The Pain Practitioner - Chronic Abdominal Pain by Academy of Integrative Pain Management

american academy of pain management

Integrative Pain Management for Optimal Patient Care

The Pain Practitioner Spring Winter 2015 2013

GUT RELATED DISORDERS

integrative approach to chronic abdominal pain ALSO INSIDE Inflammatory Bowel Disease Opioid Malabsorption Fire in the Belly Update on CRPS And More

pain practitioner Volume 25, number 1

American Academy of Pain Management

Table of contents

ACADEMY BOARD OF DIRECTORS

www.aapainmanage.org

President Robert A. Bonakdar, MD, FAAFP Vice President Christian D. GonzĂĄlez, MD Past President Alfred V. Anderson, MD, DC Secretary Thomas N. Watson, DPT, MEd Treasurer Jackie S. Rowles, CRNA, MBA, FAAPM Directors-at-Large Kevin T. Galloway, BSN, MHA, Colonel, US Army (Retired) Gerald Q. Greenfield, Jr., MD W. Clay Jackson, MD, DipTh Joanna Katzman, MD, MSPH Michael Kurisu, DO, ABIHM Arthur S. Roberts, DDS, MD

Editorâ&#x20AC;&#x2122;s Corner 4 A New Year and a New Start

By Bob Twillman, PhD, FAPM, Executive Director

Academy News 6 Newly Credentialed Members 15 You Should Know...

Executive Director Emeritus and Director of Board Development Lennie Duensing, MEd

ACADEMY STAFF AND CONSULTANTS

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Page 34

Features 18 Integrative Approach to Chronic Abdominal Pain and Irritable Bowel Syndrome By Robert A. Bonakdar, MD, FAAFP

22 Considerations in Diagnosing and Treating Pain in Patients with Inflammatory Bowel Disease By Divya Keerthy and Eva Szigethy MD, PhD

28 Opioid Malabsorption: A Cause of Pain Treatment Failure By Forest Tennant, MD, DrPH 34 Complex Regional Pain Syndrome: From Diagnosis to Treatment By Philip Getson, DO From the Clinic 40 Project ECHO Chronic Pain and Headache TeleECHO Clinic Case Study By Christine Rhodes, MS

42 Diabetic Peripheral Neuropathy: An Overview By Jessica DiLeo, PharmD 44 Second Look on a Patient with Pain Reveals Childhood Sexual Abuse By Erika Moody, MD

Commentary 46 Fire in the Belly: Gut Health, Inflammation and Chronic Pain By Nancy Cotter, MD Cover sciencesource / False-color x-ray of the abdomen

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Subscribe to The Pain Practitioner!

If you are not a member, you can still get this quarterly publication for just $50/year. Send your check to the American Academy of Pain Management, 975 Morning Star Drive, Ste. A, Sonora, CA 95370

Executive Director and Director of Advocacy and Policy Robert Twillman, PhD, FAPM Director of Education and Credentialing Debra Nelson-Hogan Director of Sales, Marketing and Events Jillian Manley Director of the State Pain Policy Advocacy Network (SPPAN) Amy Goldstein, MSW Researcher and Policy Analyst and Editor of Currents: The Monthly Index to Pain Management Katie Duensing, JD Website and Database Director Eric Blosch Account Managers Rosemary LeMay, Staci Criswell, and Sheila Miller Accounting Director Kristin Taylor Education Manager Cathleen Coneghen Office Manager Karen Hebert

THE PAIN PRACTItiONER STAFF AND CONSULTANTS Editor-in-Chief Debra Nelson-Hogan Advertising and Sales Jillian Manley, Sheila Miller Managing Editor Cathleen Coneghen Clinical Editor Christine Rhodes, MS Art Director Amy Bothwell Copy Editor Rosemary Hope The Pain Practitioner is published by the American Academy of Pain Management, 975 Morning Star Drive, Ste., A, Sonora, CA 95370, Phone 209-533-9744, Fax 209-533-9750, Email: aapm@ aapainmanage.org, website: www. aapainmanage.org. Copyright 2007 American Academy of Pain Management. All rights reserved. Send correspondance to Debra Nelson-Hogan at dhogan@aapainmanage. org. Contact Sheila Miller at 209-533-9744 regarding advertising opportunities, media kits, and prices. The Pain Practitioner is published by the American Academy of 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 American Academy of 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 expresed or implied, of a product or service.

EDITOR’S CORNER

A New Year and a New Start BY ROBERT T WILL M AN, PHD, FAPM, E XECU TI V E DIREC TOR

For the Academy, the start of 2015 really is the start of more than just a new year—it’s also the start of a new era, as I begin my tenure as Executive Director. It’s appropriate, I think, for us to use the start of a new year and new era as a cue to take stock of where we are and where we want to go as an organization. To that end, let me tell you about a couple of initiatives we are undertaking to enhance the organization and to chart our path forward from here. Enhancing our Membership

Those of you who have renewed your Academy memberships in the past few months may have noticed that we have changed the structure of our membership dues. Since the Academy’s inception, membership dues have been the same for everyone, reflecting the Academy’s treatment of all clinicians as equal partners in caring for people with pain. However, we also have recognized that our membership was skewed, with approximately 60% of our members holding MD or DO degrees. One theory for why this skew exists is that clinicians with lower incomes might find the flat membership dues to be relatively expensive, preventing them from joining the Academy. After lengthy debate, the Academy’s Board of Directors voted to implement a tiered membership dues structure, based on income. This was a difficult decision, as the Board recognized that it was risking a bit of a backlash from those whose membership dues would increase as a result. In the end, the Board felt that the increases should be affordable for those so affected, and that the lower dues now available would encourage greater participation from clinicians with lower incomes. Additionally, the Board authorized a new (free!) Student Member category as a way to encourage students to become involved with the Academy, with the hope that they will join as full dues-paying members when they graduate. It’s vital to the Academy’s current well-being and future growth that you, as members, do three things: 1) Renew your membership at the appropriate level when your renewal date comes around; 2) Recruit fellow clinicians who may have been reluctant to join because of cost; and 3) Encourage your students to join as Student Members. Filling out our membership ranks with a greater number and variety of clinicians can only enhance the programs and services that the Academy can offer you, add to our power to advocate for the right kind of pain policy, and serve to 4

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further advance the integrative pain management model that we know is the best way to care for people with pain. Tell Us What You Want And Need

In a few weeks, you will be receiving an email asking you to complete an online member survey. Periodically, we ask members how we’re doing with respect to meeting your needs, and what more we could be offering to serve you better. With the start of a new year and a new era, it seems to me that this is a good time to ask those key questions. We’re going to be asking about all of the programs we currently offer, trying to get a sense for which ones you think are most important; which ones, if any, you think might not be necessary; and what new services you would find valuable. When the survey comes, please take the time to complete it, and to give us your honest opinions—and when the survey gives you the opportunity to express your opinion in your own words, please do so. The Academy is your organization, and it really should serve your needs. As Academy staff (and, for me, as a former fellow clinician), we can make some educated guesses about programming, but when you tell us what you need, we move from acting on the basis of a guess to acting on the basis of an expressed need, and everyone ends up being more satisfied. Welcome to Our New Board Members

Finally, let me add a word of welcome to two new members of our Board of Directors. As you will see elsewhere in this edition, Kevin Galloway and Clay Jackson have joined the Board for new three-year terms. Those of you who have attended the past few Annual Clinical Meetings may have had the opportunity to see presentations by these distinguished clinicians, or to meet them during networking opportunities, and I’m confident that if you took advantage of those opportunities, you came away just as impressed as I did. They bring valuable experiences and viewpoints to the Board, and I know their presence will help move the Academy forward, as the premier organization for all clinicians who care for people with pain.

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Newly Credentialed Members The academy’s new ADVANCED DIPLOMATE credentiaL During the Annual Meeting last September in Phoenix, 28 candidates took the Advanced Credentialed Pain Practitioner exam and participated in the Objective Structured Clinical Examination (OSCE). Of those, 21 passed the examination and have earned the designation of Advanced Diplomate, American Academy of Pain Management (ADAAPM). In a survey following the examination, the majority of participants indicated the test was challenging, but fair. Many of them, however, had comments about the ability to access the reference articles suggested in the Curriculum for the Advanced Diploma in Pain Management (the Curriculum) without unrestricted access to PubMed. These high-quality references can be obtained via interlibrary loan from a local public library or they can be purchased from the publisher. We have also received suggestions about expanding certain areas of the Curriculum. The Curriculum was designed to provide a compendium of objectives that the Academy Credentialing Committee, as well as those national experts who contributed to the Curriculum, felt were necessary to guide the educational development of a clinician who practiced general noninterventional pain management. Although we will be continuing to make minor changes in the process, the Academy is pleased with the outcomes from our “freshman” class. One of the candidates, C.P. Dunbar, MD, said, “If I had not passed the ACPP it would have been OK. I just wanted to learn. I did use the Curriculum. I love it.” Joseph Hayes, MD, also stated “the test was formidable and spot on. The ACPP is not an easy credential to get. You really have to work for it.” We congratulate the new Advanced Diplomates.

ADVANCED DIPLOMATE Ayaz Mahmood Khan, MD, MS, ABDA, MBA, DAAPM, ADAAPM, Diplomate ABAM, is the

director of Pain Management of Williamsport, LLC, Williamsport, Pennsylvania. He has a passion for treating patients suffering from chronic pain with compassion and empathy. With training in anesthesiology, orthopedics, and adult psychology, he takes a multidisciplinary approach to pain management with emphasis on interventional pain management, physiotherapy, chiropractic treatment, and psychological approaches to manage chronic pain. 6

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Peter Hedrick, DO, MS, DAAHPM, DAAPM, is the medical director of

the Palliative Care Service and director of pain services at Chandler Regional Hospital in Chandler, Arizona. He is also the past chair and current co-chair of the Bioethics Committee at Mercy Gilbert and Chandler Regional Medical Centers. Dr. Hedrick is board certified in palliative medicine and family medicine. Joseph T. Hayes, MD MPH, MBA, is the medical director of the Hayes Center for Pain and Addiction at the Mercy Suburban Medical Center in East Norriton, Pennsylvania. He also manages an integrated pain and addiction practice in the North Philadelphia area. He is board-certified in occupational and preventive medicine, addiction medicine and certified by the American Board of Medical Acupuncture. He is also Diplomate of the Medical Board of Disability Evaluating Physicians. Dr. Hayes received a commission from the Governor of New Jersey to serve on the Governor’s Council on Physical Fitness and the State Noise Control Council. He was also awarded a special recognition from Horizon Blue Cross/Blue Shield for community service. Pamela Squire, MD, CCFP, FCFP, dip ISAM, CPE, is a clinical assistant professor in the

department of family medicine at the University of British Columbia, Vancouver. In 2008, she was given the inaugural Dr. Helen Hays award for excellence in pain management and in 2010 she was given the Academic Pain Educator of the Year award by the American Society of Pain Educators. Hatem Fikry A. Hamed, MD, is

the medical director of Urgent Care of Slidell, Louisiana. During his residency trainings Dr. Hamed developed his interest in treating patients with chronic pain and addiction. Dr. Hamed is licensed to prescribe Suboxone for patients with opioid addiction and he is preparing for the American Board of Addiction Medicine. It is his combined experience in addiction and chronic pain management that made Dr. Hamed a strong advocate for using a multidisciplinary approach in treating patients with chronic pain. Continued

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Continued Rodney B. Gilbert, MD, practices in Columbia, Tennessee. He trained in anesthesiology as a resident at Wake Forest University Hospitals. During that time his interest in pain management was kindled during a final one-year-concentration in studying and treating chronic pain. Dr. Gilbert practiced chronic pain management for three years, and continues to treat acute and chronic pain as a practicing anesthesiologist on a daily basis. He has a continuing interest in patient care and relieving suffering. He also has an interest in complementary and alternative medicine. John Burgess, DO, is

director of Shenandoah Preventive Medicine, Inc., in Martinsburg, West Virginia. He has incorporated a wide variety of pain modalities in an integrative practice for 30 years. Dr. Burgessâ&#x20AC;&#x2122; board certifications include anti-aging and regenerative medicine, integrative pain management, acupuncture, neuromuscular therapy, and natural therapeutics. Anson Lam, MD, is

the clinical chair of the emergency department at St. Jude Medical Center in Fullerton, California, and has practiced emergency medicine for more than 20 years. He is board certified in emergency medicine and neurocritical care. Dr. Lam is also a clinical research investigator, a fellow of American College of Emergency Physicians, and has been published in the Journal of Dermatological Surgery and Oncology. Sandra L. Durham, MD, has been the owner and medical director of The Lighthouse Pain Clinic in Hoover, Alabama, since 2000. She completed a residency in internal medicine and has practiced pain management exclusively since 1994. She has been a Diplomate of the AAPM since 1993. She has been a speaker for local, state, national, and international societies. Kent D. Vosler, DO, works

in the pain management and physical medicine department at Arrowhead Health Centers in Glendale, Arizona. He is board certified in family practice and osteopathic manipulative treatment, and is a member of the American Osteopathic Association and the Arizona Osteopathic Medical Association.

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C.P. Dunbar, MD, FAAFP, AAHPM, DAAPM, MRO, has a practice supervising four mid-

level practitioners in Batesburg-Leesville, South Carolina. He has served as Assistant Medical Director for Ascension Hospice and as Medical Director for AgapĂŠ Hospice. He is board certified as a family practitioner, and is also board certified by the American Academy of Hospice and Palliative Medicine. He has lectured on various topics including end-of-life and pain management. Bill W. Haney, MD, is

the founder and owner of East Louisville Interventional Pain Specialists, in Louisville, Kentucky, and has more than 28 years of practice experience in anesthesiology and pain management. Dr. Haney is board certified by the National Board of Medical Examiners, the American Board of Anesthesiology, the American Board of Pain Medicine, and the American Board of Interventional Pain Physicians. In addition, he is a Fellow of Interventional Pain Practice: World Institute of Pain. Dr. Haney is an active member of several general and pain medicine organizations and maintains staff privileges at major Louisville, Kentucky, hospitals. Sady Ribeiro, MD, is

a Diplomate of the American Board of Interventional Pain Physicians, American Board of Pain Medicine, and the American Board of Physical Medicine and Rehabilitation. He is also a Diplomate in Headache Medicine: The United Council for Neurological Subspecialties and the American Board of Addiction Medicine. He is a Fellow of Interventional Pain Practice: World Institute of Pain. Graeme A. Browne, CAPT MC(FS) USN. MD, DDS, MSc, practices emergency medicine

with the Mayo Clinic Health Services in Minnesota. He is board certified in emergency medicine, disaster medicine, oral and maxillofacial surgery, and family medicine. Dr. Browne is a member of the American Association of Physician Specialists and the American College of Emergency Physicians, and served in a combat role in Operation Iraqi Freedom. Aram Mardian, MD, is a family medicine doctor in Phoenix,

Arizona, and is affiliated with Phoenix Veterans Affairs Health Care System. He received his medical degree from the University of Arizona College of Medicine and has been

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in practice for 12 years. He is one of 12 doctors at Phoenix Veterans Affairs Health Care System who specializes in family medicine.

Alexandria before he moved to Dayton, Ohio, to join Dayton Pain Center in August 2012. He has published many articles and authored book chapters in pain and neurosurgery.

George Dutkewych, MD, is currently at the Delaware Chronic Pain Management and Detox Center in Wilmington, Delaware. He is board certified in general surgery. After 30 years of surgical practice, Dr. Dutkewych switched to noninterventional pain management.

