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THE INDEPENDENT NEWSPAPER FOR PAIN MANAGEMENT PainMedicineNews.com • SEPTEMBER 2013 • Volume 11 Number 7

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PRIMARY CARE

Inappropriate NSAID Prescriptions for Pain Found Common Madrid—Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently inappropriately prescribed for patients with chronic pain conditions who also have ischemic heart disease (IHD), according to a study presented at the 2013 annual meeting of the European League Against Rheumatism (EULAR). As much as 36% of patients prescribed NSAIDs already had IHD or risk factors for IHD, according to the study investigators. A second study showed that patients with pain conditions at a high risk for ulcers, cardiovascular events or acute renal failure continued to take over-the-counter (OTC) NSAIDs for longer than is deemed safe, and at higher doses. see NSAID page 26

Misplaced Nerve Blocks Frustrate Efforts at Prevention

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lthough not as sensational or disastrous as wrong-site surgeries, wrong-site peripheral nerve blocks are potentially dangerous, and according to a 10-year analysis by Pittsburgh researchers, 10 times more common than their surgical counterparts. Yet the problem can be largely—if not entirely—avoided with better planning, vigilance and engagement by the various members of the care team. “Our department instituted a standardized policy with mandatory training and process audits regarding wrong-site blocks in June 2010,” said Mark Hudson, MD, MBA, associate professor of anesthesiology and vice chair for clinical operations at the University of Pittsburgh Medical Center (UPMC). “And it’s interesting that they continued to occur even after we tried to implement stops to prevent them. So just having a policy in place, no matter how robust it may be, doesn’t completely eliminate wrong-site blocks, because it relies on people following the policy.” Dr. Hudson and his colleagues used quality see MISPLACED page 15

Algorithm Shows Promise for Reducing Opiate Use in ED Headache Treatment

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reduce the amount of imaging, number of consults and number of admissions related to headache, all while continuing to maintain or increase patients’ pain relief. “We were astonished at how much we were able to diminish the use of opiates,” said lead investigator Cynthia Bamford, MD, after she and her colleagues

mergency and pain physicians from the Cleveland Clinic in the process of refining an algorithm for headache management in the emergency department (ED) report that it has resulted in an 82% reduction in both treatment with opioids or narcotics in the ED and in discharge with prescriptions for these types of medications. The researchers also hope to EDUCATIONAL REVIEW PRINTER-FRIENDLY VERSION AVAILABLE AT PAINMEDICINENEWS.COM

Use of Topical Analgesics in Treating N Neuropathic europathic and Musculosskeletal Pain WILLIAM ZEMPSKY, MD Head, Divison of Pain and Palliative Medicine Connecticut Children’s Medical Cente er Professor of Pediatrics University of Connecticut School of Medicine Storrs, Connecticut Disclosure: Dr. Zempsky serves on the Scie entific Advisory Board of Vapogenicx, Inc.

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opical administratio on of anesthetics and analgesics can allow for the e efficient, painless delivery of medications that may reduce systemic side effec cts associated with the he e med medication dication while providing clinical advantages over o

injected or oral administration for the same clinical situation. Topical administration of nonsteroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, and other agents is useful for a range of conditions including acute and chronic musculoskeletal pain.

Background Topical medications target the site of application and ideally produce effective drug concentrations locally with minimal systemic absorption. Topical anesthetics and analgesics target the peripheral nerves and soft tissue at that site.1 A number of topical medications are beneficial for chronic musculoskeletal pain. In contrast, transdermal medications do not have to be applied over an involved site and attempt to reach systemic drug concentrations to achieve therapeutic results.2 This review will focus on topical medications (Table). Benefits of topical drug delivery include the potential for local therapeutic drug levels with reduced side effects, painless drug delivery, improved patient adherence and acceptance, ease of dose termination, avoidance of first-pass metabolism, and direct access to the target site. The skin is a barrier to drug delivery, its primary role being to prevent the ingress or egress of compounds across it.3 The stratum corneum, the upper most layer of the skin, is a thin layer of cornified nonviable keratinocytes that is an effective barrier to water-soluble

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

substances, which typically include anesthetics. Topical medications must traverse the stratum corneum to reach their site of action, which may be the peripheral transducing terminals of cutaneous sensory fibers located in the dermis and epidermis,4 or the local soft tissues including synovial fluid, synovial tissue, and cartilaginous structures.5 Three delivery methods have been used to bypass the stratum corneum barrier.6 1. Injection of local anesthetics or other medications, usually via a small-gauge hypodermic syringe, is the oldest of the methodologies. 2. Passive diffusion from creams, gels, or patches comprises the second general class of methodologies. Passive diffusion of topical agents require that they have a molecular weight under 500 DA, with a hydrophobic component to allow it to transverse the stratum corneum but also some hydrophilic features to penetrate the epidermis.7 3. Active drug delivery methods that enhance the rate of drug passage through the skin and shorten the time to onset of action. There are a diverse group of

PA I N M E D I C I N E N E W S • S E P T E M B E R 2 0 1 3

1

Use of Topical Analgesics in Treating Neuropathic and Musculoskeletal Pain See insert at page 26

see ALGORITHM page 22

NEW PRODUCT Dominion Diagnostics Scientifically Accurate Medication Monitoring (SAMM) See pages 21 & 27

POLICY & MANAGEMENT 9

| Study Warns of Dearth of U.S. Neurologists

INTERVENTIONAL PAIN MEDICINE 16 | MRI Detects Spinal Infections From Contaminated Methylprednisolone

CLINICAL PAIN MEDICINE 19 | Antibiotics Effective in Treating Pain From Herniated Disks, Study Shows

20 | Progress, If No Breakthroughs, In Chronic Post-op Pain


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PRIMARY CARE

Neuromodulation Guidelines Aim High

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esearchers from Mayo Clinic warn in a new commentary in the clinic’s medical journal that physicians should refrain from prescribing medical marijuana to adolescents with chronic pain. Although acknowledging the potentially devastating effects of chronic pain in this hard to diagnose and treat population—including impaired socialization, quality of life, activities of living and physical activity—the researchers write in Mayo Clinic Proceedings (2013 Jun 20. [Epub ahead of print]) that the potential risks associated with marijuana use in adolescents can far outweigh the potential benefits. “The consequences may be very, very severe, particularly for adolescents who may get rid of their pain—or not—at the expense of the rest of their life,” said co-author J. Michael Bostwick, MD, professor of psychiatry, Mayo

dvocates for the use of neuromodulation in the treatment of chronic pain believe the approach remains underused despite data supporting its safety and efficacy. However, newly released guidelines designed to clarify patient selection criteria and reduce complications associated with the technique may change that. Developed by a group of more than 60 pain specialists and researchers calling themselves the Neuromodulation Appropriateness Consensus Committee (NACC) and presented at the 11th World Congress of the International Neuromodulation Society (INS) in Berlin in June, the guidelines are designed to address provider training, patient screening and treatment recommendations for neuromodulation, an ever-evolving— and largely drug-free—approach

see ADOLESCENTS page 24

see GUIDELINES page 25

Experts: Medical Marijuana Not for Teens in Pain

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P Pharmacists Feeling Pain Over Restrictive AMA Resolution R Physician group blasts profession’s P ‘iintrusion into medical practice’

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bluntly worded American Medical Association (AMA) resolution that was intended to curb a barrage of retail pharmacy phone calls to physicians requesting additional

information about pain medication prescriptions has triggered a backlash from pharmacists, some of whom objected to the resolution’s sharp tone as a departure from the mostly collegial relationships that exist between the two professions. see CLASH page 34

E-NEWSLETTER Read the five most-viewed articles last month on PainMedicineNews.com See page 6

COMMENTARY 10 | ‘We Have an Epidemic on Our Hands and the Status Quo Is Failing Us’: An Interview With Lynn Webster, MD, Part 2 of 3

CLINICAL PAIN MEDICINE 21 | Early Use of MRI Does Not Lead to Better Outcomes for Low Back Pain

INTERVENTIONAL PAIN MEDICINE

28 | FDA Identifies Bacteria, Fungal Growth in Tennessee Pharmacy Compounded Products


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y drawing boundaries between their personal and professional lives, physicians can protect their practices and themselves while also still achieving their true goal: providing quality care to their patients. As an attorney, I know that lawyers and doctors are frequently strange bedfellows. However, the two professions have one thing squarely in common, and likely always will. No matter where we are or who we’re surrounded by, be it at a church, synagogue or mosque, at a dinner party, having a drink at a pub, or even when simply spending time with extended family over the holidays, the same question always comes up:“Hey, can I ask you something?” The lines between patient and professional are frequently blurred, especially in rural areas, see ABUSE page 22

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he FD DA has made public its draft directives outlining th he researrch steps drug manufacturers would need to conducct in order to label an opioid as abuse deterrent. Accordingg to an FDA official, the agency is hoping to incentivize drug companies to furtther develop safer opioids through the increased revenues that migght result from having abuse-deterrent labeling. “Labeling is the first tool the Food and Drug Administration n is looking att to incentivize the development of successful abuseedeterrence oppioids,” Douglas Throckmorton, MD, deputy directtor for regulatoryy programs at the FDA’s Center for Drug Evaluation n and Research, toldd reporters during a press teleconference. The guidan nce, which was scheduled to be finalized this month after public comments were heard and incorporated, details the research methodology and the findings companies wiill need to provide the FDA in order to claim their oppioid as abuse deterrent. For exampple, according to the draft guidan nce, they will need to carry out laboratory research documentingg “the ease with w h i c h t h e potentially abuse-deterreent properties of a formulaation can be

Biologics Reduce RA Mortal M lity, Disease-Associated Co osts

Washington— —The use of tumor necrosis factor (TNF) inhibitor therapy reduced the risk for premature death in paatients with rheumatoid arthritis (RA) by about 25%, acccording to a case-control study reported go ca D ea at the 2012 ann nual meeting of the American College of he h health vials (S g from dissent. lly do in r ca se Rheumatology (ACR). A second study suggests that RAif on e-do s flow om fo typi spec A associated costss have been substantially reduced by the singl sition little ro SDVs been see. IM ve s, po use. e e use of biologics (abstracts 2540 and 1642, respectively). PR cial at leav se vial and ha single 122, th The population in the first study was collected from a of officies th ultido vatives DA for ay 20 veenntion Canadian Miniistry of Health database on reported cases agen nlike m preser the F in M d Pre tooookk in U ntain ed by leased ol an rst of of RA treated between January 1996 and March 2006; fi tr use at re co ondnot design ment se Consition it ssible, ultiplecases were folloowed until March 2010. Patients who used resp with ically a docur Disea the po ever po er m wilill be biologics (n=2,156) were matched with controls on age, ents ov s In rs fo en pati sfaction is one ated “wh erred ation e docusee BIOLOGICS page 16 ine te igra rt sati This 12, a Cen C) repe g that is pref medic ts.” Th ldd only of m repo ent. ica 20 ine. g D statin als en tien hou h in % (C ey w ra tm er BOOK PAGE BO g go “s vi , pa 34 ig rv ea n ly Follow PMN on nly to a su ine tr e in Am by M ts of 2001 e-dose especial ultiple SDVs that “o approEvvidence-Based Interventional ec n ra 31 at g gl m d in in es e eff io in r mig igra July ng Pa ain Medicine -iiÊ«>}iÊÓ£ sin vials, d to ed th t,” an that caus ill ÃÊ ˜Vi se istere at en ence vials tionro as 37 m ti thei gs of M e on st ul Ài do pa ip id ct vi e in st e jeec e. es s on onlin ggests many din Ê ˆv adm t also a singl ample ev ingle-us.gov/in rain as su ̈œ˜ Àà e fin ished .c com, Mig rted men ed for ovide e-dose/s ww.cdc tml). «>>}}iiÊÊ19 ÀVi« ÀœÛˆ`i of th y publ study could be po ers, Ê Ê*i sum iser-sup id to ˜Êˆ˜ be us reaks pr singl p ://w ution.h -D O SE …Ìà ˜ÌÃ]Ê* stud . The what , con pa «Ìˆœ @painmednews ˆ}…ˆ} >̈i for advert not rmand , outb te use of ” (htt rdPreca SI N G LE IE F com raine on iÀVi e as A BR site iÞÊ Ê * Ê* C see pria ent harm_standa IN E >ˆ˜Ê* IN ÕÀÛ mig ericans. care by th hich w Tim n, LL ˜ VÌÊ* D IC ti 07 | - iÌÜii i E P pa vv Am health blished LC, w ing to h Unio /I M ty 8 ÞÊ rd 15, lt L A safe A IN Ê> is pu ion, y, acco , Hea June from LP ̈œ˜ E >Ê com lth Un e stud director IC A and `ÕV> œ˜Ã IC IN À>“ˆ˜ `>̈œ˜ D 15 sumers media L IN Ê E Àà C i ˆ˜ Hea duct th aging > M *i ÌÊMay con social }iÊ1 5 ˜Ãvœ | * `iÀÞÊ con A, man ia. A IN ˆÌ…Ê/À> ˆÌ…œÕ een ted d E «> 14 LP ÃÊ7 MB delph ed betw recrui gines an IG R AI N NA i`Ê7 V̈œ˜ ted T IO i ̈Ãvˆ cora it Phila onduct study ch en see M VEN Ê-> Àœˆ`ʘ }Ê ar e C er, de use ER ˜Ìà ˆ˜ˆ˜ , th m, se form he will arable. IN T >̈i Ê-Ìi T >ˆ˜Ì> iÊ 2012 raine.co EN be ur, a | * «ˆ`ÕÀ> ÃÊ Vœ`œ˜ Art He saystoo un to pain e EM 8 ÀÌ œ 1 G Mig e, Àœ « n w. NA es cess caus Þ` krai -Õ« MA e U is pillo com out ac rs be i˜ÌÊ ÌÕÃÊvœÀÊ Y& in th der h cer be with embe VՓ à L IC conÊ œ ÊÊ-Ì>Àœ`ÕVÌ O llage gun un tate can ft him mily m is  P vi i e of W home |  V…i`Õ Ìˆœ˜Ê* ve le his fa mot with a pros on a re IV tr y ha om ersity roup, Pain 20 Lˆ˜> MN Univ ies G ter for uld —In , sleeps is stage is coun imself fr

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Delayed-Release Prednisone in Rheumatoid Arthritis

