory substances (eg, interleukin-1 beta and showing significant overlap between various chronic pain tumor necrosis factor alpha) leading to a state of persistent conditions including irritable bowel syndrome, interstitial inflammation. Chronic inflammation in turn leads to pro- cystitis/painful bladder syndrome, fibromyalgia, chronic liferation of nociceptive fibers with abnormal (lower) sen- fatigue syndrome, temporomandibular disorders ( TMD), sory thresholds leading to the clinical findings of redness migraines, and vulvodynia.3,11,15,40 Central pain amplificaand allodynia. These proinflammatory substances release tion or central sensitization has been proposed as the common more proinflammatory substances thus self-perpetuating underlying neurobiological mechanism for chronic pain conthe process of inflammation resulting in what is known ditions demonstrated by lower pain thresholds in affected Q1 | 2015

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“VULVODYNiA PATieNTS TeND TO HAVe HiGHeR TRAiT ANXieTY, DePReSSiON, SOMATiZATiON, AND CATASTROPHiZiNG SCOReS. IT iS NOT CLeAR WHeTHeR PSYCHOLOGiCAL SYMPTOMS PROMOTe DeVeLOPMeNT OF VULVODYNiA, DeVeLOP AS A CONSeQUeNCe OF BeiNG iN PAiN, OR ARe BiDiReCTiONAL.”

patients compared to controls.41,42 Reed et al found that the A neurosensory exam of the vulva can be done using a cotodds of screening positive for vulvodynia were increased 2- ton-tip applicator. Applying light soft or sharp pressure to to 3-fold when a woman reported having interstitial cystitis, dermatomal areas in the S1 to S4 distribution will allow irritable bowel syndrome, or fibromyalgia.4 Zolnoun et al the provider to find areas of symmetric or asymmetric found a high rate of TMD in patients with vulvodynia.43 hypersensitivity and allodynia and to test reflexes such as Most importantly, provoked vulvodynia patients with fewer the anal wink reflex. Branches of the ilioinguinal, iliohycomorbid pain conditions have been shown to have a greater pogastric, and pudendal nerves all contribute to the senchance of successful treatment.44,45 sory innervation of the vulva.46 Light pressure can then be applied to the vestibule from the 2 o’clock to the 10 o’clock position; vulvodynia is characterized by allodynia to soft DiAGNOSiS touch with or without erythema. After inspection of the The widespread prevalence, impact, and high proportion vulva and vestibule, it is essential to assess the pelvic floor of women who do not seek care in spite of pain emphasizes muscles for strength, tone, and pain. This is accomplished the need for better screening, especially among women who by gentle insertion of one lubricated index finger into the present for treatment of other chronic pain disorders. Val- vaginal canal and asking the patient to squeeze and relax idated questionnaires are available,7 however, and patients while noting resting tone and squeeze strength. The indican be easily screened by simply asking “Have you had any vidual muscles of the pelvic floor can be palpated with pain or discomfort at the opening of your vagina lasting moderately deep pressure without discomfort. Patients can more than 3 months?” Clinicians can also screen by asking differentiate between pressure sensation, which is normal, women whether they experience pain with activities such and pain which is consistent with myalgia. The muscles that as sitting, walking, or intercourse. Aside from screening, a are accessible to palpation through the vaginal exam include careful history can help identify obvious causes of pain such the bulbocavernosus, perineal body, levator ani (pubococas acute genital infections, dermatoses, or trauma. cygeus, iliococcygeus), obturator internus, coccygeus, and pyriformis. A normal exam is minimal discomfort with The clinical evaluation should routinely start with col- moderately deep palpation, the ability to contract enough lection of cultures to rule out sexually transmitted infec- to generate a full squeeze around the examiner’s digit, and tions, candida infections, and bacterial vaginosis. In pain the ability to relax voluntarily and return the muscles to patients we also recommend carefully inspecting the vulva their soft pliable state. for abnormalities that might indicate neoplastic conditions or dermatoses (fissuring, ulceration, excessive dryness) and warrant consideration of a biopsy or colposcopy. Beyond TR ATM NT this initial step, it is helpful to categorize the physical exam As with any chronic pain condition, the treatment plan in order to identify 1) sensory abnormalities, 2) signs of for patients with vulvodynia must start with extensive chronic inflammation, 3) musculoskeletal dysfunction, and communication about treatment expectations related to 4) signs of psychological distress and/or poor quality of life. improvement in pain and quality of life, visit frequency, and

e

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adherence to treatment. Healthcare providers should be Hormonal therapy is available in a variety of preparations aware that, as a gynecologic condition, vulvodynia is asso- including suppositories, topical ointments, and pills includciated with stigmatization and isolation, and patients often ing newer selective estrogen receptor modulators (SERMs). have difficulty discussing intimate topics such as sexual pain. These types of therapies are especially helpful in postmenopausal women who present with vaginal pain, but they may Education about vulvar care is fundamental. Chronic con- also be used in reproductive aged women who present with tact dermatitis and pain can be caused by irritants such as localized allodynia, erythema, or dryness. scented soaps, detergents, and feminine hygiene products.

In addition, the pain may be worsened by repeated wash- In cases where pelvic floor muscle dysfunction is identiing or use of drying products such as powders and pads. fied, patients respond well to pelvic floor physical therapy,54 Topical emollients that are preservative-free and nonacidic muscle relaxants, and topical anesthetics. We recommend are generally recommended throughout the day, but lubri- that these patients are educated on vulvar self-care and temcation is especially needed during intercourse. Fear of porary pelvic rest, given topical anesthetics in compounded painful intercourse can promote involuntary pelvic floor nonacid bases with or without estradiol, and sent for conmuscle contraction and perpetuate the cycle of pain,47 thus sultation with pelvic floor physical therapy. Patients may intercourse should be avoided until effective pain ther- also benefit from trigger point injections, although there apy is found. In our practice desensitization methods are is limited published evidence for trigger point injections added prior to intercourse through pelvic physical therapy in the pelvic floor muscles.55 The benefit is for both immethat may include repeated light touch, dilator therapy, and diate relief and to allow patients to better tolerate physical manual therapy. therapy. Off-label botulinum toxin injections are an alternative method that we use, but reported efficacy has been A variety of pharmacologic treatments have been tried for mixed.56-59 vulvodynia. Very few of these treatments have been vetted with randomized controlled trials or have sufficient evi- Lastly, antidepressants, anxiolytics, sleep aids, and behavdence supporting their use in vulvodynia; however, there ioral interventions such as cognitive behavioral therapy, is a growing consensus amongst vulvar pain specialists as sex therapy, and relationship counseling can be helpful for to which medical treatments are beneficial.48,49 As with women with severe impairment.60,61 In prioritizing treatother neuropathic pain syndromes, vulvodynia treatment ment we recommend combining these therapies with pain is focused on neuromodulation with a variety of therapies management whenever necessary but only after trust and including analgesics, anticonvulsants, antidepressants, communication between the patient and provider is well anesthetics, and hormones. Medical interventions can be established. administered either orally or vaginally through suppositories, compounded vaginal creams, or injections. Creams are often less tolerated by patients than ointments due to CONCLUSiON preservatives and stabilizers.49 When applying vaginal for- Vulvodynia is a multifactorial and heterogeneous condimulations, use of an internal applicator can be painful and tion frequently identified in women with a variety of other should be avoided. Instead, the patient can apply a small chronic pain syndromes. Substantial data is now published amount of cream on her finger and gently apply it to her showing significant overlap between various different vagina for better comfort. Once this is comfortable, vagi- chronic pain conditions indicating potential common nal insertion can be attempted. It is important to become underlying neurobiological mechanisms. Beyond gynecolfamiliar with compounding pharmacies’ reputations since ogists, all providers have an opportunity to improve care the quality of medical formulations can vary. for women with vulvodynia simply by screening and identifying patients who often suffer in silence. Although recTopical analgesics, such as lidocaine ointment, have been ommended treatments are multifactorial and may require also shown to significantly alleviate pain and pain with multidisciplinary teams, first-line treatment should start intercourse.50,51 Tricyclic antidepressants and neurolep- with effective communication, patient education, and gentics such as gabapentin 49,52,53 are routinely used to treat eralized vulvar care. vulvodynia, but in general these therapies are reserved for patients with generalized pain or in cases where topical therapies are ineffective. Nerve blocks are usually targeted at the pudendal nerve and occasionally the iliohypogastric, ilioinguinal, and genitofemoral nerves, which have all been shown to have involvement in innervation of the vulva.46 Disclosures: The authors are conducting research for the Estrogen therapy is believed to restore normal vaginal pH National Vulvodynia Registry funded by the National Vulvodylevels and thicken and revascularize the vaginal epithelium.26 nia Association and the Patty Brisben Foundation.

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13. Arnold LD, Bachmann GA , Rosen R, et al. Assessment of vulvodynia symptoms in a sample of US women: a prevalence survey with a nested case control study. Am J Obstet Gynecol. 2007;196:128 e1–6.

14. Xie Y, Shi L, Xiong X, et al. Economic burden and quality of life of vulvodynia in the United States. Curr Med Res Opin. 2012;28:601–608.

15. Nguyen RH, Ecklund AM , Maclehose RF, et al. Co-morbid pain conditions and feelings of invalidation and isolation among women with vulvodynia. Psychol Health Med. 2012;17:589–598.

16. Nguyen RH, MacLehose RF, Veasley C, et al. Comfort in discussing vulvar pain in social relationships among women with vulvodynia. J Reprod Med. 2012;57:109–114.

17. Friedrich EG Jr. The vulvar vestibule. J Reprod Med. 1983;28:773–777.

34. McBeth J, Macfarlane GJ, Benjamin S, et al. Features of somatization predict the onset of chronic widespread pain: results of a large population-based study. Arthritis Rheum. 2001;44:940–946.

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39. Desrochers G, Bergeron S, Khalife S, et al. Fear avoidance and self-efficacy in relation to pain and sexual impairment in women with provoked vestibulodynia. Clin J Pain. 2009;25:520–527.

19. Bohm-Starke N, Hilliges M, Falconer C, et al. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest. 1998;46:256–260.

40. Alagiri M, Chottiner S, Ratner V, et al. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology.

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20. Tympanidis P, Terenghi G, Dowd P. Increased innervation of the vulval vestibule in patients with vulvodynia. Brit J Dermatol. 2003;148:1021–1027.

41. Gracely RH, Petzke F, Wolf JM , et al. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–1343.

21. Zolnoun D, Bair E, Essick G, et al. Reliability and reproducibility of novel methodology for assessment of pressure pain sensitivity in pelvis. J Pain. 2012;13:910–920.

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42. As-Sanie S, Harris RE, Harte SE, et al. Increased pressure pain sensitivity in women with chronic pelvic pain. Obstet Gynecol. 2013;122:1047–1055.

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43. Zolnoun DA , Rohl J, Moore CG, et al. Overlap between orofacial pain and vulvar vestibulitis syndrome. Clin J Pain. 2008;24:187–191.

44. Heddini U, Bohm-Starke N, Nilsson KW, et al. Provoked vestibulodynia—medical factors and comorbidity associated with treatment outcome.

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45. Granot M, Zimmer EZ , Friedman M, et al. Association between quantitative sensory testing, treatment choice, and subsequent pain reduction in vulvar vestibulitis syndrome. J Pain. 2004;5:226–232.

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47. Howard FM . Dyspareunia. In: Howard FM , Perry CP, Carter JE, El-Minawi AM , eds. Pelvic Pain: Diagnosis and Management. New York: Lippincott; 2000.

C ertified Pain Educator

AMERICAN SOCIETY OF PAIN EDUCATORS

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48. Sadownik LA . Etiology, diagnosis, and clinical management of vulvodynia. Int J Womens Health. 2014;6:437–449.

49. Haefner HK , Collins ME, Davis GD, et al. The vulvodynia guideline. J Low Genit Tract Dis. 2005;9:40–51.

50. Zolnoun DA , Hartmann KE, Steege JF. Overnight 5% lidocaine ointment for treatment of vulvar vestibulitis. Obstet Gynecol. 2003;102:84–87.

51. Bohm-Starke N, Brodda-Jansen G, Linder J, et al. The result of treatment on vestibular and general pain thresholds in women with provoked vestibulodynia. Clin J Pain. 2007;23:598–604.

52. Pagano R, Wong S. Use of amitriptyline cream in the management of entry dyspareunia due to provoked vestibulodynia. J Low Genit Tract Dis. 2012;16:394–397.

53. Nunns D, Mandal D, Byrne M, et al. Guidelines for the management of vulvodynia. Brit J Dermatol. 2010;162:1180–1185.

54. Rosenbaum TY, Owens A. The role of pelvic floor physical therapy in the treatment of pelvic and genital pain-related sexual dysfunction (CME ).