DIPLOMATE

Eric Ehlenberger, MD, is

Director of Accurate Clinic in Kenner, Louisiana, a suburb of New Orleans. Accurate Clinic offers an integrative pain management program, an opioid substance use disorder program, and is in the process of opening an intensive outpatient program. Dr. Ehlenberger is board certified in emergency medicine and addiction medicine. Gladstone C. McDowell II, MD, is the Medical Director of Integrated Pain Solutions in Columbus, Ohio. He is on the Board of the Texas Medical Institute of Technology, Community Emergency Health Initiative, and the Ohio Clinical Advisory Board of the National Multiple Sclerosis Association. Dr. McDowell has held faculty appointments at the National Patient Safety Congress meetings and National Institute for Heatlhcare Fraud. He has been the Primary Pain Consultant for Careleaders and TMIT. He recently taught at the FBI Health Care Fraud Managers Meeting and served on the 2007 and 2011 International Polyanalgesic Consensus Panel. He is a member of the American Society of Regional Anesthesia and the North American Neuromodulation Society. Dr. McDowellâ&#x20AC;&#x2122;s research is published in peer-reviewed medical journals and he has authored book chapters regarding urology and anesthesiology. Beata Grochowska, MD, is

a board-certified anesthesiologist at Interventional Spine and Pain Management in Atlanta, Georgia. Paul Thomas Sutera, MD, is an anesthesiologist at Silvercreek medical Associates, PC in Bullhead City, Arizona. Jan Jack Gouda, MD, has

extensive experience as neurosurgeon and pain specialist. He was the director of neurosurgery and pain and palliative care in Alexandria, Egypt, for more than 14 years. He pioneered to establish and direct an accredited neurosurgery residency training program in

Irvin S. Benowitz, DO, MS, received his medical degree from Des Moines University College of Osteopathic Medicine. He completed a Teaching and Learning and Educational Leadership Fellowship at the University of Southern California and also completed a Reynolds mini fellowship in geriatrics at John Hopkins University. His specialties include family medicine, preventive and areospace medicine, with additional qualifications in geriatric medicine. Christopher A. Fisher, MD, practices

with Nevada Spine Clinic as an interventional spine and pain management specialist. He also performs disability examinations for veterans in consultation with the U.S Department of Veterans Affairs. Dr. Fisher is a member of the American Association of Physical Medicine and Rehabilitation, International Spine Intervention Society, American Medical Association, Clark County Medical Society, Nevada State Medical Association, and American Mensa. He also provides continuing medical education to health care professionals through medical conferences and presentations. Emeka C. Obienu, MD, MBBS, DA(SA), MCFP, MBA, is a family physician in Canada

and the medical director of Central Avenue Medical Clinic in Prince Albert, Saskatchewan, which is a family medical practice with special interest in pain medicine. Dr. Obienu manages all aspects of chronic pain medicine. Reginald M. Smith, MD, he has been certified with the American Board of Internal Medicine since 2002. Dr. Smith currently practices in the fields of pain management and opioid addiction. He opened his own practice, Complete Pain Care, in Moody, Alabama, in September 2014. He has embraced his calling to treat those patients who suffer with chronic pain and/or battle drug addiction. He prides himself in being compassionate, caring, competent, and nonjudgmental.

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You Should Know... Jackson and Galloway Join Academy Board

The Academy is pleased to announce that W. Clay Jackson, MD, DipTh (left), and Kevin T. Galloway, BSN, MHA, US Army (retired) (right), have joined the Board of Directors. W. Clay Jackson, MD, DipTh, is clinical assistant professor of family medicine and psychiatry at the University of Tennessee College of Medicine in Memphis, where he maintains a private practice in family and palliative medicine. He is also the medical director of Comprehensive Primary Care, and of Methodist Hospice and Palliative Services. Dr. Jackson is the 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. Kevin T. Galloway, BSN, MHA, Colonel, US Army (Retired), Director At Large, is a senior project manager at the Defense and Veterans Center for Integrative Pain Management (DVICPM) in Rockville, Maryland. He recently retired from the United States Army after a distinguished 27-year career as an Army Nurse Corps officer. His career included a multitude of clinical and administrative assign-

ments, in fixed facility hospitals and military field hospitals, in emergency departments, ambulatory care clinics, and troop medical clinics. He deployed as medical support for combat, humanitarian, and peace-keeping operations in Saudi Arabia, Croatia, Iraq, Korea, and Honduras. During his last assignment in the Army’s Office of The Surgeon General, he was the chief of staff for the 2010 Department of Defense Pain Management Task Force and subsequently served as director of the Army’s Comprehensive Pain Management Program from 2011 to 2014. He is a recipient of the Order of Military Merit and the Army Surgeon General’s “A” Proficiency designator, an award used to recognize the accomplishments of senior medical leaders who have made significant contributions to the Army Medical Department.

Academy Announces New Tiered Membership Program As the premier pain management organization for all clinicians who care for people with pain, the Academy is pleased to announce the launch of a tiered membership program beginning on November 1, 2014. The new membership structure has been designed to make membership more affordable for many of our current members, attract valuable new members, and build our integrative “team.” In addition, we will be offering free membership for students and residents. The new pricing is as follows. Clinical and Affiliate Membership: • Income < $75,000.......................$95.00 US .......................................................$155.00 International • Income $75,000 - $124,999........$195.00 US .......................................................$245.00 International • Income $125,000 - $184,999......$275.00 US .......................................................$325.00 International • Income > $185,000.....................$355.00 US .......................................................$405.00 International

policy & advocacy

Clinical and Affiliate Members: Inquire about multi-year discounts on membership renewals.

The Academy is the country’s leader in pain management policy and advocacy.

Students: Student membership is 100% complimentary. Full-time registered students can access the Academy’s “Members Only” section of the website, the online learning center, and receive a printable membership certificate. Proof of student status must be provided each year.

www.aapainmanage.org/advocacy/

If you have any questions, please contact: Jillian Manley, Director of Sales and Marketing 209-533-9744, jmanley@aapainmanage.org

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The State Pain Policy Advocacy Network Your Academy’s policy and advocacy team influences positive change for you and your patients.

Legislatures are in full swing and your Academy’s policy and advocacy team is already tracking hundreds of new bills and regulations. While SPPAN works to improve pain policy yearround, late winter and early spring bring new legislative sessions, new legislators, and newly proposed bills, presenting us with countless opportunities to effect positive change—and get you involved in advocacy! Visit our newly updated website to see all we are doing, and keep reading to see a few of the issues we’ve already been working on during 2015. • Ensuring access to, and adequate insurance coverage for, evidence-supported non-pharmacological pain treatments (access to integrative pain care). As we noted in the

last issue of Pain Practitioner, this is one of SPPAN’s top goals for 2015. Already this year, we are tracking and analyzing dozens of related bills. One such bill, RI H 5046, would help to implement the Affordable Care Act’s Section 2706, a nondiscrimination provision that requires every licensed health care practitioner to be reimbursed for any service they provide within their lawful scope of practice. We fully support Section 2706 and the Rhode Island bill, and we anticipate that similar bills may be introduced soon. • Influencing the development of state pain management

guidelines and monitoring unintended consequences of restrictions on pain medications. Last year, your Academy’s

policy and advocacy team was influential in the development of guidelines for pain management in at least six states across the nation, helping to write and re-write the rules so that they reflect true best practices while taking into consideration the practicalities of everyday pain care delivery. Already in 2015, pain management guidelines have been put forth for consideration in New York, New Jersey, and New Hampshire. • Improving the effectiveness of prescription monitoring programs (PMPs) as health care delivery tools. In just the first two weeks of 2015, 15 new PMP-related bills were introduced on topics including: expanding access to PMP data to clinical laboratories, disclosing information relevant to investigations (or in the case of one state—not disclosing), required PMP checks, “red flag” indicators, and multiple bills regarding the establishment of a PMP in Missouri. We’ve even seen an interesting Kentucky bill urging Missouri to implement a PMP. As another one of SPPAN’s highest priorities, you can rest assured that we will be carefully reviewing and commenting on these PMP bills and others like them to 16

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Academy

Contributors Donations to the American Academy of Pain Management (the Academy) support the vital work of the Academy’s policy and advocacy efforts—efforts aimed at ensuring that people with pain have access to the care they need and deserve. The Academy’s commitment to this work is evidenced by the fact that it is the only pain management organization in the US with a dedicated in-house policy/advocacy team, which is guided by Bob Twillman, PhD—one of the nation’s most respected pain policy leaders. Dr. Twillman carries the Academy’s positions on key issues to policy makers on both the state and federal levels. The Academy’s growing state advocacy efforts are led by Amy Goldstein, MSW, State Pain Policy Advocacy Network (SPPAN) director. We would like to thank the following contributors for their donations in support of the Academy’s policy and advocacy effort. Angel M. Carrasco, MD Arthur Samuel Hernandez, MD Ayaz Mahmood Khan, MD Brian L. Gwartz, MD C. Samuel Verghese, ND, PhD Caroline P. Grierson Chin Se Kim, MD Chris J. Grammar, MD Claudia E. Penalba, MD Sue A. De Villez David P. Calimag, MD David W. Nadler, DC Edward Anthony Capone, DO Edward H. Shwery, PhD Edye N. Merzer, PsyD Eric E. Hansen, MD Eric K. Willmarth, PhD Grant F. Stoddard, DC Gregory L. Anderson, PhD James J. Meyer, DDS Jan J. Golnick, MD Jerry Lee, MD Johnny L. White, Jr., MD, MBA Jordana Leanne Latozas, NP Karene P. Villaronte, RN, LAc Khalid Mohamed, MD Kunnathu P. Geevarghese, MD Larry A. Dunn, DDS Larry S. Lefors, DO Lillian Matthews, DPM Manouchehr M. Karami, OMD, LAc, QME

Manuel R T Ramirez, MD Margaret I. Kruckemeyer, NP Mark D. Barhorst, MD Martin J. Goulooze, DC Obi C. Chinakwe, DC, MD Patricia M. Eye, RN Paul Valigorsky, MD Peter J. Pollachek, APN, CRNA Petra Burke-Ramirez, MD Philip Getson, DO Rafael V. De La Riva, MD Raman Kapur, MD Randy L. Gittess, DDS, PA Randy Mullins, CEO Rany A. Cherian, MD Ray Assadollahi, DC Riaz A. Shirazi, MA, MS Robert R. Facca, DC Ronald C. Stewart, DDS, MS Ronald Edward Bishop, MD Roy Randall Northcutt, DC, DAAPM Salman Saeed, MD Steven R. Kilpatrick, DDS Toa Chris Wong, D-PT Uday Bhatt, MD Vernon D. Holleman, MD Donations may be tax deductible as an ordinary business expense. If you would like to donate in support of our policy and advocacy please contact the Academy at 209-533-9744 or aapainmanage.org.

In Memory The following names are listed in memory of our deceased members. Arthur J. Zwerling, DNP, CRNA, DAAPM David L. De Villez, MD David L. Patterson, PhD Fe Quines, MD Frank Ferguson, DC

Jeffrey N. Bowman, DPM John R. Rains, PharmD Kailash C. Chopra, MD Larry G. Bauste, PhD Richard A. Nelson, MD

ensure they truly reflect best practices. Contact Amy Goldstein, SPPAN Director, at agoldstein@ aapainmanage.org if you are interested in learning more

about policy-focused activities in your state. Be sure to regularly check SPPAN’s website at sppan.aapainmanage.org for updates on policy issues that matter to you. Donations may be tax deductible 9744 or as an ordinary business expense. If aapainmanage.org. you would like to donate in support of our policy and advocacy please contact the Academy at 209-533-

Integrative Approach to Chronic Abdominal Pain and IBS

IBS affects 10% to 20% of the population in North America with a femaleto-male ratio of more than 2:1.

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GUT RELATED DISORDERS

Integrative Approach to Chronic Abdominal Pain and Irritable Bowel Syndrome

This article was excerpted from Integrative Pain Management, edited by Robert Bonakdar and Andrew Sukiennik, to be published in June 2015 by Oxford University Press, Weil Integrative Medicine Library.

Robert A . Bonak dar , MD, FA AFP

hronic abdominal pain (CAP), especially functional pain, can be a complex, difficult to treat condition that requires global assessment and individualized care. Various classifications have been proposed for CAP in adults and children that typically divide the disorder into organic or functional categories. Functional pain occurs without objective evidence of anatomic abnormalities, inflammation, or tissue damage. Functional gastrointestinal disorders (FGIDs) are characterized by regular episodes of pain that are disruptive to activities of daily living, and can be further differentiated by whether or not they are associated with changes in bowel habits or eating. While we mainly discuss irritable bowel syndrome (IBS), it is important to note that this characterization is not definitive. We know that IBS criteria can be fulfilled in those with organic findings, and, conversely, that inflammatory or infectious etiologies can be contributory factors in some cases of IBS. Thus, many of the treatments reviewed below should be considered in those with other chronic abdominal disorders due to overlapping etiologies and contributing factors. As a condition, IBS affects 10% to 20% of the population in North America with a female-to-male ratio of more than 2:1 and accounts for 10% to 15% of primary care and up to 50% of gastroenterology visits (1). Even with this high prevalence, only a quarter of those with IBS seek medical treatment for their symptoms, which on average persist for 10 years before diagnosis. IBS severity is predicted by pain as well as other gastrointestinal (GI) symptoms including bloating, straining, urgency, and concern related to the significance of symptoms. Beyond GI symptoms, those with IBS often demonstrate a higher likelihood of associated physical and behavioral comorbidities, including back pain, headache, anxiety, depression, fatigue, and insomnia (2,3). For reasons related to the condition, its comorbidities, and their effects on social and work life, a substantial burden exists for those who suffer with IBS, and the direct and indirect costs of IBS, including lost work and productivity, are estimated at $20 billion to $30 billion a year (4).

Rationale for Integrative Approach

The use of integrative approaches in IBS can be understood based on several key factors. First, currently approved IBS treatments are centered on antispasmodics, antidepressants, and serotonin receptor modulators. Although some have demonstrated benefit for patients with IBS, others have noted limitations. Second, IBS comorbidities are often unsatisfactorily treated with IBS-focused therapies. These comorbidities are known to propagate stress and catastrophizing, often without the presence of compensatory stress-coping strategies (5). It is also clear that if these comorbidities are not appropriately addressed, they can create detrimental effects including neuroplastic changes as well as worsening of the frequency and severity of the baseline IBS (2). Approach to the Patient and the Family

Due to the matrix of potential medical, psychological, and environmental factors associated with chronic abdominal pain and IBS, a biopsychosocial assessment is essential. Family pain histories are especially important in children as the frequency, severity, and level of catastrophizing is associated with the degree of pain in the family. In addition, a thorough physical exam is important in ruling out organic etiologies as well as identifying findings (such as myofascial trigger points) that may prompt individualized treatment options. Validated questionnaires, such as the IBS-Severity Scoring System (IBS-SSS), are often helpful to identify baseline disease burden as well as gauging the global benefit of treatments. A biopsychosocial assessment is valuable not only in guiding care, but also for building a therapeutic relationship, which has been linked to more positive outcomes in IBS (6). Overview of Integrative Options

Integrative options that have been evaluated for benefit in the setting of IBS include a variety of mind-body, dietary, and acupuncture approaches and are reviewed below. Mind-body therapies (MBTs). The defined link between psychological factors and GI health, often referred THE PA IN PRACTITIONE R

| VOLUME 25, NUMBER 1 |

Integrative Approach to Chronic Abdominal Pain and IBS

CASE VIGNETTE

Case Vignette

Kim is 33 years old and presents with eight years of intermittent abdominal symptoms before being diagnosed with constipationpredominant IBS. She is referred by her gastroenterologist for an integrative evaluation because of difficulty tolerating several rounds of prescription medications. She describes her symptoms as nearly daily abdominal bloating and pain that range from a 2 (uncomfortable) to an 8 (sharp pain) with symptoms typically proceeding to bouts of cramping and straining with subsequent improvement after bowel movement. She has tried various therapies including fiber and laxatives without consistent benefit. She works as a lawyer and notes symptoms during stressful work periods. Self-measures are minimal and include heat to the area after work. She notes that during a recent spa weekend that included healthy eating, she had reduced symptoms. She is single and has a good social support network and family bonds. She does not exercise regularly and

describes her diet as â&#x20AC;&#x153;grab and go.â&#x20AC;? Evaluation has been negative including a colonoscopy done after a bleeding episode. Lab studies are unremarkable other than a vitamin D level of 17 ng/ml for which she was started on replacement therapy. Physical exam is remarkable for myofascial guarding of the abdominal wall and upper back. Her IBS-SSS score is 280, indicating high moderate severity. Kim receives education and reassurance about her condition. In reviewing her goals, she is interested in reducing symptoms as well as learning tools to reduce her triggers. She is intrigued about trying acupuncture and is told that in some patients it can be particularly helpful. She has not tried any behavioral or dietary approaches thus far. After evaluation, potential treatment options are reviewed as well as online resources she may access for self-management.

