The Pain Practitioner - Nutrition, Aromatherapy and Massage

Integrative Pain Management for Optimal Patient Care

The Pain Practitioner SPRING 2018

Non-pharmacologic treatments of pain Nutrition, aromatherapy, and massage + Opioid Prescribing Survey Results

Academy of Integrative Pain Management

The Pain Practitioner

www.integrativepainmanagement.org

SPRING 2018

ACADEMY BOARD OF DIRECTORS President W. Clay Jackson, MD, DipTh Past President Joanna Katzman, MD, MSPH Vice President Paul Christo, MD Secretary George D. Comerci, Jr, MD, FACP Treasurer Kevin T. Galloway, BSN, MHA, Colonel, US Army (Retired) Directors-at-Large Lynette Cederquist, MD John Garzione, DPT Michael Kurisu, DO Joseph Matthews, DDS, MSc Roger Mignosa, DO Helen Turner, DNP Liaison to the Board Maggie Buckley

STAFF AND CONSULTANTS Executive Director Robert Twillman, PhD, FAPM Director of the State Pain Policy Advocacy Network (SPPAN) Amy Goldstein, MSW Assistant Director of Education Cathleen Coneghen Director of Legislative and Regulatory Affairs Katie Duensing, JD Member Services Manager Whitney O’Donnell Account Manager Rosemary LeMay Professional Development Project Manager MacKenzie Davis Content Consultant Debra Nelson-Hogan

THE PAIN PRACTITIONER STAFF AND CONSULTANTS Editor-in-Chief W. Clay Jackson, MD, DipTh Editor Debra Nelson-Hogan Advertising and Sales Leslie Ringe Managing Editor Cathleen Coneghen Clinical Editor Christine Rhodes, MS Art Director Peter McKinley, Pak Creative Copy Editor Rosemary Hope

The Pain Practitioner is published by the Academy of Integrative Pain Management, P: 209-533-9744, Email: aapm@integrativepain.org, website: www.integrativepainmanagement.org.

Copyright 2018 Academy of Integrative Pain Management. All rights reserved.

Send correspondence to: Debra NelsonHogan at dhogan@integrativepain.org.

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9 NOTES FROM THE FIELD The Three-Headed Monster: The Crises of Mental Health, Chronic Pain, and Prescription Opioid Abuse

By Bob Twillman, PhD, FAPM, Executive Director PAGE 11

10 EDITORIAL Harmony

By W. Clay Jackson, MD, DipTh, Editor-in-Chief 11 ADVOCACY Integrative Pain Management Strikes Washington!

By Katie Duensing, JD, Director of Legislative and Regulatory Affairs 12 Nutrition, Inflammation, and Pain: How Do We Begin to Heal?

By Christine Rhodes, MS

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16 Massage Therapy as an Alternative to Opioids

By Dolly Wallace, LMT BCTMB, president, American Massage Therapy Association 18 Scents and Sensibility: Aromatherapy for Pain Relief

By Paul Christo, MD 20 How Can We Improve Opioid Prescribing for Chronic Pain?

A Survey of Prescribers in the Trenches

By Jennifer P. Schneider, MD, PhD, and Stephen Schenthal, MD

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

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NOTES FROM THE FIELD

The Three-Headed Monster: The Crises of Mental Health, Chronic Pain, and Prescription Opioid Abuse

By Bob Twillman, PhD, FAPM, Executive Director

FOR A WHILE NOW, WHEN I’VE BEEN ASKED to speak about pain management or about the opioid misuse and overdose epidemics, I’ve made the point that we really are dealing with two public health crises that, in the final analysis, are more similar than different. Prescription opioid abuse and chronic pain share these characteristics: highly prevalent; very costly, both in economic and human terms; highly stigmatized, with patients blamed for having both conditions; poorly understood by the medical profession; under-resourced in terms of treatment; complex biopsychosocial problems with many moving parts; and sources of tremendous suffering, not only for those with the conditions, but for their friends and families, as well.

I have made the point that reaching for simple solutions to these complex problems, as policymakers have been doing for the past few years, tends to create negative unintended consequences without solving the problems. Doing so also tends to create a “zero-sum game,” wherein ameliorating one problem makes the other worse. I’ve also made the case that an integrative approach to pain management represents one solution that can help address both crises.

All of that is still true, but now I’m thinking I’ve been shortchanging things a bit, and that there really are three problems intertwined here. The third?

Mental health conditions other than substance use disorders.

We know that depression and anxiety are at least twice as common among people with chronic pain when compared to those without chronic pain. There is emerging evidence that post-traumatic stress is more common among people with chronic pain—a former colleague of mine recently presented preliminary research demonstrating that patients in his chronic pain outpatient clinic screened positive for post-traumatic stress at roughly four times the rate of the general population. We know that people with chronic pain and severe comorbid depression, anxiety, or posttraumatic stress are less likely to achieve significant pain relief if their mental health conditions are not treated effectively.

More to the point, there is emerging evidence that those with chronic pain who develop opioid use disorders, who overdose, and who die of overdoses, all are more likely to be those with diagnosable mental health conditions. Further, research that will be presented in April (for which the abstract is already published) will demonstrate that veterans with chronic pain who had their opioid doses tapered were more likely to complete a suicide attempt,

suggesting that perhaps the higher opioid dose was partially treating a mental health condition in addition to chronic pain. We have even had presentations at our annual meeting suggesting that chronic pain and depression are both neuroinflammatory conditions, and therefore co-occur at very high rates.

Clearly, if we want to be effective in addressing all the concerns people with chronic pain present and help them to experience less pain and better functioning, we must include mental health conditions in our assessment and in the treatment plan.

As for the characteristics I listed above for chronic pain and prescription opioid abuse, read the list again while thinking about mental health conditions in our country: highly prevalent; very costly, both in economic and human terms; highly stigmatized, with patients blamed for having the condition; poorly understood by the medical profession; under-resourced in terms of treatment; a complex biopsychosocial problem with many moving parts; and a source of

tremendous suffering, not only for those with the conditions, but for their friends and families, as well. I think the model fits remarkably well.

Perhaps one reason that efforts to attack prescription opioid abuse and chronic pain have not been as successful as we’d hoped is that we have been overlooking the importance of addressing mental health issues. One would think that a biopsychosocial-spiritual conceptualization of chronic pain, to which we ascribe, would cause us to be careful to include a mental health assessment in our evaluation of people with chronic pain, but perhaps that is not so. Beyond depression and anxiety, with which most clinicians should be familiar, just how well equipped are clinicians to detect and treat mental health conditions?

Furthermore, as is the case with non-pharmacological pain treatments, nonpharmacological mental health treatment may be difficult to access, especially if the clinician being sought is one with expertise in treating chronic pain. Inadequate provider panels, large patient panels for those providers, and limited insurance coverage (provisions of the mental health parity act notwithstanding) all make it challenging to obtain high-quality care.

I think if we want to achieve our goal of retuning people with chronic pain to a state of wellness, we’re going to need to do a better job of recognizing and addressing mental health issues, as we continue to sensitize ourselves to the possibility of substance use disorders in our patients.

The clinical challenge presented by people with chronic pain needs to be seen as the three-legged stool it really is, and we need to find ways to do something about all three legs if we want to succeed. n Bob Twillman, PhD, is the executive director for the Academy of Integrative Pain Management. Dr. Twillman is responsible for overseeing federal and state pain policy developments and advocating for those supporting an integrative approach to managing pain. He also serves as Chair of the Prescription Monitoring Program Advisory Committee for the Kansas Board of Pharmacy.

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EDITORIAL

Harmony

By W. Clay Jackson, MD, DipTh, Editor-in-Chief

MY FAVORITE CLINIC DAYS ARE WEDNESDAYS. That’s because on Wednesday afternoons, the West Cancer Center becomes more than a place for infusions and scans. On Wednesday afternoons, it becomes a cool hangout for a casual jam session. A guitarist, a bassist, and a flutist sit together on the third floor, making sure cancer patients and their families feel the vibe. Why? Because as a team of clinicians dedicated to the concept of integrated care, we believe that patients who feel better will do better. In other words, if the nurse from Pod C can’t quite control your nausea, “The Girl from Ipanema” will.

In addition to the music therapy offered by our jazz artists, we have a harpist and pianist who drop in to help change the atmosphere of the clinic from a sterile, Muzak-infused building into a warm, inviting space. On staff, we have psychologists who help patients work through the trauma of life change as they navigate their treatment and illness course. Our nutritionist instructs patients and families in how to prepare meals with antiinflammatory foods, and our chaplain helps to address the meaning of pain and illness. Physical therapists assist patients in functional recovery and in learning to keep their bodies moving

then offer complementary therapies in a purposeful way. We have always believed in patient-centered care, and integrative therapies allow us to treat all aspects of the patient—not just the disease process.

As a result our hope is to optimize health, quality of life, and clinical outcomes.

In this issue of The Pain Practitioner, you’ll find features highlighting the central truth found by Dr. Richey and other colleagues who are champions of the postmodern medical model: the best of complementary approaches and allopathic approaches combined is not too good for our patients; in fact, they deserve the most effective treatments,

(Left) A typical Wednesday afternoon jam at the West Cancer Center in Memphis. (Center) Music and art transform patients’ and families’ experience of the clinical space. (Right) Dr. Sylvia Richey, the director of the Division of Integrative Oncology at the West Cancer Center.