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55. Langford CF, Udvari Nagy S, et al. Levator ani trigger point injections: an underutilized treatment for chronic pelvic pain. Neurourol Urodyn.

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56. Abbott JA , Jarvis SK , Lyons SD, et al. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol. 2006;108:915–923.

57. Soares A, Andriolo RB, Atallah AN, et al. Botulinum toxin for myofascial pain syndromes in adults. Cochrane Database Syst Rev. 2012;4:CD 007533.

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59. Nesbitt-Hawes EM , Won H, Jarvis SK , et al. Improvement in pelvic pain with botulinum toxin type A—Single vs. repeat injections. Toxicon.

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60. Andrews J, Yunker A, Reynolds WS, et al. Noncyclic Chronic Pelvic Pain Therapies for Women: Comparative Effectiveness. Rockville, Maryland: Agency for Healthcare Research and Quality; 2012.

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www.painweek.org | PWJ | 21

by Robert

R. Edwards PhD, MSPH

…iNDiViDUALS DiFFeR WiDeLY

iN THeiR SeNSiTiViTY AND ReSPONSeS TO PAiN, AND THeRe iS TReMeNDOUS PeRSON-TO-PeRSON VARiABiLiTY iN HOW PAiNFUL eVeNTS iMPACT iNDiViDUAL SUFFeReRS’ LiVeS. THAT VARiABiLiTY iS MULTiFACTORiAL, AND MANY OF THe FORCeS THAT SHAPe AN iNDiViDUAL’S PeRCePTiON OF, AND ReACTiON TO, PAiN ARe PSYCHOSOCiAL iN NATURe.

e

B HAViORAL

OVeRWHeLMiNG eViDeNCe iDeNTiFieS CATASTROPHiZiNG— A SeT OF NeGATiVe AFFeCTiVe AND COGNiTiVe PROCeSSeS iNVOLViNG RUMiNATiON ABOUT PAiN, PeSSiMiSM ABOUT PAiN ReLATeD OUTCOMeS, PeRCePTiONS OF HeLPLeSSNeSS, AND MAGNiFiCATiON OF PAiN ReLATeD SYMPTOMS—AS A CRiTiCALLY iMPORTANT RiSK FACTOR FOR ADVeRSe PAiN ReLATeD OUTCOMeS iN PATieNTS WiTH A VARieTY OF CONDiTiONS.

Pain is the primary presenting symptom for a majority of physician visits, and chronically painful conditions afflict over 100 million Americans each year, with profoundly negative personal and social consequences, including enormous healthcare costs, disability, and increased mortality.1 However, individuals differ widely in their sensitivity and responses to pain, and there is tremendous person-to-person variability in how painful events impact individual sufferers’ lives. That variability is multifactorial, and many of the forces that shape an individual’s perception of, and reaction to, pain are psychosocial in nature. At this point, the biopsychosocial model of pain has almost universally replaced traditional biomedical characterizations of pain, which had generally focused on disease and injury related abstract:

24 | PWJ | www.painweek.org

activation of specific receptors in the peripheral nervous system that directly transmitted pain related information to the brain.

These “disease models” of the pain experience assumed a close correspondence between pain and injury/pathology, a concept that has been overturned by a great deal of research on chronic pain syndromes such as fibromyalgia, low back pain, and osteoarthritis. In the context of these conditions, and others, it is now widely accepted that only a modest relationship, at best, exists between identifiable physical pathology and a patient’s report of his or her pain related symptoms. That is, 2 individuals may have identical levels of objectively-documented pathology (eg, a herniated disc, or a loss of knee cartilage), but report quite different pain related experiences.

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Catastrophizing is generally measured by patient self-report on questionnaires such as the Pain Catastrophizing Scale (PCS), on which respondents indicate how often they have catastrophizing thoughts about the experience of pain—“I worry all the time about whether the pain will end,” “It’s awful and I feel that it overwhelms me,” “I keep thinking about how much it hurts,” “I wonder whether something serious may happen.”5 High levels of catastrophizing are longitudinally associated with more severe and widespread pain, more emotional disturbance, and worsening indices of physical function and disability. From a societal perspective, catastrophizing is an important variable to understand, as it relates to greater healthcare utilization and use of pain related medications in the general population, even after controlling for pain intensity. Among patients with low back pain enrolled in physical rehabilitation programs, those who report elevated scores on a catastrophizing scale are less than half as likely as their low-catastrophizing counterparts to return to work. In patients with joint pain, catastrophizing relates to higher levels of observed pain behaviors and functional limitations during standardized activity tests.6 Importantly, while pain severity is often a primary determinant of a patient’s degree of physical and occupational disability, catastrophizing predicts disability levels even after controlling for pain severity. Catastrophizing and other indices of poor pain coping are also prospectively associated with reductions in objectively measured mobility and muscle strength.7 Perhaps not surprisingly, in prospective studies in patients with acute low back pain, those with high levels of negative affect and catastrophizing are most likely to engage in extended periods of bed rest, least likely to exercise, and most likely to become physically deconditioned over time.8,9

motional and cognitive processes such as catastrophizing

can increase pain through a variety of mechanisms and play a profound role in shaping individual differences in pain responses.2 Overwhelming evidence identifies catastrophizing—a set of negative affective and cognitive processes involving rumination about pain, pessimism about pain related outcomes, perceptions of helplessness, and magnification of pain related symptoms—as a critically important risk factor for adverse pain related outcomes in patients with a variety of conditions. As with most human traits (eg, height, intelligence, extraversion), catastrophizing exists on a continuum, with some individuals engaging in frequent and intense bouts of catastrophizing during episodes of pain and others catastrophizing rarely, even in the context of a severe, recurring pain condition. This variability is observed in patients with chronic pain and in healthy, pain-free individuals; indeed, higher catastrophizing, assessed in pain-free adults, predicts the future development of chronic back pain and pain related healthcare utilization.3,4

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SOCiAL SUPPORT It is also important to note that catastrophizing impairs not just physical functioning but also social relationships. Seeking social support is one of the most common pain coping strategies, and social interactions have important influences on individuals’ pain reports and pain behaviors. Patients with persistent pain who score high on measures of catastrophizing report smaller social networks, high levels of critical responses from spouses or partners, and an insecure attachment style.2 Collectively, it appears that individuals who express frequent, intense, catastrophic concerns about their pain may gradually wear down their friends, relatives, and companions, eroding positive social relationships, which could contribute to higher levels of distress and pain. Moreover, the resultant social isolation could contribute to the amplification of suicidal thoughts, which are relatively common among patients with persistent pain conditions, and most common of all among high-catastrophizing patients.10

e

e

TR ATM NT Catastrophizing about pain appears to interfere with the beneficial effects of a variety of treatments. In studies of osteoarthritis patients recovering from knee surgery, higher preoperative levels of catastrophizing were associated with more pain and disability up to 6 months postoperatively.11,12 In other surgical studies, preoperative catastrophizing correlated with a longer length of stay, longer functional recovery time after total joint replacement, and persistence of pain www.painweek.org | PWJ | 25

BEHAVIORAL

“ELeVATeD CATASTROPHiZiNG SCOReS WeRe LiNKeD WiTH A MORe LiMiTeD CAPACiTY OF CeRTAiN BRAiN ReGiONS TO MODULATe, OR iNHiBiT, SeNSORY SiGNALS.”

after total knee replacement for up to 2 years.13-16 A number of randomized, controlled trials of analgesic treatments have shown that patients high in pretreatment catastrophizing subsequently report less benefit from topical and oral analgesics.17,18 In some trials, patients with the highest pretreatment catastrophizing scores are most likely to experience unpleasant medication side effects and to discontinue treatment.19 Surveys in patients with musculoskeletal pain have indicated that catastrophizing is the single most important pretreatment risk factor that impairs the effectiveness of pain-relieving interventions,20,21 highlighting the importance of understanding and managing catastrophizing in patients with chronic pain.

The origins of catastrophizing are presently rather mysterious; it is easy to imagine that genetic factors likely contribute to variability in catastrophizing, but to date we have not identified individual genes that are associated with higher or lower degrees of catastrophizing.

Environmental forces must surely play a substantial role, and there is evidence from family studies that parental levels of catastrophizing, particularly maternal catastrophizing, are strongly linked with children’s degree of catastrophizing. Indeed, some recent evidence indicates that child and parental frequency of catastrophizing becomes more similar over time in the context of painful events such as major surgeries.22 It appears that the early experience of pain, and particularly parental responses to that pain, exert a substantial influence on the degree to which children adopt a catastrophizing style in conceptualizing and understanding their pain experiences.

In addition, highly stressful or traumatic experiences in childhood and adolescence (eg, sexual abuse) place individuals at elevated risk for high levels of pain catastrophizing as adults.23 Collectively, the genesis of catastrophizing is almost certainly multifactorial, shaped by an array of social and environmental forces across the lifespan.

e

e

N UROiMAGiNG STUDi S Whatever its origins, there is good evidence from neuroimaging studies that, once established, catastrophizing plays an important role in shaping functional brain response to a variety of stimuli. In several studies, higher levels of catastrophizing have been related to enhanced f MRI responses to calibrated noxious stimuli in areas such

26 | PWJ | www.painweek.org

as anterior insular cortex among both patients with chronic musculoskeletal pain24 and pain free adults.25 Strigo and colleagues found that in subjects with major depression, helplessness and rumination were associated with greater activity in the amygdala during the anticipation and experience of pain.26 A recent transcranial magnetic stimulation study in fibromyalgia patients revealed a bilateral decrease (relative to controls) in intracortical inhibition, which was related to higher catastrophizing scores in the patient group.27 That is, elevated catastrophizing scores were linked with a more limited capacity of certain brain regions to modulate, or inhibit, sensory signals. These findings all highlight the amplifying effect that catastrophizing may have on the processing of pain related information in cortical and subcortical brain regions. Our research group recently showed that temporarily inducing a negative mood state increased levels of pain catastrophizing and broadly amplified cortical responses to a noxious stimulus.28 Furthermore, some reports have suggested that catastrophizing may be linked to structural as well as functional changes in the brains of patients experiencing long-term pain. Structurally, elevations in catastrophizing among patients with chronic abdominal pain were associated with thinning of the dorsolateral prefrontal cortex, a key pain modulatory site.29 Collectively, these findings substantiate the possibility that interventions which reduce catastrophizing may produce long-lasting, adaptive shifts in brain processing of pain.

e e

INT RV NTiONS Happily, we appear to have some interventions that reliably reduce the degree and impact of catastrophizing in samples of patients with chronic pain. Meta-analyses and reviews confirm that cognitive behavioral therapy (CBT ), an increasingly broadly applied treatment for sufferers of chronic pain conditions, reduces pain intensity, catastrophizing, and negative affect among individuals with a variety of persistent pain syndromes.30,31 CBT uses active, structured techniques to alter distorted thoughts and negative moods, and with as few as 2 to 4 sessions, catastrophizing is substantially reduced.32,33 Process analyses indicate that 1) changes in catastrophizing and negative affect precede changes in clinical pain, 2) CBT produces substantial reductions in catastrophizing even among Q1 | 2015

patients whose chronic pain has persisted for many years, 3) CBT provides chronic pain patients with the skills to modulate negative emotions, buffering their negative impact on subsequent pain related outcomes, and 4) CBT’s effects on catastrophizing last for months or years.32,34-36 Interestingly, as many reviews point out,34,37 we know relatively little about the mechanisms underlying CBT and other nonpharmacologic pain treatment approaches, and it may be that disparate treatments operate in part via common mechanisms; for example, changes in catastrophizing mediate the benefits of CBT,34 but also of exercise- and activity-based physical therapy interventions which do not explicitly target catastrophizing.38,39 Such findings have potentially far-reaching implications for designing and disseminating biopsychosocial pain treatments. Collectively, the theoretical underpinnings of particular treatment approaches may be far less important than whether the treatment activates crucial mechanisms (ie, catastrophizing reduction) that underlie changes in behavior, cognition, and affect.

If catastrophizing is associated with maladaptive shifts in the brain’s processing of pain related information, and if CBT diminishes catastrophizing, we might expect that CBT has the potential to “normalize” functional and potentially structural aspects of the brain that are relevant to pain. Jensen et al40 found that acceptance based group CBT treatment in a small sample of fibromyalgia patients produced changes in pain related activation and functional connectivity within regions of the prefrontal cortex, a brain region that participates in a variety of critical pain modulatory roles. Interestingly, several other CBT studies with long-term follow-up have indicated that such treatments can enlarge the volume of this brain region,41,42 highlighting the potential for nonpharmacologic treatments to reverse some of the adverse neurological consequences of sustained negative cognitive/ emotional states.