CASE RESOLUTION

Case Resolution

After initial evaluation, Kim was asked to see the dietician to plan a more balanced diet

to as the gut-brain axis, makes MBTs, including cognitive behavioral therapy, hypnosis, and biofeedback, strong candidates for IBS (7). These therapies typically require three to 12 sessions lasting 30 to 60 minutes and appear most promising for patients with less chronicity who are more compliant with clinic and home treatment. Education and reassurance set the stage for reducing obstacles and can enhance the benefit of formal treatments. Cognitive behavioral therapy (CBT) enables patients to better understand how various beliefs, thoughts, and perceptions can affect their condition and includes techniques such as restructuring, prioritization, and goal setting. Neuroimaging studies have demonstrated that CBT can help reduce the heightened limbic system activity often seen in IBS. This intervention should be freely recommended, especially in patients who exhibit psychological sequelae, as a means of better approaching their condition or compliance with other therapies. Other MBTs that should be considered include hypnosis and biofeedback. The overall evidence for hypnosis for IBS is inconclusive; however, a more specific technique known as gut-directed hypnotherapy has demonstrated significant benefit in the majority of clinical trials, with benefits continuing for nearly five years after treatment (8). Biofeedback trials in the area of chronic abdominal pain have used various techniques for autonomic and muscular retraining. In a recent comparison of hypnotherapy and biofeedback for refractory IBS, both treatments were found equally effective in reducing the IBS-SSS after three ses20

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with steady reduction of FODMAPs, a titrating dose of flax, and initiation of a clinically tested probiotic formulation. She also began a therapeutic trial of acupuncture and biofeedback over the next eight weeks along with a home regimen of walking after dinner most days of the week. At 3-month follow-up, she reports a 60% reduction in her IBS symptoms, especially abdominal pain and straining, with noticeable reduction in situation stress and neck tension. She notes that she is less fearful of her condition interfering with her work and social life and realizes that the mind-body exercises are helpful as long as she makes time for them. Her updated IBS-SSS has dropped to 160 points demonstrating upper mild severity. She is asked to continue her regular physical activity and the mind-body therapies. She will continue her dietary approach with as needed appointments with the dietician. Acupuncture visits are moved to monthly. She is asked to follow up in approximately three months.

sions (9). An often overlooked mind-body therapy for IBS is exercise. Lack of adequate physical activity often occurs with IBS and CAP, and body mass index has been positively associated with increased symptoms (10). Exercise should be emphasized with IBS patients as a treatment option both to reduce symptoms as well as to improve mood disorders that often co-exist with IBS. Other MBTs including guided imagery, self-hypnosis and journaling have also demonstrated benefit in the setting of IBS and CAP and should be considered based on clinical circumstances. Biological/dietary based therapies. Dietary approaches are considered in IBS based on their ability to modulate disruptions to the intestinal barrier caused by diet, infection, antibiotics, autonomic hypersensitivity, or comorbid conditions (such as celiac disease) (11). To maximize therapeutic outcomes, it is important to individualize therapies, such as matching specifically tested probiotics for IBS sub-types. As a starting point, a history of known triggers, such as spicy foods, can be helpful in initiating dietary modification and improving symptoms. Beyond this, the area of elimination may be broadened empirically to capture more specific triggers or testing may be initiated to help direct elimination. One area of focused elimination supported by recent research is gluten-containing foods in IBS associated with diarrhea (IBS-D), which may result in significantly less diarrhea, small bowel permeability, and serum levels of inflammatory markers including interleukin-10 (12). Another area of elimination for those with IBS includes FODMAPs, or fermentable

Integrative Approach Tto heChronic Clinician’s Abdominal Perspective Painon and REMS IBS

oligosaccharides, disaccharides, monosaccharides, and polyols (13). These are more difficult to digest sugars that can trigger abdominal gas and symptoms in those with IBS. After elimination of potential triggers, several dietary and supplemental approaches are often employed, especially when targeting specific symptoms. The typical dietary consideration is fiber as this can be helpful in modulating bowel permeability and has been found deficient in diets of some with IBS and CAP. Recent studies have demonstrated that guar gum at 5 to 10 g/day and ground flaxseeds (especially in the setting of constipation) can be significantly helpful in reducing IBS symptoms and appear better tolerated than other fiber formulations (14,15). Fiber should be titrated slowly and consumed with adequate hydration. Probiotics are promoted for their ability to modulate intestinal microflora as well as related alterations in inflammatory, immune, and permeability status. Numerous strains are touted as beneficial and having specific roles in managing the symptoms of IBS, according to a recent evidence-based international consensus statement (16). Peppermint oil has been evaluated for benefit in the setting of IBS due to its ability to block calcium channels and induce smooth muscle relaxation. A number of other herbal and dietary supplements have demonstrated benefit versus placebo in IBS trials including STW 5, STW 5-II, Tong Xie Yao Fang, Padma Lax, and certain Ayurvedic formulas (17). Other dietary interventions, including l-glutamine, zinc, and especially cromolyn sodium in diarrhea dominant cases, may also be potentially helpful. Clinicians should openly discuss these options and their potential benefit in specific scenarios, especially those that have been refractory to other dietary measures. Acupuncture. Acupuncture has potential in the setting of IBS and FGID based on its ability to modulate autonomic tone, decrease myofascial pain, and attenuate visceral hypersensitivity (18,19). In clinical trials, the results are often difficult to interpret. The 2012 Cochrane review found similar and impressive relief of pain for true acupuncture and sham controls (20). In the same review, acupuncture also demonstrated similar benefit for IBS when compared to behavioral therapy and probiotics and more significant results when compared to antispasmodics (20). When considering acupuncture it is prudent to select patients who are most likely to be compliant with a therapeutic trial by a qualified practitioner. In Conclusion

CAB and IBS are complex and debilitating disorders that have a significant and detrimental impact on the patient, family,

and health care system. As research points out, a biopsychosocial approach based foundationally on education and reassurance, as well as incorporation of individualized integrative approaches, can significantly improve patients’ quality of life. For more information, see the University of Wisconsin handout at

http://www.fammed.wisc.edu/sites/default/files/webfm-uploads/documents/ outreach/im/module_IBS_clinician.pdf.

References 1. Choung RS, Locke GR 3rd. Epidemiology of IBS. Gastroenterol Clin North Am. 2011 Mar;40 (1):1-10. 2. Lackner JM, Ma CX, Keefer L, et al. Type, rather than number, of mental and physical comorbidities increases the severity of symptoms in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013 Sep;11(9):1147-1157. 3. Spiegel B, Strickland A, Naliboff BD, Mayer EA, Chang L. Predictors of patientassessed illness severity in irritable bowel syndrome. Am J Gastroenterol. 2008 Oct;103(10):2536-2543. 4. Nellesen D, Yee K, Chawla A, Lewis BE, Carson RT. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm. 2013 Nov;19(9):755-774. 5. Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 2011 Dec;62(6):591-599. 6. Di Palma JA, Herrera JL. The role of effective clinician-patient communication in the management of irritable bowel syndrome and chronic constipation. J Clin Gastroenterol. 2012 Oct;46(9):748-751. 7. Elsenbruch S. Abdominal pain in Irritable Bowel Syndrome: a review of putative psychological, neural and neuro-immune mechanisms. Brain Behav Immun. 2011 Mar;25(3):386-394. 8. Vlieger AM, Rutten JM, Govers AM, Frankenhuis C, Benninga MA. Long-term follow-up of gut-directed hypnotherapy vs. standard care in children with functional abdominal pain or irritable bowel syndrome. Am J Gastroenterol. 2012 Apr;107(4):627-631. 9. Dobbin A, Dobbin J, Ross SC, Graham C, Ford MJ. Randomised controlled trial of brief intervention with biofeedback and hypnotherapy in patients with refractory irritable bowel syndrome. J R Coll Physicians Edinb. 2013;43(1):15-23. 10. Levy RL, Linde JA, Feld KA, Crowell MD, Jeffery RW. The association of gastrointestinal symptoms with weight, diet, and exercise in weight-loss program participants. Clin Gastroenterol Hepatol. 2005 Oct;3(10):992-996. 11. Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. Clin Gastroenterol Hepatol. 2003; 18(5):479-497. 12. Vazquez-Roque MI, Camilleri M, Smyrk T, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013 May;144(5):903-911. 13. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014;146(1):67-75. 14. Giannini EG, Mansi C, Dulbecco P, Savarino V. Role of partially hydrolyzed guar gum in the treatment of irritable bowel syndrome. Nutrition. 2006; 22(3):334-342. 15. Tarpila S, Tarpila A, Grohn P, Silvennoinen T, Lindberg L. Efficacy of ground flaxseed on constipation in patients with irritable bowel syndrome. Curr Top Nutraceutical Res. 2004;2(2):119-125. 16. Hungin AP, Mulligan C, Pot B, et al. European Society for Primary Care Gastroenterology Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice—an evidence-based international guide. Aliment Pharmacol Ther. 2013 Oct;38(8):864-886. 17. Liu JP, Yang M, Liu YX, Wei ML, Grimsgaard S. Herbal medicines for treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004116. 18. Tian SL, Wang XY, Ding GH. Repeated electro-acupuncture attenuates chronic visceral hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat irritable bowel syndrome model. Life Sci. 2008 Aug 29;83(9-10):356-363. 19. Zhou YY, Wanner NJ, Xiao Y, et al. Electroacupuncture alleviates stress-induced visceral hypersensitivity through an opioid system in rats. World J Gastroenterol. 2012 Dec 28;18(48):7201-7211. 20. Manheimer E, Cheng K, Wieland LS, et al. Acupuncture for treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2012 May 16;5:CD005111.

Robert A. Bonakdar, MD, FAAFP, is director of pain management at the Scripps Center for Integrative Medicine in La Jolla, California. He is also the president of the Academy Board of Directors.

THE PA IN PRACTITIONE R

| VOLUME 25, NUMBER 1 |

GUT RELATED DISORDERS

Considerations in Diagnosing and Treating Pain in Patients with Inflammatory Bowel Disease By Divya Keerthy and E va Szigethy MD, PhD

iagnosing abdominal pain in patients with inflammatory bowel disease (IBD) can be challenging as there are so many different possible sources of pain (1). One particularly difficult task is differentiating functional pain in the absence of inflammatory disease activity from pain that is caused by the disease process (2). Such functional pain, which is the hallmark of irritable bowel syndrome (IBS) is also common in patients with IBD (3) and is associated with increased psychopathology and reduced quality of life (4). In fact, psychological factors have predicted pain in both adolescents and adults with IBD (5,6). Unrecognized IBS-like pain can lead to the potential misinformed use or escalation of antiinflammatory IBD medications, which are costly yet often without benefit in this subset of patients (7). This review will provide an overview of the recent literature about differences and similarities between IBD and IBS followed by a review of the diagnosis, pathophysiology, and treatment of pain in IBD. Overview of IBD and IBS

Inflammatory bowel disease. IBD is a group of life-long autoimmune inflammatory conditions affecting the gastrointestinal tract. Patients with IBD often cycle through periods of active inflammation (flares) and periods of inactivity (remission). About 1.4 million Americans are affected by IBD, with the majority being diagnosed before age 30 (8). The two most common types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). In CD, active disease involves inflammation affecting any part of the GI tract from mouth to anus. Disease activity involves all layers of the GI mucosa and this transmural process facilitates the 22

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leakage of gastrointestinal (GI) inflammatory markers into the blood. Symptoms can vary but common ones include bloody diarrhea, constipation, nausea, vomiting, fever, fatigue, and abdominal pain. Weight loss and growth delays in adolescents can also occur with prolonged disease activity. Extraintestinal manifestations may also include arthritis, inflammation of eyes or skin, kidney stones, biliary duct diseases, and osteoporosis. In UC, unlike CD, the inflammation is limited to the innermost layer of the intestines and is restricted to affecting the large intestine and the rectum. Common symptoms are similar to those seen in CD but loose stools, including nocturnal diarrhea, is the most common symptom. Peripheral inflammation and extraintestinal symptoms are not seen as consistently as in active CD. The causes for IBD are unknown, though evidence suggests an autoimmune process involving an exaggerated immune system inflammatory response. Other factors, which may be synergistic in their predisposing effects, include a genetic vulnerability, environmental triggers, and an imbalance of intestinal bacteria (9-12). The current gold standard for diagnosing IBD is the presence of pathological changes in biopsies obtained by colonoscopy or endoscopy procedures. Imaging techniques are used to detect complications. Blood tests may reveal anemia and elevations in platelets, erythrocyte sedimentation rate (ESR), or C-reactive protein (CRP). Use of genetic mutations as an aid to diagnose IBD and detect the risk for disease complications is an exciting new treatment direction that has the potential to improve outcomes in the future. Currently there is no known cure for IBD. Treatment strategies are aimed at reducing symptoms and disease activity with different classes of medications including aminosalicylates, corticosteroids, immunomodulators, and biologic therapies. Antibiotics may help reduce inflammation or treat accompanying infection. Surgical intervention is often required for severe medication-refractory disease though is often palliative with eventual disease re-emergence, especially in CD. Irritable Bowel Syndrome. IBS is not a disease but instead is classified as a functional GI disorder that primarily affects the small and large intestines. About 40 million people in the US suffer from IBS symptoms such as cramping, abdominal pain, bloating, gas, diarrhea, or constipation (13,14). As in IBD, the severity of symptoms waxes and wanes. However, IBS tends not to be associated with bloody diarrhea or “alarm” symptoms such as fever, nocturnal symptoms, anemia, or extraintestinal manifestations.

Considerations in Diagnosing and T reating Pain in Patients with IBD

The cause of IBS is unknown but theories include a combination of peripheral factors such as increased visceral sensitivity to noxious stimuli (i.e., visceral hyperalgesia) and motility disturbances, as well as maladaptive processing of these visceral signals by the central nervous system (13). One cause of visceral hyperalgesia in IBS is exposure to a recent infection of the GI tract (15). A diagnosis of IBD also increases the risk of developing IBS. For females, symptoms may change in association with their menstrual cycle suggesting a role of hormones in the pathophysiology (16). Although life stress has not been causally linked

The gold standard for diagnosing IBD is the presence of pathological changes in biopsies obtained by colonoscopy or endoscopY.

to either IBS or IBD, in both conditions, stress has been associated with exacerbation of symptoms (17-19). Similarly, there are dietary factors in both disorders that have been linked with increased GI distress in certain patients, although there is no overall consensus of which food groups are to be avoided. In IBS, spicy foods, high-fiber fruits and vegetables, foods containing wheat, coffee, alcohol, and milk have been considered as precipitating factors (20,21). Unlike IBD, IBS has not been associated with serious complications such as colon cancer and is not life-threatening, however, impairment of overall quality of life, suffering, and

Considerations in Diagnosing and T reating Pain in Patients with IBD

frequent accompanying depression and anxiety are significant consequences (13). The diagnosis of IBS is symptom-based following a specific set of diagnostic criteria in which pain is associated with change in bowel habit. (Rome III) (14). There is no specific diagnostic finding or biomarker for IBS; it is a diagnosis of exclusion. When symptoms suggest IBS, diagnostic testing is conducted to rule out various disease entities. In patients with IBD, it is becoming increasingly recognized that IBS can exist in the presence of inactive IBD (e.g., IBD-IBS) (22,23). The medications used to treat IBS are targeted to specific symptoms and include laxatives (constipation), anti-diarrheal agents, antispasmodics, probiotics (to balance intestinal bacteria), and antibiotics to treat small bowel bacterial overgrowth that may occur concurrently with IBS. There are a few FDAapproved medications to treat IBS such as alosetron hydrochloride, a serotonergic (5 HT3) antagonist approved for women with IBS-D (diarrhea) and lubiprostone, a chloride channel activator approved for women with IBS-C (constipation), but these are not without potential severe side effects (13,24). Diagnosing Abdominal Pain in IBD

IBD-IBS. Abdominal pain is increased in patients who have IBD-IBS (IBS-like symptoms in the absence of active IBD inflammation or endoscopic or radiological evidence of mild or microscopic disease) (23) and this is thought to be due to visceral hyperalgesia. Abdominal pain seen in IBS alone is often described as crampy, diffuse, and relieved by a bowel movement, while pain in IBD is often more constant, in a specific location, and not relieved by a bowel movement. In addition, different risk factors predict each entity: Risk factors for IBS include functional pain in childhood, female gender, stress, prior exposure to intestinal infection, and visceral fat (18,25,26), while in IBD, cigarette smoking, living in urban settings, and childhood exposure to infections may play a role (27,28). Up to 60% of patients with IBD in remission report IBS symptoms (3,29). In one such study, patients with IBDIBS had higher levels of calprotectin, a fecal inflammatory marker specific for the colon, compared to those with inactive IBD without pain, suggesting that subclinical inflammation may explain the IBS symptoms (29). There are several factors that support IBS being a comorbid condition with IBD: 1) the higher prevalence in females than males; 2) significant correlation with anxiety; 3) higher rates of IBS in first-degree relatives of IBD patients suggesting shared genetic vulnerability; and 4) similarity in presentation be24

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tween IBD-IBS and infectious IBS (22). At a cellular level, patients with IBS-like symptoms in IBD have been shown to exhibit increased intestinal permeability, and presence of biomarkers that have been reported in IBS. Other causes of pain in IBD. In evaluating pain in IBD, it is important to detect and treat IBD-related sources or complications (30). In CD, for example, pain can be present if the inflammatory process affects the deeper layers of mucosa where enteric nerves reside. These inflammatory substances can directly and indirectly affect visceral afferent function. Afferent endings can be sensitized by cytokines and chemokines resulting in lower threshold for activation. Abdominal distress can also occur with the activation of stretch receptors in the intestinal mucosal layers from rapid intestinal distention or mesenteric stretching. Such distention can be caused by torsion, dysmotility, or gas production in small intestinal bacterial overgrowth. In addition, some complications of IBD such as strictures, bowel obstruction, ulcers, fistulas, and abscesses in CD, and bloating, ulcers, and bowel rupture in UC can be painful, as can complications of surgery such as adhesions. Another useful construct in understanding chronic abdominal pain in IBD is the biopsychosocial model, which takes into account pathways between the brain and gut in the progression of acute pain to chronic pain (13,31,32). This model posits that as pain becomes more chronic, including that in patients with IBD-IBS, there is a shift from more peripheral to central mechanisms (22). This shift can be facilitated by psychiatric comorbidities such as anxiety and depression. Life stress and negative cognitive habits such as catastrophizing can also exacerbate pain (33). Treatment of Pain in IBD