MARCH 2013

Treatment Considerations levels of proinflammatory mediheumatoid arthritis (RA) is ators, such as interleukin (IL)-6 the most common chronic Faculty and tumor necrosis factor-ι, inflammatory joint disease, Arthur L. Weaver, peak during the middle of the affecting approximately 2.8 milnight and early morning hours, lion adults in the United States MD, MS, FACP, MACR resulting in pronounced early alone.1 The symptoms of RA Clinical Professor of Medicine, Emeritus morning symptoms in patients include fatigue as well as swellSection of Rheumatology with RA,3,4 which can impact ing, pain, and stiffness of the University of Nebraska at Omaha joints 2 ; these manifestations patients’ ability to work or particOmaha, Nebraska ipate in normal activities.5 may vary in a predictable pattern throughout the day.3 In patients without RA, an Alvin F. Wells, MD, PhD, FACR increase in inflammatory cytoThis report will discuss the Director, Rheumatology and kine levels triggers a cascade pathophysiology of the diurnal Immunotherapy Center of hypothalamic corticotropinvariations of the manifestations Franklin, Wisconsin releasing hormone, pituitary of RA along with the potential production d ti off adrenocorticod ti utility tilit off a llow-dose, d d delayedl d tropic hormone, and glucocortirelease prednisone strategy to coid secretion by the adrenal cortex, which collectively treat the symptoms of RA, including morning symptoms. inhibit the production of inflammatory cytokines.6 This represents normal physiologic feedback control. In Diurnal Variations in Symptoms of patients with active RA, however, the cortisol response Rheumatoid Arthritis is impaired, which leads to a relative adrenal glucocorticoid insufficiency and unopposed cytokine-mediated Physiologic and pathophysiologic biologic circadian inflammation during the early morning hours.3,4,6 These rhythms can modulate the presentation and morbidity of various diseases. Similar diurnal variations have been observations may support a role for appropriately timed Chair observed in the clinical manifestations of RA.3 The early exogenous glucocorticoid therapy to balance the pathologic circadian mismatch between cytokine and glucocormorning severity of RA symptoms coincides with the cir3 ticoid production.4 cadian rhythm of cytokine release. Specifically, plasma

Charles E. Argoff, MD Professor of Neurology Albany Medical College Director of the Comprehensive Pain Program Albany Medical Center Albany, New York

From the Bench to the Bedside

Gregory L. Holmquist, PharmD, CPE

R

Pain and Palliative Care Specialist Certified Pain Educator Palliative Care Strategies Seattle, Washington

Patient Guides

REPORT RT Acu A ute a ment: age IONSY YS System

Despite a advances in pain management technology, the advent of acute p pain services, and professional practice guidelines aimed at iimproving postoperative pain management, inadequacies and treatm ment gaps still exist, and improvem ment remains a priority.7 An a nalgesic intervention Faculty that migh ht help to mitigate cliniSupported and Funded by: cian conc cern is the fentanyl ionHorizon Pharma, Inc. tophoretic c transdermal system (IONSYS)), a credit card–sized, self-cont ained, and preprogrammed d investigational product candidate e intended to provide ac e ed byy ad s a o o Michael H. H Huo Huo, MD pain i relie lieff ffor adult d lt iinpatients ti t or more drugs d ((eg, opioid i id and d Professor requiring opioids following surnonopioid analgesics, used in Department of Orthopedic Surgery gery.8 It is a needle-free system combination) that act by different UT Southwestern Medical Center mechanisms, and along differ mechanisms differthat is ap applied to the skin on the Dallas, Texas ent pain pathways—an approach upper arm or chest.8 A generally that is recommended by the imperceptible electrical current American Society of Anesthesithen delivers a small dose of fenologists (ASA) and the American Pain Society.5,6 However, tanyl directly through the skin and into the systemic circulation. The FDA approved IONSYS in 2006; however, it existing PCA modalities have limitations that include invawas never launched in the United States due to required sive access, challenges in titration of analgesic effect, changes in manufacturing. The enhanced design will be cumbersome pump technologies, impaired patient mobilreviewed by the FDA in the near future for use in patients ity, and limited drug preparations that have been associwith moderate to severe postoperative pain. ated with programming, medication, and dosing errors.

Clinical Pharmacology of Gabapentin

Pocket Guides Introduction )FSQFT [PTUFS BMTP LOPXO BT TIJOHMFT SFTVMUT GSPN SFBDUJWBUJPO PG FOEPHFOPVT MBUFOU WBSJDFMMB [PTUFS WJSVT JOGFDUJPO XJUIJO UIF TFOTPSZ HBOHMJB 5IJT DPOEJUJPO JT DIBSBDUFSJ[FE CZ B QBJOGVM VOJMBUFSBM WFTJDVMBS FSVQUJPO XIJDI UZQJDBMMZ PDDVST JO B SFTUSJDUFE EFSNBUPNBM EJTUSJCVUJPO Prodromal symptoms, such as headache and malaise, may PDDVS QSJPS UP SBTI POTFU XIJDI UZQJDBMMZ MBTUT  UP  EBZT Estimates suggest that one-third of the US population XJMM FYQFSJFODF BO FQJTPEF PG BDVUF IFSQFT [PTUFS EVSJOH UIFJS MJGFUJNF XJUI UIF JODJEFODF SJTL JODSFBTJOH XJUI BHF .PSF UIBO IBMG PG BMM DBTFT PG IFSQFT [PTUFS PDDVS JO JOEJWJEVBMT BHFE  ZFBST PS PMEFS In the majority of cases, IFSQFT [PTUFS FQJTPEFT SFTPMWF XJUIPVU GVSUIFS TFRVFMBF However, some patients, particularly the elderly, are at IJHIFS SJTL GPS EFWFMPQJOH QPTUIFSQFUJD OFVSBMHJB 1)/ a condition of severe, often debilitating neuropathic pain that persists for at least 3 months after the shingles rash IBT IFBMFE These symptoms can lead to impaired sleep and depression and may interfere with activities of daily MJWJOH "MMPEZOJB‰QBJO FWPLFE CZ OPSNBMMZ OPOQBJOGVM TUJNVMJ TVDI BT MJHIU UPVDI‰BMTP DBO PDDVS JO PS CFZPOE UIF PSJHJOBMMZ BGGFDUFE EFSNBUPNBM BSFBT Similar to the SFMBUJPOTIJQ CFUXFFO IFSQFT [PTUFS BOE BHF UIF SJTL G EFWFMPQJOH GPS E M J 1)/ BMTP M DPSSFMBUFT M U XJUI JUI JODSFBTJOH J J BHF

Special Reports Wall Charts

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Plasma Gabapentin, ng/mL Pl

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(3"-*4&Â&#x2122; JT B PODFEBJMZ GPSNVMBUJPO PG HBCBQFOUJO that incorporates polymer technology to promote gastric SFUFOUJPO PG UIF UBCMFU UIF (3"-*4&Â&#x2122; UBCMFU JT TVGGJDJFOUMZ small to enable swallowing, but once in contact with gastric GMVJE UIF UBCMFU TXFMMT UP B TJ[F UIBU QSPNPUFT SFUFOUJPO JO UIF GFE TUPNBDI (3"-*4&Â&#x2122; JT LOPXO UP CF TVCTUBOUJBMMZ FYDSFUFE CZ UIF LJEOFZ 3FEVDUJPOT JO (3"-*4&Â&#x2122; EPTF should be made in patients with age-related compromised SFOBM GVODUJPO (3"-*4&Â&#x2122; TIPVME OPU CF VTFE JO QBUJFOUT XJUI B DSFBUJOJOF DMFBSBODF SBUF PG MFTT UIBO  N- QFS NJOVUF PS JO QBUJFOUT PO IFNPEJBMZTJT 5IJT QSPMPOHFE retention allows gabapentin to be gradually released to the upper small intestine at a relatively constant rate over a MPOHFS QFSJPE PG UJNF 'JHVSF  SFMBUJWF UP *3 GPSNVMBUJPOT BOE QSFWFOUT TBUVSBUJPO PG UIF USBOTQPSUFS  Thus, this

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Clinical Pharmacology of GRALISEâ&#x201E;˘

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over time as well as reduce the incidence of adverse events "&T UIBU XPVME PUIFSXJTF PDDVS JO UIF DPOUFYU PG NVMUJQMF JOUSBEBZ QFBLT BOE USPVHIT JO QMBTNB ESVH MFWFMT

Indication and Usage of GRALISEâ&#x201E;˘


6 I PainMedicineNews.com

SEPTEMBER 2013

I N B RI EF

Simponi Aria Approved for Moderately to Severely Active RA

T

he FDA has approved Simponi Aria (golimumab; Janssen) for infusion for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate. Simponi Aria, the only fully human anti–tumor necrosis factor (TNF)-alpha infusible therapy, has been shown to significantly improve signs and symptoms of RA and physical function, as well as inhibit the progression of structural damage. The Simponi Aria dose regimen is 2 mg/kg given as an IV infusion at weeks 0 and 4, then every eight weeks thereafter. The infusion is given over a 30-minute period.

The approval is supported by findings from the Phase III GO-FURTHER (Golimumab, an Anti-TNF-alpha Monoclonal Antibody, Administered Intravenously, in Subjects with Active Rheumatoid Arthritis Despite Methotrexate Therapy)

trial, which evaluated 592 patients diagnosed with moderately to severely active RA. Results from the international multicenter, double-blind, placebocontrolled, crossover trial revealed 59% of patients (231 of 395) receiving treatment with Simponi Aria plus methotrexate versus 25% of patients receiving placebo plus methotrexate (49 of 197; 95% confidence interval, 25.9%-41.4%) experienced significant improvements in signs and symptoms at week 14, as demonstrated by at least 20% improvement in American College of Rheumatology criteria (ACR 20). A greater proportion of patients receiving Simponi Aria plus methotrexate achieved at least a 50% improvement in ACR criteria (ACR 50) than patients receiving placebo plus methotrexate at week 14 (30% vs. 9%, respectively). Through week 24, adverse events (AEs) occurred in 53% of patients receiving IV golimumab and 49% of patients receiving placebo, and serious AEs were reported in more IV golimumab-treated patients (4%) than placebotreated patients (2%). More information about Simponi Aria will be available soon at www.SimponiAria.com. —Based on a press release from Janssen

Read the five most-viewed articles last month on

PAINMEDICINENEWS.COM 1. Extended-Release Hydromorphone May Mitigate Drug Abuse (Web Exclusive) 2. Experts Launch Pain Management Competency Program 3. Marijuana Usage in Chronic Pain Patients: Driving and Work Guidelines for Physicians (Web Exclusive) 4. NYC Opioid Overdose Rates Show Effects of Prescription Drug Crisis in Urban Areas (August Web Exclusive—see page 8) 5. FDA Approves One Citizen Petition, Rejects Another, Clouding Picture for AbuseDeterrent Opioid Developers

DOJ Files Suit Against Louisiana Pharm Compan ny For Distributing Unapproved, Misbranded Drugss

A

cting Assistant Attorney General Stuart F. Delery announced that the Department of Justice (DOJ), on behalf of the FDA, has filed suit in the U.S. District Court for the Western District of Louisiana against Sage Pharmaceuticals, its president, Jivn-Ren Chen, MD, and its director of corporate quality, Charles L. Thomas, all of Shreveport, La. According to the complaint, the defendants violated the Federal Food, Drug, and Cosmetic Act (FDCA) by manufacturing and distributing unapproved and misbranded drug products. “Today’s action furthers the FDA’s mission of ensuring that all drugs sold to the public are safe and effective, and those companies that undermine this mission will be held accountable,” said Mr. Delery. This is the second injunctive case that the government has brought against Sage alleging the distribution of unapproved new drugs. In 2000, the government obtained an injunction against the company banning the manufacture and distribution of two unapproved new drugs.

Since then, FDA inspections have allegedly revealed that the defendants continue to manufacture and distribute other drug prod-ucts—including prescriptio on pain relievers, over-the-counter (OTC) cou ugh and cold remedies and OTC wound clea ansers—without first obtaining the requisite FD DA approvals. “As a result, the defenda ants’ products are unapproved new drugs and d misbranded drugs under the FDCA, and poten ntially unsafe and ineffective,” according to a press statement from the DOJ. The release stated that “despite numerous warnings from [the] FDA, the defendants have failed to bring their operations into compliance with the law.” The DOJ announced it will seek a permanent injunction requiring the defendants to cease all receiving, processing, manufacturing, preparing, packaging, labeling, holding and distributing activities until they comply with applicable FDA regulations.

The FDA referred this matter to the DOJ. The Consumer Protection Branch of the DOJ’s Civil Division together with the U.S. Attorney’s Office for the Western District of Louisiana brought this case on behalf of the United States. —Based on a press release from the Department of Justice


SEPTEMBER 2013

PainMedicineNews.com I 7

IN BRIEF ASIPP Releases 2013 Guidelines for Implementation of Interventional Pain Techniques

T

he American Society of Interventional Pain Physicians (ASIPP) has released its 2013 spinal interventional techniques guidelines, the seventh update, with publication in a special April issue of Drug and Pain Physician (2013;16[2S]) and acceptance for publication in the National Guideline Clearinghouse. In developing these guidelines, ASIPP convened a multidisciplinary panel of 51 experts in various fields to review the evidence and formulate the recommendations for interventional techniques in managing chronic spinal pain. According to a press release from ASIPP, the panel used the most rigorous criteria and robust outcomes for techniques to be included in the analysis. Techniques were judged as having either fair or good evidence based on criteria of the United States Preventive Services Task Force. Using these criteria, the evidence for Medicare-approved procedures was positive for 47% of the various techniques used for treatment with either fair or better evidence, and the evidence was fair to good for 62% of the techniques. According to the release, ASIPP’s “extensive evaluation process” has resulted in strict guidance for interventional techniques. “Of importance is that despite only 47% of [techniques] meeting appropriate criteria for utilization, commonly performed procedures for all types of epidural injections for disk

herniation present with fair to good evidence and fair evidence for other conditions with specific techniques,” explained Laxmaiah Manchikanti, MD, chairman of the board and CEO of ASIPP. “Similarly, radiofrequency neurotomy and facet joint nerve blocks have shown significant evidence in managing pain from facet joints in the spine. While there

was also fair evidence for percutaneous adhesiolysis in post-surgery syndrome, the evidence is limited for many other techniques.” The guidelines are available on the Pain Physician n journal website (painphysicianjournal.com), PubMed and the National Guideline Clearinghouse website (guideline.gov). “ASIPP has been in the forefront

in the effort to curb overuse, abuse and [to] eliminate fraud,” said Dr. Manchikanti, “and at the same time maintaining the access to effective techniques by developing evidencebased practice guidelines and systematic reviews, and publishing randomized controlled trials.” —Based on a press release from ASIPP

GRALISE (gabapentin) tablets are indicated for the management of postherpetic neuralgia (PHN).

PLEASE GRALISE ME! Help control the agony of PHN • 2-week titration to an effective dose1-3 • Statistically significant reduction in pain scores*1,2 • Once-daily dosing with the evening meal • The most common adverse reaction (* 5% and twice placebo) to GRALISE (gabapentin) is dizziness1

*In a 10-week clinical trial, approximately one-third of GRALISE (gabapentin) patients achieved a 50% reduction in pain from baseline and approximately one-half achieved a 30% reduction in pain with an 1800 mg once-daily dose (mean baseline pain score was 6.6 for GRALISE-treated patients).1,3

Indication and Usage

Follow

GRALISE (gabapentin) tablets are indicated for the management of postherpetic neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

Important Safety Information GRALISE is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

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Antiepileptic drugs (AEDs) including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Across all GRALISE clinical trials, the other most common adverse reactions (≥ 2%) are somnolence, headache, peripheral edema, diarrhea, dry mouth, and nasopharyngitis. Dosage adjustment of GRALISE is necessary in patients with impaired renal function. GRALISE should not be administered in patients with a creatinine clearance rate < 30 mL/min or in patients undergoing hemodialysis.