CONCLUSiON Catastrophizing, because of its impact on so many aspects of the pain experience, is an especially appealing target for treatments designed to improve pain related outcomes. As noted previously, changes in catastrophiz­ing and distress may mediate many of the improvements related to pain treatments, even those interventions that do not explicitly target cognitive and emotional factors. Several promising lines of research are exploring pathways by which the catastrophizing reducing benefits of psychosocial treatments may be further expanded. In one interesting extension of typical CBT interventions, Keefe and colleagues conducted a series of studies which suggest that systemati­cally involving partners and spouses in such interventions can amplify their benefits by increasing social support, decreasing maladaptive pain related social interactions, and improving patients’ adaptive pain coping efforts.43 Other avenues include the incorporation of mindfulness meditation techniques to buffer catastrophizing cognitions44 and the individualized tailoring of training programs to enhance the physical, cognitive, and emotional benefits of regular exercise.45 Similar efforts to refine and enrich cognitive behavioral interventions to maximize their impact on catastrophizing and distress will, in all probability, be an important focus of future research in this area.

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2012;13:715–724.

2. Edwards RR , Cahalan C, Mensing G, et al. Pain, catastrophizing, and depression in the rheumatic diseases. Nat Rev Rheumatol. 2011;7:216–224.

3. Picavet HS, Vlaeyen JW, Schouten JS . Pain catastrophizing and kinesiophobia: predictors of chronic low back pain. Am J Epidemiol. 2002;156:1028–1034.

4. Severeijns R, Vlaeyen JW, Van den Hout MA , et al. Pain catastrophizing is associated with health indices in musculoskeletal pain: a cross-sectional study in the Dutch community. Health Psychol. 2004;23:49–57.

5. Sullivan MJ, Bishop SR , Pivik J. The Pain Catastrophizing Scale: development and validation. Psychol Assess. 1995;7:524–532.

6. Keefe FJ, Lefebvre JC , Egert JR , et al. The relationship of gender to pain, pain behavior, and disability in osteoarthritis patients: the role of catastrophizing. Pain.

2000;87:325–334.

7. Evers AW, Kraaimaat FW, Geenen R, et al. Pain coping and social support as predictors of long-term functional disability and pain in early rheumatoid arthritis.

Behav Res Ther. 2003;41:1295–1310.

8. Bousema EJ, Verbunt JA , Seelen HA , et al. Disuse and physical deconditioning in the first year after the onset of back pain. Pain. 2007;130:279–286.

9. Verbunt JA , Sieben J, Vlaeyen JW, et al. A new episode of low back pain: who relies on bed rest? Eur J Pain. 2008;12:508–516.

10. Edwards RR , Smith MT, Kudel I, et al. Pain-related catastrophizing as a risk factor for suicidal ideation in chronic pain. Pain. 2006;126: 272–279.

11. Stephens MA , Druley JA , Zautra AJ . Older adults’ recovery from surgery for osteoarthritis of the knee: psychosocial resources and constraints as predictors of outcomes. Health Psychol. 2002;21:377–383.

12. Pavlin DJ, Sullivan MJ, Freund PR , et al. Catastrophizing: a risk factor for postsurgical pain. Clin J Pain. 2005;21:83–90.

13. Witvrouw E, Pattyn E, Almqvist KF, et al. Catastrophic thinking about pain as a predictor of length of hospital stay after total knee arthroplasty: a prospective study.

Knee Surg Sports Traumatol Arthrosc. 2009;17:1189–1194.

14. Forsythe ME, Dunbar, MJ, Hennigar AW, et al. Prospective relation between catastrophizing and residual pain following knee arthroplasty: two-year follow-up.

Pain Res Manag. 2008;13:335–341.

15. Sullivan M, Tanzer M, Stanish W, et al. Psychological determinants of problematic outcomes following total knee arthroplasty. Pain. 2009;143:123–129.

16. Riddle DL , Wade JB, Jiranek WA , et al. Preoperative pain catastrophizing predicts pain outcome after knee arthroplasty. Clin Orthop Relat Res. 2010;468:798–806.

17. Mankovsky T, Lynch M, Clark A, et al. Pain catastrophizing predicts poor response to topical analgesics in patients with neuropathic pain. Pain Res Manag. 2012;17:10–14.

18. Schiphorst Preuper HR , Geertzen JH, van Wijhe M, et al. Do analgesics improve functioning in patients with chronic low back pain? An explorative triple-blinded RCT. Eur Spine J. 2014;23(4):800–806.

19. Toth C, Brady S, Hatfield M. The importance of catastrophizing for successful pharmacological treatment of peripheral neuropathic pain. J Pain Res. 2014;7:327–338.

20. Hill JC , Lewis M, Sim J, et al. Predictors of poor outcome in patients with neck pain treated by physical therapy. Clin J Pain. 2007;23:683–690.

21. Karels CH, Bierma-Zeinstra SM , Burdorf A, et al. Social and psychological factors influenced the course of arm, neck and shoulder complaints. J Clin Epidemiol.

2007;60:839–848.

22. Page MG, Campbell F, Isaac L, et al. Parental risk factors for the development of pediatric acute and chronic postsurgical pain: a longitudinal study. J Pain Res. 2013;6:727–741.

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23. Sansone RA , Watts DA , Wiederman MW. Childhood trauma and pain and pain catastrophizing in adulthood: a cross-sectional survey study. Prim Care Companion CNS Disord. 2013;15(5).

44. Day MA , Thorn BE, Rubin NJ . Mindfulness-based cognitive therapy for the treatment of headache pain: A mixed-methods analysis comparing treatment responders and treatment non-responders. Complement Ther Med. 2014;22:278–285.

24. Gracely RH, Geisser ME, Giesecke T, et al. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain. 2004;127:835–843.

45. Vincent HK , George SZ , Seay AN, et al. Resistance exercise, disability, and pain catastrophizing in obese adults with back pain. Med Sci Sports Exerc.

2014;46:1693–1701.

25. Seminowicz DA , Davis KD. Cortical responses to pain in healthy individuals depends on pain catastrophizing. Pain. 2006;120:297–306.

26. Strigo IA , Simmons AN, Matthews SC , et al. Increased affective bias revealed using experimental graded heat stimuli in young depressed adults: evidence of “emotional allodynia”. Psychosom Med. 2008;70:338–344.

27. Mhalla A, de Andrade DC , Baudic S, et al. Alteration of cortical excitability in patients with fibromyalgia. Pain. 2010;149:495–500.

28. Berna C, Leknes S, Holmes EA , et al. Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness. Biol Psychiatry.

2010;67:1083–1090.

29. Blankstein U, Chen J, Diamant NE, et al. Altered brain structure in irritable bowel syndrome: potential contributions of pre-existing and disease-driven factors. Gastroenterology. 2010;138:1783–1789.

30. Eccleston C, Williams AC , Morley S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev. 2009:CD 007407.

31. Hassett AL , Williams DA . Non-pharmacological treatment of chronic widespread musculoskeletal pain. Best Pract Res Clin Rheumatol. 2011;25:299–309.

32. Turner JA , Mancl L, Aaron LA . Short- and long-term efficacy of brief cognitive-behavioral therapy for patients with chronic temporomandibular disorder pain: a randomized, controlled trial. Pain. 2006;121:181–194.

33. Litt MD, Shafer DM , Kreutzer DL . Brief cognitive-behavioral treatment for TMD pain: long-term outcomes and moderators of treatment. Pain. 2010;151:110–116.

34. Thorn BE, Burns JW. Common and specific treatment mechanisms in psychosocial pain interventions: the need for a new research agenda. Pain. 2011;152:705–706.

35. Morley S, Williams A, Hussain S. Estimating the clinical effectiveness of cognitive behavioural therapy in the clinic: evaluation of a CBT informed pain management programme. Pain. 2008;137:670–680.

36. Naylor MR , Krauthamer GM , Naud S, et al. Predictive relationships between chronic pain and negative emotions: a 4-month daily process study using Therapeutic Interactive Voice Response ( TIVR ). Compr Psychiatry. 2011;52:731–736.

37. Jensen MP. Psychosocial approaches to pain management: an organizational framework. Pain. 2011;152:717–725.

38. Smeets RJ, Vlaeyen JW, Kester AD, et al. Reduction of pain catastrophizing mediates the outcome of both physical and cognitive-behavioral treatment in chronic low back pain. J Pain. 2006;7:261–271.

39. Leeuw M, Goossens ME, Van Breukelen GJ, et al. Exposure in vivo versus operant graded activity in chronic low back pain patients: results of a randomized controlled trial. Pain. 2008;138:192–207.

40. Jensen KB, Kosek E, Wicksell R, et al. Cognitive Behavioral Therapy increases pain-evoked activation of the prefrontal cortex in patients with fibromyalgia. Pain.

2012;153:1495–1503.

41. de Lange FP, Koers A, Kalkman JS, et al. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome.

Brain. 2008;131:2172–2180.

42. Seminowicz DA , Shpaner M, Keaser ML , et al. Cognitive-behavioral therapy increases prefrontal cortex gray matter in patients with chronic pain. J Pain.

2013;14:1573–1584.

43. Keefe FJ, Blumenthal J, Baucom D, et al. Effects of spouse-assisted coping skills training and exercise training in patients with osteoarthritic knee pain: a randomized controlled study. Pain. 2004;10:539–549.

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(fenoprofen calcium capsules) 400 mg Fast and Effective, Move On With Nalfon Safety Information Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).

• Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms.

Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

Nalfon® is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon® should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Nalfon® is contraindicated in patients with a history of significantly impaired renal function.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

Request Information and Rx Co-pay Cards* Scan the QR code to request more information on Nalfon or to request co-pay cards. Your patients will pay no more than $15 on co-pays up to $50. *Valid for Initial Script and 5 Refills. View Complete Details.

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42195-308-09

(fenoprofen calcium capsules) 400 mg

What makes NALFON a unique and different non-steroidal anti-inflammatory patient option?

NALFON is Safe...

During clinical studies, Nalfon had less than 2% discontinuation rate due to gastrointestinal adverse reactions.

NALFON is Effective...

• Nalfon has more clinician use and prescriptions than any other branded NSAID with over 40 years of use and in excess of 37 million prescriptions.

• Nalfon reaches peak plasma levels within 2 hours of administration.

Peak Levels (2 hours)

0

1

2

3

90% of a single oral dose is eliminated within 24-hours as fenoprofen glucuronicle and 4-hydroxfenoprofen glucuronide, the majority urinary metabolites of fenoprofen.

4

5

6

7

8

9

NALFON is Flexible...

Unlike other commonly prescribed NSAIDs with QID dosing, Nalfon is dosed TID for better patient compliance.

NALFON is Cost Effective...

• Nalfon is covered by 90% of all commercial plans with a patient co-pay.

• Nalfon is covered by Medicare-D plans and Tri-Care.

• Only Nalfon offers patients a “Pay No More Than $15” instant pharmacy rebate.

Safety Information Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Cardiovascular Risk • Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).

• Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

For more information on Nalfon 400 mg, visit www.nalfon.com

(fenoprofen calcium capsules) 400 mg TM

Technology

• Nalfon is the only fenoprofen calcium available in a capsule preparation.

• Nalfon is rapidly absorbed with a 30-minute onset of action.

• Nalfon is readily bound to plasma proteins at 99%.

Recommended Dosing Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Nalfon is indicated: • For relief of mild to moderate pain in adults.

• For relief of the signs and symptoms of rheumatoid arthritis.

• For relief of the signs and symptoms of osteoarthritis.

After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

• The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms.

• Total daily dosage should not exceed 3200 mg.

• Nalfon may be administered with meals or with milk.

• The smallest dose that yields acceptable control should be employed.

(feno

profen calcium capsule s) 400 m

Disp

* NALFON 400 mg EP 123

*Not actual size

Use this Nalfon 400 mg capsule for identification.

g

90 C aps Take 1 Cap Q8 H PRN rs Pain Infla a n d mma tion

Contraindications Nalfon® is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon® should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Nalfon® is contraindicated in patients with a history of significantly impaired renal function.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.

Nalfon ©2011 is a registered trademark of Xspire Pharma.

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NALFON ®

(fenoprofen calcium capsules, USP) 200 mg and 400 mg

Rx ONLY

Cardiovascular Risk • Non-Steroidal Anti-Inflammatory (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).

• Nalfon® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at great-er risk for serious gastrointestinal events (see WARNINGS).

