The Pain Practitoner - New Perspectives on Cancer Pain

Integrative Pain Management for Optimal Patient Care

The Pain Practitioner Fall 2018

New perspectives in cancer pain

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Integrative Pain and Symptom Management Chemotherapy-induced Neuropathy Medical Cannabis Ketamine in Sickle Cell Disease

Academy of Integrative Pain Management

The Pain Practitioner

www.integrativepainmanagement.org

FALL 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

To access the virtual magazine, go to newsstand.aapainmanage.org

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STAFF AND CONSULTANTS

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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

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THE PAIN PRACTITIONER STAFF AND CONSULTANTS

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Editor-in-Chief W. Clay Jackson, MD, DipTh Editor Debra Nelson-Hogan Managing Editor Cathleen Coneghen Clinical Editor Christine Rhodes, MS Art Director Peter McKinley, Pak Creative Copy Editor Rosemary Hope

9 NOTES FROM THE FIELD AIPM and PAINS: A Fitting Match

By Bob Twillman, PhD, FAPM, Executive Director 10 EDITORIAL The Conversation

By W. Clay Jackson, MD, DipTh, Editor-in-Chief 11 GLOBAL SUMMIT/EDUCATION Tackling the Three-headed Monster: Chronic Pain, Opioid Use, and Mental Health

By Debra Nelson-Hogan 12 GLOBAL SUMMIT/EDUCATION AIPM Puts Nutrition for Pain Management on the Table

By Megan Sweeney, DO student, MPH candidate 15 MEMBERSHIP AIPM Adds New Members-only Benefits

By Whitney O’Donnell, Member Services Manager 16 ADVOCACY Pain Policies Impact Cancer Patients Even When They’re Not Meant To

By Katie Duensing, JD, Director of Legislative and Regulatory Affairs 17 Integrative Pain and Symptom Management Strategies for the Cancer Patient

By Larry Driver, MD 20 Chemotherapy-induced Neuropathy: Is There a Path Forward?

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

23 The Science, Politics, and Medicine of Medical Cannabis for Chronic Pain

By Mark S. Wallace, MD 27 The Use of Ketamine in Sickle Cell Disease to Reduce Pain and Opioid Dosage

Case Report and Literature Review

By Arthur S. Hernandez, MD

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The Pain Practitioner is published by the Academy of Integrative Pain Management solely for the purpose of education. All rights are reserved by the Academy to accept, reject, or modify any submission for publication.

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.

All rights are reserved by the Academy to accept, reject, or modify any advertisement submitted for publication. It is the policy of the Academy to not endorse products. Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

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NOTES FROM THE FIELD

AIPM and PAINS: A Fitting Match

By Bob Twillman, PhD, FAPM, Executive Director

I’M ABSOLUTELY DELIGHTED TO announce that AIPM is joining forces with the Pain Action Alliance to Implement a National Strategy (PAINS), formerly a program of the Kansas City-based Center for Practical Bioethics (CPB).

Founded in 2011 by Myra Christopher, CPB’s Kathleen M. Foley Chair for Pain and Palliative Care, and former President and CEO, the mission of PAINS is, in the words of the 2011 Institute of Medicine (IOM) report on chronic pain, “to change the way pain is perceived, judged, and treated.” With Myra’s retirement, CPB has decided that transitioning oversight of PAINS to AIPM is the best strategy to secure its legacy and maximize ongoing efforts to accomplish that mission.

As a fellow Kansas Citian, it has been my privilege to work with, and learn from, Myra for the last two decades. Myra has been nationally recognized as a leader in the field of bioethics. From 1997 to 2003, she was principal investigator on a Robert Wood Johnson Foundation-funded national initiative called Community-State Partnerships to Improve End-of-Life Care.

It was because of this project that Myra became interested in pain management, and it is where our work together really began. Her accomplishments in pain management have been truly remarkable; she has won numerous awards from national organizations and was a member of the IOM pain report committee, along with a former president of AIPM, the late Rick Marinelli, ND. Her work with PAINS has been just as remarkable, and it has been an honor for me to serve as a member of its steering committee since its inception.

PAINS has, like AIPM, been diligent in reaching out to other organizations and key opinion leaders to find opportunities for collaboration. PAINS has convened several meetings of leaders from organizations spanning both the pain management and substance use disorder communities, believing that solutions to the public health crises of inadequately treated chronic pain and of opioid misuse, abuse, and overdose will be found only if these communities work together.

Like AIPM, PAINS has advocated for a comprehensive, integrative model as the safest and most effective way to provide pain care. PAINS was one of three cosponsors of AIPM’s inaugural Integrative Pain Care Policy Congress, and is serving as one of two co-sponsors for the second Congress meeting, planned for this November. We truly have been the closest of partners in these endeavors.

By the time you read this column, we will have completed the transition of management for the PAINS social media accounts (Twitter and Facebook) to AIPM, as well as having completed a rebranding of the PAINS website to reflect its new status as an initiative of AIPM. All of the superb materials produced by PAINS will continue to be available at no cost through the website, and we will be looking for opportunities to continue adding to those materials.

One project established as part of PAINS, known as PAINS KC, will continue to be managed by CPB. PAINS KC brings together people with chronic pain, their families and caregivers, researchers, and health care professionals, for monthly educational and social events. As the

PAINS KC leader says, “It is not a support group; it is a supportive group.” While providing support for people with chronic pain, PAINS KC also serves an advisory role for researchers working in the field. It has been included as a patient stakeholder organization in several PCORI grant applications, and has worked with several researchers at the University of Kansas on pain-related projects. Because I live in the city where this group meets, I have been privileged to participate in several of its meetings, and I will continue to participate regularly going forward. As I told the group at a meeting last week, what they have to tell those of us who provide pain care is vitally important. I told them that I have been asked how AIPM decides on positions to take with respect to policy issues, and that my answer has always been this: “When there is more than one tenable position, we will take the one that is most right for people with chronic pain.

Ultimately, what is right for people with pain is what is right for the people who provide their pain care. It may not always be what is most lucrative for those care providers, but it will be what is right, and this is the overriding consideration.”

I’m mindful that, by accepting CPB’s gracious offer to assume management of PAINS, we are being asked to fill some ginormous shoes. Myra Christopher is a mentor to me and to many others in the pain management community, and she is irreplaceable. PAINS has served as a powerful convener, capable of bringing together disparate organizations and viewpoints for discussion in the service of finding common ground. Myra has referred to PAINS as “the Switzerland of pain management.” It is my fervent hope that we at AIPM can do the same, continuing to advance the vision and mission of both AIPM and PAINS in the service of providing optimal care for people with pain. 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.

THE PAIN PRACTITIONER

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EDITORIAL

The Conversation

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

“I DON’T CARE. I HAVE A LICENSE TO protect. I’m not filling the prescription; your patient can go somewhere else!”

The voice on the other end of the phone was strained; the exchange was intense. The pharmacist (employed by a larger supermarket chain) was refusing to fill a prescription for oxycodone/ acetaminophen, ostensibly because it had been fewer than 30 days since the last prescription was filled.

I sighed, collected my better thoughts, repressed my retorts, and tried again.

“Ma’am, this is a patient with metastatic prostate cancer*. He saw me three weeks ago and his pain was fairly well-controlled.

Since then, he’s had a material change in his condition, and I told him to take the pills every four hours instead of three times a day. That’s why he’s out, and why he needs the medication filled today.”

We went back and forth for 10 minutes. We debated the relative responsibilities of a pharmacist and a prescribing clinician in complying with current regulations. She made her case for not filling the prescription; I advocated for the patient’s right to compassionate care in the face of unrelenting cancer, which was literally chewing up his bones.

I could picture that CT scan in my mind

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as we were talking—the patient’s pelvic girdle, riddled with black holes causing excruciating pain every time he would attempt to stand or shift positions.

When the pharmacist rang off, I dropped the phone, full of righteous indignation. My pulse and respiratory rate took a long time to return to normal. I felt like I had been in a fight—because I had.

Later, when the autonomic charge left me, my emotions flooded in a different direction—that of depression or even despair. Was this the new landscape of contemporary care for patients with pain? Where clinicians and dispensers are so reluctant to contribute to the opioid overprescription problem that patients who are clearly suffering don’t have access to relief?

I wondered what frightened the pharmacist so. Was it increasing regulatory pressure? News reports? The opinion of peers? My mind went places I didn’t want it to go. Was my patient profiled? Did the pharmacist suspect him of inappropriate behaviors because he was in his 40s? Because he had tattoos?

Because he was of a different ethnicity?

As the pendulum has swung in America from relatively few prescriptions to opioids, to more, to less again over the

past two decades, we’ve told ourselves we can draw a clear line between the “good patients” and the “bad patients,” between the “legitimate prescribers” and the “drug-pushers.” I’m not convinced that those categories are clear-cut, or even helpful. Even well-meaning prescribers can make bad decisions.

And patients with substance use disorders remain patients, after all, who deserve adequate treatment for their illness, rather than being shunned and shamed into further destructive behaviors. In that context, every moment we spend going up and down on the more-or-less opioid see-saw, without adding appropriate mental health and substance abuse evaluation and treatment, while denying insurance coverage for proven nonpharmacologic therapies, is a moment that we fail patients.

Changes in the standard of care may be incremental, but they aren’t isolated—they are ecologic. They affect the environment of care for all patients. If we think our undertreatment of pain, overprescription of opioids, and undertreatment of mental illness are health care challenges that will be quickly addressed or easily solved, we have seriously underestimated the scope of the problem.

The pharmacist relented; we managed to find common ground. The patient received his prescription. He will beat the cancer, or the cancer will beat him. Either way, as of this writing, he gets to fight with dignity and comfort, rather than being wracked with pain.

But what happens tomorrow when the next patient calls? n *Some diagnostic and demographic details have been changed to protect patient confidentiality. @mydocjackson 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.

Dr. Jackson is the associate fellowship director of palliative medicine at the University of Tennessee College of Medicine.