Because every moment counts in PHN Please see adjacent page for Brief Summary of Prescribing Information. Full Prescribing Information and Medication Guide are available at GRALISE.com. References: 1. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012. 2. Sang CN, et al. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29:281-288. 3. Data on file, Depomed Inc.

May 2013, Depomed Inc. All rights reserved. GRA-409-P.1


8 I PainMedicineNews.com

SEPTEMBER 2013

POLI CY & MANAGEMENT

NYC Opioid Overdose Rates Show Effects of Prescription Drug Crisis on Urban Areas

A

possible microcosm of the ongoing prescription drug abuse epidemic may be playing itself out in New York City, as the Big Apple has seen a sevenfold increase in opioid overdoses in a 16-year span, according to new data. What’s more, New York’s opioid abuse problem may

be driven largely by white individuals residing in areas with “high-income inequality but lower-than average rates of poverty,” according to a press statement from New York University. Published in Drug and Alcohol Dependencee (2013 Jan 25. [Epub ahead of print]), Columbia University Mailman

GRALISE® (gabapentin) tablets BRIEF SUMMARY: For full prescribing information, see package insert. INDICATIONS AND USAGE GRALISE is indicated for the management of Postherpetic Neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles fi that affect the frequency of administration. DOSAGE AND ADMINISTRATION Postherpetic neuralgia • GRALISE should be titrated to an 1800 mg dose taken orally once daily with the evening meal. GRALISE tablets should be swallowed whole. Do not split, crush, or chew the tablets. • If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of one week or longer (at the discretion of the prescriber). • Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 or in patients on hemodialysis. • In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows: Table 1 GRALISE Recommended Titration Schedule Day 1 Day 2 Days 3-6 Days 7-10 Days 11-14 Day 15 Daily dose 300 mg 600 mg 900 mg 1200 mg 1500 mg 1800 mg CONTRAINDICATIONS GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. Table 2 GRALISE Dosage Based on Renal Function Once-daily dosing Creatinine clearance (mL/min) GRALISE dose (once daily with evening meal) ≥ 60 1800 mg 30-60 600 mg to 1800 mg < 30 GRALISE should not be administered Patients receiving hemodialysis GRALISE should not be administered WARNINGS AND PRECAUTIONS GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Table 3 Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in Gralise) in the Pooled Analysis Indication Epilepsy Psychiatric Other Total Placebo patients with events per 1000 patients 1.0 5.7 1.0 2.4 Drug patients with events per 1000 patients 3.4 8.5 1.8 4.3 Relative risk: incidence of events in drug patients/incidence in placebo patients 3.5 1.5 1.9 1.8 Risk difference: additional drug patients with events per 1000 patients 2.4 2.9 0.9 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that GRALISE contains gabapentin which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivoo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and preexisting tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivityy Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 359 patients with neuropathic pain associated with postherpetic neuralgia have received GRALISE at doses up to 1800 mg daily during placebo-controlled clinical studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of GRALISE-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse reactions were either “mild” or “moderate”. Table 4 lists all adverse reactions, regardless of causality, occurring in at least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for which the incidence was greater than in the placebo group. Table 4 Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group) Body system—preferred term GRALISE N = 359, % Placebo N = 364, % Ear and Labyrinth Disorders Vertigo 1.4 0.5 Gastrointestinal Disorders Diarrhea 3.3 2.7 Dry mouth 2.8 1.4 Constipation 1.4 0.3 Dyspepsia 1.4 0.8 General Disorders Peripheral edema 3.9 0.3 Pain 1.1 0.5

School of Public Health researchers from the Department of Epidemiology examined how the ongoing problem of opioid misuse and abuse is affecting major metropolitan cities. Given that much of the research in this area has focused on rural areas, which have been struck particularly hard by increases in U.S.

Infections and Infestations Nasopharyngitis 2.5 2.2 Urinary tract infection 1.7 0.5 Investigations Weight increased 1.9 0.5 Musculoskeletal and Connective Tissue Disorders Pain in extremity 1.9 0.5 Back pain 1.7 1.1 Nervous System Disorders Dizziness 10.9 2.2 Somnolence 4.5 2.7 Headache 4.2 4.1 Lethargy 1.1 0.3 In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating. DRUG INTERACTIONS Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmaxx by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of this interaction at other doses is not known. When a single dose (60 mg) of controlled-release morphine capsule was administered 2 hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin AUC values increased by 44% compared to gabapentin immediate release administered without morphine. The pharmacokinetics of morphine were not affected by administration of gabapentin immediate release 2 hours after morphine. The magnitude of this interaction at other doses is not known. An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5% when gabapentin was taken 2 hours after antacids. It is recommended that GRALISE be taken at least 2 hours following antacid administration. There are no pharmacokinetic interactions between gabapentin and the following antiepileptic drugs: phenytoin, carbamazepine, valproic acid, phenobarbital, and naproxen. Cimetidine 300 mg decreased the apparent oral clearance of gabapentin by 14% and creatinine clearance by 10%. The effect of gabapentin immediate release on cimetidine was not evaluated. This decrease is not expected to be clinically significant. Gabapentin immediate release (400 mg three times daily) had no effect on the pharmacokinetics of norethindrone (2.5 mg) or ethinyl estradiol (50 mcg) administered as a single tablet, except that the Cmaxx of norethindrone was increased by 13%. This interaction is not considered to be clinically significant. Gabapentin immediate release pharmacokinetic parameters were comparable with and without probenecid, indicating that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid. USE IN SPECIFIC POPULATIONS Pregnancyy Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in uteroo exposure to GRALISE, physicians are advised to recommend that pregnant patients taking GRALISE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Nursing Mothers Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, GRALISE should be used in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. GRALISE is known to be substantially excreted by the kidney. Reductions in GRALISE dose should be made in patients with age-related compromised renal function. [see Dosage and Administration]. Hepatic Impairment Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment. Renal Impairmentt GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCL between 15 and 30 or in patients undergoing hemodialysis [see Dosage and Administration]. DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of GRALISE has not been evaluated in human studies. OVERDOSAGE A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. CLINICAL PHARMACOLOGY Pharmacokinetics Absorption p and Bioavailabilityy Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased, bioavailability decreases. When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher Cmaxx and lower AUC at steady state compared to gabapentin immediate release. Time to reach maximum plasma concentration (TTmax) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenoma and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg/day were more than 10 times higher than plasma concentrations in humans receiving 1800 mg per day and in rats receiving 1000 mg/kg/day peak plasma concentrations were more than 6.5 times higher than in humans receiving 1800 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear. Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitroo and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans. Gabapentin did not demonstrate mutagenic or genotoxic potential in 3 in vitroo and 4 in vivoo assays. No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 11 times the maximum recommended human dose on an mg/m2 basis).

© December 2012, Depomed, Inc. All rights reserved. GRA-410-P.1

prescription painkiller misuse—the researchers describe their work as “one of the earliest and most comprehensive analyses of how the opioid epidemic has affected an urban area.” Looking to analyze changes in demographics and factors contributing to opioid overdose and fatality for both prescription opioids (analgesic and methadone, which is historically used to treat heroin addiction) and heroin, the investigators used New York City Office of the Chief Medical Examiner data from 1990 to 2006 for their analysis. One finding of note is that whites were much more likely than either blacks or Hispanics to overdose from the use of opioid analgesics, with a 2006 fatality rate nearly twice that of Latinos and threefold compared with blacks. That statistic was driven in large part by analgesic opioids, as opposed to methadone and heroin. “Analgesic overdose decedents were less likely to be black or Hispanic, while methadone overdose decedents were more likely to be black or Hispanic in contrast to heroin overdose decedents,” the investigators said in the press statement. “A possible reason for the concentration of fatalities among whites is that this group is more likely to have access to a doctor who can write prescriptions,” said Magdalena Cerdá, DrPH, assistant professor of epidemiology at Columbia’s Mailman School of Public Health and lead author on the study, in a statement. “However, more often than not, those who get addicted have begun using the drug through illicit channels rather than through a prescription.” According to the researchers, although methadone fatalities remained stable and heroin deaths dropped, analgesic opioid fatalities rose to 2.7 per 100,000 persons in 2006, up from 0.39% per 100,000 in 1990. Although overall methadone deaths did not increase, fatalities among whites resulting from methadone use jumped ninefold, while decreasing by 2% in the New York City black population. Historically, heroin has been the most commonly used and deadliest opioid in urban areas, according to the researchers, largely due to its cheaper cost compared with analgesic agents in the class. But perceptions that analgesic opioids are safer alternatives have in part driven the abuse, misuse and diversion of painkillers, according to the investigators. The researchers posit that the results suggest a much different picture of the recreational prescription drug user than those individuals abusing heroin, “with less involvement in street-based forms of drug trafficking and use of other drugs such as cocaine,” according


SEPTEMBER 2013

PainMedicineNews.com I 9

P O L I C Y & MA N A G E ME N T

Study Warns of Dearth of U.S. Neurologists

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mericans who need to see a neurologist may face longer wait times or have more difficulty finding one, reported a new study published in the April 17, 2013, online issue of Neurology, the medical journal of the American Academy of Neurology (AAN). The findings were released as nearly 150 neurologists met on Capitol Hill on April 23 to encourage Congress to protect patients’ access to neurologists. “We want Congress to act now to help alleviate this shortage,” said Timothy A. Pedley, MD, FAAN, president of the AAN, the world’s largest association of neurologists. “Neurologists are the physicians best suited to care for the one in six people currently affected by neurologic disease. It is therefore vital that they have access to neurologists who are specially trained in treating brain diseases.” “With the rapidly rising rates of brain diseases such as dementia and stroke [occurring] at the same time as the number of U.S. medical residents choosing neurology over other specialties is clearly declining, the U.S. could face a crisis,” said study author Thomas R. Vidic, MD, a neurologist in the Elkhart Clinic in Elkhart, Ind., and a fellow with the AAN. “Our study found

that long wait times for patients to see a neurologist and difficulty finding neurologists to fill vacant positions are adding to the current national shortfall. In addition, the demand for neurologists is expected to grow as people gain coverage through health care reform.” For the study, researchers created future year projections by reviewing the current number of U.S.

neurologists and simulating retirement probability, new graduates and patient care hours worked. The study found that the demand for neurologists will grow faster than the supply. Researchers reported that the estimated 16,366 U.S. neurologists is projected to increase to 18,060 by 2025, whereas demand for neurologists is projected to increase from about

18,180 in 2012 to 21,440 by 2025. The study was supported by the AAN and an educational grant from Eli Lilly. Since 2003, more than 600 members of the AAN have participated in Neurology on the Hill. View a list of neurologists participating in the 2013 Neurology on the Hill at http://www.aan.com/ news/?event=read&article_id=11201. —Based on a press release from the American Academy of Neurology

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to the Columbia press release. They stated that a different approach to the problem might be warranted, including more regulation on marketing of prescription opioid analgesics and stricter sales regulation. They also called for stronger law enforcement efforts to find “illicit networks” of prescription drugs and better education for both patients and physicians. “The distinct epidemiologic profiles exhibited by analgesic and methadone overdose fatalities highlight the need to define drug-specific public health prevention efforts,” said the researchers in their conclusion. —Donald M. Pizzi The research was supported by grants from the National Institute on Drug Abuse and a grant from the National Center for Injury Prevention and Control at the Centers for Disease Control to the Columbia University Center for Injury Epidemiology and Prevention. Based on a press release from Columbia University.

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10 I PainMedicineNews.com

SEPTEMBER 2013

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Washington State Pain Clinic Instills ‘Don’t Give Up’ Attitude

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ach week, the Rehabilitation Institute of Washington (RIW) pain management team hears patients graduating from its program, say, “Why didn’t I do this years ago?” That’s because many of them, after battling chronic pain for years, have overcome its physical limitations and are doing things they thought they’d never do again. “We see many patients who have completely lost hope that they can improve,” said James Moore, PhD, RIW’s co-founder. “Within a week in our program, they’re more active than they have been in years. This is what keeps us doing what we do.” For more than two decades, RIW’s dedicated team has used an interdisciplinary functional rehabilitation approach to help people with chronic pain restore the physical, emotional, occupational, recreational and social aspects of their lives. “Our experience has been that functional rehabilitation yields better and more lasting changes because patients learn to manage pain and maintain active lifestyles,” Dr. Moore said. Because of its success in treating chronic pain, the Seattle-based, 2011 American Pain Society Clinical Center of Excellence award winner also has become an established Washington State resource on pain and its treatments. Members of the RIW team actively train other physicians, chiropractors, physical therapists (PTs), occupational therapists (OTs), vocational rehabilitation counselors and psychologists, as well as residents, medical students and therapists at the University of Washington and other educational institutions, on how to treat chronic pain. Additionally, they serve on medical advisory committees for Washington State’s Department of Labor and Industries regarding best practices for managing pain. RIW helped design the state’s pain rehabilitation guidelines and collaborated on developing treatment protocols for complex regional pain syndrome, the use of opioids and detoxifying opioid-dependent patients. Striking Out on Its Own RIW originally was part of a large academic medical center in Seattle. According to Heather Kroll, MD, RIW’s other co-founder, the medical center “looked at its finances and goals and what kind of services it wanted to provide, and decided it didn’t want to provide this service.” With encouragement from referring physicians and patients, RIW struck out on its own in 2005, becoming a freestanding pain management clinic and eventually moving into its current location in the uptown, “Lower Queen Anne” section of Seattle. Since then, RIW has nearly tripled its business to almost 700 patients annually. The move proved that the old business axiom about “location, location, location” is true. “The neighborhood we’re in now is less intimidating to patients than the heart of downtown, where the medical center is located,” explained Dr. Moore.

“We have plenty of parking and are very accessible to public transportation. Since many patients come from elsewhere in the state, as well as other states, we’ve acquired a nearby apartment building to house patients.” RIW’s current facility is nearly 26,000 square feet, and incorporates an open floor plan. It has three gymnasiums, the most modern exercise and therapy

RIW patients perform job-specific tasks in the institute’s new “work-hardening” program, which simulates the kinds of work activities they might do in their jobs.

equipment, the latest computer capabilities and a variety of occupational workstations. “Our new space is not only larger than our old space,” Dr. Kroll said, “but it is laid out in a more efficient way that really maximizes all aspects of patient care.” Becoming an independent clinic also has given RIW much more control over its program. “As part of a large medical center, we had multiple layers of administration, and [the administration] held the decision-making power,” said Dr. Moore. “As a freestanding clinic, we’ve been able to expand (three expansions in seven years), design the space to better suit our needs, acquire new equipment, develop new programs, and control the number and composition of our staff. We’ve also given team members more control and decision-making power, which in turn has improved morale and provided a sense of ownership of the program.”