As a palliative physician, I believe in allopathic interventions. I use pharmacology with nearly every patient to alleviate acute and/or chronic pain.

Opioids, antiinflammatories, serotoninnorepinephrine reuptake inhibitors (SNRIs), and membrane modulators comprise significant components of my therapeutic armamentarium. But along with most of my oncologic colleagues at our large, multidisciplinary cancer center, I realize that relying exclusively upon the modern medical model of healing, with its emphasis on pharmacology and surgery, is inefficient at best and harmful at worst.

A one-size-fits-all approach simply doesn’t take into account the current evidence and experience base—patients respond best to an integrative approach that addresses the needs of mind and body via a variety of modalities.

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through space. Although we don’t have a massage therapist or acupuncturist on staff, we have a system in place to “fasttrack” these referrals, as we recognize the importance of these modalities in providing relief to patients as well.

Sylvia Richey, MD, the director of the division of integrative oncology at the West Cancer Center, explains that medical treatment for cancer has evolved to a point where we are attacking the disease on a molecular level; however, cancer affects patients physically, mentally, emotionally and spiritually, and all of these components need to be addressed as the patient goes through their journey. Integrative oncology uses evidence-based complementary therapies to address the mind, body and spirit. There is more to healing after a cancer diagnosis, and it is important for us to recognize a patient’s needs and

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regardless of which practitioner or specialty training “silo” is traditionally associated with its delivery. Here at the Academy, we’re not late to the party— we’ve been delivering that message of quality integrative care for 30 years.

Enjoy this issue—and never forget to feel the beat! n W. Clay Jackson, AIPM board president, is clinical assistant professor of family medicine and psychiatry at the University of Tennessee College of Medicine in Memphis, Tennessee, where he maintains a private practice in family and palliative medicine. He is also the medical director of Comprehensive Primary Care, and of Methodist Hospice and Palliative Services. Dr. Jackson is the associate fellowship director of palliative medicine at the University of Tennessee College of Medicine.

ADVOCACY

Integrative Pain Management Strikes Washington!

By Katie Duensing, JD, Director of Legislative and Regulatory Affairs

IF THE EARLY DAYS OF 2018 ARE ANY INDICATION, this year may be the turning point for integrative pain management that we in the field have all been working toward.

Within the past few weeks and months, there have been numerous exciting developments at the federal level that have the potential to greatly expand access to high quality, evidence-informed, and affordable comprehensive integrative pain management.

While the early days of tackling the opioid epidemic were mostly filled with efforts to expand treatment for substance use disorder and reduce diversion and misuse of opioids (necessary and laudable goals!), it seems that policymakers have finally begun to realize that a long-term solution to the opioid epidemic will fall short unless policies are broadened to address the underlying public health crisis of chronic pain—and further, that optimal treatment of pain often requires multiple providers from varied disciplines and multiple interventions, both pharmacologic and non-pharmacologic, all working alongside one another.

AHRQ SYSTEMATIC REVIEW The Agency for Healthcare Research and Quality (AHRQ) recently requested comments related to its “Review of Noninvasive, Nonpharmacological Treatment for Chronic Pain.” AHRQ’s systematic review is analyzing whether acupuncture, multidisciplinary rehabilitation, mindfulness practices, psychological therapies, and more may improve function or pain outcomes for specific chronic pain conditions. In order to ensure submission of balanced and thoughtful comments that truly reflect the field of integrative pain

management, AIPM arranged a call for attendees from last October’s Integrative Pain Care Policy Congress. Thirty-five advocates from a dozen disciplines, as well as patient advocates and policy experts, helped to inform the comments written and submitted by AIPM.

replacement of the lower extremity (inpatient) and percutaneous coronary intervention (inpatient or outpatient).

This program will run from October 1, 2018, through December 31, 2023, and applications to participate must be submitted by March 12, 2018.

ICER EVIDENCE REPORT

SENATE BILL 2260

The Institute for Clinical and Economic Review (ICER) released a Final Evidence Report recommending enhanced coverage of certain non-drug management options for chronic low back pain. The report assesses the comparative clinical effectiveness of acupuncture, cognitive behavioral therapy (CBT), mindfulness-based stress reduction (MBSR), tai chi, and yoga for treatment of chronic low back and neck pain, as well as the value of these therapies in chronic low back pain.

According to David Rind, MD, MSc, chief medical officer of ICER, “Good studies have shown that these other modalities can reduce pain and improve function for people with chronic low back pain, and they pose fewer risks than opioids or surgery. Unfortunately, even in the face of an opioid epidemic, many patients are not offered these alternative types of pain management. Stakeholders, particularly payers, should work to ensure that patients are able to access a broad range of evidence-based non-drug interventions with at least as much ease as they are able to access pharmacologic treatments.”

As part of ICER’s investigatory process prior to releasing this report, AIPM’s Policy Team participated in an interview with the ICER team, so we were thrilled to see this exciting report. We will remain engaged, helping to ensure this report ultimately helps to improve coverage of integrative pain management!

The Opioids and STOP Pain Initiative Act of 2017 was introduced by Sen. Brian Schatz (D-HI) in December 2017. Senate Bill 2260, which AIPM strongly supports, appropriates $5 billion over five years for new pain-related research to be directed by the National Institutes of Health (NIH).

The initiative aims to spur research into novel drugs and non-pharmacological treatments for pain; directs NIH to intensify and coordinate fundamental, translational, and clinical research related to pain; will establish a Pain Therapeutics Screening Program; and much more.

We encourage you to reach out to your Congress people and let them know you support this important bill that will improve the care of pain while also addressing our nation’s opioid epidemic.

CMS ALTERNATIVE PAYMENT MODEL The Centers for Medicare & Medicaid Services (CMS) has announced a new alternative payment model to improve quality, coordination, and costeffectiveness for both inpatient and outpatient care. The voluntary bundled payment model is called Bundled Payments for Care Improvement Advanced (BPCI Advanced). Participants may receive payments for 32 different clinical episodes, such as major joint

MORE WORK TO DO While we are very encouraged by these developments, there is still much work to be done, and your AIPM Policy Team, along with the broader Integrative Pain Care Policy Congress, looks forward to continuing to work on behalf of you, those who care for people living with pain, to increase access to, and reimbursement for, integrative pain management.

As always, our policy team encourages you to reach out to us!

Do you have a question about a particular policy requirement? Contact Katie Duensing, director of Legislative and Regulatory Affairs, at kduensing@ integrativepain.org.

Are you interested in learning more about the Integrative Pain Care Policy Congress? Contact Amy Goldstein, director of SPPAN, at agoldstein@ integrativepain.org.

Here’s to a banner year for comprehensive integrative pain management! n

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Nutrition, Inflammation, and Pain: How Do We Begin to Heal?

By Christine Rhodes, MS

In the last issue of The Pain Practitioner, we discussed how one’s diet can influence the development of inflammation, which then can evolve into pain. This article will discuss initial steps in dietary treatment, including an antiinflammatory diet to ameliorate pain and an elimination diet, to gain further insight into specific causes of food reactions. It is based on material presented by Robert A. Bonakdar, MD, and Nancy A. Cotter, MD, during the Academy’s Workshop on Nutritional Management in October.

If one thinks of inflammation as an imbalance or a deficiency in the body, then an antiinflammatory diet may be used to reset the imbalance caused by chronic inflammatory conditions. Chronic inflammation, or an unbalanced inflammatory response, is at the root of all types of pain, and inflammatory mediators act as direct and indirect pain mediators. Therefore, an antiinflammatory diet can be considered as a baseline nutritional approach to relieving pain. As in Chinese and ayurvedic traditions, using the diet for pain relief can help correct imbalances of inflammatory mediators, as well as those of GI immunity, the microbiome, and nutrients needed for metabolism and energy production.

Diet is often overlooked as a first-line tool for pain relief, but diet and lifestyle modifications may decrease or eliminate future medication use and dependence. It has been shown that eliminating some foods leads to pain relief, and consuming certain foods may prevent painful conditions (1). Each component of an antiinflammatory diet can be linked to pain modulation. There are several versions of antiinflammatory diets available online, including Dr. Andrew Weil’s antiinflammatory diet pyramid (see Figure 1).

ANTIINFLAMMATORY DIET PRINCIPLES An antiinflammatory diet (2) provides balanced amounts of omega-3 and omega-6 fatty acids and reduces inflammation, while providing a steady supply of nutrients and fiber. The ideal antiinflammatory diet to relieve pain is plant-based and low-glycemic, contains abundant phytochemical-containing fruits and vegetables and culinary herbs and spices, and includes approximately 30% fat, whole soy foods, and fish at least several times per week (3). Most carbohydrates should be in the form of less-refined, less-processed foods with a low glycemic load. Whole grains, such as brown rice and bulgur wheat, are preferable to whole wheat flour, and foods made with wheat flour and added sugar should be avoided.

Vegetables and fruits, as well as herbs, spices, and green tea contain the bioactive compounds flavonoids, carotenoids, and proanthocyanidins, which are polyphenols, or compounds found in natural plant food sources that have antioxidant properties. Flavonoids and carotenoids are phytonutrients responsible for the vivid colors of fruits and vegetables, and they also have antioxidant and antiinflammatory properties. Proanthocyanidins, found in grapes, berries, and nuts, enhance immunity and strengthen connective tissue. These compounds reduce oxidative stress resulting from chronic inflammation by reducing the arachidonic acid cascade that produces inflammatory cytokines.