GLOBAL SUMMIT/EDUCATION

Global Pain Clinician Summit 2018: Transforming How We Care for People with Pain

Tackling the Three-headed Monster:

CHRONIC PAIN, OPIOID USE, AND MENTAL HEALTH

By Debra Nelson-Hogan YOU CAN’T TALK ABOUT PAIN management today without including the three-headed monster: chronic pain, opioid use, and mental health, and AIPM will put it front and center at the Summit in November.

Bob Twillman, PhD, executive director of the AIPM, will present the topic, which will underscore the fact that there are three independent public health issues here: pain management, opioid use disorder, and mental health issues other than opioid use disorder. There has been much discussion about the first two of these, but it is necessary to add mental health issues to the mix in order to get a complete profile of the issues we are facing today.

Dr. Twillman noted in his column in the Spring issue of The Pain Practitioner that these three public health crises are more similar than different. All three

share these characteristics: highly prevalent; costly in economic and human terms; highly stigmatized, with patients blamed for having the 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 for patients as well as their friends and family.

Following Dr. Twillman’s presentation, The Town Hall will enable Summit attendees to discuss some of the challenges they are facing as they try to address their patients’ pain care, particularly around the “threeheaded monster.” Panel participants represent a broad range of experience, including a pain management expert, a substance use disorder treatment specialist with experience working as a policymaker, and a key

federal government official responsible for implementing the National Pain Strategy.

This session offers a unique opportunity for attendees to interface with key policy influencers, as they work to provide top-quality integrative pain care for their patients.

This year’s Summit is different from previous annual meetings in that its content is more focused and we believe it will also provide more opportunities for learning, interacting, and networking with other attendees. Besides the threeheaded monster, we will talk about the use of technology, the state of digital health, group medical visits, and updates about medical marijuana. There will also be a full-day certificate program on Nutritional Pain Management.

Make your plans to attend now— space is limited and is filling up quickly. n

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GLOBAL SUMMIT/EDUCATION

AIPM Puts Nutrition for Pain Management on the Table

By Megan Sweeney, DO student, MPH candidate

Robert Bonakdar, MD, and Megan Sweeney with their poster, which evaluated the AIPM Nutrition Pain Management Certification Course, at the 2018 International Congress on Integrative Medicine & Health.

THE WIDESPREAD OPIOID EPIDEMIC will continue to overwhelm the nation without more effective, safer alternatives to mitigate pain. As non-pharmacologic strategies to manage pain have gained increasing attention, it is vital that clinicians and health specialists maintain a comprehensive understanding of lifestylebased remedies and can adequately provide patient recommendations.

Bodily chemistry is altered and directly influences inflammation levels each time an individual consumes food,

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supplements, and medications (1). With urbanization, economic development, and mass marketing, global dietary patterns have shifted to include more sugarsweetened beverages, highly processed foods, animal-based foods, and fewer fruits and vegetables (2,3). Given the potential for pain to coexist with metabolic dysregulation, including obesity, metabolic syndrome, and nutrient deficiency, dietary modifications that encourage a healthy body mass index have also reduced pain in multiple populations (4,5). Leveraging

nutrition and nutraceuticals can positively result in reduced disease morbidity, mortality, and medical costs (6). Now, more than ever, medical professionals must encourage healthy dietary habits through nutrition care.

Prior research has illuminated how dietary and supplement-based interventions not only reduce pain, but also increase patient compliance and overall quality of life (7-9). In fibromyalgia patients, a pilot study involving foods rich in polyphenols proved to reduce tender points and increase quality of life (10), as antioxidant protection from bioactive compounds present in fruits and vegetables may ameliorate pain. The positive link between a Mediterranean diet, which is high in vegetables, legumes, fruits, whole grains, fish, and healthy oils but low in meat, and cardiovascular health has been validated on numerous occasions (11).

More recently, surmounting evidence has also supported the efficacy of an antiinflammatory diet in chronic pain management (12,13). Scientific research and clinical observation, for example, has verified the antiinflammatory properties of oleocanthal, a phenolic compound found in extra virgin olive oil (14).

The overall benefit of including nutrition in personalized pain medicine is formidable and highly promising. Patients and caregivers often visit their providers in search of non-opioid therapies; however, clinicians commonly neglect to mention dietary habits. Research has shown that patients who receive dietary recommendations from their physicians are more likely to adhere to recommendations and achieve more favorable nutritional states compared to patients who have not discussed this with their doctors (15). Investigations have revealed the unfortunate deficit in of nutrition education in undergraduate and graduate medical training (16,17). Clinicians and other medical professionals, as a result, are often hesitant to recommend eating habits or dietary supplements to patients. Only 14% of medical residents in a recent survey felt confident providing preventative nutrition education, the majority of whom attributed this knowledge gap to inadequate

GLOBAL SUMMIT/EDUCATION

education and clinical training (18). The absence of formally recognized, national guidelines on this topic does not help the situation (19).

Members of the Academy of Integrative Pain Management Nancy Cotter, MD, hysician lead of Integrative Health, VA Morristown, New Jersey; Robert Bonakdar, MD, and I, both of Scripps Center for Integrative Medicine, San Diego, California, developed and implemented a certification course, Nutrition Pain Management Certification Course, for multidisciplinary health care

While there is a disconnect between nutrition knowledge and dietary habits in the general population, the course discussed methods to thoughtfully and effectively teach patients how food choices abundant in society, such as processed foods packed with salt, sugar, unhealthy oils, and grain byproducts, can worsen pain states.

professionals to help them increase familiarity and confidence employing evidence-based nutritional strategies in the setting of pain. This six-hour continuing education course was designed to address key concepts of nutritional pain management, including the role of diet in augmenting pain (e.g., inflammatory, nutrient-deplete, and obesogenic diets) and in reducing pain (e.g., antiinflammatory, nutrient-specific diets). Practical ways to introduce consumption of health-promoting foods, evidence-based nutrients, and dietary supplements to those with systemic

inflammation or pain resulting from a deficiency (e.g., rheumatoid arthritis, migraine, metabolic neuropathy) were also explained. Before and after the educational session, course participants completed self-report surveys to assess prior education and experience sharing this topic with patients.

A FRESH LOOK AT DIET AND PAIN Diet profoundly influences both health promotion and disease prevention.

Designed to achieve stronger buy-in from patients—who may often have failed previous diet approaches—the course included a comprehensive overview of the diet-pain connection.

Ways in which chronic pain rewires the brain and sways food choices were also incorporated into the curriculum.

In addition, the course emphasized the importance of assessing nutritional status, which can have a direct influence on inflammation levels. Inflammation increases free-radical damage of tissues, impedes healing mechanisms, and reduces efficacy of cellular functions.

The course also introduced nutrition as a cost-effective, patient-centered approach to pain that allows clinicians and patients to work together.

While there is a disconnect between nutrition knowledge and dietary habits in the general population, the course discussed methods to thoughtfully and effectively teach patients how food choices abundant in society, such as processed foods packed with salt, sugar, unhealthy oils, and grain byproducts, can worsen pain states. Incorporating evidence-based dietary recommendations, integrative pain education, motivational interviewing, and shared decision making, the course transforms a previously difficult subject into a patient-centered, empowering discussion.

After the initial Nutrition Pain Management Certification Course in October 2017, our results show that all 115 pre-course surveys and 95 postcourse surveys were completed. Of all health care professionals in the course, 86% had received little to no previous education or training in nutritional approaches to pain. The post-course surveys showed statistically significant (P < .001) improvement across all items, including assessments on participants’ levels of familiarity, confidence, and comfort utilizing nutritional pain management. Only 31% of pre-course respondents expressed confidence

Nutrition Course Abstract Garners Award for Young Investigator Congratulations to medical student and clinical researcher MEGAN SWEENEY, who in May received an Excellent Young Investigator award at the 2018 International Congress on Integrative Medicine & Health in Baltimore, Maryland. Ms. Sweeney presented “Nutritional Management: Design, Implementation and Evaluation of a Certification Course for Diverse Pain Providers: the Nutrition Pain Management Certification Course” during the Congress, which was co-sponsored by the Academic Consortium for Integrative Medicine and Health and the International Society for Complementary Medicine Research. Ms. Sweeney is a doctor of osteopathy student and master’s degree in public health candidate and is affiliated with the Scripps Center for Integrative Medicine, San Diego, California.

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GLOBAL SUMMIT/EDUCATION

responding to patient inquiries about diet and supplements for pain, while 86% of participants felt confident upon follow up.

Over 87% felt well-educated on the topic after attending the course.

In addition to qualitative survey responses, we have taken into account these results to direct future course development and medical education initiatives in nutritional pain management.

Ultimately, medical practitioners from all disciplines should be aware of the role nutrition plays in ameliorating and exacerbating pain. This continuing education course for pain management clinicians significantly improved their understanding and comfort with providing nutritional interventions for pain management. This study indicates that a single, in-depth course is useful to expand clinical education and increase utilization of an often overlooked, though vital, nonpharmacological approach to pain. The next steps of the program will assess the long-term impact of the intervention, while offering ongoing support and continuing education opportunities to certified participants. n

REFERENCES 1. Willett, WC. Eat, drink, and be healthy: the Harvard Medical School guide to healthy eating. New York: Free Press; 2005.

2. Kearney J. Food consumption trends and drivers. Philos Trans R Soc Lond B Biol Sci. 2010 Sep 27; 365(1554): 2793-2807.

3. Popkin BM. Global nutrition dynamics: the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr. 2006; 84(2):289-98.

4. Zdziarski LA, Wasser JG, Vincent HK. Chronic pain management in the obese patient: a focused review of key challenges and potential exercise solutions. J Pain Res. 2015;8:63-77.

5. Sibille K, Steingrímsdóttir O, Fillingim R, et al. Investigating the burden of chronic pain: An inflammatory and metabolic composite. Pain Res Manage. 2016; 7657329.

6. Zaheer K, Akhtar MH. An updated review of dietary isoflavones: nutrition, processing, bioavailability and impacts on human health. Crit Rev Food Sci Nutr. Epub 2015 Nov 13.