SEPTEMBER 2013

PainMedicineNews.com I 11

PRN RIW focuses on active, exercisebased physical therapy to improve strength, endurance, flexibility, posture and body mechanics. Additionally, the program stresses occupational therapy to advance physical activity and daily function; psychological counseling to promote coping strategies and the emotional RIW physical therapists help patients become stronger, more flexible and more confident so they can resume daily activities.

Getting People Back to Work The bulk of RIW’s patients are injured workers referred for treatment through the state’s workers’ compensation system. “Private health insurance typically doesn’t pay for comprehensive rehabilitation for complex chronic pain problems,” Dr. Moore explained. “Workers’ compensation insurance covers effective treatment because, otherwise, it will end up paying disability for years.” Dealing with Washington’s workers’ compensation system can be challenging, but RIW has learned to navigate it effectively. “We have patient coordinators who take care of getting authorization for treatments and, if necessary, housing and transportation for the workers,” said Dr. Kroll. “Our vocational counselors provide one-onone counseling on workers’ compensation regulations and help injured workers understand the services to which they are entitled. Our physicians also deal directly with state case managers on the medical issues. It works smoothly because we all have the same priority—getting a person back on the job as quickly as possible.”

RIW has three gyms with the most modern exercise and therapy equipment to provide active, exercise-based physical therapies to improve strength, endurance, flexibility, posture and body mechanics.

sequelae of pain; medical management to educate patients about pain and minimize the use of harmful or dependence-causing medications; and vocational counseling to help patients return to productive employment. The institute also provides nutrition counseling and drug detoxification services. A patient arriving at RIW will undergo an intensive half-day evaluation with a physician, pain psychologist and vocational rehabilitation

counselor. On entering RIW’s program, patients spend the next 20 days, Monday through Friday, from 9 a.m. to 4 p.m., working with rehabilitation specialists to restore function, improve cardiovascular health and learn proper body mechanics and coping strategies. Physical therapy may include gait training, flexibility exercises, spinal stabilization exercises, postural exercises, neuromuscular retraining, strength training, cardiovascular exercise and more. Occupational therapy focuses on job-specific work, home or leisure activities, such as how to sit and stand comfortably, lift and carry things, walk, climb stairs, and use arms and hands. The program puts a strong emphasis on the nonphysical or psychological aspects of the pain experience. “The core psychological focus is to help patients understand that their pain might not be dangerous, and it should not affect daily activities,” said David Fordyce, PhD, an RIW psychologist. “We also deal with the myth that seeing a psychologist means their pain is imaginary. It is a worry many patients carry. We try to make them understand that their pain is absolutely real.” Dr. Fordyce estimated that nearly 80% of RIW’s patients are dealing with psychological issues. Their biggest concern: fear of their pain and an almost phobic anxiety that it will get worse, or they will reinjure themselves if they try to do something. To help patients overcome these fears, RIW’s pain psychologists not only offer cognitive and behavioral coping skills for managing fear, depression, anger and other emotional consequences of pain, but they help patients understand the very nature of chronic pain and how it affects them and their families. Dr. Fordyce pointed out that the psychological component of the program does not act independently of the physical and occupational rehabilitation, but rather is complementary. “The psychology is kind of the icing on a cake that supports our physical rehab,” he said. “Our PTs and OTs are often our strongest psychologists, because their job is to stand next to a patient who is very fearful, anxious and frustrated at being asked to do something physical in the face of his or her pain. So, from the moment a person walks in the door, the PTs and OTs tell them they know it will be difficult and scary, but they are going to support the patients in slowly moving their bodies. It will be OK.” Although the PTs and OTs spend the most oneon-one time with patients, RIW’s physicians and psychologists are frequently in the gyms, helping patients overcome any anxiety about what’s happening to their bodies. According to Dr. Kroll, this kind of teamwork and concern for patients, along with the experience the team has acquired over the years, makes the program successful. “Many of our patients have had lots of physical therapy, and it hasn’t helped,” she said. “Our staff reassures them it is safe to move, and [explains to them the] kind of symptoms they should pay attention to and which ones to ignore. Our team is very good at handling questions and negotiating a patient’s fear.” see PAIN CLINIC page 12


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I N T E R V E N T I O N A L PA I N M E D I C I N E

Increased Risk for SSI Seen in Patients With Myelopathy or Spinal Cord Injury

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ont Tremblant, Quebec—Patients who have myelopathy or a spinal cord injury are much more likely to develop a surgical site infection (SSI), according to an administrative database study of posterior cervical spine surgery. Patients who are aged 50 years or older also are associated with a small but significantly elevated risk for an SSI.

‘The follow-up for these databases is generally too short to determine the true rate and cost of infections, and as such the true infection rate is likely higher than reported. But there is no reason to suspect that the data are differentially biased with respect to neurologic damage. As such their P values are likely to be correct, even if their exact percentages and odds ratios are not.’ —Keith Baldwin, MD, MSPT, MPH

The researchers extracted data from the Nationwide Inpatient Sample on inpatients who underwent surgery between 2000 and 2009, and compared groups with radiculopathy with or without myelopathy, and traumatic cervical injury with or without a neurologic injury. The team, from Vancouver, Canada, and Philadelphia, presented the results at the Canadian Spine Society’s 2013 annual meeting. “The thought is that when looking at rates of concurrent neurologic dysfunction in such a large cohort, the effect is probably real rather than confounding,” said lead investigator Ravi Ghag, MD, a fifth-year orthopedics resident at the University of British Columbia, in Vancouver. He and his co-investigators identified 1,762,277 patients, of whom 1,389,763 had radiculopathy and 52,979 had a traumatic cervical injury. Among the radiculopathy patients, 372,514 (26.8%) had concurrent myelopathy, and 15,034 (28.4%) of the traumatic patients had concurrent neurologic injury. Patients with concurrent myelopathy and those with concurrent neurologic injury were significantly older, and more were men, than the other

patients in their respective groups (P<0.001 for both). Furthermore, there was a higher proportion of black, Asian and Hispanic individuals in the myelopathy group. Bivariate analysis revealed that the percentage of SSIs was 0.58% among patients with radiculopathy without myelopathy and 1.35% among those with radiculopathy and myelopathy (P<0.001) (Table). Multivariate regression analysis revealed that patients with radiculopathy and myelopathy had 1.82 higher odds of having an SSI than patients without myelopathy (P<0.001). Patients with a traumatic cervical injury and concomitant neurologic injury had 1.33 higher odds of having an SSI than those without a neurologic injury (P=0.07). Additionally, fusion of two or three vertebral levels among patients with trauma was protective compared with fusion of four to eight vertebral levels (odds ratio [OR], 0.49; P<0.001). Older patients with radiculopathy had a higher risk for SSI than younger patients (OR, 1.03; P<0.001), whereas female gender was protective against SSI (OR, 0.61; P<0.001).

The investigators said using an administrative database resulted in underestimating the rate of complications in all patients. This method also did not allow analysis of factors known to affect the rate of SSIs, such as diabetes, intraoperative irrigation, duration of surgery, patient age, body mass index, smoking history, length of preoperative hospital stay and antimicrobial prophylaxis. “I have used several administrative databases myself for research and also find that complications tend to be underreported,” said Keith Baldwin, MD, MSPT, MPH, assistant professor of orthopedic surgery at the Children’s Hospital of Philadelphia, who was not involved in the study. “Also, the follow-up for these databases is generally too short to determine the true rate and cost of infections, and as such the true infection rate is likely higher than reported. But there is no reason to suspect that the data are differentially biased with respect to neurologic damage. As such their  P values are likely to be correct, even if their exact percentages and odds ratios are not.” —Rosemary Frei Dr. Ghag does not have any relevant conflicts of interest to disclose. Dr. Baldwin is a consultant for Synthes Trauma and is a stockholder in Pfizer.

Table. Bi Bivariate i A Analysis l i off O Outcome V Variables i bl a Parameter

Radiculopathy Without Radiculopathy With Trauma Without Myelopathy Myelopathy Spinal Cord Injury

Trauma With Spinal Cord Injury

SSIs, %

0.58

1.35

1.76

2.44

Mean length of stay, days (interquartile range)

1 (1-2)

2 (2-4)

6 (3-10)

9 (9-15)

Unadjusted cost in 2010 US$ (interquartile range)

$27,840 ($18,900-$34,970)

$36,680 ($23,650-$49,920)

$66,730 ($40,430-$118,500)

$84,370 ($49,110-$158,100)

SSI, surgical site infection a

Comparisons between radiculopathy without myelopathy and with myelopathy, and between trauma without spinal cord injury and with spinal cord injury, both had a P value of P<0.001. P

PAIN CLINIC continued from page 11

Measurable Improvements Since becoming a freestanding pain clinic, RIW has posted impressive outcomes. For example, for patients who completed the program in 2010, more than 72% returned to work by one-year follow-up, and another 12% were in retraining. Patients improved in all measures—reported pain, pain worry, fear avoidance beliefs, depression, self-reported function and objective measures of function. Patients also had reduced use of opiates, sedatives, alcohol and tobacco. Additionally, patients

reported that after leaving the program, their newly learned coping strategies keep them more active and independent at home. RIW’s newest initiative is its “work-hardening” facility, where patients can simulate the kind of work they might do in a job, such as moving freight, running power tools or climbing ladders. “We hope to grow this program to help injured workers return to jobs that require the performance of specific work tasks and high levels of fitness and endurance,” said Dr. Moore. The institute strives to help physicians understand that its program is effective for treating anyone with

chronic pain, excessive medication use and prolonged disability. “We’d like to be able to treat patients sooner, before they undergo unnecessary surgery, become dependent on medications, or become depressed and hopeless about returning to work,” Dr. Moore continued. “We have an evidence-based treatment approach that is as effective as more invasive treatments, but less costly and less likely to result in medical complications. We hope to educate physicians about the availability of this approach, and thus provide effective care to a larger group of people with chronic pain.” —Tom McDonough


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Relieve muscle spasm with once-daily AMRIX Download the AMRIX Coupon for your patients at AMRIX.com INDICATIONS AND USAGE AMRIXX (Cyclobenzaprine Hydrochloride Extended-Release Capsules) is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, and limitiation of motion. AMRIXX should be used only for short periods (up to 2 or 3 weeks). AMRIX has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy.

IMPORTANT SAFETY INFORMATION AMRIXX is contraindicated: sin patients who are hypersensitive to any of its components. swith concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation. AMRIXX may have life-threatening interactions with MAO inhibitors. s during the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block conduction disturbances, or congestive heart failure. s in patients with hyperthyroidism. Potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine when used in combination with other drugs, such as SSRIs, SNRIs, TCAs, tramadol, bupropion, meperidine, verapamil, or MAO inhibitors. Discontinue AMRIXX and concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur and initiate supportive symptomatic treatment. Š2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. AMR-40058 June 2013 Printed in USA.

AMRIXX is closely related to tricyclic antidepressants, which have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction, and stroke. AMRIXX should not be used in elderly patients or in patients with impaired hepatic function. Because of its atropine-like action, AMRIXX should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication. AMRIXX may enhance the effects of alcohol, barbiturates, and other CNS depressants. AMRIX, X especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. In clinical trials, the most commonly reported adverse reactions (â&#x2030;Ľ3%) with AMRIXX were dry mouth, dizziness, fatigue, nausea, dyspepsia, and constipation.

Please see brief summary of Prescribing Information on adjacent page. Coupon Information: t $5 Coupon offer good at participating pharmacies t Available to eligible commercially insured patients t Out-of-pocket expenses greater than $5 will be covered up to a maximum of $480 t Not valid for cash-paying patients t Not valid for Medicaid, Medicare (including Medicare Advantage or Part D Prescription Plans), or any other public payer program t Residents of Massachusetts not eligible * Limitations apply.


BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR AMRIX® (Cyclobenzaprine Hydrochloride Extended-Release Capsules) The following is a brief summary only. For more detailed information, please read the full Prescribing Information. DESCRIPTION AMRIX is a skeletal muscle relaxant which relieves muscle spasm of local origin without interfering with muscle function. The active ingredient in AMRIX extended-release capsules is cyclobenzaprine hydrochloride, USP. AMRIX extended-release capsules for oral administration are supplied in 15 and 30 mg strengths. INDICATIONS AND USAGE AMRIX is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, and limitation of motion. AMRIX should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. AMRIX has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. CONTRAINDICATIONS UÊÞ«iÀÃi˜ÃˆÌˆÛˆÌÞÊ̜Ê>˜ÞÊVœ“«œ˜i˜ÌʜvÊ̅ˆÃÊ«Àœ`ÕVÌ° UÊ œ˜Vœ“ˆÌ>˜ÌÊÕÃiʜvʓœ˜œ>“ˆ˜iʜ݈`>ÃiÊ­"®Êˆ˜…ˆLˆÌœÀÃʜÀÊ܈̅ˆ˜Ê£{Ê`>ÞÃÊ>vÌiÀÊ̅iˆÀÊ`ˆÃVœ˜Ìˆ˜Õ>̈œ˜° UÊÞ«iÀ«ÞÀïVÊVÀˆÃˆÃÊÃiˆâÕÀiÃÊ>˜`Ê`i>̅Ãʅ>ÛiʜVVÕÀÀi`ʈ˜Ê«>̈i˜ÌÃÊÀiViˆÛˆ˜}ÊVÞVœLi˜â>«Àˆ˜iÊ­œÀÊÃÌÀÕVÌÕÀ>ÞÊ Ãˆ“ˆ>ÀÊÌÀˆVÞVˆVÊ>˜Ìˆ`i«ÀiÃÃ>˜ÌîÊVœ˜Vœ“ˆÌ>˜ÌÞÊ܈̅Ê"ʈ˜…ˆLˆÌœÀÊ`ÀÕ}ð UÊ ÕÀˆ˜}Ê̅iÊ>VÕÌiÊÀiVœÛiÀÞÊ«…>ÃiʜvʓޜV>À`ˆ>Êˆ˜v>ÀV̈œ˜]Ê>˜` ˆ˜Ê«>̈i˜ÌÃÊ܈̅Ê>ÀÀ…Þ̅“ˆ>Ã]ʅi>ÀÌÊLœVŽÊ conduction disturbances, or congestive heart failure. UÊÞ«iÀ̅ÞÀœˆ`ˆÃ“° WARNINGS Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with cyclobenzaprine when used in combination with other drugs, such as selective serotonin ÀiÕ«Ì>ŽiÊ ˆ˜…ˆLˆÌœÀÃÊ ­--,î]Ê ÃiÀœÌœ˜ˆ˜Ê ˜œÀi«ˆ˜i«…Àˆ˜iÊ ÀiÕ«Ì>ŽiÊ ˆ˜…ˆLˆÌœÀÃÊ ­- ,î]Ê ÌÀˆVÞVˆVÊ >˜Ìˆ`i«ÀiÃÃ>˜ÌÃÊ­/ î]ÊÌÀ>“>`œ]ÊLÕ«Àœ«ˆœ˜]ʓi«iÀˆ`ˆ˜i]ÊÛiÀ>«>“ˆ]ʜÀʓœ˜œ>“ˆ˜iʜ݈`>ÃiÊ­"®Êˆ˜…ˆLˆÌœÀðÊ/…iÊ Vœ˜Vœ“ˆÌ>˜ÌÊ ÕÃiÊ œvÊ ,8Ê ÜˆÌ…Ê "Ê ˆ˜…ˆLˆÌœÀÃÊ ˆÃÊ Vœ˜ÌÀ>ˆ˜`ˆV>Ìi`Ê ­ÃiiÊ CONTRAINDICATIONS®°Ê -iÀœÌœ˜ˆ˜ÊÃޘ`Àœ“iÊÃޓ«Ìœ“Ãʓ>Þʈ˜VÕ`iʓi˜Ì>ÊÃÌ>ÌÕÃÊV…>˜}iÃÊ­i°}°]ÊVœ˜vÕȜ˜]Ê>}ˆÌ>̈œ˜]ʅ>ÕVˆ˜>̈œ˜Ã®]Ê >Õ̜˜œ“ˆVʈ˜ÃÌ>LˆˆÌÞÊ­i°}°]Ê`ˆ>«…œÀiÈÃ]ÊÌ>V…ÞV>À`ˆ>]ʏ>LˆiÊLœœ`Ê«ÀiÃÃÕÀi]ʅޫiÀ̅iÀ“ˆ>®]ʘiÕÀœ“ÕÃVՏ>ÀÊ >L˜œÀ“>ˆÌˆiÃÊ­i°}°]ÊÌÀi“œÀ]Ê>Ì>݈>]ʅޫiÀÀiyi݈>]ÊVœ˜ÕÃ]ʓÕÃViÊÀˆ}ˆ`ˆÌÞ®]Ê>˜`ɜÀÊ}>ÃÌÀœˆ˜ÌiÃ̈˜>ÊÃޓ«Ìœ“ÃÊ­i°}°]ʘ>ÕÃi>]Êۜ“ˆÌˆ˜}]Ê`ˆ>ÀÀ…i>®°Ê/Ài>̓i˜ÌÊ܈̅Ê,8Ê>˜`Ê>˜ÞÊVœ˜Vœ“ˆÌ>˜ÌÊÃiÀœÌœ˜iÀ}ˆVÊ>}i˜Ìà should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with AMRIX and other serotonergic drugs is clinically warÀ>˜Ìi`]ÊV>ÀivՏʜLÃiÀÛ>̈œ˜ÊˆÃÊ>`ۈÃi`]Ê«>À̈VՏ>ÀÞÊ`ÕÀˆ˜}ÊÌÀi>̓i˜Ìʈ˜ˆÌˆ>̈œ˜ÊœÀÊ`œÃiʈ˜VÀi>ÃiÃÊ­ÃiiÊPRECAUTIONS, Drug Interactions®° s AMRIX is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred. Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. AMRIX may enhance the effects of >Vœ…œ]ÊL>ÀLˆÌÕÀ>ÌiÃ]Ê>˜`ʜ̅iÀÊ -Ê`i«ÀiÃÃ>˜Ìð As a result of a two-fold higher cyclobenzaprine plasma levels in subjects with mild hepatic impairment, as compared to healthy subjects, following administration of immediate-release cyclobenzaprine and LiV>ÕÃiÊ̅iÀiʈÃʏˆ“ˆÌi`Ê`œÃˆ˜}Êyi݈LˆˆÌÞÊ܈̅Ê,8]ÊÕÃiʜvÊ,8ʈÃʘœÌÊÀiVœ““i˜`i`ʈ˜ÊÃÕLiVÌÃÊÜˆÌ…Ê mild, moderate or severe hepatic impairment. ÃÊ>ÊÀiÃՏÌʜvÊ>Ê{ä¯Êˆ˜VÀi>Ãiʈ˜ÊVÞVœLi˜â>«Àˆ˜iÊ«>Ó>ʏiÛiÃÊ>˜`Ê>Êxȯʈ˜VÀi>Ãiʈ˜Ê«>Ó>ʅ>v‡ˆviÊ following administration of AMRIX in elderly subjects as compared to young adults, use of AMRIX is not recommended in elderly. PRECAUTIONS General Because of its atropine-like action, AMRIX should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication. Information for Patients ,8]ÊiëiVˆ>ÞÊ܅i˜ÊÕÃi`Ê܈̅Ê>Vœ…œÊœÀʜ̅iÀÊ -Ê`i«ÀiÃÃ>˜ÌÃ]ʓ>Þʈ“«>ˆÀʓi˜Ì>Ê>˜`ɜÀÊ«…ÞÈV>Ê abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of AMRIX and œÌ…iÀÊ`ÀÕ}Ã]ÊÃÕV…Ê>ÃÊ--,Ã]Ê- ,Ã]Ê/ Ã]ÊÌÀ>“>`œ]ÊLÕ«Àœ«ˆœ˜]ʓi«iÀˆ`ˆ˜i]ÊÛiÀ>«>“ˆ]ʜÀÊ"ʈ˜…ˆLˆÌœÀÃ°Ê Patients should be advised of the signs and symptoms of serotonin syndrome, and be instructed to seek “i`ˆV>ÊV>Àiʈ““i`ˆ>ÌiÞʈvÊ̅iÞÊiÝ«iÀˆi˜ViÊ̅iÃiÊÃޓ«Ìœ“ÃÊ­Ãii WARNINGS, and see PRECAUTIONS, Drug Interactions®° s Drug Interactions ,8Ê “>ÞÊ …>ÛiÊ ˆvi‡Ì…Ài>Ìi˜ˆ˜}Ê ˆ˜ÌiÀ>V̈œ˜ÃÊ ÜˆÌ…Ê "Ê ˆ˜…ˆLˆÌœÀÃÊ ­Ãii CONTRAINDICATIONS®°Ê *œÃÌmarketing cases of serotonin syndrome have been reported during combined use of cyclobenzaprine and œÌ…iÀÊ`ÀÕ}ÃÊÃÕV…Ê>ÃÊ--,Ã]Ê- ,Ã]Ê/ Ã]ÊÌÀ>“>`œ]ÊLÕ«Àœ«ˆœ˜]ʓi«iÀˆ`ˆ˜i]ÊÛiÀ>«>“ˆ]ʜÀÊ"ʈ˜…ˆLˆtors. If concomitant treatment with AMRIX and other serotonergic drugs is clinically warranted, careful œLÃiÀÛ>̈œ˜ÊˆÃÊ>`ۈÃi`]Ê«>À̈VՏ>ÀÞÊ`ÕÀˆ˜}ÊÌÀi>̓i˜Ìʈ˜ˆÌˆ>̈œ˜ÊœÀÊ`œÃiʈ˜VÀi>ÃiÃÊ­ÃiiÊWARNINGS®°Ê ,8ʓ>ÞÊi˜…>˜ViÊ̅iÊivviVÌÃʜvÊ>Vœ…œ]ÊL>ÀLˆÌÕÀ>ÌiÃ]Ê>˜`ʜ̅iÀÊ -Ê`i«ÀiÃÃ>˜ÌðÊ/ÀˆVÞVˆVÊ>˜Ìˆ`i«ÀiÃsants may block the antihypertensive action of guanethidine and similarly acting compounds. Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol. Pregnancy Pregnancy Category B:: Reproduction studies have been performed in rats, mice, and rabbits at doses up to 20 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when AMRIX is administered to a nursing woman. Pediatric Use Safety and effectiveness of AMRIX has not been studied in pediatric patients. Use in the Elderly The plasma concentration and half-life of cyclobenzaprine are substantially increased in the elderly when compared to the general patient population. Accordingly, AMRIX should not be used in the elderly.

AMRIX® (Cyclobenzaprine Hydrochloride Extended-Release Capsules) ADVERSE REACTIONS /…iʓœÃÌÊVœ““œ˜Ê>`ÛiÀÃiÊÀi>V̈œ˜Ãʈ˜Ê̅iÊÌܜʣ{‡`>ÞÊVˆ˜ˆV>ÊivwV>VÞÊÌÀˆ>ÃÊ>ÀiÊ«ÀiÃi˜Ìi`ʈ˜Ê̅iÊÌ>LiÊLiœÜ° Incidence of the Most Common Adverse Reactions Occurring in * 3% of Subjects in Any Treatment Group in the Two Phase 3, Double-Blind AMRIX Trials AMRIX 15 mg N = 127

AMRIX 30 mg N = 126

Placebo N = 128

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˜Ê >Ê «œÃ̓>ÀŽï˜}Ê ÃÕÀÛiˆ>˜ViÊ «Àœ}À>“Ê ­ÇÈäÇÊ «>̈i˜ÌÃÊ ÌÀi>Ìi` ÜˆÌ…Ê VÞVœLi˜â>«Àˆ˜iÊ £äÊ “}Ê / ®]Ê Ì…iÊ adverse reactions reported most frequently were drowsiness, dry mouth, and dizziness. Among the less frequent adverse reactions, there was no appreciable difference in incidence in controlled Vˆ˜ˆV>ÊÃÌÕ`ˆiÃʜÀʈ˜Ê̅iÊÃÕÀÛiˆ>˜ViÊ«Àœ}À>“°Ê`ÛiÀÃiÊÀi>V̈œ˜ÃÊ܅ˆV…ÊÜiÀiÊÀi«œÀÌi`ʈ˜Ê£¯Ê̜Êίʜv ̅iÊ«>̈i˜ÌÃÊÜiÀi\Êv>̈}ÕiÉ̈Ài`˜iÃÃ]Ê>Ã̅i˜ˆ>]ʘ>ÕÃi>]ÊVœ˜Ã̈«>̈œ˜]Ê`Þëi«Ãˆ>]Ê՘«i>Ã>˜ÌÊÌ>ÃÌi]ÊLÕÀÀi`Ê vision, headache, nervousness, and confusion. The following adverse reactions have been reported in «œÃ̇“>ÀŽï˜}ÊiÝ«iÀˆi˜ViʜÀÊ܈̅Ê>˜Êˆ˜Vˆ`i˜ViʜvʏiÃÃÊ̅>˜Ê£¯ÊœvÊ«>̈i˜ÌÃʈ˜ÊVˆ˜ˆV>ÊÌÀˆ>ÃÊ܈̅Ê̅iÊ£äʓ}Ê / ÊÌ>LiÌ\ Body as a Whole: Syncope; malaise. Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension. Digestive:Ê6œ“ˆÌˆ˜}ÆÊ>˜œÀi݈>ÆÊ`ˆ>ÀÀ…i>ÆÊ}>ÃÌÀœˆ˜ÌiÃ̈˜> : Ê«>ˆ˜ÆÊ}>ÃÌÀˆÌˆÃÆÊ̅ˆÀÃÌÆÊy>ÌՏi˜ViÆÊi`i“>ʜvÊ̅iÊ̜˜}ÕiÆ abnormal liver function and rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity:: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Musculoskeletal:: Local weakness. Nervous System and Psychiatric: Seizures, ataxia; vertigo; dysarthria; tremors; hypertonia; convulsions; muscle twitching; disorientation; insomnia; depressed mood; abnormal sensations; anxiety; agitation; psychosis, abnormal thinking and dreaming; hallucinations; excitement; paresthesia; diplopia; serotonin syndrome. Skin:: Sweating. Special Senses:: Ageusia; tinnitus. Urogenital:Ê1Àˆ˜>ÀÞÊvÀiµÕi˜VÞÊ>˜`ɜÀÊÀiÌi˜Ìˆœ˜° : DRUG ABUSE AND DEPENDENCE Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when AMRIX is administered, even though they have not been reported to occur with this drug. Abrupt cessation of treatment after prolonged administration rarely may produce nausea, headache, and malaise. These are not indicative of addiction. OVERDOSAGE Ì…œÕ}…ÊÀ>Ài]Ê`i>̅Ãʓ>ÞʜVVÕÀÊvÀœ“ÊœÛiÀ`œÃ>}iÊ܈̅Ê,8°ÊՏ̈«iÊ`ÀÕ}ʈ˜}iÃ̈œ˜Ê­ˆ˜VÕ`ˆ˜}Ê>Vœ…œ® is common in deliberate cyclobenzaprine overdose. As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity may develop rapidly after cyclobenzaprine overdose; therefore, hospital monitoring is required as soon as possible. DOSAGE AND ADMINISTRATION /…iÊÀiVœ““i˜`i`Ê>`ՏÌÊ`œÃiÊvœÀʓœÃÌÊ«>̈i˜ÌÃʈÃʜ˜iÊ­£®Ê,8Ê£xʓ}ÊV>«ÃՏiÊÌ>Ži˜Êœ˜ViÊ`>ˆÞ°Ê-œ“i «>̈i˜ÌÃʓ>ÞÊÀiµÕˆÀiÊÕ«Ê̜ÊÎäʓ}É`>Þ]Ê}ˆÛi˜Ê>Ãʜ˜iÊ­£®Ê,8ÊÎä “}ÊV>«ÃՏiÊÌ>Ži˜Êœ˜ViÊ`>ˆÞʜÀÊ>ÃÊÌܜ ­Ó®Ê,8Ê£xʓ}ÊV>«ÃՏiÃÊÌ>Ži˜Êœ˜ViÊ`>ˆÞ° It is recommended that doses be taken at approximately the same time each day. 1ÃiʜvÊ,8ÊvœÀÊ«iÀˆœ`Ãʏœ˜}iÀÊ̅>˜ÊÌܜʜÀÊ̅ÀiiÊÜiiŽÃʈÃʘœÌÊÀiVœ““i˜`i`Ê­ÃiiÊINDICATIONS AND USAGE®° Dosage Considerations for Special Patient Populations:: AMRIX should not be used in the elderly or in «>̈i˜ÌÃÊ܈̅ʈ“«>ˆÀi`ʅi«>̈VÊv՘V̈œ˜°Ê­ÃiiÊWARNINGS®

ˆÃÌÀˆLÕÌi`Ê Þ\ Teva Pharmaceuticals USA, Inc. œÀ̅Ê7>iÃ]Ê*Ê£™{x{ Manufactured By: Aptalis Pharma 6>˜`>ˆ>]Ê"Ê{xÎÇÇ Brief summary of AMRIX Prescribing Information AMR-005. ,8ʈÃÊ>ÊÌÀ>`i“>ÀŽÊœvÊ68ʘÌiÀ˜>̈œ˜>Ê“LʜÀʈÌÃÊ>vwˆ>Ìið ^Óää{‡Óä£ÎÊ i«…>œ˜]ʘV°]Ê>Ê܅œÞʜܘi`ÊÃÕLÈ`ˆ>ÀÞʜvÊ/iÛ>Ê*…>À“>ViṎV>Ê˜`ÕÃÌÀˆiÃÊÌ`° ,‡{ääÈäÊÊÊÊ>ÞÊÓä£ÎÊ All rights reserved.