Phytonutrients have been noted to provide beneficial effects on postsurgical pain, lower-extremity pain, complex regional pain syndrome (CRPS), fibromyalgia, gout, diabetic neuropathy,

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NUTRITION, INFLAMMATION, AND PAIN: HOW DO WE BEGIN TO HEAL?

Figure 1. Dr. Andrew Weil’s Anti-Inflammatory Diet food pyramid.

osteoarthritis, and exercise-induced muscle soreness (3). Research shows a protective effect of diallyl disulfide, a compound found in garlic, on hip osteoarthritis (4). Kaempferol, the most abundant polyphenol in tea, fruits, vegetables, and beans, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain (5).

Besides eating a diet rich in polyphenols, eating a low-glycemic diet can help reduce inflammation. There is a correlation between postprandial glucose concentration, oxidative stress, and inflammation (6). The combination of simple sugars and peptides results in the formation of advanced glycation end products (AGE), which contribute to oxidative and aging processes. A diet high in minimally processed, high-fiber, plant-based foods that creates a relatively small postprandial increase in blood glucose will positively influence inflammation.

One study showed that a low glycemic load diet decreased serum high sensitivity C-reactive protein (hs-CRP) concentrations and increased serum adiponectin concentration in overweight and obese but otherwise healthy adults (7). These results support the role of dietary modification in reducing chronic inflammation in overweight and obese individuals. A low glycemic-load diet also

affects metabolites of the metabolic cycle. For example, protective effects may occur through the increased production of kynurenate, a metabolite of tryptophan that is associated with reduced inflammation (8).

Eating 40 grams of fiber per day is optimal and will slow the absorption time of sugars and slow an insulin-driven rise in CRP. Some types of fiber act as prebiotics and promote a balanced immune response and the production of B and other vitamins (6).

Fruits, especially berries, vegetables, beans, and whole grains are good sources of fiber.

Protein sources should include fish, high-quality natural cheese and yogurt, and plants, especially beans and soybeans. The saturated fat in conventionally raised animals has a higher concentration of arachidonic acid and may contribute to inflammation, while grass-fed beef and other red meats have a higher concentration of omega-3 fatty acids (9). Cold-water fish is also a good source of omega-3 fatty acids, which help modulate the inflammatory response.

Approximately 30% of calories should come from dietary fats in a ratio of 1:2:1 of saturated to monounsaturated to polyunsaturated fat. Other ratios may be appropriate for patients with

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NUTRITION, INFLAMMATION, AND PAIN: HOW DO WE BEGIN TO HEAL?

rheumatoid arthritis and chronic headache (10,11). High levels of the omega-6 essential fatty acids in the Standard American Diet (SAD) contribute to an unhealthy level of proinflammatory activity in cell membranes. The recommended ratio is 4:1, while the SAD supplies a ratio closer to 10:1 (12).

LEAKY GUT A normal balance between sympathetic (fight or flight) and parasympathetic (rest and restore) tone results in an intact gutimmune barrier in the gut, proper acidity, a healthy mucous layer, and low bacterial growth. Only a single layer of intelligent epithelial cells separates the GI lumen and the circulatory system. These cells maintain tight junctions to prevent antigens from passing between them, and their role is to determine whether antigens should be presented to the lumen or eliminated. If this barrier is compromised, leaky gut and autoimmunity reactions occur. Several factors, including sympathetic overdrive, age, proton-pump inhibitor (PPI) use, and antacid use, work to increase permeability and bacterial overgrowth of the mucus layer by decreasing GI acidity.

Foods can cause autoimmunity when antigens such as gluten cause intestinal permeability in those with a genetic predisposition.

This sequence of events is initiated by the release of zonulin, which loosens the tight junctions in the epithelial lining causing leaky gut (13). Undigested food particles that cross the intestinal barrier cause the release of IL-15, which signals antibody formation and creates the food allergy. Many antibodies cross-react with tissues in the joints, skin, and other areas, predisposing patients to numerous chronic diseases.

Several factors can cause intestinal permeability besides gluten, including NSAID use over a lengthy period, stress, and food sensitivities. Once a leaky gut develops, antigens continue to cross the GI barrier to precipitate autoimmunological reactions. Food intolerances develop when the enzymes or pathway necessary to metabolize a nutrient is missing, such as in lactose intolerance or intolerance to FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols). Food sensitivity is a catch-all term for non-immunologic reactions to food.

ELIMINATION DIETS IgE and IgG antibody testing can help uncover causes of true food allergies and sensitivity reactions that are immune-mediated but not strictly allergies. But when someone continues to have multiple chronic, intermittent, and unexplainable symptoms, an elimination diet may help identify potential food triggers and, for a while, remove them. “Unburdening” the GI system from aggravating factors this way helps allow natural restoration so that healing can occur. Elimination diets generally have a 21-day period of restriction, which is followed by a slow reintroduction of reactive foods, one at a time over three days, to assess any reactions that occur. Reactions may be seen right away or they may take some time to develop.

Several elimination diets are available, and, depending on the individual’s current diet and willingness to change, they remove different foods. The “low-hanging fruit” diet involves elimination of junk food in those who generally eat a high-additive, low-fiber, low nutrient diet. This diet, as exemplified by the US Department of Agriculture “My plate” initiative, is a good start for those wishing to clean up their diet (14). For those who want to get even healthier, but are not adept at diet modification, a “usual suspects” diet calls for elimination of dairy and wheat.

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Figure 2. Features of an elimination diet.

The classic elimination diet (15), as developed by the Institute for Functional Medicine (IFM), is a short-term intervention that identifies food triggers, reduces inflammation, supports the microbiome, increases phytonutrients, and promotes a greater awareness of how the body reacts to specific foods (see Figure 2).

Patients should be motivated and have good control over their food intake, which can be challenging, but the benefits in relieving arthritis symptoms, skin conditions, fatigue, and other ailments may be well worth it. Undertaking an elimination diet requires planning. Nine foods that are generally considered highly reactive are eliminated: wheat, dairy, eggs, shellfish, tomatoes, corn, grapefruit, peanuts, and soy. More complex, chronic conditions warrant more restrictive plans. A medical food, containing rice or pea protein, multivitamins, and other elements that help with gut healing, may substitute for one or two meals each day, but it is not essential.

After a 21-day period of restriction, one food at a time is added back several times a day for three days. Foods with the highest index of suspicion should be added back first, and if symptoms occur immediately, the food can be stopped after one day. Each three-day block should be followed by a one-day washout. All reactions should be recorded. If there is no reaction, the food can be added back to the diet; if there is a reaction, the food can be restricted for several months and retried in small amounts.

CONCLUSION Multiple pain conditions may be exacerbated by certain foods or nutritional patterns, and inflammation is at the root of all types of pain. Nutrition can be used as an important component of a comprehensive pain management program and should be systematically tested to optimize an integrative approach to healing chronic pain. n

NUTRITION, INFLAMMATION, AND PAIN: HOW DO WE BEGIN TO HEAL?

Robert A. Bonakdar, MD, is director of pain management, Scripps Center for Integrative Medicine, and assistant clinical professor, UCSD School of Medicine. He is the Past President of the Academy of Integrative Pain Management.

Nancy A. Cotter, MD, is clinical associate professor, PMR, Rutgers NJ Medical School, and clinical director, Whole Health VANJ, “Clinical Champion, Office of Patient Centered Care.

12. Cleland LG, James MJ, Proudman SM. Fish oil: what the prescriber needs to know. Arthritis Res Ther. 2006;8(1):202.

13. Fasano A. Surprises from celiac disease. Sci Am. 2009; 301:54-61.

14. UDSA. ChooseMyPlate.gov. https://www.choosemyplate.gov/.

Accessed February 2, 2018.

15. IFM’s Elimination Diet: Personalized, Optimized Nutrition.

The Institute for Functional Medicine. https://www.ifm.org/ news-insights/ifms-elimination-diet-personalized-optimizednutrition/. Accessed February 2, 2018.

Christine Rhodes received her MS in Nutrition Science from Columbia University’s Institute of Human Nutrition and is a Certified Holistic Health Coach. She serves as clinical editor of The Pain Practitioner and is a New York Citybased medical writer.

REFERENCES

1. Lauretani F, Bandinelli S, Bartali B, et al. Omega-6 and omega-3 fatty acids predict accelerated decline of peripheral nerve function in older persons. Eur J Neurol. 2007;14(7):801-808.

2. Weil A. Dr. Weil’s Anti-Inflammatory Diet. Weil: Andrew Weil MD. https://www.drweil.com/diet-nutrition/anti-inflammatory-diet-pyramid/dr-weils-anti-inflammatory-diet/. Accessed February 1, 2018.

3. Cotter N. Diet and pain. In: Bonakdar RA, Sukiennik AW, eds. Integrative Pain Management. Weil Integrative Medicine Library. New York, NY: Oxford University Press; 2016:255-267.

4. Williams FM, Skinner J, Spector TD, et al. Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action. BMC Musculoskeletal Disord. 2010 Dec 8;11:280.

5. Kim SH, Park JG, Sung GH, et al. Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain. Mol Nutr Food Res. 2015;59(7):1400-1405.

6. O’Keefe JH, Gheewala NM, O’Keefe JO. Dietary strategies for improving post-prandial glucose, lipids, inflammation, and cardiovascular health. J Am Coll Cardiol. 2008;51(3):249-255.

7. Neuhouser ML, Schwarz Y, Wang C, et al. A low-glycemic load diet reduces serum C-reactive protein and modestly increases adiponectin in overweight and obese adults.