DESCRIPTION Nalfon® (fenoprofen calcium capsules, USP) is a nonsteroidal, anti-inflammatory, antiarthritic drug. Nalfon capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol) of fenoprofen. The 200 mg capsules contain cellulose, gelatin, iron oxides, silicone, titanium dioxide, and other inactive ingredients. The 400mg capsules contain gelatin, sodium lauryl sulfate, iron oxide yellow, FD&C Blue 1, titanium dioxide, FD&C Red 40, crospovidone, talc, and magnesium stearate. Chemically, Nalfon is an arylacetic acid derivative. Nalfon is a white crystalline powder that has the structural formula C30H26CaO6•2H2O representing a molecular weight of 558.65. At 25°C, it dissolves to a 15 mg/mL solution in alcohol (95%). It is slightly soluble in water and insoluble in benzene. The pKa of Nalfon is a 4.5 at 25°C. CLINICAL PHARMACOLOGY Nalfon is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Results in humans demonstrate that fenoprofen has both antiinflammatory and analgesic actions. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of Nalfon, aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity. In all patients with rheumatoid arthritis, the anti-inflammatory action of Nalfon has been evidenced by relief of pain, increase in grip strength, and reductions in joint swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of Nalfon has also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion). The use of Nalfon in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding Nalfon to maintenance therapy with gold salts or steroids. Whether or not Nalfon used in conjunction with partially effective doses of a corticosteroid has a “steroid-sparing” effect is unknown. In patients with osteoarthritis, the anti-inflammatory and analgesic effects of Nalfon have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown Nalfon to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with Nalfon than in aspirin-treated patients. It is not known whether Nalfon causes less peptic ulceration than does aspirin. In patients with pain, the analgesic action of Nalfon has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect. Under fasting conditions, Nalfon is rapidly absorbed, and peak plasma levels of 50 μg/mL are achieved within 2 hours after oral administration of 600 mg doses.

Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to albumin. The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of Nalfon. There is less suppression of collagen-induced platelet aggregation with single doses of Nalfon than there is with aspirin.

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Nalfon is indicated: • For relief of mild to moderate pain in adults. • For relief of the signs and symptoms of rheumatoid arthritis. • For relief of the signs and symptoms of osteoarthritis.

CONTRAINDICATIONS Nalfon is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma). Nalfon is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Nalfon is contraindicated in patients with a history of significantly impaired renal function (see WARNINGS – Advanced Renal Disease).

WARNINGS - CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may give a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS - Gastrointestinal Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension NSAIDs, including Nalfon, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Nalfon, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Nalfon should be used with caution in patients with fluid retention, compromised cardiac function or heart failure. The possibility of renal involvement should be considered. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Nalfon, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or de-bilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decomposition. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Nalfon in patients with advanced renal disease. There-fore, treatment with Nalfon is not recommended in patients with advanced renal disease. (See CONTRAINDICATIONS).

Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Nalfon. Nalfon should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma).

Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including Nalfon, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hyper-sensitivity. Pregnancy Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Ocular Studies to date have not shown changes in the eyes attributable to the administration of Nalfon. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking Nalfon. Central Nervous System Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking Nalfon. Hearing Since the safety of Nalfon has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with Nalfon.

PRECAUTIONS - General Nalfon cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Nalfon in reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Nalfon. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Nalfon. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Nalfon should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including Nalfon. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Nalfon, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Nalfon who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Nalfon should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Nalfon, like other NSAIDs, may cause serious CV side effects, such as myocardial infarction (MI) or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Nalfon, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can oc-

cur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS - Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).

3. Nalfon, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hy-persensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). 7. Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur.

Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically.

If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Nalfon should be discontinued.

Drug Interactions - ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin The coadministration of aspirin decreases the biologic half-life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine. Although the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction and displacement of fenoprofen from plasma albumin binding sites are possibilities. As with other NSAIDs, concomitant administration of fenoprofen calcium and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as post marketing observations, have shown that Nalfon can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has

been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS - Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Phenobarbital Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen. When phenobarbital is added to or withdrawn from treatment, dosage adjustment of Nalfon may be required. Plasma Protein Binding In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound, and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs. Drug/Laboratory Test Interactions Amerlex-M kit assay values of total and free triiodothyronine in patients receiving Nalfon have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroidstimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are not affected. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of fenoprofen. Studies have not been conducted to determine the effect of fenoprofen on mutagenicity or fertility.

Pregnancy - Teratogenic Effects. Pregnancy Category - C Prior to 30-Weeks Gestation; Category D starting at 30-Weeks Gestation.

Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Nalfon can cause fetal harm when administered to a pregnant woman starting at 30-weeks gestation. If this drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus. There are no adequate and well-controlled studies in pregnant women. Prior to 30-weeks gestation, Nalfon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities when given daily oral doses of 50 or 100 mg/kg fenoprofen calcium, respectively (0.15 and 0.6 times the maximum human daily dose of 3,200 mg based on body surface area comparisons). However, animal reproduction studies are not always predictive of human response. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery The effects of Nalfon on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nalfon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients under the age of 18 have not been established.

Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

ADVERSE REACTIONS During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies. Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials Digestive System— During clinical trials with Nalfon, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving Nalfon as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% Nalfon vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarkeing studies. Nervous System —The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs.

6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Nalfon was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. Skin and Appen-dages—Increased sweating (4.6% vs.

0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. Nalfon was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Special Senses—Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. Nalfon was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. Cardiovascular—Palpitations (2.5% vs. 0.4%). Nalfon was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Miscellaneous—Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs.

5.6%), and nasopharyngitis (1.2% vs. none). Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool.

Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis (see PRECAUTIONS). Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia. Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and papillary necrosis (see WARNINGS). Hypersensitivity—Angioedema (angioneurotic edema). Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia. Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia. Special Senses—Burning tongue, diplopia, and optic neuritis. Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia. Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia, and fever.

OVERDOSAGE Signs and Symptoms—Symptoms of overdose appear within several hours and generally involve the gastrointestinal and central nervous systems. They include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness, and confusion. Hyperpyrexia, tachycardia, hypotension, and acute renal failure may occur rarely following overdose. Respiratory depression and metabolic acidosis have also been reported following overdose with certain NSAIDs.Treatment—To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Con-trol Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal. Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis, and charcoal hemoperfusion do not enhance systemic drug elimination.

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs. Analgesia For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. Rheumatoid Arthritis and Osteoarthritis For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg. Nalfon may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished. Patients with rheumatoid arthritis generally seem to require larger doses of Nalfon than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed. Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy.

HOW SUPPLIED Nalfon® (fenoprofen calcium capsules, USP) are available in: The 200 mg* capsule is opaque yellow No. 97 cap and opaque white body, imprinted with “RX681” on the cap and body. NDC 42195-308-10 Bottles of 100. The 400 mg* capsule is opaque green cap and opaque blue body, imprinted with “NALFON 400 mg” on the cap and “EP 123” on the body. NDC 42195-308-09 Bottles of 90 *Equivalent to fenoprofen. Preserve in well-closed containers. Store at 20° - 25° C (68° - 77° F). (See USP Controlled Room Temperature).

ATTENTION DISPENSER: Accompanying Medication Guide must be dispensed with this product.

NSAID medicines that need a prescription Generic Name Trade Name Celecoxib Diclofenac Diflunisal Etodolac Fenoprofen Flurbiprofen Ibuprofen Indomethacin Ketoprofen Ketorolac Mefenamic Acid Meloxicam Nabumetone Naproxen Oxaprozin Piroxicam Sulindac Tolmetin

Celebrex Cataflam, Voltaren, Arthrotec (combined with misoprostol) Dolobid Lodine, Lodine XL Nalfon, Nalfon 200 Ansaid Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) Indocin, Indocin SR, Indo-Lemmon, Indomethagan Oruvail Toradol Ponstel Mobic Relafen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Daypro Feldene Clinoril Tolectin, Tolectin DS, Tolectin 600

This Medication Guide has been approved by the U.S. Food and Drug Administration.

*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

Manufactured by: Emcure Pharmaceuticals, USA East Brunswick, NJ 08896 Manufactured for: Xspire Pharma Ridgeland, MS 39157 Rev. 08/2012

References 1. Wk Prescription Sales Data, 2012 2. Podiatry Today, Vol. 19, Issue 3 3. Nalfon Package Insert, July 2009 4. Medispan, 2012

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therapy exercises are also something that I recommend to older patients to help stabilize the joints with muscular strengthening exercises. If you look beyond traditional therapies for the treatment of osteoarthritis, there are complementary alternative therapies like acupuncture that can be used.

Issues in Geriatric Pain Management Debra K. Weiner, MD

There are physiological considerations when prescribing pain medications for older people. There are certain medications that are contraindicated because older people’s kidneys don’t clear the medication like in a younger person. When prescribing narcotics or opioids, remember that older adults are much more sensitive— physiologically sensitive. We have to use much lower doses to start out with.

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The technology of neuroimaging is an exciting new area for us. We can use it to open up windows into the brain to identify potential targets for treatment. We can go after them in a multitude of ways. Pain psychology approaches have been around for decades and have been shown to work effectively. Now marrying traditional pain psychology with what we’re learning about brain mechanisms allows us to bring pain psychology into the 21st century. We can start to target specific aspects of the pain experience so that it’s tailored for a particular patient. We can also use these brain targets from a pharmacologic standpoint to go after these abnormal brain systems and help reverse or bring them back to a normal function. They’re also great targets for electrical stimulation, whether it be deep brain stimulation or something that is more accessible to pain clinicians such as transcranial magnetic stimulation.

With respect to issues of back pain, I would reference a study where the prevalence of moderate to severe spinal stenosis in asymptomatic older people was estimated at 1 in 5, and so an undue focus on the results obtained from imaging can expose these sometimes frail older people to unnecessary interventions such as surgery. The importance of being hands-on in evaluation and treatment has many important ramifications for people of all ages, but especially for the older patient.

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Drug Interactions in Palliative Care Kathryn A. Walker, PharmD, BCPS, CPE

Because patients in palliative care are often on so many medications, the clinical picture is always changing. Their organ functions change, they may have low protein stores that will affect the way drugs interact, and many patients have different distributions of enzymes. A lot of the major drug interactions are histamine-based, or dopamine-based, like antipsychotics, drugs that affect anticholinergics and cholinergic receptors, antimuscarinic effects. All of these drugs interacting with their pathophysiological environment can be a challenge in the palliative care setting. The most important thing is to implement a management and a monitoring strategy, so that when you decide to use drugs that interact, you know what to look for, what to assess, and how to help the patient. Be aware of the interactions; you may ultimately still decide to use these medications.

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Osteoarthritis Pain: Looking Beyond Traditional Therapies Paul J. Christo, MD, MBA

Osteoarthritis can affect us as we age. A lot of weightbearing joints like the hip and the knee, for example, are predisposed to osteoarthritis especially in older patients. Therapies can include pharmacologic agents like acetaminophen, but also injectable local anesthetics, and agents like hyaluronidase, which can be used to help stabilize the knee joint in cases of osteoarthritis. Topical therapies are now used even to a greater extent than before because we have more of them. Topical diclofenac gel is approved for use in osteoarthritis in the joints of the arms and lower extremities. There is also an abundance of data on the usefulness of cognitive behavioral therapy and psychological therapies for the treatment of low back pain. Physical Q1 | 2015

The Brain in Pain Sean Mackey, MD, PhD, CPE

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Virtual Education in Chronic Pain: The VA Perspective Ilene Robeck, MD

For patients, one approach to virtual delivery of education is via cell phones, which are minicomputers in our hands. Many of our younger patients really enjoy the ability to interact with apps, perhaps to learn different relaxation techniques, or techniques for minimizing painful situations, or dealing with stress, or to discuss opioid safety. It can be a way to extend the face-to-face visit. For practitioners, a common virtual method we use is e-consulting, to conduct a formal review of the chart and provide the clinician with a concise, structured menu of options to help them make clearer, better decisions for their patient.

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Complementary and Alternative Medicine (CAM) for Low Back Pain Michael Saenger, MD

It’s important for people to know that there are effective therapies from the CAM toolbox. I would group them into bridging CAM and active CAM. I think they both have a place in helping a patient with pain move toward a more independent full life. The bridging therapies could be spinal manipulation, acupuncture, and massage. While those are continuously reapplied they are mildly to moderately effective at least as much as most of our therapies and often times more effective than opioids for chronic pain patients. The problem is once those are stopped, the effect of the repetitive application in terms of pain wears off. Active CAM involves helping patients learn new life skills that have been proven to be effective: the Alexander technique, which is probably our most evidence-based, having coming out of the UK 100 years ago, and yoga, tai chi, Pilates, and similar mindful movement therapies that incorporate movement with other lifestyle changes. www.painweek.org | PWJ | 33

by Brett

B. Snodgrass MSN, APRN, FNP-C

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FRONTLiN FOCUS

Alert fatigue is a new term meaning that providers may begin to ignore alerts—on average 150 in one clinic day! abstract: Complete and thorough chart documentation is important for any clinician seeing patients in any population—it’s even more important when caring for the chronic pain patient.