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I N T E R V E N T I O N A L PA I N M E D I C I N E MISPLACED continued from page 1

improvement and billing data to determine the number of wrong-site blocks between July 2002 and June 2012 within the UPMC system. Between 2002 and 2010, each hospital was responsible for verification processes concerning nerve blocks. Following a wrong-site block in June 2010, a mandatory time-out policy was developed. This evolved in March 2011 to a system-wide policy, which was approved and introduced across all system hospitals. All but one hospital performed blocks in a preoperative holding area. UPMC clinicians performed 169,508 blocks on 85,915 patients across the system during the study period. Nine wrong-site blocks occurred, for an incidence of 1.05 per 10,000 patients. The incidence of wrong-site blocks varied from none to three per year and none to three per location. As the investigators reported at the 2013 annual meeting of the American Society of Regional Anesthesia and Pain Medicine (abstract A20), five of the nine wrong-site blocks were femoral, two were lumbar plexus, one interscalene and one cervical. “In looking at facilities, we examined sites with and without dedicated acute interventional pain programs,” Dr. Hudson told Pain Medicine News. When a member of the anesthesiology team rather

‘So just having a policy in place, no matter how robust it may be, doesn’t completely eliminate wrong-site blocks, because it relies on people following the policy.’ —Mark Hudson, MD, MBA

than the dedicated interventional pain team performed the procedure, the frequency of wrong-site blocks nearly doubled. Although wrong-site blocks were recorded after the development of various policies, the incidence fell to about half its previous rate. Furthermore, review of these post-policy cases revealed that in each instance, the care team did not follow approved policy. In one case, the team that performed the block differed from the team that performed the time-out. In the second case, the time-out was performed before the patient was positioned and marked. And in the most recent case, the patient’s marking was not visible when the block was performed.

Yet for Dr. Hudson, perhaps the study’s most disturbing finding came when he compared the incidence of wrong-site blocks with wrong-site surgeries (for which data were available for the past four years): Wrong-site blocks outnumbered wrongsite surgeries by a factor of 10. “I think there has been so much attention paid to wrong-site surgeries that now there are clearly defined policies and roles within that policy for the surgical team,” he explained. “That’s not necessarily the case for the block team.” And although the consequences may not be as serious for wrong-site blocks as they are for wrong-site surgery, that does not mean they should be taken lightly. “I think any time a procedure is done on the wrong side, there’s a risk associated with it,” Dr. Hudson said. “Either way, this should be a zero event. It should never happen.” Stephen M. Rupp, MD, medical director of perioperative services at Virginia Mason Medical Center, in Seattle, noted that preventing wrong-site blocks goes well beyond simply creating new policies. “This is more about training and culture,” Dr. Rupp said. “So you need the key opinion leaders in the department to speak up and say, ‘We’re going to do this.’ Once you’ve made that commitment, you need a poster visible in the room where the block is performed, to remind people of steps in the process,” Dr. Rupp continued. “Patients love when you create that environment; they love to hear you going through those steps. It’s reassuring to them.” —Michael Vlessides

The Wrong Side of Wrong-Site Claims aren Domino, MD, MPH, who oversees the Closed Claims database, said there are 13 wrong-site block claims among the roughly 9,800 total in the pool. Of those, seven involve blocks of the lower extremities, two of the shoulder or upper extremities and four for eye procedures. “In all cases, the wrong-side block was noted prior to start of surgery, so there were no wrong-side surgeries associated with these wrong-side blocks,” said Dr. Domino, professor of anesthesiology and pain medicine at the University of Washington, in Seattle. “In all cases, the consent and other documentation were clear regarding the surgical plan.” Injuries ranged from none to permanent but minor, she said; four claims involved temporary or nondisabling nerve injuries. At least two patients were admitted to the hospital as a result of the errant block. In at least six of the 13 cases, a payment was made on behalf of the anesthesiologists who performed the procedure, Dr. Domino said. The payout in 2012 dollars ranged from $3,750 to $19,500, she said. The most recent claim occurred in 2008, while only two were filed since 2003, the year before the Joint Commission issued its Universal Protocol on wrong-site surgery. The Closed Claims database does shed some light on why wrong-site blocks occur. According to Dr. Domino, reasons include verification—or a failure thereof—with patients who are sedated or who have dementia; lapses in confirming the correct site listed on the consent form; and, in one instance, sterile drapes covering the correct site and exposing the wrong one. “In another case, a time-out occurred, including checking with the patient regarding which side to block. However, the patient was then turned prone, and the wrong side was blocked,” she said. The lessons for clinicians from these cases are clear, Dr. Domino said: Triplecheck the patient’s consent documentation; do not rely on patients’ answers— or those of the nurses—particularly when patients are sedated or have dementia; and watch out for incorrectly placed drapes when patients are turned or prone. —PMN Staff

K


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I N T E R V E N T I O N A L PA I N M E D I C I N E

MRI Detects Spinal Infections From Contaminated Methylprednisolone

A

new study shows that magnetic resonance imaging (MRI) is able to identify patients with fungal spinal or paraspinal infection, even if the patients have no new or worsening symptoms. The patients in the study were at risk for infection because they had received

methylprednisolone injections from a contaminated lot prepared at New England Compounding Center, the source of last fall’s multistate outbreak of meningitis. Evaluating patients at a single site in Michigan, the study by Malani and colleagues ((JAMA A 2013;309:2465-2472)

identified 172 patients who had received contaminated methylprednisolone and had not sought related medical care. Of these patients, 108 (63%) had a normal MRI, 30 (17%) had an equivocal result and 34 (20%) had an abnormal MRI. The abnormalities included phlegmon; abscess; osteomyelitis or

diskitis; and arachnoiditis. Twenty-five of the patients with equivocal findings were rescreened, and two were found abnormal, for a total of 36 patients (21%) with abnormal MRIs. Of those 36, 35 met the Centers for Disease Control and Prevention’s case definition for probable fungal spinal or paraspinal infection. Thirteen of the patients with an abnormal MRI were asymptomatic: They had no change in back or neck pain, no evidence of radiculopathy and no lowerextremity weakness.

The 35 patients with probable infection received antifungal therapy: voriconazole with or without liposomal amphotericin B. Twenty-four patients underwent surgery, and 17 of those became confirmed cases when laboratory evidence of fungal infection was found. Study limitations, according to the authors, include the small numbers of patients and uncertainty as to whether early treatment due to MRI findings will improve outcomes. It also is not known, they wrote, whether the results can be generalized to all patients who received tainted methylprednisolone, especially those exposed to less heavily contaminated lots. In an accompanying editorial (JAMA ( 2013;309:2493-2495), Thompson and colleagues wrote, “Malani et al have demonstrated the possibility of largely asymptomatic fungal infection among patients previously exposed to injection with contaminated lots of methylprednisolone.” —George Ochoa

Contact the editor @ donaldp@mcmahonmed.com


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I N T E R V E N T I O N A L PA I N M E D I C I N E

Review: Nerve Blocks Prevent Pain After Major Surgery Miami Beach, Fla.—Administration of local or regional anesthesia before some major surgeries can prevent longterm pain for patients at five to six months postoperatively, according to a recent meta-analysis. “A large percentage of people have pain at six months, especially after thoracotomy, breast cancer surgery and cesarean section,” said Michael H. Andreae, MD, of the Department of Anesthesiology at Montefiore Medical Center/Albert Einstein College of Medicine, in New York City. Dr. Andreae and his wife, Doerthe A. Andreae, MD, PhD, an immunologist, identified 23 double-blind, randomized controlled trials in the literature that compared local or regional anesthesia technology (epidural, spinal or local blocks) with conventional treatment of pain (nonsteroidal antiinflammatory drugs [NSAIDs] or morphine) and grouped them according to the surgical intervention. Many studies showed that local or regional anesthesia can prevent chronic pain after different surgical interventions, but a meta-analysis could only be performed if there was more than one study in a surgical subgroup.

‘Dr. Andreae’s review is extremely important in that it clearly demonstrates that chronic pain is reduced when regional anesthesia and analgesia are used, which is a very important argument for the widespread use of these techniques.’ —Arthur Atchabahian, MD

The researchers found thoracotomy patients have a lower likelihood of chronic pain at six months if they receive regional anesthesia rather than conventional pain control (odds ratio [OR], 0.33). This result comes from pooled analysis of 250 study participants. “An epidural prevents pain six months down the road,” said Dr. Andreae. “We were surprised to find the results were so clear; this is important because chronic pain after thoracotomy is so difficult to treat.”

The analysis of 89 patients who underwent surgery for breast cancer found that those who received a paravertebral block were less likely to experience pain five or six months postoperatively (OR, 0.37). Put another way, an epidural for thoracotomy or a paravertebral block for breast cancer surgery can prevent chronic pain in one patient for approximately every

four to five patients treated. “Chronic pain can have a tremendous impact on quality of life; this is why prevention is paramount,” Dr. Andreae said. These and other findings were published Oct. 17, 2012 in the Cochrane Database of Systematic Reviews (2012, Issue 10. Art. No.: CD007105. doi: 10.1002/14651858.CD007105.pub2.). “We as anesthesiologists have to

become perioperative physicians and take a role in what happens after surgery,” Dr. Andreae said. Dr. Andreae also has a message for surgeons. “Chronic pain after surgery is underappreciated by surgeons, but it’s very important to the patient,” he said. Some surgeons don’t realize pain can persist this far into the postoperative see NERVE BLOCKS page 18

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Telomere Length Linked to Fibromyalgia Pain Washington—Considered a marker for biological aging linked to increased risk for morbidity and mortality, shortened leukocyte telomere length now has been associated with pain in fibromyalgia, researchers at the University of Michigan have found. The investigators also found that shortened telomere length was directly related to evoked pain sensitivity and altered brain structure, suggesting that pain may accelerate cellular aging. “Telomeres are protein complexes that cap and protect the ends of chromosomes,” said Afton L. Hassett, PsyD, associate research scientist in the Chronic Pain & Fatigue Research Center at the Ann Arbor institution. “Critically short telomeres put cells at risk for apoptosis and death. “This is the first study to show that telomere length is associated with clinical pain alone, as well as experimental pain. I will also caution, however, that this was a highly exploratory study.” Feeling One’s Biological Age Telomere length has been associated with a variety of age-related illnesses, including cardiovascular disease, osteoarthritis, osteoporosis and several forms of cancer. Sex, race, socioeconomic status and even level of education appear to affect the length of a person’s telomeres, as do behaviors and physical characteristics such as smoking, body mass index, stress and depression. That suggests telomere length is a measure of biological as opposed to chronological age, Dr. Hassett said. To determine the relationship, if any, between telomere length and pain, the researchers evaluated leukocyte telomere length in 66 women with

fibromyalgia and 22 healthy female controls. All volunteers completed questionnaires including the Brief Pain Inventory (BPI; 0-10 scale) and the Center for Epidemiologic Studies Depression Scale (CESD). Twelve of the women with fibromyalgia underwent quantitative sensory testing and neuroimaging. After controlling for age, pain was found to be associated with shorter telomere length (rrpartial  = –0.267; P=0.039), according to Dr. Hassett, who reported the findings at the 2012 annual meeting of the American Society of Anesthesiologists (abstract 012). Patients were categorized as experiencing high levels of pain (BPI ≥5; n=30) or lower levels of pain (BPI<5; n=31). Women who scored at least a 5 on the BPI—the cutoff for “high” levels of pain—were more likely to havee shorter telomeres regardless of thei eir chronological age (F=5.39; F P=0.0244). “This difference,” Dr. Hassett saaid, “represents approximately five years rs of aging.” That estimate is based on a previous study that linked the deter erioration of telomeres to time (Procc Natl Acad Sci USA A 1998;95:5607-56110). The researchers found no association between scores on the CE ESD and telomere length. “We also wondered wheth her combining age and depression might m have an additive effect,” Dr. Hassett continued. After e adjusting for age, patientss categorized as high pain/high depression had telomeres thatt were 265 base pair irs shorter, on average, than th those with low pain/low depression ion (P=0.043), (P

a difference consistent with approximately six years of chronological aging. In quantitative sensory testing, the researchers found a “very high correlation” between telomere length and sensitivity to pain that was statistically significant. “People with the shortest telomere lengths were by far the most sensitive to pain,” Dr. Hassett said. Neuroimaging in a subset of 12 patients found that telomere length also was related to a person’s volumee of gray matter. “We found that

the fibromyalgia patients with shorter telomeres showed less brain matter volume in pain processing areas of the brain,” Dr. Hassett said. Background Inflammation A Possible Explanation Exactly why telomere length has such a significant association with these variables is open to interpretation, although Dr. Hassett offered a possible explanation. “The predominant theory is that decreases in cortisol levels may create an environment where there’s greater low-level inflammatory activity,” she said. “Ultimately, we would really like to verify these results in a larger study and even consider chronic pain patients with other diagnoses.” pa W. Michael Hooten, MD, associate professor of anesthesiology at Mayo Clinic iin Rochester, Minn., called the study fascinating. “This is a th un nique avenue of investigation that coul uld broaden the understanding of the molecular mechanisms of chronic pain in,” Dr. Hooten said. “It’s a relatively sm mall sample, and it’ll be interesting to seee how this plays out in a larger group oof patients, to see if the findings can be replicated. “It would also be interesting to determine if treatment of the underlying pain condition can halt or retard telomere shortening,” Dr. Hooten continued. “This could have important clinical implications. For example, if an association exists between treatment response and telomere length, this could help identify and measure the effectiveness of various interventions for fibromyalgia.” —Michael Vlessides

NERVE BLOCKS continued from page 17

period, he added, or that prevention of pain with just a small amount of regional anesthesia can be very effective. “Even use of a single paravertebral block or a single-shot intervention” can alleviate significant pain. Simple infiltration of a wound before closure can be beneficial as well. “This doesn’t cost more and doesn’t increase [the rate of ] infection,” he added. Many patients also need education, Dr. Andreae said. “When we tell them about a block, some say ‘just knock me out.’” Some patients may not understand how regional anesthesia works or—as this study points out—how it can be advantageous in the long run, he said.