J Nutr. 2012;142(2):369-374.

8. Barton S, Navarro SL, Buas MR, et al. Targeted plasma metabolome response to variations in dietary glycemic load in a randomized, controlled, crossover feeding trial in healthy adults. Food Funct. 2015;6(9):2949-2956.

9. McAfee AJ, McSorley EM, Cuskelly GJ, et al. Red meat from animals offered a grass fed diet increases plasma and platelet n-3 PUFA in healthy consumers. Br J Nutr. 2011;105(1):80-89.

10. Proudman SM, Cleland LG, James MJ. Dietary omega-3 fats for treatment of inflammatory joint disease: efficacy and utility.

Rheum Dis Clin North Am. 2008;34(2):469-479.

11. Ramsden CE, Zamora D, Makriyannis A, et al. Diet-induced changes in n-3 and n-6-derived endocannabinoids and reductions in headache pain and psychological distress. J Pain.

2015;16(8):707-716.

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THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 1 |

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Massage Therapy as an Alternative to Opioids

By Dolly Wallace, LMT BCTMB, president, American Massage Therapy Association

There is a serious opioid crisis in the country. We’ve all seen the figures. More than 2 million Americans have become dependent on or abused prescription pain medications. In 2015, there were 52,404 overdose deaths, including 33,091 (63.1%) that involved an opioid. That’s an average of 91 opioid overdose deaths each day! And, in 2016, approximately 11.5 million Americans misused prescription pain medicine, according to the Substance Abuse and Mental Health Services Administration (1).

Pain is a major public health concern, significantly affecting the quality of life of approximately 100 million Americans. More than ever, it’s important to help educate all health care providers, as well as consumers, on the importance of looking at all options for pain management, while considering effectiveness, cost, side effects, and rate of follow-through. Fortunately, massage therapy provides one of a growing number of non-pharmacologic interventions, backed by significant research, that can be effective in an integrative approach to pain management.

Much of the government and media attention has been about how to deal with those already affected by opioids and how to control prescriptions. As integrative providers, massage therapists are looking at how massage therapy can be used early on—either alone or in an integrative approach with other non-addictive approaches to care—as a substitute for opioids and other drugs.

I work in a chiropractic office where I provide massage therapy as part of a holistic approach for our patients. I see firsthand how massage can relieve acute pain and chronic pain, and reduce the need for drugs. These have included clients with ankylosing spondylitis and peripheral neuropathy who got real relief from massage therapy.

Massage therapists, like many other health care providers, don’t cure the issues that cause pain. Massage therapy can ease pain and be an effective pain management approach.

And, I am glad to see that more health care organizations and governmental bodies are looking at the value and efficacy massage therapy can provide for people in pain.

The Attorney General of West Virginia was among the first in the country to look at the problem of opioids and how to redirect approaches away from addictive drugs (2). He and his office developed an overview of what that state requires for addressing pain. This approach includes massage therapy and several other non-pharmacologic therapies. In September of 2017, 37 attorneys general wrote to America’s Health Insurance Plans and said, “When patients seek treatment for any of the myriad conditions that cause chronic pain, doctors should be encouraged to explore and prescribe effective nonopioid alternatives, ranging from non-opioid medications (such as NSAIDs) to physical therapy, acupuncture, massage, and chiropractic care (3).”

This is an open challenge to insurers to pay real attention to approaches like massage therapy. They need to think differently and recognize approaches to pain that have a solid foundation for their use. This letter followed guidelines from the American College of Physicians (4) and The Joint Commission (5), which

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MASSAGE THERAPY AS AN ALTERNATIVE TO OPIOIDS

also include massage therapy among those non-pharmacologic approaches that should be pursued as alternatives to opioids.

The challenges now are education and implementation. We need a change in approach to pain that views it within the context of its cause and then working with other health care professionals on an integrative approach to each patient.

Twenty years ago, the massage therapy profession was still working to increase the number of quality research studies on the efficacy of massage therapy. Looking at what has been published since then, we now see that massage has a firm body of research that indicates its value, especially for pain. In 2016, a meta-analysis of research on massage therapy for pain through the Samueli Institute showed that massage therapy can be a significant and effective approach to manage various types of pain (6-8). Their analysis indicated massage therapy can provide significant improvement for pain, anxiety, and healthrelated quality of life for those looking to manage their pain.

The research indicates its efficacy for those with cancer pain and for those dealing with the pain of recovery from surgery. And, it indicates the value of massage to help manage pain.

People with pain also know what helps them. Each year, the American Massage Therapy Association commissions a national survey of consumers about their use of massage therapy. For at least 10 years, the number of consumers who have sought massage therapy for pain and other health-related issues has continued to rise. In the July 2017 poll, among those who said they had a massage from a massage therapist in the previous 12 months, 23% did so for pain relief/pain management, while 11% sought massage therapy for soreness/stiffness/spasms. A total of 50% sought massage therapy for a health or medical reason, while 28% did so for stress relief (9).

As massage therapists, my colleagues and I are thrilled to see more people in government and health care recognizing that massage therapy can be an important integrative element in dealing with pain, without the side effects and dangers of addictive drugs. But, the opioid problem is vast and can only be addressed by looking at pain in a more holistic manner, and adopting approaches like massage therapy to re-orient how pain is managed. To integrate massage therapy into pain management, other health care providers and consumers can look for a massage therapist near them through the American Massage Therapy Association’s free Find a Massage Therapist national locator service at findamassagetherapist.org. n

Newand

Improved MEMBERSHIP BENEFITS

Dolly Wallace is the President of the American Massage Therapy Association.

A native of Muskegon, Michigan, she has had a local massage therapy practice for more than 25 years and works in collaboration with her husband at his chiropractic practice.

REFERENCES

1. SAMHSA shares latest behavioral health data, including opioid misuse. Substance Abuse and Mental Health Services Administration News. Oct. 12, 2017. https://newsletter. samhsa.gov/2017/10/12/samhsa-new-data-mental-health-substance-use-including-opioids/ 2. West Virginia Attorney General Patrick Morrisey. Best Practices for Prescribing Opioids in West Virginia. May 2017. www.ago.wv.gov/Documents/2016.08.19%20BP%20Prescribing.PDF 3. National Association of Attorneys General. Sept. 18, 2017. https://law.georgia.gov/sites/law.georgia.gov/files/related_files/ press_release/Final%20NAAG%20Opioid%20Letter%20to%20 AHIP%20%282%29.pdf 4. Chou R, Deyo R, Friedly J, et al. Nonpharmacologic therapies for low back pain: a systematic review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2017;166(7):493-505.

5. Clarification to Standard PC.01.02.07. Joint Commission Perspectives. 2014;34(11):11.

6. Crawford C, Boyd C, Paat CF, et al. The impact of massage therapy on function in pain populations—a systematic review and meta-analysis of randomized controlled trials: part I, patients experiencing pain in the general population. Pain Med. 2016;17(7):1353-1375.

7. Boyd C, Crawford C, Paat CF, et al. The impact of massage therapy on function in pain populations—a systematic review and meta-analysis of randomized controlled trials: part II, cancer pain populations. Pain Med. 2016;17(8):1553-1568.

8. Boyd, C, Crawford C, Paat CF, et al. The impact of massage therapy on function in pain populations—a systematic review and meta-analysis of randomized controlled trials: part III, surgical pain populations. Pain Med. 2016;17(9):1757-1772.

9. American Massage Therapy Association 2017 Consumer Survey.

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THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 1 |

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Scents and Sensibility: Aromatherapy for Pain Relief

By Paul Christo, MD

This article is a summary of information, used with permission, from Dr. Christo’s book Aches and Gains: A Comprehensive Guide to Overcoming Your Pain, published in 2017 by Bull Publishing.

Aromatherapy, the medicinal therapeutic use of highly concentrated essential oils for managing stress, enhancing relaxation, and managing pain, is one of the oldest healing arts, dating back to ancient Egypt, and is found in virtually every healing culture around the world. French physician Jean Valnet popularized it during the 1950s. His book, The Practice of Aromatherapy: A Classic Compendium of Plant Medicines and Their Healing Properties, was published in 1980. In the United States, several states include clinical aromatherapy as a holistic option for nursing care.

Several studies have found beneficial effects of either inhaled or topical aromatherapy for reducing a variety of painful conditions, including: Inhaled Aromatherapy Hemodialysis

Kidney pain

Pediatric pain (Tonsillectomy or blood draw

Topical Aromatherapy Chronic back and neck pain

Episiotomy pain

Knee pain

Needlestick pain

Menstrual pain

Multiple sclerosis

Aromatherapy may also be effective for conditions such as migraine or sinusitis (see sidebar). Some patients with cancer pain, post stroke shoulder pain, and women in labor or after cesarean section have noted aromatherapy helps manage their discomfort as well.

UNDERSTANDING AROMATHERAPY

Medical aromatherapy probably alleviates pain in a couple of ways. First, as the patient inhales the odor, the molecules travel through the nose and the parts of the brain known as the hippocampus amygdala—parts of the limbic system—by way of the olfactory nerve. These regions help to process pain and may reduce unpleasant sensation. They also regulate emotions of pleasure and reward. For instance, studies have shown that in less than one second, inhaled cloves can begin to change hormones and narrow transmitters that amplify pain. It may be that the odor suppresses pain by reaching the pleasure center of the brain. Furthermore, scents activate specific memories when they reach the hippocampus. Aromatherapy may trigger pleasurable memories and the release of endorphins, both of which make us feel better and alter sensations.