When clinicians care for patients in a chronic pain specialty, a focused history and previous records and appropriate testing from a PCP may be readily available, but there are still potential problems. The unfortunate threat of litigation does exist and may potentially be higher in some specialties, including pain management. It is imperative that clinicians be refreshed on the importance of appropriate chart documentation, as well as informed about the pitfalls that can exist when using electronic medical records.

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www.painweek.org | PWJ | 35

FRONTLINE FOCUS

are of patients suffering from chronic pain is on the rise in both specialty settings and primary care. Whatever the setting, caring for the chronic pain patient can prove challenging, and it can be a balancing act where treatment is concerned. As clinicians, we must be cognizant of the symptoms and side effects of chronic pain treatment. We know that undertreatment can be a concern, yet overdose is a catastrophic potential outcome. Recently, regulatory action has occurred at the state level—including some states such as Tennessee and Washington creating chronic pain guidelines—therefore, clinicians must maintain both federal and state regulations to provide care. In some institutions a clinician’s review or merit can be based on patient satisfaction. Whether or not a clinician provides an opiate can in fact negatively affect their performance evaluations. Many aspects must be considered as patients are being treated for chronic pain.

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VOLViNG MANAG M NT Documentation of the patient’s realistic goals helps to ascertain Chronic pain management has evolved over the past few years. In the whether or not these goals are being met. What are the patient’s 1990s, the fifth vital sign—pain—became an important assessment goals? To attend a grandchild’s sporting event? To return to gardenacross the United States. Prior to that, pain was frequently under- ing? To return to work? To be able to vacation with a spouse? These treated and many patients ultimately died in pain. Since that time, the goals should be clearly written in the patient’s chart and reviewed at pendulum has swung in the opposite direction, and with it has come reasonable intervals with the patient. an increase in the amount of opiates prescribed across the nation.

Hydrocodone is now the #1 most prescribed medication in the US, long-acting opiate therapy is more widely used, and higher and higher Electronic Medical Records opiate dosing exists. We are faced with increasing overdose deaths, abuse, and misuse. It is important that we, as clinicians, provide safe We have seen the use of electronic medical records ( EMR s) rise and effective chronic pain management to the appropriate population. over the last few years. Fewer healthcare providers are using paper charting. A study in the Archives of Internal Medicine discovered that The goal of chronic pain management is not to take all pain from malpractice payouts correlate inversely with greater usages of EMR. a patient: that is neither realistic nor attainable. The patient must This is in part due to increased legibility and improved follow-up understand the true goal of pain management, which is to reduce through the electronic system, which can reduce adverse outcome pain and, most importantly, to increase her/his quality of life. and has made providers more defensible, if a lawsuit occurs.1

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Pain is a symptom, not a diagnosis. The underlying reason for that pain needs to be clearly stated within the patient’s progress note.

Are there downfalls to the electronic medical record? Yes, some. The beautiful templates and perfectly legible documents can be laden with pages of irrelevant, erroneous, repetitious information. Within this sea of communication, important information may be ignored or lost. It has also been found that EMR s actually create a dulling of the senses. “Alert fatigue” is a new term meaning that providers may begin to ignore alerts—on average 150 in one clinic day!—automated by the EMR , ranging from redundancy, suggested follow-up, or dosage discrepancies, just to name a few. With so many alerts, providers can forget to check pertinent information before prescribing, yet there is discoverable digital proof that a red flag was, in fact, waved. Prescriptions that can easily be generated with a single click can also lead to serious errors.

EMR s are time-stamped and are fully discoverable. This creates a trail of access and modifications, truly a “true digital fingerprint,” potentially leading to serious questions about a provider’s own conduct. Malpractice carriers now recommend if you are sued to NOT immediately review the record, as you would very likely want to do.

Instead, wait for a hard copy to be provided to you from the attorney.

A sudden review of the chart can be suggestive of doubts or question of care rendered by the healthcare provider. If you decide to add or change information, again, it is all discoverable.

Be aware of another issue associated with the use of EMRs. Cloning is a “copy and paste” of a portion or an entire progress note. It is imperative that information from a past visit be removed. For instance, when a patient’s family member passes away, it is often noted in the chart.

If this information gets copied, then it appears that “the patient’s grandmother passed away last Thursday” at every visit. This creates a question of validity of the entire note. It is crucial that charts with copied and pasted sections be thoroughly reviewed for any discrepancies at each visit, prior to the document being saved.

Establish a Diagnosis It is vitally important when treating any patient with pain that a diagnosis is established. Pain is a symptom, not a diagnosis. The underlying reason for that pain needs to be clearly stated within the Q1 | 2015

patient’s progress note. Liability can greatly increase if a patient is treated long-term with a controlled substance without a definitive diagnosis. A chronic pain patient’s healthcare record should include nonpharmacologic therapies tried and their effectiveness to reduce pain and increase functionality noted. Nonpharmacologic therapies—such as physical therapy, massage, transcutaneous nerve stimulation, exercise, yoga, and cognitive behavioral therapy—have all been found to reduce pain in some patients. Patients must be willing to participate in different forms of therapy for chronic pain, and each failure or effectiveness should be clearly documented.

In some chronic pain diagnoses, invasive pain interventions may be appropriate. Pain treatment interventions may include less invasive therapies, such as trigger point injections for musculoskeletal pain syndromes or botulinum toxin injections for migraine headaches or more invasive therapies, such as epidural blocks or implantable pain stimulators. These therapies have been shown to provide opiatesparing relief from chronic pain. Even if they have been tried and failed, it is imperative to document these interventions.

Opioids?

Opiate medication is not central to oral pain therapy. There are other oral preparations that used alone or in conjunction with opiate therapy can provide pain reduction in the chronic pain patient. Research shows medications such as anti-inflammatories, anticonvulsants, and mood modulators to be effective. If any of these therapies are contraindicated, or if the patient has tried them at appropriate doses and failed to achieve a reduction in pain, the information must be clearly documented in the patient’s medical record.

It is our job as providers to ascertain if a patient is or is not appropriate for opioid therapy. When opioids are deemed appropriate for the treatment of chronic pain, the medical record must clearly establish this indication. Many considerations must be taken into account prior to and when prescribing opioid therapies. First, consider illnesses relevant to the effects of opioids and their metabolism, including pulmonary disease, cognitive impairment, hepatic and renal disease, and constipation and nausea.2 According to Zacharoff et al, illnesses www.painweek.org | PWJ | 37

FRONTLINE FOCUS

Malpractice carriers now recommend if you are sued to NOT immediately review the record… A sudden review of the chart can be suggestive of doubts or question of care rendered by the healthcare provider.

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ASS SSiNG ABUS RiSK Assessment of each chronic pain patient for the risk of abuse should include history of substance use and psychiatric history. Inquire about current and past abuse of prescription medications, illegal substances, alcohol, as well as a family history of substance abuse The Clinical Interview and psychiatric disorders. Question a patient about preadolescent sexual abuse history, as this too has been found to increase a patient’s Thorough documentation of the clinical interview with a focus on risk for opioid abuse. Assessment tools, such as the Opioid Risk Tool, pain and treatment history helps to guide chronic pain management. can be given to the patient to complete or can be performed by the Important questions to ask and document are: What relieves the provider during the interview process.7 According to Webster et al, pain? What causes or increases the pain? What effect does the pain the Opioid Risk Tool has been found to have high specificity and have on the patient’s physical, emotional, and psychosocial func- sensitivity for detecting risk potential.8 tion? On a pain scale, what is the patient’s current pain? What’s the best and worst pain score? As pain scores are being used less in the When treating the chronic pain patient utilizing opioid therapy, it management of pain, providers are finding that focusing more on is recommended to use a patient provider agreement that includes a patient’s functionality rather than a pain score is more indicative informed consent. This written agreement reinforces expectations of effective pain treatment: What were they not able to do prior to for appropriate and safe opioid use. According to Chou et al,2 the initiating therapy, especially opioid therapy? And now what activities agreement should state that the patient will: are they able to do with pain therapy?3,4 Interviewing the chronic pain patient can provide robust data regarding past use, current use, ❶ Obtain opioids from a single prescriber or office dosages, as well as simply the general effectiveness of therapies. The interview not only includes direct interaction with the patient, it is ❷ Fill opioid prescriptions at a designated pharmacy also imperative that the provider or their representative query the state Prescription Drug Monitoring Program, where available, to ❸ Safeguard opioids confirm the patient’s report of past and current medication usage, ▸ Do not store in medicine cabinet obtain an appropriate drug screen, get prior medical records for ▸ Keep locked (eg, use a safe) review, and include this information in the patient’s record as well.4,5 ▸ Do not share or sell medications that possess a potential link to a previous or current substance abuse history include hepatitis, HIV, tuberculosis, sexually transmitted infections, trauma, burns, and cellulitis.3

It is essential in the treatment of chronic pain to perform a thorough evaluation and assessment of the pain the patient is experiencing.

Components of a patient evaluation include general findings such as vital signs, appearance, posture, gait, and pain behaviors. Staff in your office can be helpful in reporting behaviors, as they are likely to spend more time overall with the patient. Documentation of a neurological examination as well as a complete musculoskeletal examination—inspection, palpation, percussion, auscultation, and provocative maneuvers—are important in reaching an appropriate individualized diagnosis and plan of care for your patients.6

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❹ Dispose of no longer needed drugs by following the instructions provided ❺ Comply with appropriate monitoring ▸ Random urine drug testing and pill counts ❻ Enumerate behaviors that may lead to opioid discontinuation The agreement should also comment on frequency of refills and include an exit strategy.

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DOCUM NTATiON OF OFFiC ViSiTS Treatment strategies and therapies prescribed must be adequately documented at the first visit and all subsequent visits. At every visit, monitor and document whether or not the patient is meeting functional goals and adhering to the dosing schedule. It is important to recognize and document aberrant behavior through a patient’s self-report and by accessing available prescription drug monitoring databases. Consider your state and federal regulations for compliance in terms of both the prescription drug monitoring database and urine drug testing.

Urine drug testing is not only beneficial to assess if the patient is taking the medication prescribed, but also to make sure there are no other nonprescribed medications or illicit drugs present.2 Urine drug testing can differ: it is important that confirmation occurs through gas chromatography/mass spectrometry or liquid chromatography/ mass spectrometry and that the results are included on the patient record at appropriate intervals.9 Inappropriate results of a urine drug test should be taken into consideration and discussed with the patient at the follow-up appointment or sooner if needed. Discontinuation of therapy or reduction of doses may be appropriate and should be thoroughly documented in the patient record.

4. Heapy A, Kerns RD. Psychological and behavioral assessment. In: Benzon H, Rathmell JP, eds. Raj’s Practical Management of Pain. 4th ed. Philadelphia, PA: Mosby Elsevier; 2008:279–295.

5. Department of Veterans Affairs, Department of Defense. Clinical practice guideline: management of opioid therapy for chronic pain. May 2010. Available at: www.va.gov/PAINMANAGEMENT/docs/CPG_opioidtherapy_summary.pdf 6. Lalani I, Argoff CE . History and physical assessment of the pain patient. In: Benzon H, Rathmell JP, eds. Raj’s Practical Management of Pain. 4th ed. Philadelphia, PA: Mosby Elsevier; 2008: 177–188.

7. Fleming MF, Davis J, Passik SD. Reported lifetime aberrant drug-taking behaviors are predictive of current substance use and mental health problems in primary care patients. Pain Med. 2008;9(8):1098–1106.

8. Webster LR , Webster RM . Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2005;6(6):432–442.

9. Gourlay DL , Heit HA . The art and science of urine drug testing. Clin J Pain.

2010;26(4):358.

10. Tennessee Department of Health. (2014) Tennessee chronic pain guidelines.

Clinical practice guidelines for outpatient management of chronic non-malignant pain. September 2014. Available at: health.state.tn.us/Downloads/ChronicPainGuidelines.pdf.

Different populations may require more documentation. For instance, according to the Tennessee Chronic Pain Guidelines, “the provider shall advise every woman of child-bearing potential on opioids that she be on a method to prevent unintended pregnancy specifically considering long-acting contraceptive methods.”10 It is important that a patient of child-bearing potential know to contact the provider immediately if she becomes pregnant while on opioid therapy. It is also recommended that this population be referred to a high-risk obstetrician. According to the Opioid Risk Tool, patients between the ages of 18 to 45 can have a higher risk of abuse and misuse of an opioid.8 Special care must be given to show that these patients are appropriate for opioid therapy and may require a referral to a pain management specialist. Patients with extensive psychiatric history should be referred to psychiatric treatment, if opioid therapy is warranted.

chro n

in patient

for t he

CONCLUSiON Thorough documentation is of the utmost importance when treating chronic pain patients. Practitioners should be up-to-date on the multiple facets of documentation as well as the pitfalls that exist. Electronic medical records are a valuable tool when fully understood and used appropriately. Providers strive to give patients the best possible care and documentation can reflect that they did.

a ic p

References 1. Virapongse A, Bates DW, Shi P, et al. Electronic health records and malpractice claims in office practice. Arch Intern Med. 2008;168(21):2362–2367.

2. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–130.

3. Zacharoff KL , Menefee Pujol L, Corsini E. PainEDU.org: A Pocket Guide to Pain Management. Newton, MA: Inflexxion; 2010:222.

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www.painweek.org | PWJ | 39

by Martin

D. Cheatle PhD

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K Y TOPiC

abstract: There is an ongoing controversy regard-

ing the efficacy and safety of long-term opioid therapy in patients with chronic noncancer pain.

Persuasive evidence shows rising rates of prescription opioid misuse, abuse, and opioid related fatal overdoses. While a number of patients benefit from opioid therapy and do not misuse or abuse opioids, there is also a subset of patients with chronic pain who are at risk when exposed to prescription opioids. This article reviews the current efforts to assess and mitigate risk of misuse and abuse of prescription opioids and explores the potential of discovering a biomarker for opioid use disorders.

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“Opioids became more frequently prescribed, which led to relief of pain and improvement in functionality in a number of patients, but also to misuse, abuse, opioid related fatalities, and the development of opioid use disorders in a subgroup of patients and nonpatients obtaining them illicitly.”

nociceptive and neuropathic pain with an effect size ranging from 0.56 to 0.60. Regarding long-term effectiveness, a Cochrane Review

by Noble et al reviewed 26 studies of long-term opioid therapy greater than 6 months.5 Twenty-five studies were case series or uncontrolled long-term trial continuations. Many patients discontinued opioids due to adverse effects (23%) or insufficient pain relief (10%) with some evidence that patients who continued on opioids did experience longterm pain relief. Methodological issues inherent in case series, which use a descriptive study design not allowing for hypothesis testing, and uncontrolled trials, which lack a control or alternative therapy group, make it difficult to interpret these data. Chaparro et al examined studies that compared opioids to placebo or other treatments for chronic low back pain (CLBP).6 Results indicated that there was low to moderate quality evidence that opioids provided short-term efficacy for both pain and function in treating CLBP as compared to placebo.

The authors concluded that beginning long-term opioid therapy should be done carefully and only after completing a comprehensive evaluation of potential risk factors for abuse.

▌ Pain and Prescription Opioid Abuse

has been estimated that approximately one-third of the American population suffers from chronic pain,1,2 and this number will continue to rise with the large number of aging baby boomers. The 2011 Institute of Medicine Report, “Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research,”3 outlined several guiding principles with respect to pain management: ❶ Effective pain management is a moral imperative ❷ Pain should be considered a disease with a distinct pathology ❸ There is a need for interdisciplinary treatment approaches ❹ There is a serious problem of diversion and abuse of opioid drugs

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ROL OF OPiOiD TH RAPY iN CHRONiC NONCANC R PAiN

▌ Long-Term Efficacy

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There is an ongoing debate regarding the long-term efficacy of opioid therapy for patients with chronic noncancer pain (CNCP). In a study

by Furlan, 62 random controlled trials were reviewed in a metanalysis where duration of opioid therapy was less than 16 weeks in 61 of the trials.4 It was found that opioids were more effective than placebo for

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In the 19th century, opioids and cocaine were virtually unregulated and were prescribed or used for a variety of ailments including addiction and acute and chronic pain. In 1914, the Harrison Narcotic Act was enacted and was ratified by the Supreme Court in 1919.

The act stipulated that a physician could distribute opioids “in the course of his professional practice only.” This was interpreted that physicians could not prescribe opioids to addicts since addiction at that time was not considered a disease. Physicians who prescribed opioids to addicts as maintenance therapy were censored, lost their license, or in some cases were incarcerated. This heightened concern over prescribing opioids led to undertreating legitimate pain. Many years of advocacy to improve the treatment of pain, in conjunction with published articles on the safety and efficacy of opioids, led to an opioid focused model where pain management equaled opioids.

This model was developed for a number of reasons including a focus and emphasis of the pharmaceutical industry and generalizing the opioid model from end-of-life and cancer populations to patients with CNCP. Opioids became more frequently prescribed, which led to relief of pain and improvement in functionality in a number of patients, but also to misuse, abuse, opioid related fatalities, and the development of opioid use disorders (OUD) in a subgroup of patients and nonpatients obtaining them illicitly.

Data from SAMHSA looking at first-time use of specific drugs among persons aged 12 or older revealed that only marijuana was higher than pain relievers.7 Examining the national Vital Statistics system from 1999 to 2008, as the sales of prescription opioids increased, deaths from opioid related overdoses paralleled that increase, as did admissions to treatment centers for treatment of OUDs.8 In 2010 there were 740,000 individuals who received treatment for pain reliever abuse.9 There has been burgeoning concern regarding this surge of opioid related fatalities and complications, which has led to some states stipulating upper dosing of opioids for noncancer pain and emphasizing the development of useful risk assessment and mitigation strategies. www.painweek.org | PWJ | 43

KEY TOPIC

▌ Pain and Addiction

Mere exposure to opioids over time does not create or lead to a substance use disorder. Addiction is a confluence of biological factors and genetic predisposition interacting with the environment and the actual properties of the drug, filtered through brain mechanisms.

Individuals respond differently to opioid exposure, with a subgroup of patients developing an addictive disease after opioid exposure, as compared to patients who have no addictive disease due to lack of exposure and those exposed to opioids who do not develop an OUD. This creates a treatment dichotomy: there is an effective medication that can relieve pain and suffering and improve functionality in a subgroup of patients with CNCP, but there is also a subgroup of patients who have a predisposition to addiction and, when exposed to opioids, will develop a second layer of suffering, that of an OUD. A key issue is developing sensitive measures to accurately assess who is at risk for misusing or abusing opioids and mitigating risk to preserve access to opioid therapy for those patients who benefit from it and identifying early those patients who may develop an OUD.

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RiSK ASS SSM NT, MONiTORiNG, AND MiTiGATiON—TH PR S NT Currently, risk assessment and monitoring of opioid therapy consists of 5 components:

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❶ Clinical interview ❷ Risk screening tools ❸ Urine drug screening

misuse and abuse (see Table). There are several tools that are used to assess risk in patients prior to beginning long-term opioid therapy. Examples of these include the Opioid Risk Tool,12 the Screener and Opioid Assessment of Patients with Pain,13 and the Diagnosis, Intractability, Risk, & Efficacy Score.14 There are also tools that have been developed to assess misuse once opioid treatment has been initiated. Examples of these instruments include the Pain Medication Questionnaire,15 the Current Opioid Misuse Measure,16 and the Prescription Drug Use Questionnaire.17 Use of these tools is considered to be part of the standard of practice when prescribing or considering prescribing opioid therapy.

Table. Examples of Opioid Risk Assessment Tools Tool

# of Items

For patients being considered for long-term opioid therapy: ORT Opioid Risk Tool

5

Patient administered

SOAPP® Screener and Opioid Assessment for Patients with Pain

24, 14, & 5

Patient administered

DIRE Diagnosis, Intractability, Risk, and Efficacy Score

7

Clinician administered

❹ Psychological assessment

To characterize misuse once opioid treatment begins:

❺ Prescription drug monitoring programs

PMQ Pain Medication Questionnaire

26

Patient administered

COMM Current Opioid Misuse Measure

17

Patient administered

▌ Clinical Interview

The clinical interview is an important first step in evaluating patients PDUQ Prescription 40 Clinician who may be at risk for developing an OUD. It is imperative to take a Drug Use Questionnaire administered detailed patient medical history inquiring about various comorbidities, both psychiatric and medical. It is also critical to assess pain and treatment history: obtaining a description of pain location, intensity, quality, onset, and duration; learning what relieves and increases pain; discovering the effects of pain on physical, emotional, and psychosocial function; and understanding the patient’s pain and functional goals.10 Next ▌ Urine Drug Screening the interview should assess past and current use of opioids, including Two of the most valued opioid prescribing guidelines, from the querying the state prescription drug monitoring database, examining American Pain Society/American Academy of Pain Management18 past medical records, and obtaining an initial urine drug test (UDT). and the Canadian guideline for safe and effective use of opioids for Dosage and general effectiveness of opioids should also be noted.10 chronic noncancer pain,19 state that high risk individuals on longThe last step in an initial encounter is performing a thorough physical term opioid therapy should have a UDT confirming adherence to examination and possibly obtaining further diagnostic testing.11 the opioid therapy plan of care. It is also suggested that urine drug monitoring be utilized in patients not considered to be high risk.

Many state medical boards have endorsed urine drug monitoring ▌ Risk Screening Tools as a strategy to ensure safe and effective use of opioids, but only in A variety of risk assessment tools have been developed based on general terms. Urine drug monitoring cannot diagnose drug addicknown risk factors and identified aberrant behaviors suggestive of tion, physical dependence, or impairment. Oftentimes an absence of

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“It is critical that psychological assessment be part of the initial risk assessment and also used in monitoring patients on long-term opioid therapy.”

prescription opioids is considered to reflect diversion, but it can also be indicative of hoarding: the patient may not be confident that their physician will continue to prescribe opioids long-term. An absence of opioids in a UDT can be an indication of depression and suicidal ideation, as a subgroup of these patients have significant psychiatric comorbidities.20 Some patients may hoard a portion of their medications for a future suicide attempt.

▌ Psychological Assessment

generally suboptimal. PDMP vary in who can access the system, and information is not typically available across state borders, limiting some of its usefulness.

RiSK STRATiFiCATiON Once risk assessment has been completed through the clinical interview, urine drug monitoring, psychological assessment, and use of PDMP, patients can be delegated to:

Patients with chronic pain oftentimes experience concomitant mood ❶ A low risk group—patients with no personal or family history of and anxiety disorders. Opioid analgesics can have anxiolytic and antisubstance use disorder, or no/minimal comorbid psychopatholdepressant effects and there may be a subgroup of patients that selfogy—to be managed by the primary care physician treat their mood and anxiety disorders with opioids. It is critical that psychological assessment be part of the initial risk assessment and also ❷ A moderate risk group—patients with a history of substance use used in monitoring patients on long-term opioid therapy. When the disorder, family history of substance use disorder, and/or current patient’s mood and anxiety disorders are effectively managed, opioid moderate psychiatric disorders—that would require a PCP who demand may decrease. There are a number of validated and reliable has support from a specialist mental health screening tools. The Beck Depression Inventory (BDI)21 and the Profile of Mood States (POMS)22 are 2 that have been recom- ❸ A high risk group—patients who are actively addicted or unstamended by an expert consensus panel on measuring emotional funcble with major psychiatric disorders—that should be managed tioning in chronic pain.23 Other measures of depression include the in specialty care, such as an addiction treatment program and/or Zung Self-Rating Depression Scale,24 the Center for Epidemiologic psychiatric program.33 Studies Depression Scale,25 and the Patient Health Questionnaire (PHQ-9).26 Instruments for assessing anxiety include the Beck Anxiety In a recent article, Chang and Compton outlined a more detailed Inventory 27 and the State Trait Anxiety Inventory.28 Tools designed to model where risk stratification is assessed on screening tools and assess both depression and anxiety include the Hospital Anxiety and patients are placed in low, medium, or high risk groups.34 In each Depression Scale,29 Hopkins Symptom Checklist,30 and the PHQ-4.31 of these risk categories, frequency of urine drug monitoring and querying the PDMP is stipulated along with suggested opioid dosing.

▌ Prescription Drug Monitoring Programs

PDMP are now available in most states. A recent study by Reifler et al examined data from the RADAR® System Poison Control Center and Opioid Treatment surveillance databases to assess opioid misuse and abuse and found an association between PDMP and reduced opioid abuse trends.32 Use of the PDMP is inconstant and tends to be

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RiSK MiTiGATiON There have been numerous strategies to mitigate the risk of a patient misusing, abusing, or developing an OUD or suffering from an opioid related fatality, including dose limitation, educational strategies, and opioid abuse deterrent formulations. www.painweek.org | PWJ | 45

KEY TOPIC

“There is fairly persuasive evidence indicating that the risk for opioid addiction has substantial genetic origins.”