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7. Tick H. Nutrition and pain. Phys Med Rehabil Clin N Am. 2015;26(2):309–320.

8. Leonard BE. Pain, depression and inflammation: are interconnected causative factors involved? Mod Trends Pharmacopsychiatry. 2015; 30:22–35.

9. De Gregori M, Muscoli C, Schatman ME, et al. Combining pain therapy with lifestyle: the role of personalized nutrition and nutritional supplements according to the SIMPAR Feed Your Destiny approach. J Pain Res. 2016; 9: 1179-1189.

10. Costa de Miranda R, Paiva ES, Suter Correia Cadena SM, Brandt AP, Vilela RM. Polyphenol-Rich foods alleviate pain and ameliorate quality of life in fibromyalgic women. Int J Vitam Nutr Res. 2016 Nov 21:1-10.

11. Houston M. The role of nutrition and nutraceutical supplements in the treatment of hypertension. World J Cardiol. 2014;6(2):38–66.

12. Forsyth C, Kouvari M, D’Cunha NM, et al. The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies. Rheumatol Int. 2018 May;38(5):737-747.

13. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc.

2003;78:1463–70.

14. Beauchamp GK, Keast RS, Morel D, et al. Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature.

2005;437:45-46.

15. Hever J. Plant-Based Diets: A Physician’s Guide. Perm J. 2016 Summer; 20(3): 93-101.

16. Adams KM, Butsch WS, Kohlmeier M. The State of Nutrition Education at US Medical Schools. Am J Clin Nutr.

2014;2014(83):941S-944S. 17. Aggarwal M, Devries S, Freeman AM, et al. The deficit of nutrition education of physicians. Am J Med. 2018 Apr;131(4):339-345.

18. Mitka M. Virtual textbook on pain developed: Effort seeks to remedy gap in medical education. JAMA. 2003;290:2395.

19. Tappenden KA, Quatrara B, Parkhurst ML, Malone AM, Fanjiang G, Ziegler TR. Critical role of nutrition in improving quality of care: an interdisciplinary call to action to address adult hospital malnutrition.

J Acad Nutr Diet. 2013;113(9): 1219-1237.

MEMBERSHIP

AIPM Adds New Members-only Benefits

By Whitney O’Donnell, Member Services Manager

THE MAIN REASON WHY MEMBERS come to AIPM and remain loyal to us is because we are the only pain management organization that has always focused on an integrative model of pain care, and that accepts all health care professionals as full and equal members. We offer unique member benefits that are geared to assist all members of the pain care team, regardless of their discipline or specialty. This year we’ve launched the following new benefits that only AIPM members have access to: •

•

Concierge service With 13 years of AIPM work-experience, our concierge knows the ins and outs of integrative pain management. In talking with doctors and clinicians over the years, our concierge has learned a lot. As calls and emails come in, our concierge works promptly and professionally to get our members what they need. It could be showing them how to log in and access free CME in our Pain Care Learning Center or directing them to our on-staff policy and advocacy experts. From credentialing to membership, benefits to payment assistance, our concierge is always ready to assist. If our concierge doesn’t have the answer, she knows who does! We encourage our members to utilize their AIPM resources and this is just one of them!

FREE Pain Outcome Profile (POP) kit We revised and digitalized this 24-page pain care assessment tool, exclusive to our members. AIPM members can now download, print, and use the POP kit in their office/ clinic, as part of their overall treatment

strategy. Our POP kit contains a 23-item questionnaire that utilizes 11-point (0 to 10) Numerical Rating Scales to assess a number of relevant dimensions in the pain patient’s experience. Patients and payers alike increasingly demand accountability on the part of treatment providers, and our POP kit is a helpful tool to assist in that.

•

AIPM in Action e-newsletter In April we launched this messaging outlet to keep our members consistently informed on what we are doing, where we stand, and any other pertinent news. We update them on items like our executive director’s speaking engagements, relevant articles about AIPM, members who have made an impact, and policy/advocacy advances that may affect them.

•

Member-only Discounts We’ve partnered with numerous providers to offer exclusive discounts to AIPM members. More than half of our partners have agreed to give AIPM members 50% off their products/ services. These products cover items like medical waste disposal, coding and documentation, medical supplies, software, and more. The most notable discount is on a chart review with the country’s most knowledgeable and experienced pain management defense attorney, Jen Bolen, JD, and her compliance team at The Legal Side of Pain. Due to recent changes in licensing boards’ controlled substance prescribing requirements, and the upswing in controlled substance prescribing investigations on medical professionals, we feel this partnership

will assist our members in ensuring they have the most up-to-date documentation. This partnership discount stemmed from an increasing number of requests from our members on medical coding and documentation requirements. To go along with this, we also partnered with Flash Code, who specializes in medical coding software. Their software covers all official CPT®, HCPCS, ICD-9-CM, and ICD-10-CM codes and descriptions plus guidelines, coding notes, and alphabetic indexes and provides instant lookups for procedure, diagnosis, and supply/injection codes. In addition, it offers Medicare Part B Compliance Edits and physician fee schedules and fees for Medicare lab, DME, and Part B drugs. Flash Code is a division of the leading independent publisher of medical coding books and compliance resources, PMIC, who has also agreed to offer our members 50% off their products. If software and books aren’t a preference, another partner, ScribeAmerica, provides medical scribes virtually so our members can reduce costly overhead and ensure their records are compliant.

Their on-call scribe approach helps our members all over the nation who might otherwise be limited by location and busy schedules. Additionally, we have partnered with MedPro Disposal who offer our members deep discounts on their medical/biohazardous waste removal and document shredding services and The Betty Mills Company, a leading superstore in cleaning, sanitary, medical supplies, and devices. We continue to add new partners each month that we know help our members become more efficient and skilled.

In addition to these newly added member discounts, we continue to enhance our No. 1 rated benefit: free online CME in our Pain Care Learning Center. With 100+ courses available on-demand, we offer the most up-to-date pain education for all clinicians looking to provide optimal patient care.

Offering many tailored benefits that surpass the cost of membership dues may be why 33% of our members have been with us for over 20 years! n

THE PAIN PRACTITIONER

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ADVOCACY

Pain Policies Impact Cancer Patients Even When They’re Not Meant To

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

The law does not apply to an opioid prescription for a patient who is in active treatment for cancer.

Or does it?

When it comes to the many new laws and regulations related to pain and opioids, it would be easy to assume that people living with cancer are still able to obtain adequate pain medication to deal with the effects of cancer and its treatment. After all, most laws that limit opioids include a “cancer exemption,” and the CDC Guideline for Prescribing Opioids for Chronic Pain applies only to the use of opioids in treating chronic pain in the primary care setting, specifically exempting active cancer treatment, palliative care, and end-of-life care (1).

Why, then, are cancer patients and survivors experiencing such difficulty obtaining their medications at the pharmacy, having it covered by their insurance, and even having it prescribed at their doctor’s office? According to a new survey from the American Cancer Society Cancer Action Network (ACSCAN), there has been a significant increase in cancer patients and survivors being unable to access their opioid prescriptions since 2016 (which coincides with the release of the CDC’s guideline) (2). In ever-increasing numbers, cancer patients and survivors are being told that their pharmacy no longer stocks the specific drug prescribed (up to 41% in 2018 from 16% in 2016); that their pharmacist won’t dispense their medication, even though it is in stock (up to 27% from 12%); and that their insurance will not cover their medication (up to 30% from 12%). And finally, a whopping 48% of those surveyed said that their doctor indicated that his or her treatment options for pain were limited by laws, guidelines, or insurance coverage.

If those with cancer are meant to be exempt from new opioid policies, why are they being so severely impacted?

MISINTERPRETATION AND MISAPPLICATION Many proposed opioid policies purport to follow the CDC guideline, but they often represent both a misinterpretation and a misapplication of the guideline. This year, for example, Missouri HealthNet (Medicaid) proposed a rule that would have adopted large portions of the CDC guideline.

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However, the proposed rule misinterpreted the guideline, mutating what should have been a 90 MMED threshold dose (triggering a consultation) into a 90 MMED ceiling dose—despite the fact that CDC has cautioned policymakers against turning their recommendations into rules and laws.

Further, the proposal misapplied the guideline by applying the proposed rule to all patients, regardless of diagnosis or treatment setting—despite the fact that the guideline was intended for use in the primary care setting and specifically exempted cancer, palliative care, and end-of-life care.

CONFUSING REQUIREMENTS AND EXEMPTIONS As policymakers grapple with how best to address the opioid overdose and misuse epidemics, they often quickly pass new policies without entirely anticipating the negative unintended consequences to patients living with pain. Often, even when they do attempt to account for those consequences, the resulting policies are confusing when put into practice. For example, on July 1 of this year, Florida’s House Bill 21 went into effect (3). Under this law, there are strict three-day and seven-day duration limits for opioids used to treat acute pain; however, those being treated for cancer are specifically exempted from these limits. Due to these exemptions, it would be easy for a prescriber to assume that he or she doesn’t need to do anything new when writing an opioid prescription for a cancer patient. Nevertheless, that assumption would create problems for the patient when picking up their medication, as the law creates a presumption for pharmacists that all opioid prescriptions are for acute pain unless they specifically state otherwise: the prescriber must write “NONACUTE PAIN” on the prescription or the pharmacist will not be able to fill the prescription for more than a threeday supply.

INAPPROPRIATE DISTINCTIONS Finally, there are the ever-present, and always inappropriate, distinctions made by policymakers between “cancer pain”

and “noncancer pain” (also referred to as “malignant pain” and “nonmalignant pain”). AIPM and its partners, the American Cancer Society and ACSCAN, have argued in a number of settings, including in testimony submitted to the US Food and Drug Administration, that, in the context of opioid therapy, making a distinction between “cancer pain” and “noncancer pain,” or “malignant pain” and “non-malignant pain” (or any other type of pain) is inappropriate and scientifically unsupported. Physiologically and pharmacologically, pain is the same, whether it results from cancer, cancer treatment, or a noncancer cause. What should be at issue in rule promulgation is the physiology underlying a painful condition and the response to pharmacological treatment of that condition. Further, the prevailing medical opinion is that “cancer pain” should include pain caused either by the cancer itself, or by treatments used to address the cancer (e.g., surgery, radiation therapy, and chemotherapy).