Second, when an essential oil, such as thyme, is inhaled, the molecules of the oil travel into the lungs, often opening airways and making breathing easier. Pleasant odors often cause breathing to slow and deepen, and research suggests that this change in breathing patterns induced by aromatherapy reduces pain perception. In addition, slow, deep breathing can suppress the sympathetic nervous system (part of the autonomic nervous system responsible for our fight or flight response), which in turn influences pain processing.

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Unlike artificial fragrances, essential oils are small and chemically simple compounds, made mostly from carbon and hydrogen. They are extracted from plants through distillation, or in the case of citrus peels, through pressing. Oils that are rubbed into the skin can absorb into the bloodstream transdermally, but are also vaporized by body heat and thus inhaled. Once in the lungs, the odor molecules are absorbed into the capillaries and enter the bloodstream.

Essential oils produce pain-relieving effects in unique ways.

For instance, clove has been shown to stimulate the production and release of GABA, a neurotransmitter that interferes with nerve firing and controls pain transmission. Clove has been used as a local anesthetic before needle insertion, and applying one drop of clove oil on a cotton swab tip can help with toothaches.

Eucalyptol, the active agent found in eucalyptus, rosemary, and other plants, has a direct pain relieving effect, but studies show it also suppresses the release of inflammatory compounds such as interleukins and leukotrienes. Furthermore, eucalyptol could be a digestive aid as well. By improving digestive function, it reduces overstimulation of the pancreas and the excessive release of insulin.

Other essential oils that offer pain relief include: • German chamomile, which has actually been shown to alter the adrenal gland production of cortisol and DHEA, which in turn alters mood. It seems that it can act like an opioid pain reliever as well as block the effects of opioids.

• Oil made from grapefruit increases the release of epinephrine and acts as a natural antidepressant.

• Lemon oil produces a cheering effect.

• Frankincense is antiinflammatory along with stress relieving.

• Peppermint oil stimulates cold receptors in the skin that take away the heat from the inflammation (consider applying it after sunburn).

• Birch and wintergreen oil both contain large amounts of salicylic acid, very similar to aspirin, which can soothe arthritic pain.

• For muscle spasms in the low back, marjoram has been shown to have effective anti-spasmodic qualities and also increases GABA. • Pelvic pain associated with pre-menstrual syndrome or dysmenorrhea can be decreased with yarrow, chaste tree berry, sage, and German or Moroccan chamomile massaged into the skin. These seem to reduce inflammation and histamine release as well as balance estrogen and progesterone.

• Several oils, including eucalyptus, lavender, geranium, fennel, and clary sage, massaged into the skin or taken orally, could be used for fibromyalgia.

Overall, peppermint, clove, lemongrass, eucalyptus, and German chamomile have the best track record for relieving pain. Eucalyptus may be more effective for inflammatory pain, while clove may better modify nerve pain. Rose, balsam fir, German chamomile, lavender, and fennel can have positive effects on bone pain, and rose might be particularly helpful in metastatic cancer pain.

CHOOSING AROMATHERAPY

Inhaling essential oils offers relief within seconds, but the effects of inhalation also last for a brief time. Oils can be inhaled safely every one to two hours when placed on a cotton swab. Alternatively, oils

SCENTS AND SENSIBILITY: AROMATHERAPY FOR PAIN RELIEF can be placed in a diffuser, allowing patients to vaporize the scent continuously. Effects from rubbing essential oils into the skin are felt within minutes and should last for several hours, after which oils can be reapplied. When essential oils are taken orally (typically two or three times a day under the guidance of a physician or certified medical aroma therapist) it may take an hour or two for the onset of relief of symptoms, but relief should last for most of the day. Aromatherapy patches can be worn on the skin. The easiest way to inhale essential oils is with an ultrasonic diffuser (similar to a vaporizer).

Aromatherapy probably works best when combined with standard pain management therapies. It offers exciting possibilities for managing pain and stress as an inexpensive treatment with few side effects. It’s important to remember that essential oils are real chemical compounds and should be recommended for medicinal use by qualified aroma therapists. Certain forms of thyme and holy basil, for instance, can be toxic to the mouth and throat. Always ask practitioners for their certification. n Paul Christo, MD, is an associate professor in the division of pain medicine at the Johns Hopkins University School of Medicine. He served as director of the Multidisciplinary Pain Fellowship Program and the Blaustein Pain Treatment Center at Johns Hopkins. Dr. Christo is vice-president of the Academy of Integrative Pain Management Board of Directors.

Bibliography Boehm K, Blessing A, Ostermann T. Aromatherapy as an adjuvant treatment in cancer care—a descriptive systematic review. Afr J Tradit Complement Altern Med. 2012;9(4):503-518.

Buckle J. Clinical aromatherapy and AIDS. J Assoc Nurses AIDS Care. 2002;13(3):81-99.

Busch V, Magerl W, Kern U, Haas, J, Hajak G, Eichhammer P. The effect of deep and slow breathing on pain perception, autonomic activity, and mood processing—an experimental study. Pain Med. 2012;13(2):215-228.

Dhany AL, Mitchell T, Foy C. Aromatherapy and massage intrapartum service impact on use of analgesia and anesthesia in women in labor: A retrospective case note analysis.

J Altern Complement Med. 2012;18(10):932-938.

Gedney JJ, Gover TL, Fillingim RB. Sensory and affective pain discrimination after inhalation of essential oils. Psychosom Med. 2004;66(4)599-606.

Kim JT, Wajda, M, Cuff G, et al. Evaluation of aromatherapy in treating postoperative pain: pilot study. Pain Pract. 2006;6(4):273-277.

Koyanagi S, Himukashi S, Mukaida K, Shichino T, Fukada K. Dopamine D2-like receptor in the nucleus accumbens is involved in the antinociceptive effect of nitrous oxide.

Anesth Analg. 2008;106(6):1904-1909.

Lakhan SE, Sheafer H, Tepper D. The effectiveness of aromatherapy in reducing pain: A systematic review and meta-analysis. Pain Res Treat. 2016. http://dx.doi. org/10.1155/2016/8158693 Masaoka Y, Takayama M, Yajima H, Kawase A. Takakura N, Homma I. Analgesia is enhanced by providing information regarding good outcomes associated with an odor.

Placebo effects in aromatherapy? Evid Based Complement Alternat Med. 2013;921802. doi: 10.1155/2013/921802 Rouwette T, Vanelderen P, Roubos E, Kozicz T, Vissers K. The amygdala, a relay station for switching on and off pain. Eur J Pain. 2012;16(6): 782-792.

Shin, BC, Lee MS. Effects of aromatherapy acupressure on hemiplegic shoulder pain and motor power in stroke patients: A pilot study. J Altern Complement Med. 2007;13(2):247-251.

CASE STUDIES

AROMATHERAPY TREATS MIGRAINE AND SINUSITIS PAIN

Since her mid-twenties, Amanda had suffered from chronic sinus infections, bronchitis, and asthma, which led to pounding pressure and pain in her right ear and eye. She had to “mouth breathe,” developed ear infections, and couldn’t concentrate. A nasal steroid resolved many of her symptoms, but Amanda was afraid of its detrimental effect on her glaucoma. After years of taking over-the-counter medications such as Allegra-D (for allergy and congestion) and Mucinex (an expectorant) she began taking even stronger prescription antihistamines and decongestants. Unfortunately, these left her tense and interfered with her sleep, and, eventually her glaucoma forced her to discontinue her prescription medication because of the side effects.

Lana, a retired administrator, suffered for 50 years from migraine headaches. A typical headache would leave her bedridden for two to three days. She would feel the pain in the back of her neck and forehead; experience blurred vision, nausea, and eventually “couldn’t function as a normal human being.” Lana had injections and took countless prescription medications including beta blockers, nortriptyline, and verapamil, but still experienced migraines almost weekly.

Both Lana and Amanda were introduced to aromatherapy later in their lives but found its positive effects to be more potent than they could’ve imagined. Initially, Amanda was skeptical of aromatherapy because she had already discovered that certain perfumes and fragrances aggravated her medical conditions. But under the guidance of a doctor trained in aromatherapy, she tried a tincture—an oral dose of essential oils—made up of black pepper, peppermint, lavender, clove bud, frankincense, and lemongrass oil. In addition to taking the tincture twice a day, she also rubbed essentials oils on her forehead and inserted a cotton swab with the oils into each nostril.

Amanda didn’t like the process at first, and for the first several days, applying the oils felt like a strange ritual, but after about two weeks her congestion dissipated almost completely. Within two months, she completely weaned herself off all prescription and over-the-counter medications. Lab tests confirmed that her histamine levels dropped from 900 to about 190. For the first time in over 25 years Amanda felt relaxed, calm, and able to breathe freely. The tincture reduced the number of ear infections, too. Both her ear and eye pain went away along with the pressure pain she felt in her sinuses.

And the effects have lasted. As long as Amanda sticks to her essential oils regimen, she finds that her sinusitis resurfaces only when she’s exposed to heavy levels of

Valnet, J. The Practice of Aromatherapy Saffron Walden, UK: C. W. Daniel; 1980.

smoke, dust, or pollen. “If I forget to use the aromatherapy, the stuffiness can return, but I can even exercise for an hour now without getting winded,” she said.