“Dr. Andreae’s review is extremely important in that it clearly demonstrates that chronic pain is reduced when regional anesthesia and analgesia are used, which is a very important argument for the widespread use of these techniques,” said Arthur Atchabahian, MD, of the Department of Anesthesiology at New York University Langone Medical Center, in New York City. “A next step might be to evaluate possible longterm benefits from other modalities of acute postoperative pain control, such as multimodal pharmacologic analgesia,” said Dr. Atchabahian, who was not involved with the current study. The dichotomous responder analysis (patients either had pain or did not) made for a very clean study, “but

chronic pain is a very complex concept that is not well captured by a yes/no answer,” Dr. Andreae said. Another potential limitation was the intermediate quality of the studies included in the meta-analysis, and the authors cautioned against overinterpretation of findings based on a small number of studies. The investigators only included studies of adults. In the future, Dr. Andreae said he would like to assess chronic pain in children after surgery, as well as expand his current findings to another meta-analysis that looks at different types of surgical procedures. —Damian McNamara Drs. Andreae and Atchabahian reported no relevant financial conflicts of interest.


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C L I N I C A L PA I N ME D I C I N E

Antibiotics Effective in Treating Back Pain From Herniated Disks, Study Shows

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atients undergoing surgery for lumbar disk herniation had a 46% rate of infection with Propionibacterium acnes, according to Danish researchers ((Eur Spine J 2013;22:690696). In a companion study, the researchers reported that using amoxicillin clavulanate for a period of 100 days resulted in a significant improvement in pain and disability among patients with chronic back pain ((Eur Spine J 2013;22:697-707). Hanne Albert, PT, MPH, PhD, associate professor at The University of Southern Denmark, Odense, and her colleagues cultured nuclear material from 61 patients undergoing primary surgery for lumbar disk herniation. They found that microbiologic cultures were positive in 46% (28) of patients, and anaerobic cultures were positive in 43% (26). Of the latter, 15% (four) had more than one microbial infection with both anaerobic and aerobic organisms. P. acnes was present in 86% (24 of 28) of positive cultures. Furthermore, 80% (20 of 25) of patients who had vertebrae adjacent

to disks from which anaerobic bacteria were isolated, developed new Modic changes (MC). In contrast, there were no MC in vertebrae adjacent to disks in which aerobic bacteria were detected. The next study Dr. Albert and her colleagues conducted was a randomized, controlled trial in patients with chronic low back pain, previous disk herniation and MC type 1 in the vertebrae next to the site of herniation. The investigators randomized the patients to either one dose of amoxicillin clavulanate (500 mg/135 mg; Bioclavid, Sandoz) three times a day; a double dose three times a day; one dose of placebo three times a day; or a double dose of placebo three times a day. Treatments were continued for 100 days and the patients were followed for one year from baseline. All patients attended a 90-minute education session that included an explanation of MC, why they are so painful, and why the patients were asked not to exercise during treatment. The patients taking antibiotics experienced significant improvement in primary outcomes for a year, compared

with those taking placebo. Primary outcomes were measured using scores on the Roland Morris Disability Questionnaire and the Low Back Pain Rating scale. These patients also had significantly greater improvements in other measures such as the degree of back pain (100% to 67.5% in antibiotic group vs. 100% to 94% with placebo; P=0.0001); having constant pain (75.3% to 19.5% vs. 73.1% to 67.2%, respectively; P=0.0001) and having disturbed sleep at night due to pain (74% to 29.9% vs. 76.1% to 61.2%, respectively; P=0.001). The double dose of antibiotics did not produce statistically significant superior results compared with the single dose, but there was a strong trend toward superior results. Of patients on antibiotics, 65% had adverse events (AEs) compared with 23% of those on placebo. Most were low-grade gastrointestinal side effects. One patient in the placebo group had an AE, whereas none of the antibiotic patients had serious side effects. David Solsberg, MD, PC, a neuroradiologist and interventional pain physician

in Englewood, Colo., said larger studies are needed to confirm the effectiveness of antibiotic therapy for back pain. “The study is very interesting and ... supports the hypothesis of infectious diskitis causing ‘degenerative’ disk disease. It may also explain why ozone therapy helps back pain because ozone is an effective antimicrobial agent,” Dr. Solsberg said. “[But] I’m skeptical of the relatively high response rate to antibiotic therapy. The reported incidence of infection in cultured disks is about one-third and yet [the researchers] are reporting treatment response in several categories of pain of up to 80%.” Dr. Solsberg suggested that a study be done in which patients’ herniated disks are biopsied and cultured before antibiotic therapy so that researchers can correlate the response to therapy with disk culture results. In response, Dr. Albert said, “We assumed 100% of the patients were infected since they developed Modic changes in the disks adjacent to the previously herniated discs ... all cultures were done with state-of-the-art methods and confirmed with PCR [polymerase chain reaction analysis].” —Rosemary Frei, MSc Drs. Albert and Solsberg reported no relevant conflicts of interest.

Pain Post-CABG Sternotomy: Prevalent and Relevant to Patients Miami Beach, Fla.—Nearly one-third of patients experience moderate to severe chronic pain following coronary artery bypass graft surgery with sternotomy, a long-term follow-up survey has found. Many of these patients do not seek medical attention to manage their pain, which they often describe as burning, shooting or constant aching. For this and other reasons, post-sternotomy pain after coronary artery bypass graft (CABG) procedures may be underrecognized and undertreated, researchers said. “We don’t ask, the patients don’t offer and we’re more interested in outcomes like strokes, deaths and recurrence of angina or heart-related chest pain,” study coauthor Dimitri Petsikas, MD, attending surgeon at Kingston General Hospital in Ontario, Canada, told Pain Medicine News. “Surgeons don’t see it as an issue, whereas the patients do see it as an issue because it affects them every day,” said Dr. Petsikas, who also is associate professor of surgery at Queens University in Ontario. Dr. Petsikas and his colleagues called 100 patients six to 18 months after they underwent CABG with sternotomy at their institution in 2011. Thirty

patients (30%) reported chronic post-sternotomy pain. The researchers asked about post-sternotomy pain and use of health care. They also assessed pain severity and its effect on daily activities using the Short-Form McGill Pain Questionnaire and the Brief Pain Inventory interference subscale. The researchers defined chronic poststernotomy pain as pain at the surgical site that persisted for six months or more and was distinct from preoperative pain. Pain scores greater than 4 on a 0 to 10 rating scale were considered moderate to severe. Of the 30 patients who reported chronic pain, 11 (37%) reported moderate to severe pain as their worst level of discomfort in the previous 24 hours. In addition, half described moderate to severe pain during movement. “It’s distinct from angina-type pain,” Dr. Petsikas said. “It is not exercise-related and is more movementrelated, in the sense that it can come on spontaneously but it’s not related to any exertion.” Patients report post-sternotomy pain emanating from the shoulder, neck and/or anywhere in their chest. “Patients move their arm a certain way or shift positions a certain way [and feel the pain],” Dr. Petsikas said. “It can also be a chronic, low-grade, smoldering

discomfort that they just pass off and figure it’s part of the game.” Dr. Petsikas recommended that clinicians counsel patients that they might experience chronic pain months after CABG with sternotomy and to seek medical attention if they do. Daniel Mok, a medical student at Queens University, presented the study findings at the 2013 annual meeting of the Society of Cardiovascular Anesthesiologists (abstract 2). “Patients might expect it’s a normal or expected part of the healing process,” Mr. Mok said at the meeting. “There is considerable interference with daily activities from this pain syndrome,” Mr. Mok said. More than 30% of those with chronic pain described moderate to severe interference with general activity (nine patients), sleep (11) and normal work (12) activities. Even so, 63% (19) did not consult their primary care physician for treatment. James H. Abernathy III, MD, MPH, associate professor of anesthesiology at the Medical University of South Carolina, in Charleston, said that some patients in the study responded “none” when asked about their worst pain in the previous 24 hours. “There is a large portion of people for whom their pain does not seem to interfere with their daily life,” Dr. Abernathy said. Dr. Abernathy asked if researchers identified any predictors of which patients are most likely to see CABG page 21


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Progress, If No Breakthroughs, In Chronic Post-op Pain Washington—The emerging recognition that many patients develop chronic pain after surgery has spurred a host of behavioral and anatomic research. So far, these studies have yet to produce any breakthroughs in the understanding, and more importantly for

patients, the treatment of the problem. But during a session at the 2012 annual meeting of the American Society of Anesthesiologists, experts said the question was not whether, but when, those treatments would arrive. “Not surprisingly, chronic postsurgical pain has become a popular topic,”

said Timothy Brennan, MD, PhD, the Samir Gergis Professor and Vice Chair for Research at the University of Iowa’s Roy J. and Lucile A. Carver School of Medicine, in Iowa City. “Compared with a patient who develops an

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injury after a car accident, with surgical patients we know when our patients are going to get injured, and we know what type of injury is going to occur: the surgery. So, I think our goal will be to study surgical patients and evaluate their pain responses when they don’t have this premeditated injury, then follow them through the postoperative period in the hope that we can learn to predict chronic postsurgical pain and the factors related to its development.” Several studies have associated the development of chronic postsurgical pain and other unfavorable long-term outcomes with somatic and psychological predictors. A 2007 Dutch investigation ((Ann Surg 2007;245:487-494) in 625 patients, for example, found that psychological factors such as fear of long-term consequences and lack of optimism were predictors of persistent pain, disability and low quality of life after surgery. “I think, sometimes, functional limitations and lower quality of life may impact a patient’s perception of their pain and certainly the development of persistent pain afterward,” Dr. Brennan noted. “This reminds us that there are many psychological factors associated with the development of persistent pain.” More recently, a team of Norwegian researchers followed more than 12,000 patients, 2,043 of whom had undergone surgery within three months of the start of the study (Pain 2012;153:13901396). Persistent pain in the area of surgery was reported by 40.4% of the patients. The researchers also found strong associations between sensory abnormalities and persistent pain. “Broad studies such as these cast a wide net, and are certainly continuing to point to this relevant problem of disability after surgery and significant pain reports,” Dr. Brennan said. Few studies, however, have shed as much light on the anatomic changes that occur in response to pain as a longitudinal investigation by Baliki and colleagues, reported last year in Nature Neuroscience (2012;15:11171119), to determine the mechanism of brain reorganization as pain moves from acute to chronic. The researchers followed patients with subacute back pain for more than a year, stratifying them into


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C L I N I C A L PA I N ME D I C I N E those whose pain did not resolve and those whose pain improved, and also compared them with a group of healthy controls. Patients whose pain persisted showed decreases in the density of gray matter in the brain. “The researchers also looked at the connectivity between various parts of the pain network and what I call the emotional network,” Dr. Brennan said. They found that an initially greater level of connectivity between a section of the brain called the nucleus accumbens, which is critical to the sensation of pleasure, and the prefrontal cortex predicted pain persistence. This increased connectivity, they inferred, suggests that corticostriatal circuitry is causally involved in the transition from acute to chronic pain. “The medial prefrontal cortex is one of those areas in the brain that signals the affective component of pain,” Dr. Brennan explained. “When pain is well connected to the nucleus accumbens, pain pathways are strongly linked

CABG continued from page 19

experience more significant pain, but they did not do so, Mr. Mok said. Some surgical risk factors for this pain syndrome are not modifiable, including female sex and obesity. However, surgeons could reduce the risk with their choice of bypass graft, Dr. Petsikas said. Use of the internal thoracic artery, for example, is associated with a greater likelihood of post-sternotomy pain. The study was single-center, retrospective research, Dr. Petsikas said. “It would be good if [it was] done across multiple institutions, but it’s a small pilot study.” Another limitation is that pain is subjective. “Some people may not be bothered by large amounts of pain and others might be crawling the walls from small amounts of pain,” he said. Use of reliable, validated pain questionnaires is a strength of the research, he added. Dr. Petsikas said his group plans to study if spreading the breastbone apart more slowly could reduce postoperative sternotomy pain. Traditionally, surgeons use a retractor to separate the breastbone quickly, which does not allow time “for your ligaments to stretch in your back or between your spine and ribs to stretch. It’s like doing aggressive stretching exercises without warming up first.” —Damian McNamara

to psychological pathways. This link was found to be an accurate predictor of the transition from subacute to chronic pain. Now, whether or not this applies to a perioperative situation certainly remains to be seen,” he continued. “We know that there are similarities between back pain patients and postsurgical patients, but more research needs to be performed.” For clinicians, of course, the physiology of how postoperative pain becomes chronic is most important if it leads to

ways of preventing the transformation. “The literature suggests it may not be that easy,” Dr. Brennan said. Eugene R. Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University, in Philadelphia, noted that the magnitude of chronic postsurgical pain is vastly underestimated by most anesthesiologists and surgeons. “I agree with Dr. Brennan that a link with severe acute pain alone is probably too simplistic,” said Dr. Viscusi.

“My opinion is that since the causes are likely multifactorial, there will not be a single solution. What’s more, some patients may just have an inherent risk. Nevertheless, several interesting studies support that preoperative and postoperative pregabalin [Lyrica, Pfizer] and ketamine may reduce longer-term pain after surgery. The best current evidence suggests that a multimodal analgesic approach and adjustment of surgical technique may make a difference.” —Michael Vlessides


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CL INI CA L PAIN MEDICINE ALGORITHM continued from page 1

presented the details of the algorithm implementation in poster form at the 2013 International Headache Congress, held recently in Boston. “The director of the emergency department really worked hard with his team to get them to utilize this algorithm, and to educate them about opiate use—and it really made a difference.” The initial version of the algorithm

was tested in the ED of Lakewood Hospital in Lakewood, Ohio. According to the investigators, it was quite dense and complex, with lists of “red flags” such as fever and chills, “yellow flags” such as recurrent ED visits without appropriate follow-up care, and detailed criteria for migraine without aura and cluster headache. Nonetheless, the ED physicians were able to significantly reduce opiate use after implementation of the algorithm in February 2013. Two-thirds

of patients were treated with opiates or narcotics between October 2012 and January 2013, compared with only 12% in the post-implementation period of February to April 2013. Furthermore, the percentage of patients discharged with prescriptions for opiates or narcotics fell from 44% to 8%. The percentage of patients undergoing imaging remained relatively constant, at 48% pre- and 54% postimplementation, as did the number of patients for whom consults were called

‘Narcotic misuse is becoming a great concern in this country, and evidence-based treatment protocols that represent safe, appropriate and timely patient care are of great interest.’ —Brad Uren, MD

(8% and 6%, respectively), and admissions (8% in both periods). Pain relief did not suffer during the drop in opiate use, with 63% of preimplementation patients experiencing greater than 50% pain relief and 68% having this amount of pain relief after the ED doctor implemented the algorithm. Three other metrics the team measured—time from arrival at the hospital to discharge, time from evaluation to treatment, and time from treatment to discharge—also remained constant. Based on the ED doctors’ feedback on the algorithm, Dr. Bamford and her colleagues removed unnecessary elements and created one that has three simple steps to treatment. Each step is used in sequence if the previous one does not result in halving of the patient’s pain within two hours. Brad Uren, MD, clinical assistant professor, Department of Emergency Medicine, University of Michigan, Ann Arbor, and president of the Michigan College of Emergency Physicians, who was not involved in the study, said further validation of the algorithm will show whether it will hold up in various ED settings. “This proposed treatment algorithm and others like it are useful adjuncts to the treatment of headaches in the emergency department,” he said. “Narcotic  misuse is becoming  a great concern in this country, and evidencebased  treatment protocols that  represent safe, appropriate and timely patient care are of great interest.” —Rosemary Frei, MSc