Policymakers, however, often limit their exemptions to opioid limitations to pain caused only by the cancer itself, and/or to pain in people receiving active cancer treatment, leaving the ever-increasing population of long-term cancer survivors without an avenue for obtaining pain medication for the chronic conditions they face after the cancer itself is gone. n

REFERENCES 1. CDC guidelines for prescribing opioids for cancer pain. Centers for Disease Control and Prevention web site. https://www.cdc.gov/drugoverdose/ prescribing/guideline.html. Updated August 29, 2017. Accessed July 20, 2018.

2. American Cancer Society Cancer Action Network. Key findings summary: opioid access research project. https://www.acscan.org/sites/default/ files/ACS%20CAN%20PQLC%20 Opioid%20Research%20Project%20 Key%20Findings%20Summary%20 Memo%20FINAL.pdf. Published 2018.

Accessed July 20, 2018.

3. Florida HB21: Controlled Substances. https://www.flsenate.gov/Session/ Bill/2018/21/BillText/er/PDF

INTEGRATIVE PAIN AND SYMPTOM MANAGEMENT STRATEGIES FOR THE CANCER PATIENT

Integrative Pain and Symptom Management Strategies for the Cancer Patient

By Larry Driver, MD

Why do we treat pain? Why do we treat the collateral symptoms that go along with pain? There are two ethical principles that we consider when we are taking care of patients: nonmaleficence, or do no harm, and also beneficence, which is trying to do something helpful or good that will benefit the patient.

Pain care is a complex undertaking, as can be seen in Figure 1. Our goal is to improve the patientâ&#x20AC;&#x2122;s overall quality of life, but at each level of health outcome, there are an increasing number of inputs that cannot be controlled by clinicians or the health care system (1).

Most patients with cancer experience cancer-related pain.

Significant pain may be present at any stage of the disease and may be present for long periods of time, even for the duration of the disease. At the time of diagnosis, 30% to 40% of patients may have pain; during treatment, 50% to 70% have pain; with advanced disease, 70% to 90% of cancer patients will have pain (2). Usually

the more advanced the disease, the worse the pain will be. In a meta-analysis of 54 studies, 33% had persistent pain after curative treatment, 64% of those with advanced or metastatic disease had pain, and 53% had pain at all disease stages. Of those with pain, more than one-third graded their pain as moderate or severe (3).

However, it is not just pain that is experienced by cancer survivors. In a comparison of cancer survivors and the general population taken from the National Health Interview Survey, the rates of ongoing pain, psychological distress, and insomnia were 34%, 26%, and 30%, respectively, and were significantly higher (P < .001) than controls without a history of cancer (18%, 16%, and 17%) (4). The interaction of psychological distress with persistent pain leads to more suffering among cancer survivors. Factors that can confound the pain picture include delirium, anxiety or panic attacks, depression, somatization, pseudoaddiction or drug-seeking behavior, and aberrant behaviors that appear to be addiction.

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A variety of stressors affect patients with cancer as well as those with chronic disease, including unrelieved severe pain, fear of not being believed, existential or spiritual suffering, impact of pain on family and friends, medication adherence or compliance issues, and financial and insurance issues. In addition, we have become increasingly aware of the problem of opioid abuse in the cancer pain population, with emerging data indicating addiction rates up to 15%.

WHAT IS INTEGRATIVE MEDICINE? The NIH defines conventional, Western, or allopathic medicine as that practiced by holders of MD or DO degrees and by allied health professionals such as physical therapists, psychologists, and registered nurses. Complementary and alternative medicine approaches are defined as healing philosophies, approaches, and therapies that mainstream Western medicine does not commonly use, accept, study, understand, or make available. Complementary medicine refers to the use of non-mainstream practice together with conventional medicine. Alternative medicine is the use of nonmainstream practice in place of conventional medicine. Integrative practice combines both conventional and complementary treatments for which there is evidence of safety and effectiveness.

The National Center for Complementary and Integrative Health (NCCIH) extends the definition of integrative medicine to include approaches that leverage therapies or therapeutic lifestyle changes that enhance one’s innate abilities to recover from illness and heal and maintain good health (5).

The integrative approach draws from both traditional and nontraditional approaches, including naturopathic, manual, functional, nutritional, and behavioral. The therapist is not the mechanic fixing a problem but rather the gardener tending and weeding the garden to help the healthy plants grow better. Integrative medicine reaffirms relationships between health care professionals and patients, focusing on caring for the whole person rather than a problem or disease. It makes use of all appropriate therapeutic approaches and interdisciplinary health care professionals to achieve optimal health and healing (6,7).

By providing patients nonpharmacological treatment modalities that reduce symptom burden and improve quality of life, physicians enable patients to have an active role in their care, which in turn improves the physician-patient relationship, the quality of cancer care, and the well-being of patients and their families (8).When we talk to patients about integrative approaches we must acknowledge their interest, explain that some modalities have no scientific merit and may not be safe, discuss the interaction of the mind, body, and spirit, consider comprehensive lifestyle assessment and possible changes, answer questions as honestly and completely as possible, and follow up. The follow-up visit can be the most helpful because patients have digested what you have told them during the first visit and then usually return with more questions.

The National Center for Complementary and Integrative Health (NCCIH) is the federal government’s lead agency for scientific research on complementary and alternative medicine (CAM. The NCCIH groups CAM practices into four domains, recognizing that

FIGURE 1. QUALITY OF LIFE CONCEPTUAL MODEL Characteristics of the Indvidual

Symptom Amplification

Biologic and Physiological Variables

Symptom Status

Psychological Supports

Personality Motivation

Functional Status

Social and Economic

Characteristics of the Environment

Value Preferences

General Health Perceptions

Overall Quality of Life

Social and Psychological Supports

Nonmedical Factors

From “Linking Clinical Variables with Health-Related Quality of Life: A Conceptual Model of Patient Outcomes,” by B. Wilson and P.D. Cleary, 1995, JAMA, 273, p.60.

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INTEGRATIVE PAIN AND SYMPTOM MANAGEMENT STRATEGIES FOR THE CANCER PATIENT

TABLE 1. COMPLEMENTARY AND ALTERNATIVE MEDICINES(9) Biologically Based Dietary supplements Botanicals/herbal products Probiotics

Manipulative and Body-based Spinal manipulation Massage therapy Movement therapies • Feldenkrais method • Alexander technique • Pilates • Rolfing structural integration • Trager psychophysical integration • Strain CounterStrain

Energy Medicine Magnet therapy Light therapy Qi gong Reiki Healing touch Ki Iki Jutsu Acupuncture

Mind-body Medicine Meditation Yoga Deep-breathing exercises Guided imagery Hypnotherapy Progressive relaxation Qi gong Tai chi

Whole Medical Systems Naturopathy Homeopathy Traditional Chinese medicine (TCM) Ayurveda

there may be some overlap, and also studies CAM whole medical systems, which cut across all domains (see Table 1) (9).

At MD Anderson our Integrative Medicine Group provides consultation and includes integrative medicine physicians and a variety of therapists and specialists in acupuncture, yoga, Tai Chi, mindfulness and other types of meditation, massage therapy, music therapy, and art therapy, among others. All of these modalities working together, rather than just opioids or nerve blocks, help the patient more than any one of them could alone.

PALLIATIVE CARE We are seeing an evolution in our thinking about palliative care.

Historically, palliative care was the domain of hospice care. But it

has come to encompass a focus on relief from symptoms, pain, and stress and improvements in the quality of life for any patient with serious illness and their family. Treatment teams include physicians, nurses, and other health care professionals who work with the patient’s primary care provider to provide an extra layer of support. It is appropriate for patients of any age and at any stage of a serious illness and can be provided concurrently with curative treatment. Palliative care delivers value to patients, providers, and the health care system by improving the quality and the efficiency of care, as well as cost reduction.

In the traditional approach to palliative care, the cancer patient receives anticancer treatment and is either cured or treated until a point at which the oncologist says there is nothing left to offer except hospice care. We have finally evolved into an approach in which anti-cancer treatments and palliative care run concurrent and parallel to each other.

We can cure sometimes, but we certainly can comfort patients and provide care always. I think that we have an obligation and commitment as health care professionals to do the best we can for every patient every time that we have an opportunity to do so. We should conduct our daily lives both professionally and personally with compassion for ourselves, for each other, for our patients, and for our society so that we can be the best that we can possibly be every waking moment, as persons and health care professionals. n Larry Driver, MD, is professor in the department of pain medicine and professor in the Section of Integrated Ethics at the University of Texas MD Anderson Cancer Center in Houston.

REFERENCES 1. Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA. 1995;273:60.

2. Svendsen KB, Andersen S, Arnason S, et al. Breakthrough pain in malignant and non-malignant diseases: a review of prevalence, characteristics, and mechanisms. Eur J Pain.

2005;9(2):195-206.

3. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years.

Ann Oncol. 2007;18(9):1437-1449.

4. Mao JJ, Armstrong K, Bowman MA, Xie SX, Kadakia R, Farrar JT. Symptom burden among cancer survivors: impact of age and comorbidity. J Am Board Fam Med. 2007;20)56):434-443.

5. Complementary, alternative, or integrative health: what’s in a name? National Center for Complementary and Integrative Health web site. September, 24, 2017. https://nccih.nih.gov/ about/ataglance. Accessed July 19, 2018.

6. Vision, mission and history. Academy of Integrative Health & Medicine web site. https://www.aihm.org/page/vision.

Accessed July 19, 2018.

7. Integrative Medicine Defined. American Board of Physician Specialties web site. https://www.abpsus.org/integrativemedicine-defined. Accessed July 19, 2018.

8. Deng G, Cassileth B. Complementary or alternative medicine in cancer care—myths and realities. Nat Rev Clin Oncol.

2013;10(11):656-664.