The primary treatment of persistent pain in IBD involves treating any potential medical causes (active inflammation, infection, or painful complications) (1). If such causes have been treated and pain persists, much of the pain management is similar to that for patients with IBS (13). A solid doctorpatient relationship to establish trust, and an emphasis on the science behind IBS as a biopsychosocial disorder are the pillars for any other medical or psychosocial approach (34). Pharmacological therapy. The first-line treatment for visceral pain is to treat underlying disease activity by reducing inflammation. Antispasmodics (e.g., hyoscyamine) have been used, although obstruction and worsening dysmotility are potential side effects (35,36). Relatively nonabsorbable antibiotics (e.g., metronidazole, rifaximin) can reduce pain due

Considerations in Diagnosing and T reating Pain in Patients with IBD

to bacterial overgrowth. Long-term use of nonsteroidal antiinflammatory medications or cyclooxygenase-2 inhibitors is not recommended due to increased risk of disease activity (1). In treating IBS-like pain in IBD, most of the supporting evidence comes from studies in patients with functional abdominal pain, including IBS (13). Most of the psychotropic agents used can have both peripheral effects at the nerve endings and central effects in the brain and spinal cord. As the ratio of pain severity to disease activity increases, more central agents are needed. Certain types of antidepressants have support for treating visceral pain in functional GI disorders, particularly tricyclic antidepressants (TCAs) and serotonin noradrenergic reuptake inhibitors (SNRIs) (37). These two drug classes share a common target, the noradrenergic pathway, and they also act as weak antiinflammatory agents (38). There is no evidence that selective serotonin reuptake inhibitors (SSRIs) have a direct effect on pain; however, they can be effective in treating comorbid anxiety and depression (39,40). Certain mood stabilizers (gabapentin, pregabalin) show evidence for positive effects on neuropathic pain and have been used successfully for visceral pain as well (1,41). Several other psychotropic agents such as mirtazapine, quetiapine, and memantine have support from case series or clinical consensus, but still require more rigorous testing to establish their efficacy (13,24,42). Opioids are often used postoperatively in patients with IBD for analgesia. However, they are not recommended for chronic use because of risks of ileus, abuse, infection, fulminant colitis, toxic megacolon, and, in vulnerable IBD patients, narcotic bowel syndrome (NBS) (42,43). There is no empirical support for the efficacy of opioid use for any type of non-cancer chronic abdominal pain. Behavioral interventions. Cognitive behavioral therapy (CBT) and hypnosis have support as clinically effective methods in reducing pain and the frequency, intensity, and duration of IBS symptoms (44-46). Hypnotherapy and mindfulness meditation also have some support in reducing inflammation in IBD (47,48). In a recent randomized trial of depressed adolescents with CD, CBT had a greater effect on depression and disease activity than did supportive therapy (49). A recent meta-analysis showed that psychological interventions also can alleviate the symptoms of IBS and the psychological distress reported among sufferers (50). In addition, those interventions with a specific target such as self-monitoring of symptoms and cognitions, problem-solving, and assertiveness training showed greater improvement in IBS symptoms. Hypnosis studies have shown that reduced pain percep26

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tion at the level of the brain improved immune function in IBD and IBS, reduced stress and anxiety, and increased feelings of control over symptoms (44,45,51,52). In one study of IBS patients, hypnotherapy was equally effective when therapy was in a group in comparison to individual therapy, and thus may offer a less expensive alternative (53). It is possible that positive expectancy regarding treatment and conditioning may play a role as active ingredients for reducing pain in any psychosocial intervention, as evidenced by placebo studies (54,55), and ways to maintain these effects need to be further explored. Stress can also be managed through other means, such as meditation, guided imagery, or biofeedback. Some general strategies to address stress include recognizing control, and identifying which stressors are controllable or modifiable and which are not (e.g., having a diagnosis of IBD). Sleep disturbance often accompanies chronic pain and can amplify pain perception and has been effectively targeted with behavioral intervention in other populations (56,57). Studies are needed to evaluate the effects of behavioral interventions for insomnia in patients with IBD. Alternative medicine approaches. Acupuncture has not been studied in IBD patients and shows conflicting data in IBS studies; therefore, it is not recommended as management in patients with IBD (58). Other potentially useful relaxation techniques include mind/body exercises, such as yoga, tai chi, and meditation (59,60). These methods and other stress-management programs (61) may help normalize digestion by causing slower gastric emptying, higher acid secretion, and changes in the rate of intestinal motility (62). Lifestyle modifications. While many patients with IBD have strong beliefs that diet plays a causal role in their disease, current clinical data does not support this claim. However, diet may affect symptomology, although no specific diet is recommended. Foods should be eliminated on an individual basis. CD patients must avoid becoming malnourished due to their poor digestion and absorption. If the patient presents with diarrhea as a symptom, specific attention must be paid toward hydration. Cramping may be reduced by eating smaller, more frequent meals, reducing fat intake, limiting milk products, and limiting high-fiber foods. Probiotic therapy may be used to help control immune response (inflammation) and pouchitis in IBD, and may help with IBS (20,63,64). Procedures. There is limited evidence supporting the use of nerve blocks in treating functional abdominal pain either in IBD or IBS. Since the etiology of pain is complex, particularly in IBD-IBS, it does not seem likely that

Considerations in Diagnosing and T reating Pain in Patients with IBD

blocking one nerve in the periphery would have significant effects in reducing pain perception at the level of the brain. However, new stimulation techniques being developed may have more potential in the future (47,65,66). Summary

Although challenging, the etiology of pain in patients with IBD can be diagnosed and treated accordingly. Pain interventions with the most empirical support include behavioral interventions such as CBT and hypnosis and certain non-opioid pain medications. It is critical that these strategies occur in the context of a strong doctor-patient relationship where the patient feels his or her needs are being heard. There is no evidence for the regular dosing of opioids to treat chronic abdominal pain in IBD, and, in fact, they may increase pain as well as cause increased risk of other morbidities and even death. References 1. Srinath AI, Walter C, Newara MC, Szigethy EM. Pain management in patients with inflammatory bowel disease: insights for the clinician. Therap Adv Gastroenterol. 2012; 5(5): 339-357. 2. Bercik P, Verdu EF, Collins SM. Is irritable bowel syndrome a low-grade inflammatory bowel disease? Gastroenterol Clin No Amer. 2005; 34(2): 235-245, vi-vii. 3. Halpin SJ, Ford AC. Prevalence of symptoms meeting criteria for irritable bowel syndrome in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2012; 107(10): 1474-1482. 4. Farrokhyar F, Marshall J, Easterbrook B, Irvine E. Functional gastrointestinal disorders and mood disorders in patients with inactive inflammatory bowel disease: prevalence and impact on health. Inflamm Bowel Dis. 2006; 12(1): 38-46. 5. Srinath AI, Goyal A, Zimmerman LA, et al. Predictors of abdominal pain in depressed pediatric inflammatory bowel disease patients. Inflamm Bowel Dis. 2014;20(8):1329-1340. 6. Lix LM, Graff LA, Walker JR, et al. Longitudinal study of quality of life and psychological functioning for active, fluctuating, and inactive disease patterns in inflammatory bowel disease. Inflamm Bowel Dis. 2008; 14(11): 1575-1584. 7. Zimmerman LA, Srinath AI, Goyal A, et al. The overlap of functional abdominal pain in pediatric Crohn’s disease. Inflamm Bowel Diseases 2013; 19(4): 826-831. 8. Inflammatory Bowel Disease. Centers for Disease Control and Prevention. Updated September 16, 2014. http://www.cdc.gov/ibd/ibd-epidemiology.htm. Accessed February 9, 2015. 9. Hansen JJ, Sartor RB. Therapeutic Manipulation of the Microbiome in IBD: Current Results and Future Approaches. Curr Treat Options Gastroenterol. 2015;Jan 18. 10. Major G, Spiller R. Irritable bowel syndrome, inflammatory bowel disease and the microbiome. Curr Opin Endocrinol Diabetes Obes. 2014; 21(1): 15-21. 11. Graham DB, Xavier RJ. From genetics of inflammatory bowel disease towards mechanistic insights. Trends Immunol. 2013; 34(8): 371-8. 12. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev. 2004; 3(5): 394-400. 13. Dekel R, Drossman DA, Sperber AD. Abdominal Pain in Irritable Bowel Syndrome (IBS). In: Kapural L, ed. Chronic Abdominal Pain: An Evidence-Based, Comprehensive Guide to Clinical Management. New York: Springer Science; 2015:59-67. 14. Drossman DA, Dumitrascu DL. Rome III: New standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis. 2006; 15(3): 237-41. 15. Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome--a meta-analysis. Am J Gastroenterol. 2006; 101(8): 1894-1899; quiz 942. 16. Mulak A, Taché Y, Larauche M. Sex hormones in the modulation of irritable bowel syndrome. World J Gastroenterol. 2014;20(10):2433-2448. 17. Graff LA, Walker JR, Clara I, et al. Stress coping, distress, and health perceptions in inflammatory bowel disease and community controls. Am J Gastroenterol. 2009; 104(12): 2959-2969. 18. Elsenbruch S. Abdominal pain in Irritable Bowel Syndrome: a review of putative psychological, neural and neuro-immune mechanisms. Brain Behav Immun. 2011; 25(3): 386-394.

19. Mayer EA, Tillisch K. The brain-gut axis in abdominal pain syndromes. Annu Rev Med. 2011; 62: 381-96. 20. MacDermott RP. Treatment of irritable bowel syndrome in outpatients with inflammatory bowel disease using a food and beverage intolerance, food and beverage avoidance diet. Inflamm Bowel Dis. 2007; 13(1): 91-96. 21. El-Salhy M, Ostgaard H, Gundersen D, Hatlebakk JG, Hausken T. The role of diet in the pathogenesis and management of irritable bowel syndrome (Review). Int Journal Mol Med. 2012; 29(5): 723-731. 22. Grover M, Herfarth H, Drossman DA. The functional-organic dichotomy: postinfectious irritable bowel syndrome and inflammatory bowel disease-irritable bowel syndrome. Clin Gastroenterol Hepatol. 2009; 7(1): 48-53. 23. Long MD, Drossman DA. Inflammatory bowel disease, irritable bowel syndrome, or what?: A challenge to the functional-organic dichotomy. Am J Gastroenterol. 2010; 105(8): 1796-1798. 24. Drossman DA. Beyond tricyclics: new ideas for treating patients with painful and refractory functional gastrointestinal symptoms. Am J Gastroenterol. 2009; 104(12): 2897-2902. 25. O’Malley D, Quigley EM, Dinan TG, Cryan JF. Do interactions between stress and immune responses lead to symptom exacerbations in irritable bowel syndrome? Brain Behav Immun. 2011. 25(7):1333-1341. 26. Lee CG, Lee JK, Kang YS, et al. Visceral abdominal obesity is associated with an increased risk of irritable bowel syndrome. Am J Gastroenterol. 2015;110(2):310-319. 27. Cosnes J. Smoking, physical activity, nutrition and lifestyle: environmental factors and their impact on IBD. Dig Dis. 2010; 28(3): 411-7. 28. Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 2006; 12 Suppl 1: S3-9. 29. Keohane J, O’Mahony C, O’Mahony L, O’Mahony S, Quigley EM, Shanahan F. Irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease: a real association or reflection of occult inflammation? Am J Gastroenterol. 2010; 105(8):179-194; quiz 1795. 30. Srinath A, Young E, Szigethy E. Pain management in patients with inflammatory bowel disease: translational approaches from bench to bedside. Inflamm Bowel Dis. 2014;20(12):2433-2449. 31. Tanaka Y, Kanazawa M, Fukudo S, Drossman DA. Biopsychosocial model of irritable bowel syndrome. J Neurogastroenterol Motil. 2011; 17(2): 131-139. 32. Drossman DA, ed. Multi-Dimensional Clinical Profile (MDCP) for the Functional Gastrointestinal Disorders. Raleigh NC: The Rome Foundation; 2015. 33. Grover M, Drossman DA. Functional abdominal pain. Curr Gastroenterol Rep. 2010; 12(5):391-398. 34. Drossman DA. 2012 David Sun lecture: helping your patient by helping yourself— how to improve the patient-physician relationship by optimizing communication skills. Am J Gastroenterol. 2013; 108(4): 521-528. 35. Ford AC, Talley NJ, Spiegel BM, et al. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 2008; 337: a2313. 36. Makharia GK. Understanding and treating abdominal pain and spasms in organic gastrointestinal diseases: inflammatory bowel disease and biliary diseases. J Clinical Gastroenterol. 2011;45(Suppl): S89-93. 37. Wall GC, Bryant GA, Bottenberg MM, Maki ED, Miesner AR. Irritable bowel syndrome: a concise review of current treatment concepts. World J Gastroenterol. 2014;20(27):8796-8806. 38. Drossman DA. Treatment of residual inflammatory bowel disease symptoms with low-dose tricyclic antidepressants: why not? J Clinical Gastroenterol. 2014; 48(5): 390-392. 39. Mikocka-Walus AA, Turnbull DA, Moulding NT, Wilson IG, Andrews JM, Holtmann GJ. Controversies surrounding the comorbidity of depression and anxiety in inflammatory bowel disease patients: a literature review. Inflamm Bowel Dis. 2007; 13(2): 225-234. 40. Rahimi HR, Shiri M, Razmi A. Antidepressants can treat inflammatory bowel disease through regulation of the nuclear factor-kB/nitric oxide pathway and inhibition of cytokine production: A hypothesis. World J Gastrointest Pharmacol Ther. 2012; 3(6): 83-85. 41. Finnerup NB, Jensen TS. Clinical use of pregabalin in the management of central neuropathic pain. Neuropsychiatr Dis Treat. 2007; 3(6): 885-891. 42. Drossman DA, Szigethy EM. The narcotic bowel syndrome: a recent update. Am J Gastroenterol. 2014;2(Suppl 1):22-30. 43. Grunkemeier DM, Cassara JE, Dalton CB, Drossman DA. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin Gastroenterol Hepatol. 2007;5(10):1126-1139;quiz 1-2. 44. Moser G. The role of hypnotherapy for the treatment of inflammatory bowel diseases. Expert Rev Gastroenterol Hepatol. 2014:8(6):601-606. 45. Palsson OS, Whitehead WE. Psychological treatments in functional gastrointestinal disorders: a primer for the gastroenterologist. Clin Gastroenterol Hepatol. 2013;11(3): 208-216; quiz e22-3.

References and Author Bios continued on page 48 THE PA IN PRACTITIONE R

| VOLUME 25, NUMBER 1 |

GUT RELATED DISORDERS

Opioid Malabsorption: A Cause of Pain Treatment Failure By Forest Tennant MD, DrPH

Introduction

The gastrointestinal (GI) tract has a critical role in pain management and influences pain severity, healing, and immunologic effectiveness. Gastrointestinal malabsorption is a serious disorder that can interfere with proper nutrition and thwart treatment with some therapeutic agents, particularly opioids (1,2). Some patients with chronic and severe pain may not find enough relief to even function or carry on activities of daily living if they have opioid malabsorption and it is not recognized. Fortunately, however, when opioid malabsorption exists, it can easily be recognized, and a treatment can be instituted to save patients from needless suffering. Importance of Malabsorption to Pain Management

Absorption is the term used to describe the movement or transport of nutrients and pharmaceuticals from the lumen of the intestine into the bloodstream. MalabsorpSome chronic tion is the inability of the pain patients intestine to accomplish cannot properly this critical physiologic absorb opioids function. from the intesProper intestinal tine into the absorption is dependent bloodstream. upon a delicate balance of bacterial flora (micro biome), enzymes, and motility (3-7). The small intestine must remain in constant, rhythmic motion to maintain or “stir” the pool of enzymes and flora so it will properly absorb nutrients and pharmaceuticals. Motion and motility of the intestine are maintained by the autonomic (“involuntary) nervous system. Some of the tiny nerve connections to the intestine are from the vagus nerve, which originates in the brain and progresses down through the neck and chest into the abdominal cavity where it innervates the stomach and intestine. Splanchnic nerves, which come directly from the sympathetic ganglia along the spine, help control intestinal 28

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motility. It is poorly appreciated that any injury or disease process that impairs the complex system of intestinal nerve connections, including head, neck, or spine trauma including surgery, may adversely impact the proper intestinal absorption of some nutrients and pharmaceuticals (3-7). Malabsorption Syndrome

The term “malabsorption syndrome” is typically applied to children and adults who have a disease such as celiac or Crohn’s, in which a wide range of nutrients and pharmaceuticals will not be absorbed. This syndrome is characterized by weight loss, weakness, and anemia. Usual symptoms are diarrhea, vomiting, bloating, pain, steatorrhea, and undigested food in stools. Steatorrhea is the presence of excess undigested fat in stools, which make stools that are large, bulky, light-colored, and float on water. Many conditions that cause full-blown malabsorption may produce severe, chronic pain. These include Crohn’s disease, chronic pancreatitis, diabetic enteropathy, and surgical bowel resection (1,2). What is more common in pain practice, however, is partial or selective malabsorption. This issue has barely been studied in chronic pain patients, but millions of pain patients have diseases or have had spine, pelvic, or abdominal surgery that may cause partial or selective malabsorption. Head and neck trauma and autoimmune disorders may also adversely affect intestinal absorption. As a result, some patients are not achieving adequate pain control due to varying degrees of malabsorption. Malabsorption of Opioids

Since our patients with the most severe pain must take opioids, anything that interferes with opioid metabolism is of high interest. It is now clear that some chronic pain patients cannot properly absorb opioids from the intestine into the bloodstream (1,2). Consequently these patients may be considered treatment failures simply because opioid malabsorption has not been recognized. In contrast to other pharmaceuticals, opioids are greatly affected by malabsorption because opioids and the intestine have a unique relationship. First, the lining, or mucosa, of the

Opioid M al absorp tion: A C ause of Pain Treatment Failure

Table 1.