Amanda notices no side effects; however, in some cases, essential oils can cause slight irritation but seem to be regarded as safe by the FDA. Rarely, essential oils can cause photosensitivity if taken orally in large amounts. Similar to reports of patients in research studies, Amanda experiences a lot less anxiety as well. Aromatherapy studies have found that patients feel less depressed and better satisfied with their treatment, too.

Lana has a similar success story. She began to rub a combination of peppermint, black pepper, lavender, lemon grass, clove bud, and frankincense oils behind her ears, on the back of her neck, and on her temples and forehead whenever she felt a migraine was imminent. This amounted to applying aromatherapy oils a couple of times per week. Incredibly, Lana finds this allows her to elude the onset of the migraine more than 95% of the time. She’s discovered that applying the oil soon after sensing the migraine prevents it from becoming a debilitating headache. The oils need just 5 to 10 minutes to take effect before the headache goes away.

The ability to fend off the headaches that used to keep her in bed for days has allowed Lana to live her life much more fully than before. For example, she can perform daily tasks at home and have a normal day. “It’s wonderful,” she said, “I’d be bedbound during the migraines if I didn’t have the aromatherapy.” Like Amanda, Lana has experienced no side effects even after three years of regular treatment.

FURTHER READING

Aromatherapy and Essential Oils (PDQ®): Health Professional Version.

PDQ Cancer Information Summaries National Cancer Institute. 2017. https://www.ncbi.nlm.nih.gov/books/NBK65874/

Essential Oils Natural Remedies: The Complete A-Z Reference of Essential Oils for Health and Healing.

Berkeley, CA: Althea Press; 2015.

Kennedy, Anne. Aromatherapy for Natural Living: The A-Z Reference of Essential Oils Remedies for Health, Beauty, and the Home. (n.p.) Berkeley, CA: Althea Press; 2016.

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 1 |

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How Can We Improve Opioid Prescribing for Chronic Pain?

A Survey of Prescribers in the Trenches

By Jennifer P. Schneider, MD, PhD, and Stephen Schenthal, MD

There is a need for better education for practitioners who are well meaning but who lack adequate knowledge of the intricacies required to safely and effectively treat pain patients.

Best-care practice includes risk assessment, psychosocial evaluation, appropriate use of opioids, documentation, benefits of multiple modalities, and knowledge of the rules and regulations that are required to protect not only patients but also the public. This paper presents a summary of the most common errors of opioid prescribing, according to a survey of practitioners. We invite readers to take the survey and compare their answers to the participants’ responses.

METHODS

The study population consisted of 395 prescribers who took a 21-CME remedial and proactive prescribing course, “Opioids, Pain, and Addiction,” between 2013 and 2016. Most were primary care providers, and the remainder were psychiatrists,

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interventional pain specialists, physiatrists, orthopedic surgeons, emergency room doctors, physician assistants, nurse practitioners, and other clinicians.

On a pretest survey consisting of a list of statements regarding their prescribing of controlled substances (CSs), attendees checked whether each statement applied to them never, seldom, sometimes, frequently, or always. This report includes the pretest results of six true or desirable statements that were too often believed to be false or bad practice, and 14 false or undesirable statements with which too many agreed.

PRETEST SURVEY AND RESULTS DESIRABLE ACTIONS

The statements below describe practices that should be a standard part of evaluation and treatment of chronic pain and the responses from the survey participants.

HOW CAN WE IMPROVE OPIOID PRESCRIBING FOR CHRONIC PAIN?

1. On the initial visit, when a new patient’s complaint is long-standing chronic pain, I have the patient sign releases for the records from previous treating physicians.

Response: 15% never or rarely, 8% sometimes, 77% frequently or always Previous medical records should be a standard part of the initial evaluation. They can provide details about the patient’s history, diagnostic testing, and response to specific previous drug doses and procedures, and may also provide valuable information about the patient’s reliability, or reason for the change of provider. A patient’s refusal to facilitate obtaining old records is considered a red flag and should trigger the provider to ask, “Is there something to hide?”

5b. If a patient violates part of the opioid agreement he/she signed, I document in the chart what action I took.

Response: 23% never or rarely, 6% sometimes, 71% frequently or always When treating chronic pain, the clinician needs to document his/her thinking and decision-making, and note any potential red flags. Not only is this in the best interest of the patient, but it also protects the prescriber from claims of negligence.

2. I ask patients who are being seen for chronic pain their pain level at every visit.

Response: 31% never or rarely, 25% sometimes, 44% frequently or always A major goal of the follow-up visit is to assess the outcome of treatment by evaluating the “four A’s” (1): Analgesia, Activities of daily living, Adverse effects, Aberrant drugrelated behaviors (ran out early, meds were stolen, etc.), plus a fifth A, Affect. At the top of the list is the patient’s assessment of their pain!

1. When a patient tells me that one opioid works better for him than another, I consider it likely that he’s a drug abuser looking for his drug of choice.

Response: 20% never or rarely, 38% sometimes, 42% frequently or always There are legitimate reasons why patients may prefer one opioid to another. For example, in some patients the histamine-producing effect of morphine (but not oxycodone) produces itching; others may poorly metabolize codeine (to morphine) and thus find it ineffective.

3. In male patients on chronic opioids, I routinely order a serum testosterone level early on.

Response: 65% never or rarely, 19% sometimes, 16% frequently or always Opioids impact the hypothalamic-pituitary axis, resulting in subnormal testosterone levels in most men (2-4).

Testosterone replacement for hypogonadism is now believed NOT to increase the risk of prostate cancer (5,6). It’s good practice to check serum testosterone levels (total and free testosterone) in men being prescribed chronic opioids and consider testosterone replacement if the level is subnormal.

4. I phone the lab or ask a knowledgeable colleague for clarification of a urine drug test (UDT) result that I don’t understand.

Response: 24% never or rarely, 9% sometimes, 67% frequently or always Practitioners who order urine drug tests have an ethical obligation to act on the results, which of course requires an understanding of the results. At times this is not simple, because several commonly used opioids have metabolites that routinely appear in the urine. In addition, routine enzyme immunoassays screen for classes of opioids rather than individual ones and will usually not detect semisynthetic or synthetic opioids (such as fentanyl, oxycodone, buprenorphine, or methadone).

It is important for the clinician to look into any unexpected result whose explanation is not clear. Patients are sometimes unfairly discharged because of the purported drug misuse; on the other hand, the appearance of other unexpected drugs in the urine may be a clear indication of misuse, which does require action on the part of the prescriber.

5a. I document in the record actions I took as a result of any unexpected result on a UDT. Response: 26% never or rarely, 8% sometimes, 66% frequently or always

UNDESIRABLE ACTIONS

The statements below describe practices that are not desirable or beliefs that are not true, or that are warranted only at times followed by the responses from the survey participants.

2. I am comfortable prescribing opioids only to patients who are able to manage them safely, i.e., who are of normal intelligence, do not have organic brain syndrome, and do not have significant psychiatric illness.

Response: 21% never or rarely, 10% sometimes, 69% frequently or always Patients who have ongoing pain and who are also cognitively impaired, who have dementia, or who have psychiatric disorders affecting their judgment still deserve to be treated effectively for their pain. The key is to identify another responsible relative or caregiver with whom to discuss the patient’s medications. If, however, the patient has an active addiction disorder, referral for addiction evaluation and treatment is needed before it is safe to continue prescribing opioids.

3. I am comfortable prescribing opioids only if I can objectively identify the patient’s pain generator (source of pain).

Response: 28% never or rarely, 14% sometimes, 58% frequently or always For the most common type of chronic pain seen by physicians—chronic back pain—the specific pain generator can be found in only about 15% of cases (7). In other common types of chronic pain, including headaches and fibromyalgia, one can rarely find the pain generator.

If a specific pain generator is not apparent, or surgery is not an option, then the pain itself needs to be treated, with the goal of decreasing the pain and improving the patient’s function. A comprehensive approach is optimal, keeping in mind that opioids are often the most effective analgesics, and there is no reason to exclude them because the specific pain generator is uncertain.

4. When I maintain chronic pain patients on opioids, I write in the chart that they are opioid dependent.

Response: 51% never or rarely, 17% sometimes, 32% frequently or always THE PAIN PRACTITIONER

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HOW CAN WE IMPROVE OPIOID PRESCRIBING FOR CHRONIC PAIN?

5. I anticipate that my patient will become addicted to the opioid that I am prescribing for him/her for chronic pain.

Response: 37% never or rarely, 23% sometimes, 40% frequently or always Calling a patient “opioid dependent” is still likely to be construed as “opioid addict.” Although the current Diagnostic and Statistical Manual of Mental Disorders uses the classification “opioid use disorder” instead of “addiction,” (8,) clinicians may still be accustomed to DSM-4, which used the term “opioid dependent” to mean addicted to opioids (9). Almost all patients who are on more than minimal doses of opioids for more than a couple of weeks are physically dependent; only a small percent of patients become addicted as a result of being put on an opioid.

Physical dependence is a property of opioids (and several other drug classes, such as corticosteroids).

Its impact is that abrupt cessation produces a specific set of withdrawal symptoms, which are preventable by tapering the drug rather than simply stopping it. This is a different phenomenon than addiction, which can be viewed as a type of psychological dependence. The key characteristics of opioid use disorder (that is, addiction) (8) are: • Loss of control (i.e., compulsive use) • Continuation despite significant adverse consequences • Obsession or preoccupation with obtaining, using, and recovering from the effects of the substance The best way to make it clear in the chart whether you are referring to the patient’s physical dependence or addiction is to avoid altogether using the term “opioid dependence” and instead always specify if your intention is to document “physical dependence” or “addiction/substance use disorder.”