9. National Center for Complementary and Integrative Health.

Updated September, 24, 2017. https://nccih.nih.gov/about/ ataglance. Accessed July 19, 2018.

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CHEMOTHERAPY-INDUCED NEUROPATHY: IS THERE A PATH FORWARD?

Chemotherapy-induced Neuropathy: Is There a Path Forward?

By W. Clay Jackson, MD, DipTh

neuropathy in the oxaliplatin group and in 45% in the docetaxel group (2). CIPN is not just a nuisance side effect; it profoundly affects the quality of life for many cancer patients. Even worse, severe, acute CIPN may require chemotherapy dose reduction or cessation (1), which can allow the cancer to progress. If we can help prevent some of the negative outcomes of CIPN, we may unshackle our oncology colleagues to be more aggressive in the pursuit of the cancer.

A FIRE WITH MANY FUELS

Chemotherapy-induced peripheral neuropathy (CIPN) is a common condition that causes pain and nerve dysfunction as a result of cancer treatment. In a meta-analysis of more than 4,000 patients, the prevalence of CIPN was 68% when measured in the first month after chemotherapy, 60% at three months, and 30% at six months or more (1). However, with some classes of drugs CIPN is quite persistent. In a prospective questionnaire study of 174 patients receiving adjuvant oxaliplatin or docetaxel, chronic CIPN symptoms of tingling and numbness in the feet at one-year follow-up were present in 64% of patients without preexisting

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The precise pathophysiology underlying the symptoms of CIPN remains complex and appears to be medication-specific. Recent research has identified potential pathophysiological processes, including a disruption in microtubule-mediated axonal transport, axonal degeneration, dorsal root ganglion (DRG) damage, mitochondrial dysfunction, and release of inflammatory cytokines or central or peripheral sensitization (3). Different drug classes are associated with different mechanisms.

The most common offenders are the platinum agents and the taxanes, both of which tend to produce a sensory neuropathy. Acute peripheral neuropathy, while usually transient and self-limited, is seen in more than 90% of patients receiving oxaliplatin treatment (4). In a minority of patients, the neurotoxicity is long-lasting, with 10% of patients reporting residual symptoms two years post-treatment (5). Multiple mechanisms for hyperexcitability in the peripheral nervous system have been detected, including a prolongation of the open phase of voltage-gated sodium channels and an upregulation of the transient receptor potential (TRP) channels in the DRG (3).

Multiple mechanisms are thought to be responsible for taxane pathophysiology, including axonal degeneration, secondary demyelination; mitochondrial damage, and TRP upregulation in the DRG (3).

The vinca alkaloids are unique, in that they often cause sensory and motor neuropathy, the latter beginning early in treatment. Vincristine, for example, exhibits multiple effects including hypersensitivity and allodynia, caused by such changes as microtubular dysfunction, which ultimately leads to cell death, and a reduction in endomorphin-2, which produces an analgesic effect through its action on the mu-opioid receptors (3). Thalidomide, which was introduced for the treatment of multiple myeloma in 1999, is associated with sensory neuropathy caused by microvascular changes. We try to treat CIPN according to the particular chemotherapeutic agentâ&#x20AC;&#x2122;s pathophysiologic mechanism. For instance, we use opioids in many patients who develop peripheral neuropathy with vincristine, and we try a sodium channel blocker in patients treated with oxaliplatin.

Even some of the newer immunotherapy anti-neoplastic drugs can cause neuropathy. Targetable lesion therapy, such as that provided by the immunotherapy drug bortezomib, is a remarkable advance, but despite having very few side effects, bortezomib is associated with sensory neuropathy. Bortezomib exerts its mechanism of action by inhibiting the 26S ribosome subunit

CHEMOTHERAPY-INDUCED NEUROPATHY: IS THERE A PATH FORWARD?

and ultimately causing cell cycle arrest and apoptosis. However, this also causes microtubular polymerization disturbances, vacuolation of DRG mitochondria, increased tumor necrosis factor-alpha (TNF-Îą) and the production of reactive oxygen species (ROS) and activation of TRP channels, all of which have been implicated in the development of neuropathic pain (3).

ARE THERE RISK FACTORS FOR CIPN? Certain conditions seem to be a perfect storm for the development of CIPN. Research has shown that patients using taxane therapy with antecedent type 2 diabetes mellitus, regardless of control, have an increased risk of CIPN (6). This increase depends on the duration of diabetes, not control of blood sugar, with patients who had diabetes for more than five years having a 75% rate of peripheral sensory neuropathy.

Yet patients treated with taxane who have either no diabetes or diabetes for less than five years have approximately a

50% chance of developing neuropathy (6). Another study of genetic variants associated with vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia (ALL) detected an inherited polymorphism in the promoter region of the CEP72 gene that was associated with increased risk and severity of neuropathy (7).

Other conditions may be risk factors for CIPN or predict its response to treatment. A functional vitamin B12 deficiency in cancer patients, in which B12 levels are normal but metabolites such as methylmalonic acid or homocysteine are elevated, may cause increased rates of CIPN (8). When it comes to treatment, poor emotional well-being may predict a lack of response to treatment with duloxetine. In a study of patients with oxaliplatininduced painful CIPN who were randomized to receive duloxetine or placebo, higher baseline emotional functioning predicted duloxetine response (OR 4.036; P = .050), and duloxetine-treated patients with high baseline emotional functioning were more likely to experience pain reduction (P = .026) (9). This is counterintuitive to the (mistaken) belief that pain is relieved by antidepressants simply because depression is relieved.

HOW MIGHT WE PREVENT CIPN?

Thank you

to our Corporate Council Members and Member Discount Providers!

For more information, contact Whitney Oâ&#x20AC;&#x2122;Donnell at wodonnell@integrativepain.org or 209-533-9744 x117

Guilongtongluofang (GLT), a traditional Chinese medicine that was evaluated for the prevention of peripheral neurotoxicity induced by oxaliplatin in patients with colorectal cancer, showed a 30% decrease in peripheral neuropathy after two and six cycles of chemotherapy with no reduction in tumor response (10).

Goshajinkigan (GJG), a traditional Japanese medicine, showed a significantly lower incidence of grade 3 peripheral neuropathy in patients treated with oxaliplatin compared to the control group (P < .01) (11). In this study, the incidence of grade 3 peripheral neuropathy after 10 courses was 0% in the GJG group and 12% in the control group; after 20 courses, the incidence was 33% in the GJG group and 75% in the control group (11).

However, of 15 pharmacologic studies approved by the National Cancer Institute to assess the prevention and treatment of CIPN, only one study with duloxetine demonstrated therapeutic benefit (12-14). In the duloxetine trial, patients receiving 60 mg/day reported a mean decrease in average pain of 1.06 on the Brief Inventory-Short Form compared with those receiving placebo (9). Another Japanese trial compared duloxetine 40 mg daily with vitamin B12 1.5 mg/day, and obvious decreases in the mean visual analog scale (VAS) scores for numbness and pain were observed for the periods of duloxetine administration (15).

Agents tested that proved to be ineffective in randomized controlled trials included alpha-lipoic acid, calcium/magnesium, glutathione, topical ketamine, and amitriptyline (16-19). However, individual patients may respond to other agents, including gabapentinoids, sodium channel membrane modulators, opioids, topical agents, and certain vitamin supplements (14).

Since the clinical efficacy of pharmacological agents has been disappointing, patients often seek alternative treatment options for CIPN. Animal studies have shown that acetyl-Lcarnitine inhibits the development of paclitaxel- and oxaliplatinevoked neuropathy and prevented the deficits in mitochondrial function caused by these agents (20). Other agents, including phytochemicals, plant extracts, and herbal formulas have been shown to reduce vinca alkaloid- and platinum agent-induced peripheral neuropathy (21). Unfortunately, some alternative agents work so well they interfere with the tumor response because they disrupt the antineoplastic effect of the chemotherapy drug. However, unlike many alternative agents, GLT and GJG

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CHEMOTHERAPY-INDUCED NEUROPATHY: IS THERE A PATH FORWARD?

were studied in randomized, rigorous trials with relatively large numbers of patients and showed no differences in tumor response (10,11). Some nonpharmacologic therapies do hold promise. A study of acupuncture-like transcutaneous nerve stimulation (ALTENS) showed a significant improvement in Modified Total Neuropathy Scores (mTNS) at six months after treatment (P < .001) (22).

In summary, CIPN is common, but it generally improves for most patients with time. However, with certain drugs, such as oxaliplatin, it remains for years. CIPN is multifactorial and, based on its poor response to many allopathic pharmacologic treatments, nonpharmacological and alternative therapies may offer the best path forward. n

13.

14.

15.

REFERENCES 1.

Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain.

2014;155(12):2461-2470.

2. Ventzel L, Jensen AB, Jensen AR, Jensen TS, Finnerup NB. Chemotherapy-induced pain and neuropathy: a prospective study in patients treated with adjuvant oxaliplatin or docetaxel. Pain. 2016;157(3):560-568.

3. Addington J, Freimer M. Chemotherapy-induced peripheral neuropathy: an update on the current understanding.

F1000Res. 2016; 5(F1000 Faculty Rev):1466.

4. Cersosimo RJ. Oxaliplatin-associated neuropathy: a review.

Ann Pharmacother. 2005;39(1):128-135.

5. Land SR, Kopec JA, Cecchini RS, et al. Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol.

2007;25(16):2205-2211.

6. Kus T, Aktas G, Kalender ME, et al. Taxane-induced peripheral sensorial neuropathy in cancer patients is associated with duration of diabetes mellitus: a singlecenter retrospective study. Support Care Cancer.

2016;24(3):1175-1179.

7. Diouf B, Crews KR, Lew G, et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA. 2015;313(8):815-823.

8. Solomon LR. Functional vitamin B12 deficiency in advanced malignancy: implications for the management of neuropathy and neuropathic pain. Support Care Cancer.

2016;24(8):3489-3494.

9. Smith EM, Pang H, Ye C, et al. Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial – CALGB/ alliance 170601. Eur J Cancer Care (Engl). 2017;26(2).