▌ Dose Limitation

or coformulated with medications that block the euphoric effects of There has been some indication that dose limitations have led to a opioids or produce a noxious side effect when altered. The long-term decrease in opioid related deaths. The state of Washington enacted a effectiveness of ADFs has yet to be established; however, there has state dosing guideline recommending that the prescription of a daily been a reduction in the abuse of extended release oxycodone since dose of opioids in CNCP greater than 120 mg morphine-equivalent the introduction of the ADF product.36 The ADFs are typically not dose ( MED) would require a consultation with a pain medicine used in short acting opioids and hydrocodone is still the most abused specialist. One study examined the effect of this dosing policy on prescription opioid to date.37 prescribing patterns and opioid related deaths in a cohort of injured workers. Compared to prior to the implementation of the guidelines they discovered a substantial reduction of workers receiving doses RiSK ASS SSM NT—TH FUTUR greater than 120 mg/day MED and a 50% decrease from 2009 to There has been a great deal of scholarly activity devoted to attempt2010 in the number of opioid related deaths.35 The data was obser- ing to discover biomarkers of addiction. These biomarkers theoretvational and was subject to confounding, and the overdose trend ically would ensure continued access to opioids for patients who are was based on a single year. In a random controlled trial a stable low risk patients and would identify early patients who might develop dosing schedule was compared to an escalating dosing schedule in an OUD and require more frequent monitoring or alternative nona cohort of veterans. Results revealed no difference in usual pain or opioid therapies. functional disability between the groups, but doses were relatively low (<60 MEDs). There is a need for further study of the effect of dose limitations on opioid misuse and opioid related deaths and the HUMAN G N TiCS OF OPiOiD D P ND NC impact on pain and functionality.

There is fairly persuasive evidence indicating that the risk for opioid addiction has substantial genetic origins.38 There have been several candidate genes studied in human OUD (OPRM1, A11AG, CYP2D6), ▌ Educational Strategies but the results of these studies have been mixed due to small sample The FDA under the Food and Drug Administration Amendments sizes, mixed ethnic groups, only one sequence variant genotype, variAct of 2007 was provided the authority to require a Risk Evaluation ation in case definition, and lack of matched control cohort. While and Mitigation Strategy ( REMS) from manufacturers to safeguard there is some preliminary data that is very promising we have yet to that the benefits of a drug outweigh its risks. In 2012 the FDA discover the genetic markers for opioid addiction. approved REMS for long acting or extended release opioid products emphasizing prescriber and patient education regarding the benefits and potential risks of opioids and assessment and moni- CONCLUSiON toring safeguards to ensure proper use. Currently this is voluntary Pain is extremely complex with patients often experiencing signifprescriber continuing education, which is not required for DEA icant concomitant psychiatric and medical comorbidities. Opioids licensure. It is too early to see if this will have an effect on clinical can be efficacious for some patients with chronic pain, but there is practice or outcomes. a serious crisis of opioid abuse, diversion, and fatal overdose. We require more evidence to understand the optimal risk assessment, opioid selection dosing, monitoring, risk mitigation, and discontin ▌ Abuse Deterrent Formulations uation strategies. Assessing risk of abuse in patients receiving longAbuse determent formulations (ADF ) for extended release products term opioid therapy is a dynamic, ongoing process, and discovering have been approved by the FDA or are undergoing FDA approval pro- genetic markers for opioid addiction requires further investigacess. These are formulations that are designed to be tamper resistant tion. No opioid is totally safe. Opioids can cause numerous adverse

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effects—opioid induced constipation, androgen deficiency, sleep disturbance, respiratory depression, etc—including misuse and abuse. More selective and cautious prescribing appears indicated while waiting for better evidence. Clinicians need to assess risk as standard practice and routinely integrate risk mitigation strategies, matched with level of assessed risk. There is a need for readily available effective nonopioid treatments for chronic pain, including those addressing psychosocial factors.

Acknowledgments: MDC would like to acknowledge the support from Grant 1R01DA032776–01 from the National Institute on Drug Abuse, National Institutes of Health in the writing of this manuscript.

References 1. Tsang AM , Von Korff S, Lee J, et al. Common chronic pain conditions in developed and developing countries: Gender and age differences and comorbidity with depression-anxiety disorders. J Pain. 2008;9(10):883–891.

2. Johannes CB, Kim Le T, Zhou X, et al. The prevalence of chronic pain in United States adults: results of an internet-based survey. J Pain. 2010;11(11):1230–1239.

3. IOM (Institute of Medicine). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011.

4. Furlan AD, Chaparro LE, Irvin E, et al. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain. Pain Res Manage. 2011;16(5):337–351.

5. Noble M, Treadwell JR , Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;1. CD 006605.

6. Chaparro LE, Furlan AD, Deshpande A, et al. Opioids compared to placebo or other treatments for chronic low-back pain. Cochrane Database Syst Rev. 2013;8.

CD 004959.

7. SAMHSA . (2012). Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-44, HHS Publication No. (SMA ) 12–4713. Rockville, MD. 8. National Vital Statistics System, 1999–2008; Automation of Reports and Consolidated Orders System ( ARCOS) of the Drug Enforcement Administration (DEA ), 1999–2010; Treatment Episode Data Set, 1999–2009.

9. Substance Abuse and Mental Health Services Administration, Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-41, HHS Publication No. (SMA ) 11–4658. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2011.

10. Heapy A, Kerns RD. Psychological and behavioral assessment. In: Benzon H, Rathmell JP, eds. Raj’s Practical Management of Pain. 4th ed. Philadelphia, PA: Mosby Elsevier; 2008;279–295.

11. Lalani I, Argoff CE . History and physical examination of the pain patient. In: Benzon H, Rathmell JP, eds. Raj’s Practical Management of Pain. 4th ed. Philadelphia, PA: Mosby Elsevier; 2008:177–188.

12. Webster LR , Webster RM . Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med. 2005;6:432–442.

13. Butler S, Budman S, et al. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain. 2004;112(1–2):65–75.

14. Belgrade M, Schamber C, Lindgren B. The DIRE score: predicting outcomes of opioid prescribing for chronic pain. J Pain. 2006;7(9):671–681.

16. Butler S, Budman SH, Fernandez KC , et al. Development and validation of the Current Opioid Misuse Measure. Pain. 2007;130(1–2):144–156.

17. Compton PA , Wu SM , Schieffer B, et al. Introduction of a self-report version of the Prescription Drug Use Questionnaire and relationship to medication agreement noncompliance. J Pain Symptom Manage. 2008;36(4):383–395.

18. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113–130.

19. National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic noncancer pain. Hamilton, ON: McMaster University; 2010. Available at: nationalpaincentre.mcmaster.ca/opioid/cgop_a00_executive_ summary.html. Accessed January 15, 2015.

20. Cheatle MD. Depression, chronic pain, and suicide by overdose: On the edge.

Pain Med. 2011;12 suppl 2:S43–48.

21. Beck A, Ward C, Mendelson M, et al. An inventory for measuring depression.

Arch Gen Psychiatry. 1961;4:561–571.

22. McNair D, Lorr M, Droppleman L. Profile of Mood States. San Diego, CA: Educational and Industrial Testing Service; 1971.

23. Dworkin R, Turk DC , Farrar JT, et al. IMMPACT. Core outcome measures for chronic pain trials: IMMPACT recommendations. Pain. 2005;113(1–2):9–19.

24. Zung W. A self-rating depression scale. Arch Gen Psychiatry. 1965;12:63–70.

25. Radloff L. The CES -D scale: A self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385–401.

26. Kroenke K, Spitzer RL , Williams JB . The PHQ -9: Validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–613.

27. Beck AT, Epstein N, Brown G, et al. An inventory for measuring clinical anxiety: Psychometric properties. J Consult Clin Psychol. 1988;56(6):893–897.

28. Spielberg C, Gorsuch R, Lushene R. Manual for the State-Trait Anxiety Inventory.

Palo Alto, CA: Consulting Psychologists; 1970.

29. Bjelland L, Dahl AA , Haug TT, et al. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res. 2002;52(2):69–77.

30. Derogatis LR , Lipman RS, Rickels K, et al. The Hopkins Symptom Checklist (HSCL): A self-report symptom inventory. Behav Sci. 1974;19(1):1–15.

31. Kroenke K, Spitzer RL , Williams JB, et al. An ultrabrief screening scale for anxiety and depression: the PHQ -4. Psychosomatics. 2009;50(6):613–621.

32. Reifler LM , Droz D, Bailey JE, et al. Do prescription monitoring programs impact state trends in opioid abuse/misuse? Pain Med. 2012;13(3):434–442.

33. Gourlay DL , Heit HA , Almahrezi A. Universal Precautions in Pain Medicine: A Rational Approach to the Treatment of Chronic Pain. Pain Med. 2005;6(2):107–112.

34. Chang YP, Compton P. Management of chronic pain with chronic opioid therapy in patients with substance use disorders. Addict Sci Clin Pract. 2013;16;8:21.

35. Franklin GM , Mai J, Turner J, et al. Bending the prescription opioid dosing and mortality curves: Impact of the Washington State opioid dosing guideline. Am J Ind Med. 2012;55(4):325–331.

36. Cicero TJ, Ellis MS, Surratt HL . Effect of abuse-deterrent formulation of OxyContin. N Engl J Med. 2012;367(2):187–189.

37. Cicero TJ, Ellis MS, Surratt HL , et al. Factors influencing the selection of hydrocodone and oxycodone as primary opioids in substance abusers seeking treatment in the United States. Pain. 2013;154(12):2639–2648.

38. Kreek MJ, Bart G, Lilly C, et al. Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev. 2005;57:1–26.

15. Holmes CP, Gatchel RJ, Adams LL , et al. An opioid screening instrument: long-term evaluation of the utility of the Pain Medication Questionnaire. Pain Pract.

2006;6(2):74–88.

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with

Michael E. Schatman PhD, CPE, DASPE

Michael Schatman is Executive Director of the Foundation for Ethics in Pain Care in Bellevue, Washington. He is also the Editor-inChief of Journal of Pain Research.

48 | PWJ | www.painweek.org

Q1 | 2015

“I’d probably sell my soul to the devil to create a new pain treatment paradigm in the United States.”

What inspired you to become a healthcare provider?

What do you consider your greatest achievement?

I was pre-law throughout college at Columbia and was set to go to law school. I decided at the last moment to run away to Oregon to pick mushrooms and throw a Frisbee. There, at a party, I met a doctoral student in clinical psychology, who told me to become a shrink. It sounded like it would beat working for a living.

Without a doubt, being named the American Society of Pain Educators’ 2011 Clinical Pain Educator of the Year. I had a “Rocky moment,” and wish I’d known someone named Adrienne, as I would have held up my plaque and said, “Yo Adrienne—I did it!”

Why did you focus on pain management?

Our department also had a doctoral program in behavioral medicine, which appealed to me. I was lucky enough during my 3rd year to get a half-time practicum at the Texas Back Institute, which was at the forefront of interdisciplinary pain management. I haven’t looked back!

Who were your mentors?

I’ve had several mentors. As a pain bioethicist, Jim Giordano taught me that I didn’t need to be angry to be principled. As a writer and editor, Mac Gallagher taught me the value of rapprochement. As a bourbon drinker, John Peppin taught me everything I know If you weren’t a healthcare provider, what would you be?

Believe it or not, I’d probably be a personal injury plaintiff’s attorney. In my current job(s), patient advocacy is central. Doing a good amount of personal injury medicolegal work, I have come to recognize that at least a minority of personal injury attorneys are principled individuals who are truly invested in advocating for their clients. Go figure.

What is your most marked characteristic?

What is your favorite language?

All 5 of the 5 languages of love.

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?

The book would be Thomas Mann’s Doctor Faustus, as I’d probably sell my soul to the devil to create a new pain treatment paradigm in the United States. The movie would be a Kubrick piece—perhaps A Clockwork Orange—as it blends psychology with a tastefully unhealthy combination of sex and violence. The piece of music would be John Mayer’s Neon because it reminds me of the woman I love.

What would you like your legacy to be?

I’d truly like to be one of the individuals responsible for the paradigm change in American pain medicine, participating in the transformation of pain medicine from a “business” to a “profession.”

What is your motto?

“Salud, dinero, y amor, y tiempo a gustarlos!”

Spanish for “Health, money, and love, and the time to enjoy them!” (Okay, it’s a toast, not a motto.)

As an editor, I have a reputation of knowing very little yet being able to convince people much smarter than am I to engage in projects that make me look good.

Q1 | 2015

www.painweek.org | PWJ | 49

MOVANTIK™ (naloxegol) tablets, for oral use BRIEF SUMMARY of PRESCRIBING INFORMATION For full Prescribing Information, see package insert.

INDICATIONS AND USAGE MOVANTIK (naloxegol) is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.

DOSAGE AND ADMINISTRATION Administration • Discontinue all maintenance laxative therapy prior to initiation of MOVANTIK. Laxative(s) can be used as needed if there is a suboptimal response to MOVANTIK after three days.