8. When a family member phones, I decline to continue the call if the patient has not already signed a release for me to talk with his or her family member.

Response: 22% never or rarely, 9% sometimes, 69% frequently or always HIPAA rules regarding phone calls from a patient’s relatives or friends are misunderstood by most clinicians. HIPAA rules require that we not provide any information in the absence of written consent, but they do not prevent us from listening (15). Family members who tried unsuccessfully to provide relevant information to the clinician are a major source of medical board complaints and lawsuits if a bad outcome occurs.

9. I obtain a urine drug test (UDT) at every visit from patients on opioids for chronic pain.

Response: 55% never or rarely, 22% sometimes, 23% frequently or always Obtaining regular UDTs is now considered standard of care for patients on chronic opioids and is one of the CDC’s recent guidelines (16). Those guidelines, however, do not specify how often to order a UDT. Too many clinicians believe that getting a UDT on every visit is the most effective way of monitoring a patient’s compliance.

But, an unexpected UDT is likely to provide a lot more information than a routine one and is more cost-effective.

Physical dependence is a property of opioids (and several other drug classes, such as corticosteroids).

Its impact is that abrupt cessation produces a specific set of withdrawal symptoms, which are preventable by tapering the drug rather than simply stopping it.

6. When a patient on a chronic CS no longer needs the medication, I document in the chart how I “detoxed” the patient.

Response: 38% never or rarely, 12% sometimes, 50% frequently or always The term “detoxification,” or “detox,” defined by the DEA as getting a drug addict off of their drug, is permitted only with an “X waiver,” which permits treating drug addicts with controlled drugs (10). Physicians without the X waiver are permitted to taper or wean patients off opioids that were prescribed for chronic pain, but not to detoxify addicts. When a practitioner writes in a patient’s chart that he “detoxed” that patient, he is, according to the DEA, identifying that patient as an addict, and he can treat that patient with an opioid only under an X waiver.

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7. I advise patients who are on chronic opioids that they should not drive.

Response: 30% never or rarely, 27% sometimes, 43% frequently or always Most practitioners automatically advise patients on opioids not to drive, but studies support driving after a week or two of maintaining a stable schedule II drug dose (11).

After that, psychomotor and cognitive performance are indistinguishable from that in drivers who do not use opioids.

(12-14). Even so, there are risks.

| TH E PAI N P R AC TITIO N E R | S P R I N G 2018

10. I renew a CS prescription only as part of an office appointment.

Response: 14% never or rarely, 16% sometimes, 70% frequently or always For long-term, stable patients, there is often no medical reason for them to be seen every month for their chronic pain. Yet most insurance companies will approve a prescription for only 30 days. The DEA allows issuing multiple prescriptions for up to a 90-day supply of a schedule II-controlled substance (17). Often a visit every two months will suffice for a stable patient. At the office

HOW CAN WE IMPROVE OPIOID PRESCRIBING FOR CHRONIC PAIN?

visit, the patient can be provided with two sets of prescriptions, one set to be kept in a safe place by the patient and filled the following month.

11. If a patient on opioids reports sedation or constipation, I attempt to reduce the dose.

Response: 17% never or rarely, 22% sometimes, 61% frequently or always Sedation and constipation are common side effects of opioids. Sedation is usually transitory; constipation, on the other hand, persists. The ongoing use of a bowel stimulant or a combination bowel stimulant plus stool softener may provide relief. Persistent sedation can be treated with modafinil or methylphenidate.

Choosing to deal with opioid side effects by reducing the opioid dose is likely to increase pain and decrease function. Maintaining an effective analgesic opioid dose allows the patient to continue with decreased pain and improved quality of life and function.

12. If a patient breaks a rule to which he has agreed in his opioid agreement, I discharge him.

Response: 32% never or rarely, 22% sometimes, 46% frequently or always This may be the most efficient approach by the clinician, but it is not necessarily in the patient’s best interest. A more ethical response is to have a discussion with the patient about why this happened; there may be legitimate reasons. The only times when a single bad behavior requires you to immediately stop prescribing are 1.) when you learn that the patient has diverted a prescribed medication, 2.) when continuing to prescribe presents an imminent risk to the patient and/or others, and 3.) when there is active addiction.

13. I anticipate that I will have to gradually increase the patient’s opioid dose because of development of tolerance to the drug.

Response: 35% never or rarely, 27% sometimes, 38% frequently or always) Tolerance is defined as a need for increasing doses to get the same effect. Who develops tolerance and to which effect is very individualized. Development of tolerance to the analgesic effect of opioids remains controversial. Most clinicians and patients believe that tolerance to pain relief will develop, although it may occur over months rather than days. A minority of clinicians, however—those who have actually provided long-term opioid treatment to some of their pain patients—have found that many patients can be maintained on the same dose, whether high or low, for years, unless their disease worsens or there is a new source of pain. This was demonstrated, for example, in a study of long-term opioid dosing in 197 patients maintained on opioids for a mean of 4 years 8 months. (18).

Where Change Begins®

14. If I have a nurse practitioner or PA working with me, I am willing to pre-sign blank prescriptions to facilitate their prescribing opioids.

Response: 96% never or rarely, 2% sometimes, 2% frequently or always All prescribers of controlled substances should know it is against DEA regulations (19) to pre-sign a blank prescription.

LIMITATIONS

This paper does not purport to be comprehensive in that it did not discuss areas in which most respondents are doing well.

This includes initial urine drug testing, use of risk assessment tools such as the Opioid Risk Tool (20), and regularly accessing online the state’s Prescription Monitoring Program. Also, this paper did not provide data on clinicians’ beliefs about teambased care when treating chronic pain because this is only now beginning to be understood. There is a great need for not only familiarity with appropriate opioid treatment but also about the need for behavioral health and physical therapy integration into a holistic treatment plan which recognizes the complexity of pain (21). Finally, the participants were a mixed group, including some who were mandated by their state licensing board to take a prescribing course because of inadequate understanding of opioids and opioid treatment.

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HOW CAN WE IMPROVE OPIOID PRESCRIBING FOR CHRONIC PAIN?

CONCLUSIONS

This study shows that a large proportion of clinicians who treat chronic pain with medications misunderstand significant aspects such as the characteristics of opioids, appropriate treatment, relationship to addiction, appropriate risk assessment, documentation requirements, and the need for ongoing communication with patients. There is still an ongoing need for education of physicians and other clinicians who treat chronic pain. The best time for this would be early in the clinician’s career, but this education is still not being regularly provided. n Jennifer P. Schneider, MD, PhD, is certified in internal medicine, addiction medicine, and pain management, and spent many years in non-interventional treatment of chronic pain.

For several years she has been teaching a live national remedial/proactive prescribing course, “Opioids, Pain Management, and Addiction,” through Professional Boundaries, Inc. She also does medicolegal consulting in this area.

Stephen Schenthal MD, MSW, is the founder and CEO of Professional Boundaries, Inc. and is trained as a psychiatrist and clinical social worker. Dr. Schenthal created Professional Boundaries, Inc., a medical education company, with the goal of offering courses to protect professionals and the public they serve by preventing the occurrence of boundary, ethical, prescribing, and medical documentation violations.

13. ECRI. Federal Motor Carrier Safety Administration Report: Licit Schedule II Drug Use and Commercial Motor Vehicle Driver Safety. https://www.fmcsa.dot.gov/sites/fmcsa.dot.gov/files/ docs/Final-Schedule-II-Drug-Use-Exec-Summary-prot.pdf. October 21, 2006. Accessed January 22, 2018.

14. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Can patients taking opioids drive safely? A structured evidencebased review. J Pain Palliat Care Pharmacother. 2002;16(1):9-28.

15. US Department of Health and Human Services. HIPAA Survival Guide. 4th Edition. 2017.http://www.hipaasurvivalguide.com/hipaa-regulations/hipaa-regulations.php. Accessed January 22, 2018.

16. Centers for Disease Control and Prevention. Guideline for Prescribing Opioids for Chronic Pain. 2016. https://www.cdc.gov/drugoverdose/ pdf/Guidelines_Factsheet-a.pdf. Accessed January 22, 2018.

17. Valid Prescription Requirements: Schedule II Substances. Diversion Control Division. Drug Enforcement Administration. US Department of Justice web site. https://www.deadiversion. usdoj.gov/pubs/manuals/pract/section5.htm Accessed January 22, 2018.

18. Schneider JP, Kirsh KL. Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. J Opioid Manage. 2010;6(6):385-395.

19. Manner of Issuance of Prescriptions. Diversion Control Division. Drug Enforcement Administration. US Department of Justice web site. https://www.deadiversion.usdoj.gov/21cfr/ cfr/1306/1306_05.htm. Accessed January 22, 2018.

20. 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.

21. Davis B, Vanderah TW. A new paradigm for pain? JFam Pract.

2016;65(9):598-605.

REFERENCES

1. Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids. Adv Ther.

2000;17(2):70-80.

2. Finch PM, Roberts LJ, Price L, Hadlow NC, Pullan PT. Hypogonadism in patients treated with intrathecal morphine.

Clin J Pain. 2000;16(3):251-254.

3. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3(5):377-384.

4. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E.. Hypogonadism and sexual dysfunction in male cancer survivors receiving chronic opioid therapy. J Pain Sympt Manage. 2003;26(5):1055-1061.

5. Michaud JE, Billups KL, Partin AW. Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. Ther Adv Urol. 2015. 7(6):378-387.

6. Safety of testosterone replacement therapy. Med Letter.

2016;58(1490):33-34.

7. Deyo RA, Weinstein JN. Low back pain. New Engl J Med. 2001;344(5):363-370.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013:541.

9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 2000.Definitions. Diversion Control Division. Drug Enforcement Administration. US Department of Justice web site. https://www.deadiversion.usdoj. gov/21cfr/cfr/1300/1300_01.htm. Accessed January 22, 2018.

10. Definitions. Diversion Control Division. Drug Enforcement Administration. US Department of Justice web site. https:// www.deadiversion.usdoj.gov/21cfr/cfr/1300/1300_01.htm.

Accessed January 22, 2018.

11. Sabatowski R, Schwalen S, Rettig K, Herberg KW, Kasper SM, Radbruch L.. Driving ability under long-term treatment with transdermal fentanyl. J Pain Symp Manage. 2003;25(1):38-47.

12. AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc. 2002;50(6 Suppl):S205-224.

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| TH E PAI N P R AC TITIO N E R | S P R I N G 2018

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THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 1 |

25

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) CONTRAINDICATIONS: NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extendedrelease products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a or injecting the dissolved product will result in the uncontrolled potentially fatal overdose of tapentadol. delivery of tapentadol and can result in overdose and death.

Profound sedation, respiratory depression, coma, and death Opioids are sought by drug abusers and people with addiction may result from the concomitant use of NUCYNTA ER with disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, reduce these risks include prescribing the drug in the smallest muscle relaxants, general anesthetics, antipsychotics, other appropriate quantity and advising the patient on the proper opioids, alcohol). Because of these risks, reserve concomitant disposal of unused drug. Contact the local state professional prescribing of these drugs for use in patients for whom licensing board or state controlled substances authority for alternative treatment options are inadequate. information on how to prevent and detect abuse or diversion of this product.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants (continued) Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.

Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: NUCYNTA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Alternatively, consider the use of non-opioid analgesics in these patients.

Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.

Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.

There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics).

Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock.

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

Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

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

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

Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication.

Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

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

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

Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing NUCYNTA ER, gradually taper the dose.

Do not abruptly discontinue NUCYNTA ER.

© 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0029 02/18

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use NUCYNTA ER safely and effectively. See full Prescribing Information for NUCYNTA ER. INDICATIONS AND USAGE NUCYNTA ER (tapentadol) is indicated for the management of: • pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

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

• NUCYNTA ER is not indicated as an as-needed (prn) analgesic.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning.

• NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur.

Monitor closely, especially upon initiation or following a dose increase.

Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.3).

• Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7).

CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product (see Adverse Reactions).

• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see Drug Interactions).

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse.

Because extended-release products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present (see Drug Abuse and Dependence).

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death (see Overdosage).

Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the

proper disposal of unused drug (see Patient Counseling Information). Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see Overdosage). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential (see Dosage and Administration). Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see Use in Specific Populations, Patient Counseling Information).

Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol (see Clinical Pharmacology).

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions).

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Drug Interactions and Patient Counseling Information).

Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: NUCYNTA ER treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER (see Warnings and Precautions).

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see Warnings and Precautions).

Alternatively, consider the use of non-opioid analgesics in these patients.

Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration (see Warnings and Precautions).

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs.

Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic

antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see Drug Interactions). This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that.

Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock.

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

Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi.

Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

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

Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms (see Drug Interactions).

When discontinuing NUCYNTA ER, gradually taper the dose (see Dosage and Administration). Do not abruptly discontinue NUCYNTA ER (see Drug Abuse and Dependence).

Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication (see Patient Counseling Information).

Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment (see Dosage and Administration and Clinical Pharmacology). Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known (see Clinical Pharmacology).

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see Warnings and Precautions) • Life-Threatening Respiratory Depression (see Warnings and Precautions) • Neonatal Opioid Withdrawal Syndrome (see Warnings and Precautions) • Interaction with Benzodiazepine or Other CNS Depressants (see Warnings and Precautions)

• Serotonin Syndrome (see Warnings and Precautions) • Adrenal Insufficiency (see Warnings and Precautions) • Severe Hypotension (see Warnings and Precautions) • Gastrointestinal Adverse Reactions (see Warnings and Precautions) • Seizures (see Warnings and Precautions) • Withdrawal (see Warnings and Precautions) Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The most common adverse reactions (reported by ≥10% in any NUCYNTA ER dose group) were: nausea, constipation, dizziness, headache, and somnolence.

The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA ER dose group for NUCYNTA ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively.

Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients.

Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The most commonly reported ADRs (incidence ≥10% in NUCYNTA ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache.

Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients.

Postmarketing Experience The following adverse reactions have been identified during post approval use of tapentadol.

Psychiatric disorders: hallucination, suicidal ideation, panic attack Serotonin syndrome: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in NUCYNTA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see Clinical Pharmacology).

DRUG INTERACTIONS Clinically Significant Drug Interactions with NUCYNTA ER Alcohol Clinical Impact:

Concomitant use of alcohol with NUCYNTA ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol.

Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy.

Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Due to additive pharmacologic effect, the concomitant use of Impact: benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical The concomitant use of opioids with other drugs that affect Impact: the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.6].

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.

Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs) Clinical MAOI interactions with opioids may manifest as serotonin Impact: syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].

Intervention: Do not use NUCYNTA ER in patients taking MAOIs or within 14 days of stopping such treatment Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical May reduce the analgesic effect of NUCYNTA ER and/or Impact: precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Tapentadol may enhance the neuromuscular blocking action of Impact: skeletal muscle relaxants and produce an increased degree of respiratory depression.

NUCYNTA ER (tapentadol) extended-release tablets, CII BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION (continued) Muscle Relaxants (continued) Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUCYNTA ER and/or the muscle relaxant as necessary.

Diuretics Clinical Opioids can reduce the efficacy of diuretics by inducing the Impact: release of antidiuretic hormone.

Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical The concomitant use of anticholinergic drugs may increase Impact: risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions).

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications.

Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see Warnings and Precautions).

Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor. Opioid analgesics, including NUCYNTA ER, can prolong labor.

Lactation Risk Summary There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded.

Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER. Clinical Considerations Monitor infants exposed to NUCYNTA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

Pediatric Use The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established.

Geriatric Use Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients.

Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see Warnings and Precautions).

Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment (ChildPugh Score 10-15) is not recommended. In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), dosage reduction of NUCYNTA ER is recommended (see Dosage and Administration).

Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended.

DRUG ABUSE AND DEPENDENCE Controlled Substance NUCYNTA ER contains tapentadol, a Schedule II controlled substance.

Abuse NUCYNTA ER contains tapentadol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA ER can be abused and is subject to misuse, addiction, and criminal diversion (see Warnings and Precautions).

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

NUCYNTA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of NUCYNTA ER NUCYNTA ER is for oral use only. Abuse of NUCYNTA ER poses a risk of overdose and death. The risk is increased with concurrent use of NUCYNTA ER with alcohol and other central nervous system depressants.

With intravenous abuse the inactive ingredients in NUCYNTA ER can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

NUCYNTA ER should not be abruptly discontinued (see Dosage and Administration). If NUCYNTA ER is abruptly discontinued in a physicallydependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see Use in Specific Populations).

OVERDOSAGE Clinical Presentation Acute overdosage with NUCYNTA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

© May 2017, Depomed, Inc. All rights reserved. APL-NUCX-0249

© 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0029 02/18

NONPROFIT ORG US POSTAGE PAID BURL VT 05401 PERMIT #19 8700 Monrovia Street, Suite 310, Lenexa, KS 66215

TIME TO DUAL

TW O O NE SOURCES SOURCE

OF PAIN OF RELIEF

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

Not an actual patient.

INDICATIONS AND USAGE NUCYNTA ER (tapentadol) is indicated for the management of: • Pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • Neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

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

IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse NUCYNTA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant can lead to overdose and death. Assess each patient’s risk prior to prescribing NUCYNTA ER, and monitor woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate all patients regularly for the development of these behaviors and conditions. treatment will be available.

Life-threatening Respiratory Depression Interaction With Alcohol Serious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA ER. Monitor for Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products respiratory depression, especially during initiation of NUCYNTA ER or following a dose increase. Instruct that contain alcohol while taking NUCYNTA ER. The co-ingestion of alcohol with NUCYNTA ER may result in patients to swallow NUCYNTA ER tablets whole; crushing, chewing, or dissolving NUCYNTA ER tablets can increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. cause rapid release and absorption of a potentially fatal dose of tapentadol.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Accidental Ingestion Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in a fatal overdose including alcohol, may result in profound sedation, respiratory depression, coma, and death. of tapentadol.

• Reserve concomitant prescribing of NUCYNTA ER and benzodiazepines or other CNS depressants for Neonatal Opioid Withdrawal Syndrome use in patients for whom alternative treatment options are inadequate.

Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, • Limit dosages and durations to the minimum required. which may be life-threatening if not recognized and treated, and requires management according to • Follow patients for signs and symptoms of respiratory depression and sedation.

Please see additional Important Safety Information, including BOXED WARNING, and Brief Summary on the adjacent pages.

Nucynta ER is a registered trademark of Depomed, Inc. © 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0029 02/18