10. Liu Y, Zhu G, Han L, Liu J, Ma T, Yu H. Clinical study on the prevention of oxaliplatin-induced neurotoxicity with guilongtongluofang: results of a randomized, double-blind, placebo-controlled trial. Evid Based Complement Alternat Med. 2013;2013:541217.

11. Nishioka M, Shimada M, Kurita N, et al. The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen. Int J Clin Oncol.

2011;16(4):322-327.

12. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with

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16.

17.

18.

19.

20.

21.

22.

chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309(13):1359-1367.

Majithia N, Temkin SM, Ruddy KJ, Beutler AS, Hershman DL, Loprinzi CL. National Cancer Institutesupported chemotherapy-induced peripheral neuropathy trials: outcomes and lessons. Support Care Cancer.

2016;24(3):1439-1447.

Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol.

2014;32(18):1941-1967.

Hirayama Y, Ishitani K, Sato Y, et al. Effect of duloxetine in Japanese patients with chemotherapy-induced peripheral neuropathy: a pilot randomized trial. Int J Clin Oncol.

2015;20(5):866-871.

Guo Y, Jones D, Palmer JL, et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer. 2014;22(5):1223-1231.

Loprinzi CL, Qin R, Dakhil SR, et al. Phase III randomized, placebo-controlled double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol.

2014;32(10):997-1005.

Leal AD, Qin R, Atherton PJ, et al. North Central Cancer Treatment Group/Alliance trial N08CA-the use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebocontrolled study. Cancer. 2014;120(12):1890-1897.

Gewandter JS, Mohile SG, Heckler CE, et al. A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study of 462 cancer survivors. Support Care Cancer. 2014;22(7):1807-1814.

Zheng H, Xiao WH, Bennett GJ. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol.

2011;232(2):154-161.

Cheng XL, Liu HQ, Wang Q, Huo JG, Wang X, Cao P. Chemotherapy-induced peripheral neurotoxicity and complementary and alternative medicines: progress and perspective. Front Pharmacol. 2015;6:234.

Wong R, Major P, Sagar S. Phase 2 study of acupuncture-like transcutaneous nerve stimulation for chemotherapy-induced peripheral neuropathy. Integr Cancer Ther. 2016;15(2): 153-164.

W. Clay Jackson, MD, DipTh, is the president of AIPM and is also 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. Dr. Jackson is the Associate Fellowship Director of Palliative Medicine at the University of Tennessee College of Medicine. He is board certified in family practice and hospice and palliative medicine, and is a frequent presenter at national conferences on the treatment of chronic pain. His work has been published in a number of leading academic journals and he is a recipient of numerous teaching honors.

THE SCIENCE, POLITICS, AND MEDICINE OF MEDICAL CANNABIS FOR CHRONIC PAIN

The Science, Politics, and Medicine of Medical Cannabis for Chronic Pain

By Mark S. Wallace, MD

Medicinal cannabis dates back over 5,000 years and has been used consistently for pain relief. References to its use are found in the medical literature in the mid-1800s but the early 20th century brought increasing scrutiny because of its psychoactive effects and recreational use. In 1942, against the advice of the American Medical Association, it was removed from the pharmacopoeia and made a schedule 1 drug. However, despite continuing controversy, preclinical studies continued, confirming its medicinal properties and analgesic effects.

Thirty-four states plus the District Columbia have legalized medicinal use and seven states plus the District of Columbia have legalized recreational use, but it remains illegal on the federal level. Possession limits range from 2 oz. to 24 oz. Some states only allow extracts, which contain a single cannabis component, but the leaf contains many active constituents and therefore may be more efficacious.

There is no federal regulatory oversight of the production and distribution of marijuana. This is left up to the states or even

the counties. Furthermore, laws vary widely from state to state defining indicated medical conditions, physician responsibilities, quantity of marijuana possession allowed, and oversight of dispensaries. No state requires a written prescription. Some states, such as California, provide physician guidelines. Patients must apply through their county of residence and their medical record must document diagnosis of a serious medical condition such as chronic pain or glaucoma, or any chronic medical condition that limits the ability to participate in life activities and/ or may cause serious harm.

CANNABIS-OPIOID INTERACTIONS Studies support the safety and efficacy of cannabis as an opioid-sparing substance. In a study that examined the association between a stateâ&#x20AC;&#x2122;s medical cannabis laws and its opioid analgesic overdose mortality rate, the only significant correlation with a reduction in overdoses was the enactment of a law allowing access (1). None of the other factors, which

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included the use of a prescription drug monitoring program, the ability for pharmacists to obtain patient information, an increase in state oversight of pain management clinics, or the state’s unemployment rate, was associated as strongly.

Another study showed that from 1997 to 2014 medical marijuana legalization was associated with a 23% reduction in hospitalizations related to opioid dependence or abuse and a 13% reduction in hospitalizations related to opioid overdose (2). There was no change in marijuana-related hospitalizations.

A retrospective survey of patients with chronic pain examined whether using medical cannabis changed their pattern of opioid use (3). Medical cannabis users reported a 64% decrease in opioid use, fewer side effects, and a 45% improvement in quality of life vs the opioid-alone users. Indeed, a study of chronic pain patients comparing those with controlled use of cannabis to non-users found no significant adverse events after one year (4).

Although cannabis abuse is prevalent, animal studies indicate it is not as robust as it is with heroin, cocaine, or nicotine (5).

Studies in both animals and humans show a preference for low-dose over high-dose cannabis, because low-doses produce more pleasant effects. With chronic cannabis use, tolerance develops to its physiological and subjective effects (6,7), but not to its analgesic effects. Physiologically, cannabis causes an increase in heart rate and a drop in blood pressure. Abrupt termination in habitual users results in withdrawal symptoms similar to those occurring with opioids, however, they are less likely to occur with lower dose consumption (8).

PHYSIOLOGY OF THE CANNABINOIDS The cannabinoids bind to two receptors: cannabinoid one (CB1) and cannabinoid two (CB2). Activation of the CB2 receptor, for example, produces a strong antiinflammatory effect by preventing release of mediators from peripheral inflammatory cells. Binding to CB1 receptors, which are located on the peripheral nerve terminals in the spinal dorsal horn, reduces the transmission of pain signals to the supraspinal regions such as the basolateral amygdala, periaqueductal gray, and rostroventral medulla and activates a descending inhibition of spinal dorsal horn transmission. This triple effect on the nervous system is in contrast to that seen with opioids, which is concentrated on the dorsal horn and the brain with no peripheral effects.

Cannabinoids refer to a variety of compounds.

Endocannabinoids include the endogenous cannabinoids; phytocannabinoids are derived from cannabis plants; and synthetic cannabinoids, which are very different from the natural substances, and can be more potent. The endocannabinoid system is implicated in processes such as pain, perception, mood, memory, and reward (9). Two endocannabinoids, anandamide and 2-arachidonyl glycerol or 2-AG, are made on demand and induced by stressors such as exercise, stress, and pain.

CLINICAL PHARMACOLOGY

Marijuana contains more than 500 compounds of which approximately 107 are referred to as the cannabinoids. Delta-9tetrahydrocannabinol (THC) is the main psychoactive cannabinoid in the leaf, which also includes varying proportions of cannabidiol (CBD), cannabinol (CBN), terpenes, and other substances.

Cannabinoids are extremely lipid soluble, which makes them poor oral agents.

The concentration of TCH in recreational marijuana has increased over time from an average of 3% in the 1980s For 34 years, Sierra Tucson has pioneered the integration of behavioral health care to 13% in 2009. CBD is the second most with traditional medical evaluation, providing evidence-based treatment therapies abundant compound, and the trend is that address the underlying causes of pain. toward production of marijuana with higher CBD concentrations.

Cannabinoids possess biphasic Our residential Pain Recovery Progam includes treatment for: effects. For THC alone, a dose of 5 mg • Post-Surgical Pain • Neck and Back Disorders produces a calming and analgesic • Central Nervous System Sensitivity, • Opioid-Induced Hyperalgesia effect; with a 10-15 mg dose, users including pain due to nervous system start developing paranoia. Higher doses, • Complex Regional Pain Syndrome trauma such as Fibromyalgia such as 20 to 25 mg, lead to psychosis, • Musculoskeletal and Rheumatic sedation, and increasing pain. With • And more Conditions low-dose CBD, users experience a feeling of alertness; increasing doses lead to increased sleep; and higher doses produce anxiolytic and antipsychotic effects.

Patients who take CBD say they don’t feel high; they feel a little calm and their pain is relieved. THC is the principal psychoactive compound and, as a partial CB1 and CB2 agonist, has only a weak affinity for these receptors. In addition, 11-hydroxy-THC is a metabolite with a strong psychoactive effect, which explains why patients have a delayed and prolonged euphoric effect. THC Where Change Begins® also has medicinal effects, including analgesic, antiinflammatory, antiemetic, antispasmodic, and sedative effects.

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| TH E PAI N P R AC TITIO N E R | FA L L 2018

THE SCIENCE, POLITICS, AND MEDICINE OF MEDICAL CANNABIS FOR CHRONIC PAIN

Community-based studies suggest that products that are high in THC but low in CBD are particularly hazardous for mental health (10). As a result, investigators are examining the potential of CBD as an effective, safe, and well-tolerated antipsychotic compound (11). The metabolism of THC can be slowed, thereby reducing the peak levels of 11-hydroxy-THC and reducing the psychoactive effects, by combining THC with CBD. CBD seems to have different medicinal properties than THC. It also has a very low affinity for the receptors, has very minimal to no psychoactive effect, and has a serotonin receptor agonism, which produces anxiolysis and some antidepressant effects. As an allosteric modulator of the delta opioid receptor, CBD may produce some mild opioid effects along with other properties, such as the anti-seizure effects being investigated in Dravet syndrome. Some caution is warranted, however, as CBD has an effect on the CYP 450 system and may affect the metabolism of anti-seizure drugs and perhaps warfarin, as well as plasma glucose levels.