Opioid Malabsorption Screening Questionnaire

Date____________ Name___________________________________________________________________ 1. Have you ever taken any of these opioid drugs by mouth that did not provide pain relief? • Codeine (Fioricet®) Yes No • Hydrocodone (Lortab®, Norco®, Vicodin®) Yes No • Hydromorphone (Dilaudid®) Yes No • Meperidine (Demerol®) Yes No • Methadone Yes No • Morphine Yes No • Oxycodone (Percocet G®, Oxycontin®) Yes No • Oxymorphone (Opana®) Yes No • Tramadol (Ultram®) Yes No

2. If yes, list the names of the opioids that did not give pain relief. __________________________________________________________________________________________ 3. Were you ever given an injection of an opioid that gave you good pain relief?

Yes

4. If yes, which ones. (List) __________________________________________________________________ 5. Do you have any of the following conditions? • Crohn’s Disease • Ulcerative Colitis • Chronic Pancreatitis • Diverticulitis • Celiac Disease • Endometriosis • Diabetes

Yes Yes Yes Yes Yes Yes Yes

No No No No No No No

6. Have you ever had an abdominal surgery? (Check “Yes” to any you have had) • Bowel Resection Yes No • Gastrectomy (Stomach) Yes No • Cholecystectomy (Gall Bladder) Yes No • Hysterectomy Yes No • Oophorectomy Yes No • Cesarean Section Yes No • Appendectomy Yes No • Weight Loss Procedure Yes No • Bowel Blockage Yes No • Other (List):___________________________________________________________________________ 7. How many total abdominal or pelvic surgeries have you had? Number __________ 8. Have you now or previously had any of the following conditions? (Check “Yes” to any you have had) • Traumatic Brain Injury Yes No • Cervical Spine Surgery Yes No • Lumbar Spine Surgery Yes No • Diabetes Yes No • Autoimmune Disorder Yes No • Abdominal or Pelvic Infection Yes No • Arachnoiditis Yes No 9. Do you have any of the following symptoms on most days of the week? (Check “Yes” to any you have) • Diarrhea Yes No • Bloating Yes No • Nausea Yes No • Vomiting Yes No • Bulky, light colored stools Yes No • Undigested food in stools Yes No

THE PA IN PRACTITIONE R

| VOLUME 25, NUMBER 1 |

Opioid M al absorp tion: A C ause of Pain T reatment Failure

Table 2.

Table 3.

Common Causes of Opioid Malabsorption

Commercially Available Non-oral Opioids*

• Multiple abdominal/ pelvic surgeries* • Multiple cytochrome P450 defects • Gastrointestinal diseases • Traumatic brain or neck injury • Spine surgery* • Autoimmune diseases

Transdermal Patch • Fentanyl • Buprenorphine

* Any surgery that affects the autonomic innervation of the gastrointestinal tract may cause motility dys-function, adhesions, and selective malabsorption.

Transmucosal • Fentanyl • Buprenorphine Injections • Hydromorphone • Meperidine • Morphine Suppository • Opium • Hydromorphone * Other non-oral opioids can be compounded or specially made for clinical use.

small intestine is filled with opioid receptors. Their purpose is somewhat unclear, but they apparently are there, in part, to help transport opioids from the intestinal lumen into the serum. Since this is the case, it is easy to understand why surgical bowel resection or a disease that affects the mucosal lining may cause malabsorption of opioids. The second unique aspect involving opioids and the intestine is the newly discovered finding that cytochrome P450 enzymes (CYP450) are very plentiful in the intestine and are involved in the absorption of opioids (8-14). Next to the liver, the intestine is the most plentiful location of these enzymes. Commercial CYP450 enzyme testing has become universally available in recent years. Patients with multiple CYP450 defects commonly report that oral opioids are not effective and they require opioids that are not orally administered (15,16). Metabolism of opioids actually begins in the intestine, and effective transport of opioids into the serum depends on normal CYP450 activity (10-14). Discovery of Opioid Malabsorption

In 1975, I established a clinic within the Los Angeles 30

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County Public Health System to evaluate and treat patients with chronic and severe pain who had failed standard pain therapy and required opioid treatment. The original mission of the clinic remains today. In trying to find causes for treatment failure, malabsorption was initially suspected several years ago. The first clue came when some patients on oral opioids were found to have very low serum opioid levels (17,18). Other patients would occasionally report that they experienced no effect with an oral opioid but obtained relief when the same opioid was injected in an emergency room or hospital. Sometimes patients who underwent abdominal surgery, including bariatric surgery, reported that oral opioids were effective before the surgery but not afterward. An identical report was also related by some patients who sustained head or neck trauma. An oral opioid was effective before but not after the injury. Now that cytochrome CYP450 enzyme testing is widely available, many patients who claim that oral opioids have little or no pain-relieving effect are found to have multiple CYP450 enzyme defects (15,16). How to Recognize Opioid Malabsorption

The most likely candidates for opioid malabsorption are patients with chronic and severe pain who fail to find adequate relief with standard pain treatments. Failure is defined here as inadequate pain relief despite a variety of non-pharmacologic measures and clinical trials with antiinflammatories, antidepressants, neuropathic (“anti-seizure”) agents, muscle relaxants, and oral opioid daily dosages up to about 80 to 100 mg of morphine equivalence. In my clinic, we have found that 20 to 30% of “failures” are actually a failure to recognize opioid malabsorption. Part of our past difficulty in recognizing opioid malabsorption was that most patients with opioid malabsorption do not have full blown malabsorption syndrome but have selective malabsorption. Today, every pain patient referred to us for failure of standard pain treatment is evaluated for opioid malabsorption. We have developed a short, nine-question screening tool for patients to complete (Table 1). The presence of opioid malabsorption can almost always be suspected based on this questionnaire. Opioid malabsorption almost always occurs due to a gastrointestinal disorder, previous abdominal, pelvic, or spine surgeries, head or neck trauma, or autoimmune disorder (Table 2). We now routinely test for CYP450 defects since multiple defects commonly render some oral opioids ineffective (15). Sometimes we give a hydromorphone or morphine injection challenge to con-

Opioid M al absorp tion: A C ause of Pain Treatment Failure

firm the diagnosis of opioid malabsorption. Once opioid malabsorption is confirmed, patients are simply switched to non-oral routes of opioid administration (Table 3). Oral Ineffectiveness: The Tip-Off

The universal complaint of pain patients with opioid malabsorption is that oral opioids are ineffective. Too often these patients are dismissed as drug seekers or complainers. Patients who complain of ineffective oral opioid administration or inadequate opioid dosing should immediately be asked if they have had abdominal, pelvic, or spine surgery, head or neck trauma, and any history of gastrointestinal or autoimmune disease. Often the patient will report effectiveness with an injectable opioid in contrast to oral administration. The key point to be made is that a patient’s complaint of oral opioid ineffectiveness should not be ignored and that opioid malabsorption should be suspected as a possible cause. Summary

There is a group of patients with chronic and severe pain

who respond poorly, if at all, to oral opioids. In order to relieve their pain, these patients must be managed by nonoral opioid administration. Opioid malabsorption does not have to be part of a general malabsorption syndrome such as is seen with celiac or Crohn’s disease. Any damage to the autonomic nervous system that interferes with or impairs intestinal control or motility can cause opioid malabsorption. In modern society, multiple abdominal or pelvic surgeries are perhaps the most common cause of opioid malabsorption. Multiple surgeries may produce neurologic impairments, disturbances of bacterial flora, and formation of adhesions. Head and neck trauma including surgery may apparently cause opioid malabsorption likely due to damage of the autonomic nerves, including the vagus nerve, which regulate gastrointestinal motility. Spine surgery may also injure the autonomic splanchnic nerves that emanate from the sympathetic ganglia that surround the spine and help control intestinal motility. Some patients appear to have opioid malabsorption at least, in part, due to multiple, defective CYP450 enzyme function. Patients with opioid malabsorption may have multiple causes making it some-

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THE PA IN PRACTITIONE R

| VOLUME 25, NUMBER 1 |

Opioid M al absorp tion: A C ause of Pain T reatment Failure

times difficult to precisely identify a single underlying cause of this condition. Opioid malabsorption, regardless of its precise cause may be a reason for pain treatment failure, so its recognition is essential for opioid management. References 1. Tennant F. Malabsorption of opioid medications. Pract Pain Mgt. 2013;13(6):31-34. 2. Tennant F. Poor oral opioid response and malabsorption. Poster presented at: 25th Annual Clinical Meeting of the American Academy of Pain Management; September 2014; Phoenix, AZ. 3. Husebye E. Gastrointestinal motility disorders and bacterial overgrowth. J Intern Med.1995;237(4):419-427. 4. Virally-Monad M, Tielman D, Kevarkian JP, et al. Chronic diarrhea and diabetes mellitus: prevalence of small intestinal bacterial overgrowth. Diabetes Metab. 1998;24(6):530-536. 5. Karras PJ, Pfeifer MA. Diabetic gastrointestinal autonomic neuropathy. Curr Ther Endocrinol Metab. 1997;6:462-465. 6. Lai Ping So A, Mayer L. Gastrointestinal manifestations of primary immunodeficiency disorders. Semin Gastrointest Dis. 1997;82(1):22-32. 7. Washington K, Stenzel TT, Buckley RH, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol. 1996;20(10):1240-1252. 8. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 “PIE.” Drug Metab Dispos. 2006;34(5):880-886. 9. Kaminsky LS, Zhang QY. The small intestine as a xenobiotic-metabolizing organ. Drug Metab Dispos. 2003;31(12):1520-1525.

Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos. 1999;27(7):804-809. 11. Yang J, Tucker GT, Rostami-Hodejan A. Cytochrome P-450 3A4 expression and activity in the human small intestine. Clin Pharmacol Ther. 2004;76(4):391. 12. Obach RS, Zhang QY, Dunbar D, Kaminsky LS. Metabolic characterization of the major human small intestinal cytochrome P-450s. Drug Metab Dispos. 2001;29(3):347-352. 13. Paine MF, Khalighi M, Fisher JM, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther. 1997;283(3):1552-1562. 14. Paine MF, Schmiedlin-Ren P, Watkins PB. Cytochrome P-4501s expression in human small bowel: interindividual variation and inhibition by ketoconazole. Drug Metab Dispos. 1999;27(3):360-364. 15. Tennant F. Opioid regimens in chronic pain patients with multiple cytochrome p450 defects. J Opioid Mgt. (In Press) 16. Tennant F. Cytochrome P450 testing in high dose opioid patients. Prac Pain Mgmt. 2012;12(7):43-58. 17. Tennant FS. Inadequate morphine serum levels despite high oral dosages in severe, chronic intractable pain patients. Abstract presented at the 60th Annual Meeting of the College on Problems of Drug Dependence; 1998; Scottsdale, AZ. 18. Tennant F. Opioid serum concentrations in patients with chronic pain. J Palliat Med. 2007;10(6): 1253-1254.

Forest Tennant, MD, Dr. P.H., is the owner

of Veract Intractable Pain Clinic in West Covina, California.

10. Zhang QY, Dunbar D, Ostrowska A, Zeisloft S, Yang J, Kaminsky LS.

SAVE THE DATEs Join us for THE 2015 & 2016 Annual Clinical Meetings Gaylord National Washington, D.C. Sept. 17 - 20, 2015 JW Marriott San Antonio, Texas Sept. 22 - 25, 2016

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Complex Regional Pain Syndrome: From Diagnosis to Treatment By Philip Ge t son, DO

omplex regional pain syndrome (CRPS) is a debilitating neuropathic pain disorder most often characterized by severe burning pain and vasomotor instability due to autonomic nervous system dysfunction. While it usually exists in an extremity, it can affect any part of the body. To state that this is a poorly understood and undertreated pathologic entity would be an understatement. Estimates abound regarding the number of individuals afflicted with this disorder and range from approximately 1 million to 10 million. In addition, it is postulated that an equal number of individuals suffer from the disorder but remain undiagnosed. With such a large patient population, why then does the disease remain so poorly understood? CRPS (or, as it was formerly called, reflex sympathetic dystrophy) generally falls into the medical school teaching category of neurology and/or pain medicine. In fact, it is most often the primary care physician who sees its initial signs and symptoms. Unfortunately, there is little to no teaching about this disorder in today’s medical and nursing schools. It is either a footnote to other diseases or mentioned as one of the differential diagnoses for chronic intractable pain. To understand the disorder, some history is necessary. The first reference in the medical literature to CRPS occurred in the 17th century when Ambroise Paré described RSD as severe burning pain following a peripheral nerve injury (1). In 1864 S.W. Mitchell in his paper “Gunshot Wounds and Other Injuries” coined the term causalgia meaning “burning pain” to describe the persistent symptoms following gunshot wounds to the peripheral nerve (1). In 1993 the International Association for the Study of Pain (IASP) initiated the term CRPS and then categorized reflex sympathetic dystrophy to CRPS Type I and CRPS II. Type II is characterized by the presence of an initiating event such as surgery or traumatic injury of a major nerve (2). Many theories have been offered as to the pathophysiology of the disorder and no consensus has occurred. The most common belief is that CRPS occurs when a persistent noxious stimuli from an injured body region leads to

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peripheral and central sensitization upon which a primary afferent nociceptive mechanism demonstrates abnormally heightened sensation including spontaneous pain and hyperalgesia. Allodynia and hyperalgesia occur when central nervous system somatosensory processing misinterprets normal, non-painful, mechanical stimuli such as light touching of the skin as painful (3). As a general rule, CRPS begins with pain most often described as a “burning” pain. Other terms include aching, throbbing, sharp, dull, or lancinating. The severity of the discomfort is described as being out of proportion to the inciting event. The pain usually begins spontaneously in a single limb but most often spreads to other regions of the body such as another limb, the spine, or the internal organs (4). Other symptoms include skin color and temperature changes, edema, vasomotor and pseudomotor abnormalities, motor dysfunction, and trophic changes. The skin can be hot or cold and bluish-purple, fiery red, dusky, and mottled in color. Edema is usually significant and refractory to diuretic therapy. The swelling can be so significant that the skin may be tight, shiny, and may even show sloughing. Muscle spasm, atrophy, and weakness can occur. Hyperhidrosis (increased perspiration) can be seen on the affected limb. Hair and nail growth may be increased or decreased. Loss of strength, difficulties initiating movement, abnormal posturing of the hands or feet (dystonia), muscle spasm, or fasciculations occur in the majority of cases. CRPS is more predominant in females than males (5). The most commonly afflicted individuals range from 37 to 50 years of age, but CRPS can affect children as young as 10. In my experience, there is a genetic predisposition for CRPS. A specific gene has not been identified; however, in my clinical practice I have seen 17 families where more than one member of the family has a working diagnosis of CRPS. This occurs in both parent-sibling genetics as well as siblingsibling genetics. Further research into this facet is ongoing. Differential Diagnosis

When evaluating a patient for chronic persistent pain, the

Comple x Regional Pain S y ndrome: From Diagnosis to Tre atmen t

history and the mechanism of injury become of paramount importance. Most of my 900 cases have fallen into the Type II category, with an identifiable stretch injury to a nerve or a traumatic injury such as a fracture or one requiring surgery. By means of differential diagnosis, there are myriad alternatives. Diabetic neuropathies would be one of the first. CNS manifestations of neoplasm, spinal cord injury, radiculopathy, and plexopathy must also be considered. Lyme disease is often concurrent with a diagnosis of CRPS and the interrelation between the two is currently under investigation. Entrapment neuropathies such as carpal tunnel syndrome, cubital tunnel syndrome, and tarsal tunnel syndrome often lead to sympathetic dysfunction. Morton’s neuromas and brachial plexopathies are two of the most common initial causes of the disorder and need to be included in the differential diagnosis. Infectious and toxic etiologies and heavy metal exposure for neurologic abnormalities must also be considered as should alcohol-related

[CRPS] pain usually begins spontaneously in a single limb but most often spreads to other regions of the body.