• Alteration in analgesic dosing regimen prior to initiating MOVANTIK is not required.

• MOVANTIK has been shown to be efficacious in patients who have taken opioids for at least 4 weeks. Sustained exposure to opioids prior to starting MOVANTIK may increase the patient’s sensitivity to the effects of MOVANTIK [see Clinical Studies (14) in Full Prescribing Information].

• Take MOVANTIK on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal.

• Swallow tablets whole, do not crush or chew.

• Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK. • Discontinue MOVANTIK if treatment with the opioid pain medication is also discontinued.

Adult Dosage The recommended MOVANTIK dosage is 25 mg once daily in the morning.

If patients are not able to tolerate MOVANTIK, reduce the dosage to 12.5 mg once daily [see Clinical Pharmacology (12.2) in Full Prescribing Information].

Dosage in Adult Patients with Renal Impairment The starting dosage for patients with creatinine clearance (CLcr) < 60 mL/min (i.e., patients with moderate, severe or end-stage renal impairment) is 12.5 mg once daily. If this dosage is well tolerated but OIC symptoms continue, the dosage may be increased to 25 mg once daily taking into consideration the potential for markedly increased exposures in some patients with renal impairment and the increased risk of adverse reactions with higher exposures [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) in Full Prescribing Information].

Dosage Recommendations due to Drug Interactions Avoid concomitant use of MOVANTIK with moderate CYP3A4 inhibitor drugs (e.g., diltiazem, erythromycin, verapamil). If concurrent use is unavoidable, reduce the MOVANTIK dosage to 12.5 mg once daily and monitor for adverse reactions [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) in Full Prescribing Information].

DOSAGE FORMS AND STRENGTHS MOVANTIK (naloxegol) is available in two strengths: • Tablets: 12.5 mg supplied as mauve, oval, biconvex, film-coated, intagliated with “nGL” on one side and “12.5” on the other side.

• Tablets: 25 mg supplied as mauve, oval, biconvex, film-coated, intagliated with “nGL” on one side and “25” on the other side.

CONTRAINDICATIONS MOVANTIK is contraindicated in: • Patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation [see Warnings and Precautions (5.1) in Full Prescribing Information].

• Patients concomitantly using strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) because these medications can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning [see Drug Interactions (7.1) and Pharmacokinetics (12.3) in Full Prescribing Information].

• Patients who have had a known serious or severe hypersensitivity reaction to MOVANTIK or any of its excipients.

WARNINGS AND PRECAUTIONS Gastrointestinal Perforation Cases of gastrointestinal perforation have been reported with use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases).

Take into account the overall risk-benefit profile when using MOVANTIK in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent or worsening abdominal pain; discontinue MOVANTIK in patients who develop this symptom [see Contraindications (4) in Full Prescribing Information].

Opioid Withdrawal Clusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning have occurred in patients treated with MOVANTIK [see Adverse Reactions (6.1) in Full Prescribing Information]. In addition, patients receiving methadone as therapy for their pain condition were observed in clinical trials to have a higher frequency of gastrointestinal adverse reactions that may have been related to opioid withdrawal than patients receiving other opioids [see Adverse Reactions (6.1)]. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using MOVANTIK in such patients. Monitor for symptoms of opioid withdrawal in such patients.

ADVERSE REACTIONS Serious and important adverse reactions described elsewhere in labeling include: • Gastrointestinal perforation [see Warnings and Precautions (5.1) in Full Prescribing Information] • Opioid withdrawal [see Warnings and Precautions (5.2) in Full Prescribing Information] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to MOVANTIK in 1497 patients in clinical trials, including 537 patients exposed for greater than six months, and 320 patients exposed for 12 months.

The safety data described in Table 1 are derived from two double-blind, placebo-controlled trials (Studies 1 and 2) in patients with OIC and non-cancer related pain [see Clinical Studies (14) in Full Prescribing Information].

Study 3 (n=302) was a safety extension study that allowed patients from Study 1 to continue the same blinded treatment for an additional 12 weeks. Safety data for patients in Study 3 are similar to those listed in Table 1.

Study 4 (n=844) was a Phase 3, 52-week, multi-center, open-label, randomized, parallel group, safety and tolerability study of naloxegol versus usual care treatment for OIC (as determined by the investigator and excluding peripheral opioid antagonists) in patients with non-cancer related pain. The population enrolled in Study 4 was similar to that of the other studies. Eligible patients were randomized in a 2:1 ratio to receive either naloxegol 25 mg once daily or usual care treatment for OIC. The most commonly used laxatives in the usual care group were rectal stimulants (e.g., bisacodyl), oral stimulants (e.g., senna), and oral osmotics (e.g., macrogol, magnesium). Safety data for patients in Study 4 are similar to those listed in Table 1.

Table 1 lists adverse reactions in pooled Studies 1 and 2 occurring in ≥ 3% of patients receiving MOVANTIK 12.5 mg or 25 mg and at an incidence greater than placebo.

Table 1. Adverse Reactions* in Patients with OIC and Non-Cancer Pain (Studies 1 and 2) Adverse Reaction

MOVANTIK 25 mg (n=446)

MOVANTIK 12.5 mg (n=441)

Placebo (n=444)

Abdominal Pain

21%

12%

7%

Diarrhea

9%

6%

5%

Nausea

8%

7%

5%

Flatulence

6%

3%

3%

Vomiting

5%

3%

4%

Headache

4%

4%

3%

Hyperhidrosis

3%

<1%

<1%

*Adverse reactions occurring in ≥ 3% of patients receiving MOVANTIK 12.5 mg or 25 mg and at an incidence greater than placebo.

Opioid Withdrawal Possible opioid withdrawal, defined as at least three adverse reactions potentially related to opioid withdrawal that occurred on the same day and were not all related to the gastrointestinal system, occurred in less than 1% (1/444) of placebo subjects, 1% (5/441) receiving MOVANTIK 12.5 mg, and 3% (14/446) receiving MOVANTIK 25 mg in Studies 1 and 2 regardless of maintenance opioid treatment. Symptoms included but were not limited to hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Patients receiving methadone as therapy for their pain condition were observed in Studies 1 and 2 to have a higher frequency of gastrointestinal adverse reactions than patients receiving other opioids [39% (7/18) vs. 26% (110/423) in the 12.5 mg group; 75% (24/32) vs.

34% (142/414) in the 25 mg group].

MOVANTIK™ (naloxegol) tablets, for oral use

Nursing Mothers It is unknown whether MOVANTIK is present in human milk; however, naloxegol is present in rat milk and is absorbed in nursing rat pups. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

DRUG INTERACTIONS Effects of Other Drugs on MOVANTIK Table 2 displays the effects of other drugs on MOVANTIK. Table 2. Effects of Other Drugs on MOVANTIK Concomitant Agent

Mechanism of Action

Clinical Recommendation

CYP3A4 Inhibitors Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, Increase plasma clarithromycin) naloxegol concentrations and may increase Moderate CYP3A4 the risk of adverse inhibitors reactions [see Clinical (e.g., diltiazem, Pharmacology (12.3)]. erythromycin, verapamil)

Use with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4)].

Avoid use with moderate CYP3A4 inhibitors; if unavoidable, decrease the dosage of MOVANTIK to 12.5 mg once daily and monitor for adverse reactions [see Dosage and Administration (2.4)].

Weak CYP3A4 inhibitors (e.g., quinidine, cimetidine)

Clinically significant increases in naloxegol concentrations are not expected.

Grapefruit or grapefruit juice*

Can increase plasma Avoid consumption of grapefruit naloxegol concentrations. or grapefruit juice during treatment with MOVANTIK [see Dosage and Administration (2.1)].

No dosage adjustments are necessary.

CYP3A4 Inducers Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s Wort)

Significantly decrease plasma naloxegol concentrations and may decrease the efficacy of MOVANTIK [see Clinical Pharmacology (12.3)].

Use with strong CYP3A4 inducers is not recommended.

Other Drug Interactions Other opioid antagonists

2

Potential for additive Avoid use of MOVANTIK effect of opioid receptor with another opioid antagonist. antagonism and increased risk of opioid withdrawal.

*The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparationdependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength)

USE IN SPECIFIC POPULATIONS

Pediatric Use The safety and effectiveness of MOVANTIK have not been established in pediatric patients.

Geriatric Use Of the total number of subjects in clinical studies of MOVANTIK, 11 percent were 65 and over, while 2 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

MOVANTIK exposure was higher in elderly healthy Japanese subjects compared to young subjects [see Clinical Pharmacology (12.3) in Full Prescribing Information]. No dosage adjustment is needed in elderly patients.

Renal Impairment Some subjects with creatinine clearance (CLcr) values < 60 mL/minute (i.e., moderate, severe or endstage renal disease) were shown to exhibit markedly higher systemic exposure of naloxegol compared to subjects with normal renal function. The reason for these high exposures is not understood. However, as the risk of adverse reactions increases with systemic exposure, a lower starting dosage of 12.5 mg once daily is recommended. No dosage adjustment is needed in patients with mild renal impairment [see Dosage and Administration (2.3), and Clinical Pharmacology (12.3) in Full Prescribing Information].

Hepatic Impairment The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol has not been evaluated. Avoid use of MOVANTIK in patients with severe hepatic impairment, as the dosage in these patients has not been determined. No dosage adjustment is required for patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

OVERDOSAGE In a clinical study of patients with OIC a daily dose of 50 mg (twice the recommended dosage), administered over 4 weeks, was associated with an increased incidence of GI adverse reactions, such as abdominal pain, diarrhea and nausea. These adverse reactions frequently occurred within 1-2 days after dosing.

No antidote is known for naloxegol. Dialysis was noted to be ineffective as a means of elimination in a clinical study in patients with renal failure.

If a patient on opioid therapy receives an overdose of naloxegol, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

MOVANTIK is a trademark of the AstraZeneca group of companies. © AstraZeneca 2014

Pregnancy

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850

Pregnancy Category C

3097305 2/15

Risk Summary There are no adequate and well-controlled studies with MOVANTIK in pregnant women. The use of MOVANTIK during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. No effects on embryo-fetal development were observed following administration of naloxegol in pregnant rats during the period of organogenesis at doses up to 1452 times the human AUC (area under the plasma concentration-time curve) at the maximum recommended human dose. No effects on embryo-fetal development were observed following administration of naloxegol in pregnant rabbits during the period of organogenesis at doses up to 409 times the human AUC at the maximum recommended human dose. MOVANTIK should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data Oral administration of up to 750 mg/kg/day naloxegol in rats (1452 times the human AUC at the maximum recommended human dose) and 450 mg/kg/day naloxegol in rabbits (409 times the human AUC at the maximum recommended human dose) during the period of organogenesis produced no adverse effects on embryo-fetal development. Oral administration of up to 500 mg/kg/day in rats (195 times the maximum recommended human dose based on body surface area) during the period of organogenesis through lactation produced no adverse effects on parturition or the offspring.

Revised 01/2015

IN ADULT PATIENTS WITH CHRONIC NON-CANCER PAIN

HOW DO YOU TREAT

OPIOID-INDUCED C O N S T I PAT I O N ?

MOVANTIK™ (naloxegol) tablets, a once-daily oral tablet, is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain1 IMPORTANT SAFETY INFORMATION ABOUT MOVANTIK

• Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning, occurred • MOVANTIK is contraindicated in: in patients treated with MOVANTIK. Patients — Patients with known or suspected gastrointestinal receiving methadone in the clinical trials were (GI) obstruction and patients at increased risk of observed to have a higher frequency of GI adverse recurrent obstruction due to the potential for reactions that may have been related to opioid GI perforation withdrawal than patients receiving other opioids.

Patients with disruptions to the blood-brain barrier — Patients receiving strong CYP3A4 inhibitors (eg, may be at increased risk for opioid withdrawal or clarithromycin, ketoconazole) because these reduced analgesia. Monitor for symptoms of opioid medications can significantly increase exposure withdrawal when using MOVANTIK in such patients to naloxegol which may precipitate opioid withdrawal symptoms • The most common adverse reactions with MOVANTIK in clinical trials were abdominal pain — Patients with a known serious or severe (21%), diarrhea (9%), nausea (8%), flatulence (6%), hypersensitivity reaction to MOVANTIK or any vomiting (5%), headache (4%), and hyperhidrosis (3%) of its excipients • Cases of GI perforation have been reported with the use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural e . integrity in the wall of the GI tract. Monitor for pl ials m r severe, persistent, or worsening sa ate abdominal pain; discontinue s s if this symptom develops ce d m Please see the Brief Summary of full Prescribing Information on the adjacent pages.

Reference: 1. Prescribing Information for MOVANTIK. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

MOVANTIK is a registered trademark of the AstraZeneca group of companies. ©2015 AstraZeneca.

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