ROUTE-DEPENDENT PHARMACOLOGY Leaf combustion releases all cannabinoids in the smoke, along with tar, whereas vaporization, which occurs at just below combustion levels, results in the selective release of cannabinoids and some terpenes.

One of the disadvantages of inhalation is a quick peak in venous blood levels within about five or 10 minutes after initiating smoking, but a relatively short duration of effect. Oral ingestion is quite different than inhalation. Because oral cannabis is lipid soluble, oral delivery is associated with a very erratic and delayed absorption and an unpredictable peak effect, but these can be increased with ingestion of a fatty meal. Because of this unpredictability, patients often prefer to ingest it at night because its effects last six to eight hours.

Sublingual delivery is an attractive route of administration.

Because cannabis is lipid soluble it penetrates the mucosa very rapidly. Absorption is more predictable with peak plasma levels similar to oral delivery but faster onset within 30 minutes to an hour and a duration of about four hours.

Our first analgesia study with inhaled cannabis was conducted in healthy volunteers using injection of the red chili pepper-derived capsaicin, which causes a bee-sting like pain that lasts five to 10 minutes. After the pain is gone, individuals are left with a sensitivity to touch. In a randomized, cross-over, blinded protocol, subjects were exposed to three doses of cannabis (2%, 4%, and 6%) and placebo, inhaling and holding for 10 seconds before exhaling, for a total of four times (12).

Five minutes after dosing with cannabis, subjects were stung with capsaicin on one arm, and 45 minutes after dosing they were stung on the other arm. At five minutes, the doses correlated with peak high feeling, but there was no effect of the cannabis in any dose on the pain. However, at 45 minutes, subjects started coming off of their high; the low dose had no effects over placebo, the medium dosed reduced their pain, and the high dose actually increased their pain.

We followed this with a study in patients with diabetic peripheral neuropathy pain using placebo and the three cannabis doses, and followed patients for four hours with sensory testing (13). Based on measurements of low and high blood levels of THC, we found an inverted U correlation with pain relief in which pain decreases as THC levels rise, but then starts moving in the opposite direction in a biphasic effect. The therapeutic window of pain relief occurred between 16 and 31 ng/ml of THC. These results also occurred in Phase II studies of nabiximols, a THC-CBD combination sublingual spray. The significance of this biphasic effect is important for patients to understand, as dispensaries generally assume strong doses for pain will be most effective.

Most of the analgesia studies are single site trials, with no large-scale randomized multicenter trials reported. The bulk of the placebo-controlled evidence is with the sublingual spray for neuropathic pain, although our clinical experience also indicates efficacy in arthritis, fibromyalgia, and low back pain.

CANNABIS AND DRIVING Concerns about the impact of medical marijuana use on driving ability prompted researchers to determine the relationship between medical marijuana laws and US traffic fatalities. Using data from the 1985-2014 Fatality Analysis Reporting System, they found that, on average, states with such laws had lower traffic fatality rates than those without medical marijuana laws (14). In our cannabis studies, there were few effects on motor and cognitive functioning and only a slight, but not significant, trend showing worsening of cognitive performance.

While cannabis alone seems to have little effect, the concern is that combining cannabis with alcohol can cause severe impairment. Indeed, recent evidence shows that mixing cannabis with alcohol produces a synergistic effect. My general rule is no driving for eight hours following ingestion, and no driving for four hours after transmucosal intake. Following inhalation, a two-hour wait before driving is generally sufficient.

Although I document in the patientâ&#x20AC;&#x2122;s medical record that there is no evidence of intoxication when I evaluate them in the clinic, that will not prevent a traffic citation if someone is stopped or is in a traffic accident and tests positive for THC.

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 3 |

25

THE SCIENCE, POLITICS, AND MEDICINE OF MEDICAL CANNABIS FOR CHRONIC PAIN

In our clinic at UCSD, we offer medical cannabis as an option to patients for whom conservative therapies have failed, before we resort to an opioid.

We provide authorization, either as a letter or using the Department of Public Health form.

Mark S. Wallace, MD, is professor of clinical anesthesiology and chair of the division of pain medicine in the department of anesthesiology at the University of California San Diego. He is the director of the UCSD Center for Pain Medicine. Under his leadership, the center was named a Clinical Center of Excellence in Pain Management in 2010 and 2014 by the American Pain Society. He is the recipient of numerous awards, including the Leonard Tow Humanism in Medicine Award. He is highly regarded as a teacher and a physician and has received numerous awards as a top doctor in San Diego.

REFERENCES 1.

2.

3.

4.

PATIENT SELECTION AND MONITORING Controversies exist about whether patient selection criteria for medical cannabis should be as strict as they are for opioids. In particular, should urine drug testing be performed? My feeling is that we should use urine drug testing as a way to document that patients show no signs of intoxication even with a positive test for THC. However, in my practice if patients test positive for opioids they will have to make a choice, because I generally will not prescribe both. The two substances are generally safe to combine, and we can take advantage of this synergistic effect to ultimately reduce or eliminate the opioid; however, I do not believe opioids are effective for chronic pain. If patients are using opioids for chronic pain I wean them first; however, I may introduce the cannabis sooner if patients are compliant and experiencing severe withdrawal symptoms.

In our clinic at UCSD, we offer medical cannabis as an option to patients for whom conservative therapies have failed, before we resort to an opioid. We provide authorization, either as a letter or using the Department of Public Health form. I refer patients to a Doctor of Naturopathic Medicine for consultation on dosing and delivery methods and guidance on what to ask for from the dispensary, and then they follow up with me.

One of the challenges for patients is the lack of insurance coverage for cannabis, yet many patients are willing to pay out of pocket. Another challenge is ensuring patients come in for regular follow up, at least initially. Chronic pain patients switched to cannabis generally reduce their health care utilization and may return only yearly to renew their authorization. It is important to emphasize the need for more frequent follow-up. Ultimately, the challenge for providers is understanding the various types of cannabis, its dosing, and its interactions with other medications.

We hope to perform a national survey of educational needs and develop an educational program that can be integrated into medical schoolsâ&#x20AC;&#x2122; curricula. n

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| TH E PAI N P R AC TITIO N E R | FA L L 2018

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668-1673.

Shi Y. Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever. Drug Alcohol Depend.

2017;173:144-150.

Boehnke KR, Kitinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. J Pain. 2016;17(6):739-744.

Ware MA, Wang T, Shapiro S, Collet JP, COMPASS study team. Cannabis for the management of pain: Assessment of Safety Study (COMPASS). J Pain. 2015;16(12):1233-1242.

Cooper ZD, Haney M. Actions of delta-9tetrahydrocannabinol in cannabis: relation to use, abuse, dependence. Int Rev Psychiatry. 2009;21(2):104-112.

Benowitz NL, Jones RT. Cardiovascular and metabolic considerations in prolonged cannabinoid administration in man. J Clin Pharmacol. 1981;21(8-9 Suppl):214S-223S. Hart CL, Haney M, Ward AS, Fischman MW, Foltin RW. Effects of oral THC maintenance on smoked marijuana self-administration. Drug Alcohol Depend. 2002; 67(3):309-309.

Haney M, Hart CL, Vosburg SK, et al. Marijuana withdrawal in humans: effects of oral THCor divalproex.

Neuropsychopharmacology. 2004;29(1):158-170.

Di Marzo V, Piscitelli F, Mechoulam R. Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes. Handb Exp Pharmacol. 2011; 203:75â&#x20AC;&#x201C;104.

Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampaldependent memory impairment. J Psychopharmacol.

2013;27(1):19-27.

Iseger TA, Bossong MG. A systematic review of the antipsychotic properties of cannabidiol in humans.

Schizophr Res. 2015;162(103):153-161.

Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology.

107(5):785-796, 2007.

Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Effect of inhaled cannabis on painful diabetic neuropathy.

J Pain. 2015;16(7):616-627.

Santaella-Tenorio J, Mauro CM, Wall MM, et al. US traffic fatalities, 1985-2014, and their relationship to medical marijuana laws. Am J Public Health. 2017;107(2):336-342.

THE USE OF KETAMINE IN SICKLE CELL DISEASE TO REDUCE PAIN AND OPIOID DOSAGE

The Use of Ketamine in Sickle Cell Disease to Reduce Pain and Opioid Dosage Case Report and Literature Review

By Arthur S. Hernandez, MD

CASE REPORT RH is a 32-year-old African-American man who suffers from sickle cell disease (SCD). The patient has suffered from severe chronic pain secondary to SCD vaso-occlusive episodes since age 10. He has been bedridden most of his life and hospitalized at least twice each month. He describes the pain as very severe (VAS score at least 10) and localized to his joints and along the right lower thorax. He attempts to reduce the pain by striking his thorax repeatedly with his fist.

During hospitalizations, he has generally been given IV hydromorphone or morphine at very high doses. During a recent hospitalization he was treated with IV hydromorphone at 4 mg q 10 minutes, which could cause respiratory arrest in an opioid-naïve patient. Even with this dose of hydromorphone, he still complained of chronic and severe pain. His life consisted of constant pain and inability to perform simple self-care techniques such as bathing or eating because of the intensity of the pain. He was unable to sit for a haircut, and his appearance became disheveled.

The patient suffered from severe insomnia whenever a vasoocclusive episode occurred. He would lie awake all night, tossing and turning and begging his mother, his caretaker, for additional opioids. His mother would also stay awake all night taking care of him, and then be incapable of performing her duties the next morning at her employment. These frequent episodes caused significant disruption in the family. Because of the chronic pain, insomnia, and disruption in his family, the patient suffered from intense depression.

PROCEDURE

Ketamine, an NMDA (N-methyl-D-aspartate) receptor antagonist, has been used as a primary analgesic for various neuropathic pain syndromes. The use of ketamine to reduce pain associated with vaso-occlusive episodes in sickle cell disease remains infrequently studied. A Medline search for “sickle cell disease” and “ketamine infusion” resulted in only 10 references.