disorders and nutritional causes. Raynaud’s phenomenon is often confused with CRPS as are venous and arterial insufficiency. Psychological overlays often lead the clinician to believe that the problem is due to hysterical conversion reactions or symptom magnification in the case of underlying medical legalities. Autoimmune and rheumatologic disorders and demyelinating problems such as multiple sclerosis must also be considered in the differential diagnosis. Diagnosis

In the past, the diagnosis has been one of exclusion. There is no specific laboratory test for CRPS. Inflammatory markers such as C-reactive protein are often quite high, but these are nonspecific, as are ANA and sedimentation rate. Rheumatic factor can be elevated for other reasons. Radiologic studies such as x-ray, CT scan, and MRI can rule out other causes of CRPS or concurrent disorders but do not provide a definitive diagnosis for the disorder. A triple phase bone scan, once thought to be the “gold standard” of diagnosis, has fallen into disfavor because it confirms fewer than 20% of CRPS cases. Electrodiagnostic testing most often will be misleading because it is a measure of motor and not sensory dysfunction. In addition, the mechanism of testing is extremely painful for patients with CRPS and frequently cannot be completed. In my opinion, the best available diagnostic test to definitively rule in CRPS is infrared imaging or thermography. Numerous opinions have been offered regarding the use of thermography in the evaluation of patients with CRPS (6-9). In the past 20 years I have never seen a case in which the thermogram failed to illustrate the diagnosis of CRPS. Symptomatology

In addition to the neurologic manifestations mentioned above, cognitive dysfunction is frequent in CRPS. There is short-term THE PA IN PRACTITIONE R

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Comple x Regional Pain S y ndrome: From Diagnosis to Tre atmen t

memory loss and a general “dulling” of the senses. Patients find word retrieval extremely difficult. Thought processing is impaired. The simplest of recalls (the patient’s home telephone number, etc.) are difficult. The problem is worsened by inactivity and lack of mental stimulation, which patients often experience because of the severity of the disease. The patient’s vibrational sense also is altered. For example, a patient might report significant pain from the vibrations of a loud car radio, particularly if the bass is accentuated, in an adjacent car. Syncope is a significant problem and is common in patients with CRPS. It is theorized that CRPS patients are predisposed to syncope because of autonomic dysregulation of lower extremities that leads to impaired sympathetic vasoconstriction and venous pooling (10). Double-vision, blurred vision, scotomata, and especially photophobia are common. Changes in visual acuity are frequently seen as well. Patients suffer from increased acuity to hearing or, more often, otophobia. They are extremely sensitive to loud noises. Dysphagia is common. Hoarseness occurs because of irritation of the brachial plexus. Facial pain from irritation at C2 and mouth pain, especially in the gums, is prevalent. Because of its effect on the nerve roots to the teeth, poor dentition is common and many patient’s teeth literally break and fall out. Full dental extractions in teenagers have been seen because of the “rotting” of the teeth, even in individuals who take “good care” of their teeth. Atypical chest pain has been noted. Evidence of sensitization of the intercostobrachial nerve has been reported as a cause for atypical chest pain (11). Tachycardia is often seen, especially in adolescents and teenagers. Bradycardia to the degree a pacemaker is necessary in patients with no evidence of intrinsic heart disease has also been reported. Dyspnea at rest or with minor exertion is seen, but to a lesser degree than other symptoms. The most common gastroenterologic sign and symptom that I have seen is gastroparesis, which is refractory to most conventional medications or treatments. Gastric emptying studies show significant gastroparesis and the best therapeutic endeavor for this disorder has been botulinum toxin A injections into the pyloric sphincter. Other GI complications also include nausea, vomiting, intermittent diarrhea, symptoms of irritable bowel syndrome, indigestion, dysphagia, gastroesophageal reflux disease (GERD), and abdominal pain frequently mistaken for gallbladder disease. Patients have shown manifestations of neurogenic bladder that is frequently confused with interstitial cystitis. The symptoms are similar and lead to a diagnostic dilem36

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ma for urologists. As with all other pain disorders, one must rule out neuromusculoskeletal causes such as disc herniations, entrapment neuropathies, or radiculopathies, among others. Concomitant posttraumatic injuries create a dilemma for the treating physician due to the tremendous overlap in symptoms. Similarly, CRPS and fibromyalgia share defining characteristics, such as chronic pain and allodynia, as well as other important clinical features such as onset after trauma, female predominance, paresthesias, vasomotor instability, response to sympathetic blockade and anxiety/depression (12,13). I believe that fibromyalgia is not a separate entity and that it is actually a subset or variation of CRPS. If this is correct then the number of CRPS patients increases to about 50 million. There can be no doubt that there are psychological ramifications of CRPS, which can be said of all chronic persistent diseases. Patients with such disorders suffer from varying degrees of depression. They have had a generalized disruption of their entire lives—occupational, social, personal, emotional, familial, and other areas. Such a disruption leads to a depressive symptomatology frequently with a concurrent anxiety component. Physicians not versed in the diagnosis of CRPS often believe it to be a psychological or psychiatric disorder. While I will grant that there are psychological manifestations of the disease, it is a very real clinical neurological problem. Treatment

Physical therapy. Treatment of CRPS is multifaceted and requires an individualized and multidisciplinary approach. While there is no “one size fits all” therapy, the first step in the treatment process is mobilization. Movement of the affected limb prevents secondary complications, such as frozen shoulder in a patient with an upper extremity issue. Physical therapy and/or occupational therapy in the hands of a therapist well versed in the treatment of the disorder are the next step in the pathway. It is imperative that the treating therapist understands the manifestations of the disorder and the “do’s and don’ts.” For example, movements of the upper body that stretch an already irritated brachial plexus will significantly worsen the disorder. Medication. There are multiple medications that should be considered. I have always maintained that there are four separate “pains” in CRPS and each of these should be dealt with individually. For muscle spasms, muscle relaxants are appropriate and should be taken on an as-needed basis. For

Comple x Regional Pain S y ndrome: From Diagnosis to Tre atmen t

inflammation, antiinflammatory medications are appropriate and also should be taken on an as-needed basis, taking care to avoid exacerbating the gastroenterologic symptoms that frequently accompany CRPS. Many other medications have been tried, including calcium channel blockers, dextromethorphan, tricyclic antidepressants, and, more recently, serotonin-norepinephrine reuptake inhibitors (SNRIs). I have not seen any evidence that tricyclic antidepressants provide significant relief, and the side effects are plentiful, particularly weight gain. The concept that SNRIs, such as duloxetine, bring pain relief is a reasonable one in patients with mild pain; however, the extent and severity of the pain in patients with CRPS is often so accelerated that their use is fruitless for pain relief alone. Their value may lie most in treating the depression that accompanies chronic pain. The burning and associated neuropathic pain symptoms can be treated with anticonvulsants. All of the currently available drugs have been used off label with varying degrees of success. Some of these agents do cause significant weight gain, which can accelerate physical symptoms as well as depression, especially in CRPS patients who are relatively inactive.

For CRPS pain it is always preferable to stay away from opioids because of the risk of hyperalgesia. Non-opioid agents such as tramadol can be initiated and other analgesics added if they are ineffective. These include Schedule III agents such as hydrocodone with acetaminophen and short and long-acting opioids in oral or topical formulations. Interventional procedures. Specialists in interventional pain can perform a number of useful procedures. Sympathetic blocks both to the stellate ganglia and lumbar sympathetic chain can be helpful either in the earliest stages of the disease or as a concomitant treatment to other forms of therapy for exacerbations and flares. Epidural injections are helpful when there is a concurrent radiculopathy. The insertion of spinal cord stimulators has met with mixed responses. I believe that such devices should only be used in individuals with documented “one-limb” disease. In patients whose disease has spread to internal organs or other limbs, the benefits to be obtained are few and the risks great. The use of intrathecal pumps is also offered, but in my opinion this is a treatment of last resort because it is simply the administration of medication to minimize spasm or pain

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THE PAIN PRACTITIONE R

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Comple x Regional Pain S y ndrome: From Diagnosis to Tre atmen t

rather than treatment of the underlying cause. Hospitalbased epidural infusions can deliver higher doses than outpatient infusions and may be of benefit in conjunction with other treatments. There are still some clinicians performing surgical sympathectomies although it has been my experience that these are rarely beneficial. I believe that the risk outweighs the benefit in such procedures. Ketamine. Currently, ketamine is being used for the treatment of CRPS when conservative or conventional treatments have been unsuccessful. Much has been written about ketamine and the treatment of CRPS beginning with the case report from Harbut and Correll in 2002 (14). Since that time the use of ketamine in its subanesthetic dose has accelerated.

We have also found that the use of alternative modalities of treatment such as Reiki, acupuncture, and therapeutic touch have been beneficial. In 2005, Himmelseher and Durieux reported on the benefit of ketamine for perioperative pain management (15). Schwartzman and colleagues clearly showed the effectiveness of ketamine for the treatment of CRPS versus a placebo in 2009 (16). In collaboration with German clinicians, he also showed its value in anesthetic doses that are not permitted in the US (17). Dr. Schwartzman and I published a study in which more than 40 patients, all of whom were under active treatment for CRPS, were given ketamine intraoperatively for various types of surgery from dental procedures to podiatric. In my portion of the study, none of the patients who was administered intraoperative ketamine displayed an extension of CRPS that is frequently found when ketamine is not used. This leads to great hope that the use of ketamine intraoperatively may at least prevent the spread of the disorder (18). I have given subanesthetic ketamine to more than 100 patients on an outpatient basis. The patients present to a dedicated infusion suite in my office with full cardiac and pulse oximetry monitoring under the direct supervision of a nurse. More than 80% of these patients have shown improvement, which I consider as fulfilling one of the following three criteria: 38

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• An objective improvement in symptoms, including diminished allodynia, hypersensitivity, color and temperature alterations, and edema. • A subjective improvement in pain on a VAS pain scale, which coincides with an increase in overall activity and physical capabilities. • The ability to reduce medication and still increase functional capability. Patients had no side effects that were attributable to ketamine. Treatments were discontinued in two patients because of side effects that were independent of the ketamine. Half of the patients who did not improve actually showed initial improvement, but their symptoms recurred within days after the infusion was discontinued. Alternative therapies. Based on my 14 years of treating patients with CRPS, I believe the patient’s diet is of paramount importance. There is no question in my mind that patients who adopt a healthy protocol do better. We have recently found that patients who were willing to go completely gluten-free have a significant reduction in subjective and objective signs and symptoms. We stress dietary discretion and proper eating and have found that it has had a significant impact on the patient’s condition. We have also found that the use of alternative modalities of treatment such as Reiki, acupuncture, and therapeutic touch have been beneficial. In one patient, for example, we were able to see her infrared images change from being asymmetrical to symmetrical over a six-week time frame with no adjustment in treatment modalities save for the initiation of Reiki treatments. We have found that a positive attitude and spirituality have had a great impact on patients’ wellbeing. We encourage patients to undertake hobbies or begin spiritual practices that will lead them to relaxation. We have found that patients who relax in one form or another are clearly better and offer less subjective and objective symptomatology. Conversely, patients with traumas in their life (such as deaths of loved ones, financial disaster, physical trauma, or interpersonal difficulties within the family) experience an acceleration of the total symptom complex, especially the pain. Current Research

Stem cell research is beginning. Comprehensive evaluation of brain functioning is being studied, specifically the evaluation of glia. Genetics, as mentioned, are being investigated and endocrinologic and infectious manifestations of CRPS are being researched as well. Continued on page 48

FROM THE CLINIC

A Patient with Diabetes and Chronic Pain Project ECHO Chronic Pain and Headache TeleECHO Clinic Case Study

Project ECHO (Extension for Community Healthcare Outcomes) was developed by the University of New Mexico to treat chronic and complex diseases in rural and underserved areas of New Mexico. This case-based distance learning teaches physicians and advanced practice providers, such as nurse practitioners and physician assistants, pharmacists, clinicians, and others about chronic pain issues. Throughout the state, providers in solo practice are working with very little access to specialty care referrals. Through Project ECHO these providers learn how to care for patients in their own community, without the patient having to travel five or six hours for a consultation. The tele-education program also solves the problem of a patient needing a chronic pain consultation and having to wait three months to be seen. The physician, the nurse practitioner, the physician assistant, or other practitioner can call the clinic every week to get a consultation. Unlike a telemedicine program, the ECHO team does not see the patient on the other side of the video or the television. They see the providers, who earn continuing medical education credit for every hour they participate. Providers sign up with the program and they participate using either video or audio connection. The program includes a 30-minute didactic presentation by an invited faculty member and then a review of cases submitted by the participants to the EHCO team (patients are de-identified for HIPAA compliance). Providers get their consultation from a virtual interdisciplinary team, which makes formal treatment recommendations. Thus, the pain clinic combines actual patient case studies with didactic learning on pain management topics. This case was presented to the entire ECHO Pain network on May 22, 2014. All patient health information has been removed. The presenter was Charles Monroe, PA-C (name has been changed for confidentiality), in Yuma, Arizona, a primary care clinician who is a pain champion in his local clinic. The case was viewed by the network members and discussed by the following faculty: • Joanna G. Katzman MD, neurology • Daniel J. Duhigg DO, addiction psychiatry • George D. Comerci MD, internal medicine • Brian M. Shelley MD, family medicine and myofascial pain expert • Tom Arnold, DC, chiropractic

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Mr. Monroe:

Mr. X is a 54-year-old Caucasian male with diabetic endstage renal disease on hemodialysis, who also has low back pain and lower extremity neuropathy. He is unemployed and married, and he completed college. My main question is how to improve this patient’s poor pain control, yet possibly decrease his current opioid dose. He has low back pain and severe pain in his feet and legs, with burning, sharp stabbing, and numbness (see figure). Average pain severity is 8/10. The pain is exacerbated by almost everything, and ameliorated by medications. Current medications include alprazolam 1 mg BID, zolpidem 12.5 mg daily, oxycodone extended-release 60 mg TID, and oxycodone immediate release 30 mg q4h. Previous medications that were not useful included gabapentin and pregabalin. Cyclobenzaprine and massage have been helpful. In addition to diabetes, ESRD, and chronic pain, Mr. X has cirrhosis, Mr. X has low back pain and severe pain in his feet and legs, with burn- obstructive sleep apnea ing, sharp stabbing, and numbness. and is on CPAP, with moderate adherence. He also had bariatric surgery for obesity. He denies depression, and has a recent PHQ-2 Score of 0. However, he does have generalized anxiety. Physical examination shows normal sensation and strength in all extremities. Lumbar range of motion is normal, but the area is diffusely tender. Supine straight leg raise testing is negative bilaterally. No imaging studies of the lumbar spine or lower extremities are available. Recent pertinent laboratory studies show the following: WBC: 3.6; HGB: 8.2; HCT: 25; Platelets: 106; Sodium: 139; Potassium: 3.8; Chloride: 96; Glucose: 101; BUN: 24; Creatinine: 6.2; Calcium: 8.3; Total Protein: 6; Albumin: 3.4; Total Bilirubin: 0; Alkaline Phosphatase: 78; AST/SGOT: 17; ALT/SGPT: 15; Hemoglobin A1C: 6.3.

FROM THE CLINIC

Dr. Katzman:

Thank you for presenting this patient to us. First, let’s see if anybody on the network has other questions about the facts of this case. Dr. Arnold:

Has this fellow had any acupuncture yet? I am also very curious about his nutritional status. Mr. Monroe:

He has not yet tried acupuncture. I am not sure it is available around here. Dr. Shelley:

His diabetic peripheral neuropathy is well explained but what is his low back pain diagnosis? Mr. Monroe:

We are trying to obtain some imaging, but it has been difficult with his dialysis schedule and remote location. Dr. Katzman:

I would like to invite Dr. Duhigg to comment on his medical regimen. Dr. Duhigg:

Thanks, Joanna. Charles, I share your concern about managing pain in this patient, and I agree that he does indeed need a reduction of his daily opioid dose. He is currently at a daily morphine equivalent dose of 360 mg/ day, which is very high, and puts him at very high risk of death. Added to that are the problems of sleep apnea and benzodiazepine use. Another cause for concern is the fact that his pain is still so high on such a large dose. It raises the question of whether the opioids themselves are contributing to the pain, also known as opioid-induced hyperalgesia.

helpful here too, if it hasn’t been tried. Mr. Monroe:

Thank you to our Dr. Duhigg: Buspirone would beCorporate a good choice for this guy. Dr. Katzman: Charles, we hope theseCouncil suggestions are helpful. But we would love to hear Members! back about him in several months to learn about his progress. We wish you all the best in taking

I can look into those things when I see him again. If I have to stop the benzodiazepines, what can I use instead for his anxiety?

care of this patient.

American Academy of Pain Manageme

Editor’s note: We invite our readers to comment on theseCorporate cases CounCil from your perspective. We believe each specialty looks forContact cer- sheila Miller (s Jillian Manley (Jillian@a tain signs during the diagnostic process and makes treatment become a Corporate recommendations that enhance the patient’s well-being. toPlease email your comments about this case and upcoming ones to cconeghen@aapainmanage.org.