The dosage of ketamine infusions remains quite variable in the literature. Doses recommended in the literature vary from .5 mg/kg over 45 minutes x 3 infusions, to a nonspecific “low dose infusion.” Usually “low dose infusion” is synonymous with subanesthetic infusion. The dosage of ketamine required to produce an alteration of CNS sensitivity to pain varies greatly from individual to individual.

Continuous monitoring of blood pressure, pulse rate, respiratory rate, and pO2 is required for maximum patient safety and is required by the American Society of Anesthesiologists. To minimize the occurrence of dissociative central nervous system events, the patient should be in a quiet room and accompanied by a trusted relative. The length of the infusion has been reported as short as 45 minutes and as long as four hours and may be given by slow continuous infusion or repeat boluses.

After informed consent, the patient was taken into an exam room specially prepared for ketamine infusions. The patient was placed in a hospital bed and an intravenous line was started in the left external jugular vein, as no peripheral IV access could be obtained. Monitors were applied for recording of blood pressure, pulse rate, respiratory rate, and pO2. In addition to an anesthesiologist in attendance, an LVN was also present. Ketamine 500 mg was added to a 250 ml bag of normal saline, i.e., a 2 mg/ ml concentration. A pump was used to administer the ketamine infusion. Multiple infusions, each on different days, were performed as noted below and the amount of ketamine given was also noted.

The first infusion lasted 1.2 hours and each subsequent infusion was of longer duration (see Table). During each infusion, the patient was sedated with the ability to follow commands given by his mother. The patient slept during each infusion as if recovering from exhaustion. He denied any pain during the infusion, and he recalled vivid, pleasant dreams. Each infusion was terminated by slowly reducing the rate of infusion. The patient was observed for 1 full hour after each infusion was terminated.

RESULTS The use of a continuous ketamine infusion for this patient resulted in a variable reduction of pain after several infusions. The patient’s ability to function was significantly improved after each infusion, even when the VAS score remained unchanged. His pain slowly THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 3 |

27

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TH E PAIPain N PManagement R AC TITIOisNnot E Raffiliated L 2018

THE USE OF KETAMINE IN SICKLE CELL DISEASE TO REDUCE PAIN AND OPIOID DOSAGE

decreased over a period of one month. His functional capacity was dramatically increased. He was no longer bedridden and he was no longer hospitalized during the infusions. He is now able to leave his house on a regular basis and perform simple selfcare activities such as bathing, sitting quietly in one place for an extended period of time, and walking more than just a few steps.

Concurrently, his opioid load was reduced by 25% daily.

It should be noted that after October 21, 2016, the patientâ&#x20AC;&#x2122;s pain seemed much more difficult to control. At that time that the patient had an infected open wound to his right lower extremity, which had been treated with hyperbaric oxygen with less than satisfactory results.

The patient has remained significantly improved compared to his pre-ketamine state. He continues to have a reduced opioid daily dose and remains much more active than he was prior to the ketamine. He has expressed a desire to continue receiving ketamine infusions during severe vaso-occlusive episodes. He uses nasal ketamine daily to control pain exacerbations. Most significantly, he has been able to remain out of inpatient hospital visits or emergency room visits.

DISCUSSION The use of ketamine infusions has been advocated for various neuropathic states (1-3). In this paper, we discuss the successful use of ketamine in sickle cell disease. As documented in other medical literature (4-7) regarding the use of a ketamine infusion for the severe pain of a sickle cell crisis, the patient presented here noticed a reduction in pain, an increase in function, and an overall sense of well-being. He was able to avoid repeated visits to the emergency room or repeated inpatient admissions because of severe pain. The patient noted his usual pain medications were more effective after each infusion. He has required a monthly infusion to maintain his pain level at a tolerable level.

The use of ketamine has not become widespread for sickle cell patients (3,4,8,9). I propose that a large double-blind study of the pain relief in sickle cell patients using ketamine is warranted. n

Arthur S. Hernandez, MD, graduated from the USC School of Medicine in 1971. He completed Board Certification in Family Practice in 1974 and finished an Anesthesiology Residency in 1980.

He is an Advanced Diplomate of the AIPM.

REFERENCES 1. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol.

2014 Feb;77(2):357-367.

2. Zorumski CF, Nagele P, Mennerick S, Conway CR. Treatment-resistant major depression: rationale for NMDA receptors as targets and nitrous oxide as therapy.

Front Psychiatry. 2015;6:172.

3. Visser E, Schug SA. The role of ketamine in pain management.

Biomed Pharmacother. 2006;60(7):341-348.

4. Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014 Feb;47(2):334-340.

5. Meals CG, Mullican BD, Shaffer CM, Dangerfield PF, Ramirez, RP. Ketamine infusion for sickle cell crisis pain in an adult.

J Pain Symptom Manage. 2011 Sep;42(3):E7-E9.

6. Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014 May;93(5):769-771.

7. Gowhari M, Chu A, Golembiewski J, Molokie RE. Low-dose ketamine infusion in adult patients with sickle cell disease Impact on management of acute painful episodes. Blood.

2013; 122(21):2249.

8. Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother. 2013;27(2):150-154.

9. Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain.

2010;26(2):163-167.

TABLE. KETAMINE INFUSION RESULTS Infusion

Infusion Period

Total amount

mg/kg/hr

VAS start

VAS end

7/07/16

1.2 hr

115 mg

1.3 mg/kg/hr

10

8

7/08/16

3.7 hrs

1000 mg

3.6 mg/kg/hr

10

7

7/11/16

3.0 hrs

1000 mg

4.4 mg/kg/hr

7

3

7/28/16

3.0 hrs

500 mg

2.2 mg/kg/h

10

7

10/21/16

2.6 hrs

260 mg

1.4 mg/kg/hr

8

2

11/25/16

2.0 hrs

300 mg

2.0 mg/kg/hr

9

5

12/14/16

3.2 hrs

300 mg

1.25 mg/kg/hr

10

7

12/19/16

2.2 hrs

280 mg

1.6 mg/kg/hr

10

10

12/22/16

3.1 hrs

400 mg

1.7 mg/kg/hr

8

8

12/23/16

3.3 hrs

500 mg

2.1 mg/kg/hr

9

9

12/30/16

3.5 hrs

600 mg

2.3 mg/kg/hr

9

6

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 3 |

29

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| TH E PAI N P R AC TITIO N E R | FA L L 2018

Newand

Improved MEMBERSHIP BENEFITS

Pain Outcome Profile Kit for Your Practice A FREE Benefit of AIPM Membership

P a in o ut c o m e p ro f il e

P ain O utco m es P ro f ile

Scoring Instrument

patie nt name patie nt id#

date

Mobility

(______) + (______) + (______) + (______) = ______ x 100 = ______________ Item 7

Mobility

Item 11

Item 16

Item 20

Vitality

Item 12

Item 17

Item 21

Item 9

Physical Index

% MOB

Negative Affect

Item 13

Item 18

% ADL

% VIT

3

Percent of Total Score

Physical Index

(______) + (______) + (______) + (______) + (______) = ______ x 100 = ______________ Item 6

Item 10

Item 15

Item 19

Item 22

50

Percent of Total Score

(______) + (10 -___) = ______ x 100 = ______________ Item 14

Affective Index

% NA

100

9

90

PERCENTAGE OF TOTAL SCORE

10

8 7 6 5 4 3 2 1 0

% Fear

20

2

Percent of Total Score

Affective Index

pop

Pain Outc ome s

80

Pro f ile

Cumulative Pa

70 60 50

tient Scoring Re

patie nt name

40 30

cord

patie nt id#

20

date

10

Mobility

0 Mobility

ADL’s

Vitality

Mobility

SCALE SCOR ING

Average Pain

Item 23

(______) + (______) = ______ = ______

(optional)

PAIN INTENSITY

Percent of Total Score

30

(______) + (______) + (______) = ______ = ______

(optional)

Current Pain

Percent of Total Score

40

30 – (______ + ______ + ______) = ______ x 100 = ______________

Fear

l Instruction Manua

40

(______) + (______) + (______) + (______) = ______ x 100 = ______________ Item 8

SCALE SCORING

pop

pop

Negative Affect

(______) + ( ______) +

Fear ItemPhysical Affective 7 11 Index Item Index

Item 20

______ x 100 = ______________ 40

Percent of Total

Score

(______) + ( ______) = ______ x Item 12 100 = ____________ Item 17 Item 21 __ 40 Percent of Total 30 – (______ + Score ______ + ______) = Item 9 ______ x 100 = ______ Item 13 ________ Item 18 30

Physical Index

(______) + ( ______) +

(optional)

Fear

Item 16

Item 8

Vitality

Negative Affect

(______) + ( ______) =

(______) + ( ______) +

% MOB

% ADL

(______) + ( ______) + Item 6

Item 10

Percent of Total

3

Item 15

Item 19

Physical Index

(______) = ______ x 100 = ______ ________ Item 22 50

(______) + (10 ___) = Item 14

Affective Index

(______) + ( ______) =

(optional)

% NA

Score

(______) = ______ = ______ % VIT

(______) + ( ______) +

% Fear

10

Item 23

Percent of Total

Score

______ x 100 = ______ ________ 20 Percent of Total

Score

______ = ______ 2

Affective Index

100

E OF TOTA L SCOR E

9

7

90 80

70

6

60

5

50

4

PERCE NTAG

PAIN INTEN SITY

8

3

2 1 0 Current Pain

Average Pain

40

30 20 10 0 Mobility

ADL’s

Vitality

Negative Affect

Fear

Physical Index

Affective Index

The Pain Outcome Profile (POP) is a 23-item questionnaire that utilizes 11-point (0 to 10) Numerical Rating Scales to assess a number of relevant dimensions in the pain patient’s experience.

Easy to use, the POP assesses three domains of a patient’s pain experience: • Pain perception • Perceived physical impairment due to pain • Several aspects of emotional functioning

AIPM members receive a digital version of the POP Kit for FREE so that they can print as many as they want for use in their own pain practice.

Not a member yet? See all the member benefits and join here: www.integrativepainmanagement.org/page/Membership THE PAIN PRACTITIONER | V O L U M E 2 8 , N U M B E R 3 | 31

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