Thank you to our Corporate Council Members!

Mr. Monroe:

What would be the best way to taper him? Dr. Duhigg:

You can simply reduce his dose by about 10% each week. Dr. Comerci:

I’d like to weigh in on the diabetic peripheral neuropathy issue too. DPN is probably the cause of the neuropathy, but it can be caused by other conditions, such as heavy alcohol use, heavy metal exposure, and non-alcoholic chronic liver disease caused by various entities such as hemochromatosis, Wilson’s disease, and Hepatitis B- and C-related liver disease. Given that he has cirrhosis, he may need a workup for these disease entities. Amitriptyline may be

Become a Corporate Council Member today! Contact sheila Miller at smiller@aapainmanage.org, or Jillian Manley at jmanley@aapainmanage.org (209) 533-9744

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| VOLUME 25 NUMBER 1 |

FROM THE CLINIC

Compounded Medications Provide Relief for Diabetic Peripheral Neuropathy By Jessic a DiLeo, PharmD

Diabetic Peripheral Neuropathy: An Overview

Diabetes mellitus is a lifelong health issue. In fact, by 2030, it is estimated that the worldwide prevalence of diabetes will reach an alarming 366 million (1). With the incidence of diabetes mellitus climbing each year, the complications associated with this condition will continue to rise as well. Neuropathies are among the most common of all complications associated with diabetes mellitus, affecting up to 50% of patients (2). More specifically, diabetic peripheral neuropathy is by far the most common diabetic neuropathy, causing dysfunction of the peripheral nerves (2,3). Furthermore, the incidence of diabetic peripheral neuropathy increases with the duration of diabetes mellitus (1). Diabetic peripheral neuropathy can be characterized by multiple symptoms, including burning pain, knife-like pain, electric shock-like pain, tingling, and prickling (2). There are a number of medications that are often prescribed for the management of these pain symptoms associated with this condition, including tricyclic antidepressants, anticonvulsants, and anesthetics (2). Compounding: An Overview

Compounding is the art and science of preparing specialized medications with an individual patient in mind. Unlike the “one-size-fits-all” nature of mass-produced manufactured medications, compounded medications are individualized and “made from scratch”—ingredients are mixed together in the exact strength and dosage form required by the patient at the request of the prescriber. This preparation method allows the compounding pharmacist to work with the patient and the prescriber to customize a medication to meet the patient’s specific needs. Compounding may be recommended for reasons including, but not limited to, the following situations: • Patients may be allergic to a specific preservative, dye, or binding agent found in a manufactured product. A compounding pharmacist would be able to compound the same product without the allergy-causing agent. • If a manufactured medication is discontinued, a compounding pharmacist may be able to obtain the bulk powder form 42

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of the medication and compound it into a similar dosage form. • Pediatric or veterinary patients who may require a different dosage form (i.e., a solution rather than a tablet) or flavoring could benefit from having their medication compounded. • A compounding pharmacist is able to combine multiple medications into one convenient dosage form, often increasing patient compliance. • When patients are sensitive to medications, such as stomach upset from antiinflammatory medications, a compounding pharmacist can prepare a transdermal formulation (i.e., cream/gel) that the patient would apply directly to the site of pain, avoiding adverse side effects. Case Study

A 64-year-old male was diagnosed with diabetic peripheral neuropathy affecting the feet and toes one year ago by his family physician. He was initially started on Lyrica® but was switched to gabapentin due to the cost of Lyrica. He was instructed to take one gabapentin 400 mg capsule three times daily. The patient reported that he noticed some improvement in his feet after taking the gabapentin for a couple of weeks, but he was still bothered by the burning and tingling, especially after being on his feet for long hours. He then made an appointment with a podiatrist who prescribed a compounded transdermal cream containing ketamine 10%, gabapentin 6%, imipramine 3% and bupivacaine 2%. He was instructed to apply one gram of the medication to the feet and toes three to four times daily. After applying the transdermal medication as prescribed for a week, the patient reported that his feet were much more comfortable. He reported that his pain level typically decreased from an 8 to 9 on a scale of 10, down to 2 to 3 on a scale of 10 within 30 minutes after application of the topical medication, and the pain relief lasted a couple of hours. He stated, “After rubbing the medicine on my feet at night, I’m asleep within 20 minutes!” Discussion

The use of tricyclic antidepressants for the management of pain associated with diabetic peripheral neuropathy is sup-

FROM THE CLINIC

ported by several randomized, controlled studies. While the mechanism of action of these agents is not clear, it is thought that they inhibit the reuptake of norepinephrine and serotonin as well as affect sodium channels and N-methyl-Daspartate (NMDA) receptors (2). Despite the fact that this drug class is considered as a first line medication in the treatment of diabetic peripheral neuropathy, it is often not used due to its side effect profile. The anticholinergic effects of these medications, including dry mouth, blurred vision, and postural hypotension, make them an undesirable choice for treatment. In fact, up to one-third of patients who are prescribed tricyclic antidepressants are unable to tolerate these agents (2). It is unfortunate that these patients are unable to reap the benefits of these medications simply because of the side effects associated with them. However, via compounding these patients can receive the benefits while avoiding unwanted side effects of this class of medications. Because transdermal delivery allows medications to travel directly to the site of pain rather than having to be taken systemically, there are little to no side effects experienced. Among other neurotransmitters involved in pain perception associated with diabetic peripheral neuropathy, NMDA receptors sites reside in the neural periphery (4). Both NMDA glutamate receptor antagonists, dextromethorphan and memantine, have been evaluated in painful diabetic neuropathy with results confirming their effectiveness (5). Antidepressants and ketamine produce multiple pharmacological effects that contribute to peripheral analgesia. According to an open-label study using topical amitriptyline 2% and ketamine 1%, an NMDA antagonist, in the treatment of neuropathic pain syndromes long-term pain reduction was achieved. Furthermore, there was no significant systemic absorption of either medication (6). Of the anticonvulsants used in the management of diabetic peripheral neuropathy, gabapentin is the most widely used. Damaged or demyelinated nerves spontaneously fire, have excess voltage and have extra-sensitive electrolyte channels in the affected area (7). Gabapentin is a calcium channel blocker that works to inhibit the release of excitatory neurotransmitters. There are undesirable side effects associated with gabapentin taken orally as well, including sedation, dizziness, and headache (7). There are a number of studies that have determined the efficacy of lidocaine when used topically in the treatment of neuropathy, and more specifically diabetic neuropathy. The mechanism of action of lidocaine is believed to â&#x20AC;&#x153;reflect decreased ectopic discharges within peripheral sensory afferents

(i.e., a selective effect on hyperexcitability), as pain relief occurs in the absence of anesthetic effectsâ&#x20AC;? (8). Because inflammatory processes can contribute to the pain associated with diabetic peripheral neuropathy, these agents prove even more beneficial since they also provide antiinflammatory effects (8). Until a few years ago, there were no studies performed to determine the ability of a transdermal cream to deliver medications through the human skin. This study proved that multiple medications could be rapidly delivered through the skin simultaneously (9). The transdermal delivery vehicle used in the compounded formulation utilizes liposomes to facilitate the movement of medications through the various layers of the skin. A liposome is a tiny vesicle made out of the same material as a cell membrane (10). These phospholipid bilayers encapsulate the medications and carry them through the skin to their action site. Conclusion

Diabetic peripheral neuropathy is a common and serious complication of diabetes mellitus. If not properly managed, further complications such as foot ulcers and amputations may occur. Because of the side effect profiles of many of the first line treatment medications, compounded transdermal pain relief formulations, supporting multiple medications, may offer a beneficial alternative for those patients with diabetic peripheral neuropathy. References 1. Cheing G. Diabetic peripheral neuropathy. Int J Ther Rehabilitation. 2010; 17(1):8-9. 2. Boulton A. Management of diabetic peripheral neuropathy. Clin Diabetes. 2005;23(1):9-15. 3. Illa I. Diagnosis and management of diabetic peripheral neuropathy. Eur Neurol. 1999;41(suppl 1):3-7. 4. Jones M. Chronic neuropathic pain: pharmacological interventions in the new millennium. IJPC. 2000;4(1):6-15. 5. Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology. 2002;96(5):1053-1061. 6. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study. J Pain. 2005;6(10):644-649. 7. Wamboldt C, Kapustin J. Evidence-based treatment of diabetic peripheral neuropathy. J Nurse Pract. 2006;2(6):370-378. 8. Sawynok J. Topical analgesics in neuropathic pain. Curr Pharm Design. 2005;11(23):2995-3004. 9. Evaluation of percutaneous absorption of ketamine HCl, gabapentin, clonidine HCl and baclofen in Lipoderm and Lipoderm ActiveMax. PCCA, Document #93881. 10. What is a liposome? 2011. http://www.news-medical.net/ health/What-is-a-Liposome.aspx. Accessed January 22, 2015.

Jessica DiLeo, PharmD, is a compounding pharmacist at Custom Meds, Inc. in Inverness, Florida. Dr. DiLeo received her doctorate of pharmacy in 2009 from the University of Florida and eventually became the owner of Custom Meds compounding pharmacy in 2011. She can be contacted at jessica@custommeds.com.

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| VOLUME 25 NUMBER 1 |

FROM THE CLINIC

Second Look on a Patient with Pain Reveals Childhood Sexual Abuse By Erik a Moody, MD

It is crucial to approach the patient in pain from a biopsychosocial perspective. Health care professionals must assess not only the physical sources of pain through clinical examination and diagnostic testing but also identify psychosocial problems, which may have preceded or resulted from pain, in order to fully understand all factors that influence the nature, severity, disability, and persistence of symptoms (1). In this case report, the patient was initially referred for complaints of low back pain after evaluation by several primary care practitioners and specialists. On further investigation, it was discovered that the patient had multiple additional symptoms, had undergone extensive medical work-up, and had failure of numerous pain management treatments. Additional history was obtained, which revealed that the patient had a history of childhood sexual trauma. This important historical information had not been evaluated or treated previously. In fact, a report published by the Journal of Pediatric Health Care states that only 5% of patients report sexual abuse history to their physicians (2).

The patient became tearful when asked about a history of abuse.

Case Report

A 15-year-old female with history of normal birth and development was referred for low back pain to a pediatric rehabilitation medicine clinic. The patient’s past medical history was notable for a history of osteomyelitis of the lumbar spine diagnosed at age two, which was treated with six weeks of intravenous antibiotics. She also had a history of L3-4 discitis diagnosed at age 11 after a minor physical trauma. The patient reported a history of diffuse pain in her right leg for as long as she could remember. Over several years, the patient subsequently developed increasingly severe and diffuse pain complaints. She had undergone extensive evaluation by multiple practitioners, including specialists in rheumatology, neurosurgery, orthopedic 44

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surgery, and immunology. She did not have any clinical findings or diagnostic studies supportive of an underlying immunologic, autoimmune, or neurological disorder. Upon evaluation by orthopedic surgery, it was concluded that the patient may be a candidate for elective lumbar spinal fusion in the future, given findings of intervertebral disc degeneration on imaging. The patient presented to the clinic with complaints of burning pain in her stomach, dizziness episodes, night terrors, depressed mood, recurrent nausea, diaphoretic spells with palpitations, and perioral discoloration. She had been given a trial of numerous medications without relief of her pain symptoms, including a lidocaine patch, meloxicam, baclofen, tramadol, gabapentin, hydrocodone/acetaminophen, ibuprofen, and acetaminophen with codeine phosphate (Tylenol No. 3). She had been treated for depression in the past with a selective serotonin reuptake inhibitor, which was ineffective. The patient had undergone numerous diagnostic tests including multiple spinal MRIs, which were unremarkable. The physical examination was significant for multiple areas of tenderness including the bilateral trapezius, levator scapulae, and gluteal musculature and the sacroiliac joints. She had a mild leg length discrepancy. Upper and lower extremity reflexes were symmetrical. Manual muscle testing was 5/5 strength in all extremities. Sensation was intact to light touch in all distributions. Straight leg raise, slump, Adam’s Forward Bending test, and facet loading tests were negative. ASIS distraction, Gaenslen’s, FABER, and sacral compression tests were negative. The patient demonstrated a flat affect with depressed mood and became tearful when asked about a history of abuse. She reported that she had been sexually abused at age five. Discussion

The U.S. Department of Health and Human Services reported that nearly 80,000 American children were victims of sexual abuse in 2006. It is estimated that only one in 20 cases of sexual abuse is identified by or reported to the authorities, based on retrospective studies of adults (2). Sexu-

FROM THE CLINIC

ally abused children have a disproportionally higher risk than non-abused children of having “medically unexplained symptoms” such as irritable bowel syndrome, chronic pain and fatigue syndrome, mental illness, and higher health care use. The etiology of these symptoms in abused individuals remains disputed although several theories have been proposed (3). While there are no validated theories to explain the association between sexual abuse and chronic somatic disorders, neuroendocrine dysfunction is believed to be an important process in underlying pathophysiology. Both animal studies and analyses in women with a history of childhood sexual abuse have demonstrated early life stress to be associated with dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). Most notable are changes in corticotropinreleasing factor (4). Stress activates both the central and peripheral components of the stress system, which include the HPA axis and the sympathetic system. It is believed that exposure of the developing brain to severe or prolonged stress may result in hyperactivity or hyperreactivity of these systems. This results in amygdala hyperfunction, decreased activity of the hippocampus and mesocorticolimbic dopaminergic system, and hyperactivation of the HPA axis. Additionally, there is suppression of reproductive, growth, thyroid, and immune functions, as well as changes in pain perception (5). This is further supported by studies using neuroimaging. A study by Noll-Hussong, et al., using functional MRI in patients with multisomatoform pain found that sexually abused participants demonstrated higher activation in the left lateral and medial superior frontal gyrus as well as a nonsignificant response of the right supplementary motor area. The non-abused patients demonstrated higher activation in the left hippocampus. There were no significant differences in subjective pain ratings between groups (6). The comorbidity of pain and depression is well established. Sachs-Ericsson, et al., studied 1,727 patients and examined the relationship between childhood abuse and pain reports to determine whether depression mediated this relationship. They concluded that childhood abuse was associated with more reported pain but that after controlling

Sexually abused children have a higher risk of having “medically unexplained symptoms.”

for differences in health problems depression was not found to mediate the relationship between abuse and pain reports. In other words, the higher rate of depression found among abuse victims was not the primary factor for the increased pain reports (7). This patient was prescribed duloxetine, a physical therapy program, and psychology referral for cognitivebased therapy. Studies have found that trauma-focused cognitive-based therapy for the symptomatic child to be the most effective for child sexual abuse (2). At follow-up, the patient had some relief of depression and pain symptoms and continues to undergo treatment. Conclusion

It is important that clinicians ask their patients specifically about a history of abuse in order to provide appropriate treatment strategies for often unaddressed problems. There is a need for heightened awareness of these health associations to improve health care delivery and outcomes. As highlighted in this case, failure to recognize this association may lead to exposing patients to increased rates of surgeries, adverse medication effects, chronic opioid use, and dependence. References 1. Turk D, Audette J, Levy RM, Mackey SC, Stanos S. Assessment and treatment of psychosocial comorbidities in patients with neuropathic pain. Mayo Clin Proc. 2010; 85(3 Suppl):S42-S50. 2. Horner G. Child sexual abuse: consequences and implications. J Pediatr Health Care. 2010; 24(6):358-564. 3. Nelson S, Baldwin N, Taylor J. Mental health problems and medically unexplained physical symptoms in adult survivors of childhood sexual abuse: an integrative literature review. J Psychiatr Ment Health Nurs. 2012; 19(3):211-220. 4. Paras M, Murad MH, Chen LP, et al. Sexual abuse and lifetime diagnosis of somatic disorders: a systematic review and meta-analysis. JAMA. 2009; 302(5):550-561. 5. Charmandari E, Kino T, Souvatzoglou E, Chrousos GP. Pediatric stress: hormonal mediators and human development. Horm Res. 2003; 59(4):161-179. 6. Noll-Hussong M, Otti A, Laeer L, et al. Aftermath of sexual abuse history on adult patients suffering from chronic functional pain syndromes: An fMRI pilot study. J Psychosom Res. 2010; 68(5):483-487. 7. Sachs-Ericsson N, Tackett-Kendall K, Hernandez A. Childhood abuse, chronic pain, and depression in the National Comorbidity Survey. Child Abuse Negl. 2007; 31(5):531-547.

Erika Moody, MD, is a resident physician in the department of

physical medicine and rehabilitation at Baylor College of Medicine in Houston, Texas. She obtained her medical degree at the University of Cincinnati. She is a recipient of the Arnold P. Gold Foundation Humanism and Professionalism in Medicine Award and also earned a master of biological science degree at Drexel University. Her practice goals are to treat patients with complex pain conditions using a multimodal and comprehensive approach with a focus on functional restoration.

THE PAIN PRACTITIONE R

| VOLUME 25 NUMBER 1 |

COMMENTARY

NUTRITION

Fire in the Belly: Gut Health, Inflammation, and Chronic Pain By Nanc y Cot ter , MD

Pain and gut function are two areas that we don’t usually think of as related, but if we take a look at the digestive process and the potential repercussions when it is poorly functioning, we realize that in the treatment of chronic pain, addressing gut function holds significant potential for relief. All chronic pain is associated with either local or systemic inflammation, which has been shown in various chronic pain conditions to be related to nutrition and GI function. Healthy gut function depends on a variety of factors, including the ability to: • Break down food particles to components that can be modified by intestinal bacteria and eventually absorbed. • Separate nutrients from pathogens and toxins (“friend from foe”). • Contain pathogens and toxins and prevent them from being absorbed. • Absorb nutrients through an intact and functional intestinal lining. • Transfer absorbed nutrients to the circulation for transport to organs and tissues to support metabolic needs, including those of the gut tissue itself. The breakdown of food substances into absorbable nutrients requires adequate stomach acid and enzymes. Digestive enzymes are necessary for the breakdown of proteins, as well as fats and carbohydrates. Stomach acid also kills or impairs ingested pathogens. Stomach acid decreases with aging and as a result of excessive antacid intake. Antacids have been shown to inhibit protein digestion and are associated with food allergy (1). Once the partially digested food is ushered into the intestinal lumen, the GI barrier must separate friend from foe. Nutrients may pass through to the layer of enterocytes that line the gut and into the circulation via transport through cell membranes (intracellular transport) or through tight junctions between cells (paracellular transport). Tight junctions occur at regular intervals along the intestinal border. From there, nutrients are transported to the organs and tissues to support metabolic processes. Healthy tight junctions limit the transport of large 46

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molecules across the epithelium. Unhealthy junctions allow large molecules such as pathogens and antigenic molecules to pass and cause disturbances. Increased intestinal permeability is also associated with inflammatory bowel disease (IBD), fibromyalgia, celiac disease, rheumatoid arthritis, and other rheumatic diseases, and with local and sometimes systemic pain. Interestingly, NSAIDs, which are taken to reduce inflammation and pain, are also associated with increased intestinal permeability and inflammation (2). Gut-associated Lymphoid Tissue

Over 80% of immunoglobulin producing cells are located within the mucosa of the GI tract and are part of a system known as GALT or gut-associated lymphoid tissue. In the mucosal layer of the GI lining, secretory antigens (sIgA) provide the first line of defense against viruses and non-friendly antigens, and these are passed into the feces without reaching the systemic circulation. Ig-A-associated neutralization involves mast cell degranulation, which results in the release of inflammatory mediators, such as proteases and cytokines, that can affect intestinal permeability. Without adequate repair mechanisms, the passage of allergens is increased, which can further perpetuate an inflammatory reaction (3). The pathogens and antigens that do penetrate the mucosa are exposed to more specific IgG and IgE antibodies in the GALT, which induces a systemic immune response including antibody production and inflammation. This response is prolonged with persistent pathological bacterial and antigen exposure and results in increased intestinal permeability and increased production of inflammatory cytokines (4). Inflammatory bowel disease is associated with inflammatory musculoskeletal conditions in approximately 33% of cases (5). An example of possible association between prolonged immune response to a pathogen and painful systemic processes is the relationship between antibodies to Proteus mirabilis and rheumatoid arthritis. Higher titers of antibodies to P. mirabilis have been documented in rheumatoid arthritis patients (6). Proteus spp. are not considered pathogens in all people, but an amino acid sequence on the surface membrane of the bacteria mimics a sequence (HLA) DR1 molecule associated with rheumatoid arthritis. This has given rise to the proposal that the presence of P. mirabilis in a

COMMENTARY

patient with both increased intestinal permeability and genetic susceptibility may increase destructive rheumatoid arthritis antibody activity in joints and other tissues. A similar relationship is thought to exist with ankylosing spondylitis and Klebsiella (7). Another example of increased intestinal permeability in association with systemic inflammation and pain is celiac disease. Antibodies to gliadin, a protein found in wheat, cause immune complexes to be deposited at the GI border. This gives rise to inflammation at the brush border, increased intestinal permeability, and impaired barrier function and nutrient absorption. When large molecules such as antibody complexes are permitted to penetrate the tight junctions, they can deposit in joints and other organs. Gut inflammation is associated with increased intestinal permeability, and has been associated with prolonged stress, as well as multiple chronic pain states such as fibromyalgia, IBD, rheumatoid arthritis, and ankylosing spondylitis (4,8). Many inflammatory cytokines are also pain mediators, and thus as inflammatory activity heightens, so does the level of pain mediators. Nuclear factor kappa B (NF-KB) binds to DNA to increase transcription of proinflammatory cytokines. Some cytokines such as IL-1β and IL-6 act as pain generators, while others, such as prostaglandins, sensitize peripheral nociceptors. Decreasing pro-inflammatory activity is essential to decreasing the levels of associated pain mediators. The Role of the Intestinal Microbiome

NUTRITION

diet. One example is stomach acid, which naturally decreases with age, and which is necessary for the initial breakdown of proteins and inactivation of microorganisms. Digestive enzymes may be helpful in some individuals. An antiinflammatory diet that is rich in nutrients and tailored to the individual is recommended. Laboratory testing to assess nutrient and digestive status is helpful but not absolutely necessary. 3. Reinoculate by using a probiotic to reestablish a healthy gut flora population. Beneficial bacteria use competitive inhibition and, in some cases, produce inhibitory substances to decrease the growth of pathogenic bacteria. Use a preparation that includes lactobacilli and bifidobacteria and at least 1 million colony-forming units (CFU). 4. Repair by adding nutrients that benefit enterocytes such as glutamine, short-chain fatty acids, and essential fatty acids. Some botanical substances such as deglycyrrhizinated licorice, marshmallow extract, and slippery elm bark have been used to increase and augment production of the mucous layer. 5. Rebalance stress, lifestyle, and eating patterns. Summary

Although GI function is often not the first area to be addressed in the assessment and treatment of chronic pain, there is ample evidence that healthy digestion prevents, and a poorly functioning GI tract contributes to, many conditions that give rise to and perpetuate chronic pain. The importance of establishing healthy gut function in patients with chronic pain is a proactive and positive step toward healing chronic pain.

Bacteria in the large intestine are described as beneficial, pathogenic, and commensal (neither beneficial nor pathogenic). Beneficial bacteria such as lactobacilli and bifidobacteria produce vitamins, especially the B group and vitamin K, References E, Jensen-Jarolim E. The role of protein digestibility and antacids on and short chain fatty acids, which are a preferred fuel for the 1. Untersmayr food allergy outcomes. J Allergy Clin Immunol. 2008;121(6):1301-1308. intestinal mucosal cells (9). Beneficial bacteria also multiply 2. Bjarnason I, Takeuchi K. Intestinal permeability in the pathogenesis of NSAIDinduced enteropathy. J Gastroenterol. 2009;44 Suppl 19:23-29. and competitively inhibit pathogenic bacteria. Bacteria and 3. Perrier C; Corthésy B. Gut permeability and food allergies. Clin Exp Allergy. yeast interact with the GI border in multiple ways (10). 2011;41(1):20-28 A functional medicine approach to most chronic conditions, 4. Liska D, Bland J. Digestion and excretion. In: Textbook of Functional Medicine. Washington, DC: The Institute for Functional Medicine; 2010:189-202. including pain, nearly always includes an assessment of and a 5. Rodriguez-Reyna T; Martinez-Reyes C, Yamamoto-Furusho JK. Rheumatic manifestations of inflammatory bowel disease. World J Gastroenterol. 2009;15 plan to heal the gut. In order to heal the gut, several steps have (44):5517-5524. proved helpful in improving GI health and the associated in6. Rashid T, Ebringer A. Rheumatoid arthritis is linked to Proteus—the evidence. Clin Rheumatol. 2007;26(7):1036–1043. flammation that can cause pain. The following “5 R Approach” 7. Ebringer A, Rashid T, Tiwana H, Wilson C. A possible link between Crohn’s is a helpful guide to assist patients in establishing a healthy gut: disease and ankylosing spondylitis via Klebsiella infections. Clin Rheumatol. 2007;26(3):289-297. 1. Remove any known offending substances from the 8. Lambert GP. Stress-induced gastrointestinal barrier dysfunction and its inflamdiet or environment. An allergy-elimination diet—outlined matory effects. J Animal Sci. 2009; 87(14 Suppl):E101-8 in last edition of Pain Practitioner—is one tool that can be 9. Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev. 1997;6(Suppl 1):S43-45. used to identify foods that cause increased inflammation 10. Isolauri E, Sutas Y, Kankaanpaa P, Arvilommi H, Salminen and exacerbate immunologic activity. In some cases, chronic S. Probiotics: effects on immunity. A J Clin Nutr. 2001;73 (2 Suppl):444S-450S. infection or overgrowth with bacteria and yeast may need to be addressed. Nancy Cotter, MD, serves as lead physician in integrative medicine at VA NJ Healthcare in 2. Replace substances and nutrients that may be lacking East Orange, New Jersey. due to lack of production, poor absorption, and/or inadequate THE PAIN PRACTITIONE R

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Continued from page 38

Consider ations in Diagnosing and Tre ating Pain in Patients with IBD

Comple x Regional Pain Sy ndrome: From Diagnosis to Tre atment

46. Knowles SR, Monshat K, Castle DJ. The efficacy and methodological challenges of psychotherapy for adults with inflammatory bowel disease: a review. Inflamm Bowel Dis. 2013;19(12):2704-2715. 47. Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013; 144(1): 36-49. 48. Mawdsley J, Jenkins D, Macey M, Langmead L, Rampton D. The effect of hypnosis on systemic and rectal mucosal measures of inflammation in ulcerative colitis. Am J Gastroenterol. 2008;103(6): 1460-1469. 49. Szigethy EM, Gonzalez-Heydrich J, Bujoreanu SI, et al. Effect of two psychotherapies on depression and disease activity in pediatric Crohn’s disease. Inflamm Bowel Dis. 2015; in press. 50. Henrich JF, Knittle K, De Gucht V, Warren S, Dombrowski SU, Maes S. Identifying effective techniques within psychological treatments for irritable bowel syndrome: A meta-analysis. J Psychosom Res. 2014 Dec 19. 51. Whorwell PJ, Prior A, Faragher EB. Controlled trial of hypnotherapy in the treatment of severe refractory irritable-bowel syndrome. Lancet. 1984; 2(8414): 1232-4. 52. Moser G, Tragner S, Gajowniczek EE, et al. Long-term success of GUTdirected group hypnosis for patients with refractory irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2013;108(4): 602-609. 53. Flik CE, van Rood YR, Laan W, et al. A randomised controlled trial on hypnotherapy for irritable bowel syndrome: design and methodological challenges (the IMAGINE study). BMC Gstroenterol. 2011; 11: 137. 54. Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 2004;303(5661): 1162-1167. 55. Kaptchuk TJ, Friedlander E, Kelley JM, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One 2010; 5(12): e15591. 56. Currie SR, Wilson KG, Pontefract AJ, deLaplante L. Cognitive-behavioral treatment of insomnia secondary to chronic pain. J Consult Clin Psychol. 2000; 68(3): 407-16. 57. Germain A, Shear MK, Hall M, Buysse DJ. Effects of a brief behavioral treatment for PTSD-related sleep disturbances: a pilot study. Behav Res Ther. 2007; 45(3): 627-32. 58. Manheimer E, Wieland LS, Cheng K, et al. Acupuncture for irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2012; 107(6): 835-847; quiz 848.

We have opened many doors and others will follow shortly. It is, however, important to note that CRPS is not the simple diagnosis that it once appeared to be in a patient with a swollen, red, hairy limb. Rather, it is an extremely complex and difficult diagnostic and therapeutic entity. References 1. Singh MK, Patel J, Grothusen J, Foye PM. Physical medicine and rehabilitation for complex regional pain syndromes. Medscape. Updated March 6, 2013. http://emedicine.medscape.com/article/328054-overview#showall. Accessed February 7, 2015. 2. Classifications of Chronic Pain: Description of Chronic Pain Syndrome and Definition of Pain Terms. 2nd edi. Seattle, Washington: IASP Press; 1994. 3. Wheeler AH. Complex Regional Pain Syndromes. Medscape. Updated September 8, 2014. http://emedicine.medscape.com/article/1145318-overview#a0104. Accessed February 7, 2015. 4. Maleki J, LeBel AA, Bennett GJ, Schwartzman RJ. Patterns of spread in complex regional pain syndrome, type I (reflex sympathetic dystrophy). Pain. 2000;88(3):259-266. 5. Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet. 1993;342(8878):1012-1016. 6. Krumova EK, Frettlöh J, Klauenberg S, Richter H, Wasner G, Maier C. Long-term skin temperature measurements—a practical diagnostic tool in complex regional pain syndrome. Pain. 2008;140(1):8-22. 7. Huygen FJ, Niehof S, Klein J, Zijlstra FJ. Computer-assisted scan video thermography is a highly sensitive quality tool in the diagnosis of monitoring complex regional pain syndrome type I. Eur J Appl Physiol. 2004;91(5-6):516-524. 8. Getson P. The use of thermography in the diagnosis of CRPS: A physician’s opinion. Pain Practitioner. 2006;16(1):2006:72-73. 9. Bruehl S, Lubenow TR, Nath H, Ivankovich, O. Validation of thermography in the diagnosis of reflex sympathetic dystrophy. Clin J Pain. 1996;12(4):316-325. 10. Smith JA, Karalis DG, Rosso AL, Grothusen JR, Hessen SE, Schwartzman RJ. Syncope in complex regional pain syndrome. Clin Cardiol. 2011;34(4):222-225.

59. Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/alternative approaches. Altern Med Rev. 2011; 16(2): 134-51.

11. Rasmussen JW, Grothusen JR, Rosso AL, Schwartzman RJ. Atypical chest pain: evidence of intercostobrachial nerve sensitization in complex regional pain syndrome. Pain Physician. 2009;12:E329-E334.

60. Hilsden RJ, Verhoef MJ, Rasmussen H, Porcino A, DeBruyn JC. Use of complementary and alternative medicine by patients with inflammatory bowel disease. Inflam Bowel Dis 2011; 17(2): 655-62.

12. Martinez-Lavin M. Is fibromyalgia a generalized reflex sympathetic dystrophy? Clin Exp Rheumatol. 2001;19(1):1-3.

61. Garcia-Vega E, Fernandez-Rodriguez C. A stress management programme for Crohn’s disease. Behav Res Ther. 2004; 42(4): 367-83. 62. Konturek PC, Brzozowski T, Konturek SJ. Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 2011; 62(6): 591-9.

14. Harbut RE, Correll GE. Successful treatment of a nine-year case of complex regional pain syndrome type I (reflex sympathetic dystrophy) with intravenous ketamine-infusion therapy in a warfarin-anticoagulated adult female patient. Pain Med. 2002;3(2):147-155.

63. Thomas A, Quigley EM. Diet and irritable bowel syndrome. Curr Opin Gastroenterol. 2015;31(2):166-171.

15. Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology. 2005;102(1):211-220.

64. Lee D, Albenberg L, Compher C, et al. Diet in the Pathogenesis and Treatment of Inflammatory Bowel Diseases. Gastroenterology. 2015 Jan 15.

16. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147(1-3):107-115.

65. Gupta M, Goodson R. Transverse abdominal plane neurostimulation for chronic abdominal pain: a novel technique. Pain Physician. 2014; 17(5): E619-22.

17. Kiefer RT, Rohr P, Ploppa A, et al. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study. Pain Med. 2008;9(8):1173-1201.

66. Rana MV, Candido KD, Raja O, Knezevic NN. Celiac plexus block in the management of chronic abdominal pain. Curr Pain Headache Rep. 2014; 18(2): 394.

18. Schwartzman RJ, Samudralwar R, Getson P and Alexander GM Ketamine as adjunctive anesthesia in refractory complex regional pain syndrome patients: a case series. J Clin Case Reports. 2012;2(12): doi:10.4172/2165- 7920.1000186

Eva Szigethy MD, PhD, works in the departments of psychiatry, medicine and pediatrics at the University of Pittsburgh. She is also the clinical director at the Visceral Inflammation and Pain Center.

Divya Keerthy is a student at the University of Pittsburgh School of Medicine.

13. Wurtman RJ. Fibromyalgia and the complex regional pain syndrome: similarities in pathophysiology and treatment. Metabolism. 2010;59(Suppl 1):S37-S40.

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Dr. Getson is an assistant professor of medicine in the department of neurology at the Drexel University College of Medicine. He is a Board Certified Family Practitioner and has a clinical practice in Marlton, New Jersey. He has evaluated close to 1,000 patients with complex regional pain syndrome. He is a board certified medical thermologist and vice president of the American Academy of Thermology.

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| VOLUME 25, NUMBER 1 |

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