SEPTEMBER 2013

PainMedicineNews.com I 23

C L I N I C A L PA I N ME D I C I N E

Patient Opioid Disengagement By Tory McJunkin, MD, Paul Lynch, MD, Leila Micklos, MS, FNP-BC, and Edward Swing, PhD

Dear Arizona Pain Specialists, I have several patients who are not compliant with the opioid prescriptions I’ve written them. I want to help all of my patients, but I’m concerned about the safety issues these patients present. How should I deal with patients who aren’t able to take their opioid medications responsibly? Sincerely, Struggling with Noncompliance

Dear Struggling with Noncompliance,

T

his is a great question and one that we frequently hear. Managing opioid compliance is an essential piece of the practice and begins with the development of a robust management plan. This plan is intended to improve the quality of life for the patient by meeting his or her pain management

needs, as well as meeting the regulatory requirements of the practice. In an attempt to prevent noncompliance in your practice, it is best to develop a protocol designed to optimize patient selection and set the foundation for prescription opioid therapy compliance. Why Monitor Opioid Compliance? In the past 20 years, the use of prescription opioid therapy has significantly

increased.1 Coupled with the increased use of opioids, clinicians and regulatory officials have seen an increase in prescription opioid abuse, diversion, overdose and deaths. Opioids are responsible for more overdoses in the United States than all other illicit drugs combined.2 It is our responsibility as clinicians to help our patients with the best and safest treatments available to them. This implies that we screen for and identify patients who are at high risk and/or poor candidates for opioid therapy. A thorough patient interview including psychosocial history must accompany the physical exam and review of past medical records. Further patient evaluation and clinical consideration must be conducted in patients with histories of aberrant drug-related behaviors.1 Patients who are typically considered poor candidates for opioid therapy include those with a history of illicit drug abuse as well as a personal or family history of illicit drug or alcohol abuse. It’s also important to look at their overall condition. Do they have pathology that warrants the risk associated with long-term use of opioids? see DISENGAGEMENT page 24


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CL INI CA L PAIN MEDICINE

Pfizer Testing Abuse-Deterrent Compound Of Oxycodone and Naltrexone New Orleans—A unique formulation of an extended-release oxycodone plus sequestered naltrexone (an opioid antagonist), ALO-02, may deliver safety and efficacy for pain control and also mitigate the drug “high” from tampering with the capsule (e.g., crushing) that often occurs with abuse of prescription opioids. The compound is currently in Phase III of testing. “We are one of the first companies to advance this technology as an abuse deterrent. Each pellet within each capsule contains oxycodone and a sequestered core of naltrexone. The naltrexone is not intended to

DISENGAGEMENT continued from page 23

How active are they? What are their short, moderate and long-term goals for their pain? Tools for Compliance Monitoring An appropriate opioid therapy program for your practice should be understood by all and documented. You should employ the use of the monitoring tools available to clinicians. These tools include the following: Opioid Therapy Agreements (Contracts). An opioid therapy agreement is a written and signed contract between the patient and the clinical practice that outlines the goals of treatment as well as the stipulations required by the patient in order to continue prescription opioid therapy. The agreement should lay out all the common and worst-case problems that can occur. You may want to include an agreement that the patient will not receive prescriptions for pain medications from any other providers while under your care. This can help reduce the chances of the patient receiving prescriptions from multiple providers that add up to dangerously high doses of opioids. This agreement should be discussed at length with the patient so that he or she fully understands the real risks involved with opioid therapy. Regular Pharmacy Board Review. Currently, 48 U.S. states and one territory either have active prescription monitoring programs or are in the process of implementing such a program.3 Once registered, clinicians will have access to patients’ prescription histories. This report will include name of opioid prescribed, the date prescribed and filled, the prescriber’s name, the quantity dispensed and the dispensing pharmacy.4 This is a very helpful tool that allows clinicians to see if patients are honest, have received medications from

be released if the capsule is taken as prescribed. But if a person tries to manipulate the capsule by crushing it, naltrexone is released, possibly reducing the analgesic and euphoric effects of oxycodone. This may mitigate the quick high,” said Kenneth Sommerville, MD, vice president, Clinical Sciences, Pfizer Pharmaceuticals Inc. At the 2013 annual meeting of the American Pain Society, Dr. Sommerville and his colleagues presented the first report of safety data from a 12-month, open-label, single-arm study that see ABUSE-DETERRENT page 26

multiple providers, the dosages the patients have received and whether the patients have a history of polypharmacy. Regular Urine Drug Screens. Regular urine drug screens (UDS) must be consistent with the prescription opioid therapy established for the patient. Discovering an absence of prescribed opioids or the presence of nonprescribed opioids during the UDS could be indicative of noncompliance. Additionally, an inconsistent UDS may reveal a patient’s use of illicit drugs, a serious discovery that must trigger a review and modification of the patient’s plan of care. When To Disengage a Patient From Opioids Making the decision to disengage a patient from prescription opioid therapy should be conducted on a caseby-case basis and should follow your standard protocol. You should take all factors of noncompliance into consideration when making a decision. You must thoroughly discuss with the patient anytime he or she violates your opioid compliance program. The clinical consequences of the violation must be documented in the patient’s record, as well as expectations for future patient behavior. Violations that are clear indicators of threat to patient safety and/or that place you or your practice in a medicolegal risk (e.g., prescription forgery) are grounds for immediate disengagement. For example: Patient Jones currently receives opioids for chronic back pain. He went to a hospital emergency department and was admitted for a kidney stone. Patient Jones received a short prescription for an opioid. This outside prescription violated the opioid contract. In this case, however, you might determine that issuing the patient a warning, educating that patient about contacting you in advance when receiving an outside prescription

and documenting the exchange in Patient Jones’ medical record is sufficient. Patient Smith received a warning several months ago for failing to take medications as prescribed. This patient then tests positive for several illicit drugs in a UDS and this result is confirmed in outside testing. This patient is a clear risk to himself and should be disengaged from opioids. How Do You Disengage a Patient From Opioids? Once the decision has been made to disengage a patient from opioid therapy, the patient must be informed. The communication can be accomplished through an office visit discussion and/or through a detailed patient letter delivered via certified mail. We like to meet face to face with a patient in the office and explain that he or she has violated our agreement and we can no longer prescribe chronic opioids for the condition. Usually we explain that we are happy to have the patient continue receiving care in our practice, but with treatments other than narcotics. Appropriate referrals to an addictionologist, in-patient treatment center, counselor and/or psychiatrist are considered at this time. It is also important to notify the patient’s referring physician and/or primary care physician of this update so that they are aware of the patient’s condition. As clinicians, we have a responsibility to prevent harm to our patients. If the patient feels that he or she must continue opioid medications, a list of clinical providers and their contact information should be provided to the patient to arrange future care. Additionally, providing a final 30-day opioid prescription or a tapering dose to the patient may be appropriate to prevent withdrawal symptoms. This also should provide the patient adequate time to locate and establish care

with a new provider, so that they cannot make “abandonment claims.” This 30-day continuation of treatment after a patient leaves a practice is considered standard of care in Arizona. Consider the standards in your state when establishing your disengagement policies. If your practice uses opioid therapy, it is imperative that your patients are aware of the great risk this therapy holds. It also is important that your practice has well-thought-out guidelines for prescribing, monitoring and withdrawing patients from this therapy. As always, it’s important to follow all Drug Enforcement Administration recommendations, state guidelines and society “best practices.” We also recommend you discuss this issue and other common occurrences with a qualified health care attorney in your area. Drs. Lynch and McJunkin own and operate Arizona Pain Specialists, a comprehensive pain management practice that provides minimally invasive, clinically proven treatments, with five locations in the greater Phoenix area. Drs. Lynch and McJunkin also provide consulting services to other pain doctors around the country through their partner company, Boost Medical. For more information, visit ArizonaPain.com and BoostMedical.com.

References 1. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130. 2. Paulozzi LJ, Jones CM, Mack KA, et al. Vital signs: overdoses of prescription opioid pain relievers—United States, 19992008. MMWR. 2011;60:1487-1492. 3. Alliance of States with Prescription Monitoring Programs. (2013). About the Alliance. http://www.pmpalliance.org/node/2. Accessed July 25, 2013. 4. Lynch PJ, McJunkin TL, Anderson JK, et al. Responsible use of opioids for chronic pain. Pain Medicine News. 2012;10(10):10-11.


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Inappropriate NSAID Prescriptions for Pain Found Common Madrid—Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently inappropriately prescribed for patients with chronic pain conditions who also have ischemic heart disease (IHD), according to a study presented at the 2013 annual meeting of the European League Against Rheumatism (EULAR). As much as 36% of patients prescribed NSAIDs already had IHD or risk factors for IHD, according to the study investigators. A second study showed that patients with pain conditions at a high risk for ulcers, cardiovascular events or acute renal failure continued to take over-the-counter (OTC) NSAIDs for longer than is deemed safe, and at higher doses. see NSAID page 26

Misplaced Nerve Blocks Frustrate Efforts at Prevention

A

lthough not as sensational or disastrous as wrong-site surgeries, wrong-site peripheral nerve blocks are potentially dangerous, and according to a 10-year analysis by Pittsburgh researchers, 10 times more common than their surgical counterparts. Yet the problem can be largely—if not entirely—avoided with better planning, vigilance and engagement by the various members of the care team. “Our department instituted a standardized policy with mandatory training and process audits regarding wrong-site blocks in June 2010,” said Mark Hudson, MD, MBA, associate professor of anesthesiology and vice chair for clinical operations at the University of Pittsburgh Medical Center (UPMC). “And it’s interesting that they continued to occur even after we tried to implement stops to prevent them. So just having a policy in place, no matter how robust it may be, doesn’t completely eliminate wrong-site blocks, because it relies on people following the policy.” Dr. Hudson and his colleagues used quality see MISPLACED page 15

Algorithm Shows Promise for Reducing Opiate Use in ED Headache Treatment

E

mergency and pain physicians from the Cleveland Clinic in the process of refining an algorithm for headache management in the emergency department (ED) report that it has resulted in an 82% reduction in both treatment with opioids or narcotics in the ED and in discharge with prescriptions for these types of medications. The researchers also hope to EDUCATIONAL REVIEW PRINTER-FRIENDLY VERSION AVAILABLE AT PAINMEDICINENEWS.COM

Use of Topical Analgesics in Treating N Neuropathic europathic and Musculosskeletal Pain WILLIAM ZEMPSKY, MD Head, Divison of Pain and Palliative Medicine Connecticut Children’s Medical Cente er Professor of Pediatrics University of Connecticut School of Medicine Storrs, Connecticut Disclosure: Dr. Zempsky serves on the Scie entific Advisory Board of Vapogenicx, Inc.

T

opical administratio on of anesthetics and analgesics can allow for the e efficient, painless delivery of medications that may reduce systemic side effec cts associated with the he e medication med edication while providing clinical advantages over o

injected or oral administration for the same clinical situation. Topical administration of nonsteroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, and other agents is useful for a range of conditions including acute and chronic musculoskeletal pain.

Background Topical medications target the site of application and ideally produce effective drug concentrations locally with minimal systemic absorption. Topical anesthetics and analgesics target the peripheral nerves and soft tissue at that site.1 A number of topical medications are beneficial for chronic musculoskeletal pain. In contrast, transdermal medications do not have to be applied over an involved site and attempt to reach systemic drug concentrations to achieve therapeutic results.2 This review will focus on topical medications (Table). Benefits of topical drug delivery include the potential for local therapeutic drug levels with reduced side effects, painless drug delivery, improved patient adherence and acceptance, ease of dose termination, avoidance of first-pass metabolism, and direct access to the target site. The skin is a barrier to drug delivery, its primary role being to prevent the ingress or egress of compounds across it.3 The stratum corneum, the upper most layer of the skin, is a thin layer of cornified nonviable keratinocytes that is an effective barrier to water-soluble

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

substances, which typically include anesthetics. Topical medications must traverse the stratum corneum to reach their site of action, which may be the peripheral transducing terminals of cutaneous sensory fibers located in the dermis and epidermis,4 or the local soft tissues including synovial fluid, synovial tissue, and cartilaginous structures.5 Three delivery methods have been used to bypass the stratum corneum barrier.6 1. Injection of local anesthetics or other medications, usually via a small-gauge hypodermic syringe, is the oldest of the methodologies. 2. Passive diffusion from creams, gels, or patches comprises the second general class of methodologies. Passive diffusion of topical agents require that they have a molecular weight under 500 DA, with a hydrophobic component to allow it to transverse the stratum corneum but also some hydrophilic features to penetrate the epidermis.7 3. Active drug delivery methods that enhance the rate of drug passage through the skin and shorten the time to onset of action. There are a diverse group of

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reduce the amount of imaging, number of consults and number of admissions related to headache, all while continuing to maintain or increase patients’ pain relief. “We were astonished at how much we were able to diminish the use of opiates,” said lead investigator Cynthia Bamford, MD, after she and her colleagues see ALGORITHM page 22

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26 I PainMedicineNews.com

SEPTEMBER 2013

PRI MA RY CARE NSAID continued from page 1

The first study sought to quantify inappropriate use of NSAIDs in patients with rheumatoid arthritis (RA), musculoskeletal diseases or other chronic pain–related conditions in conjunction with IHD or other cardiovascular risk factors at a single center. “We have known that long-term use of prescription NSAIDs increases the risk of cardiovascular events, and less well known is a recent study showing that even short-term use of NSAIDs increases the risk of death and recurrent myocardial infarction [MI] in patients with prior MI [Circulation 2011;123:2226-2235],” said lead author Carl Orr, MD, a researcher in the Department of Medicine at the Royal College of Surgeons, Dublin, Ireland. Dr. Orr and other experts at the

meeting agreed that safer alternatives to NSAIDs are needed and that guidelines should incorporate the increased risk for death or MI, even with shortterm prescribing of NSAIDs. “The landscape has changed, and we know that NSAIDs increase the risk of death and myocardial infarction with both long- and short-term use,” Dr. Orr said. “Previously presented data demonstrate an immediate increase in the risk of death and MI, challenging the safety of even short-term use [less than one week]. The introduction of physician guidelines to assist safe prescribing in this class of drug is vital, and is the only way to keep patient safety at the forefront of disease management.” He noted that it may be possible to include an electronic alert, linked to the electronic health records of patients with known cardiovascular risk factors, that is displayed when

‘The introduction of physician guidelines to assist safe prescribing in this class of drug is vital, and is the only way to keep patient safety at the forefront of disease management.’ —Carl Orr, MD

ABUSE-DETERRENT continued from page 24

included a total of 395 adult patients with moderate to severe, chronic noncancer pain (abstract 414). Doses of ALO-02 could be adjusted upward or downward; the total daily dose range was 20 to 160 mg of oxycodone. A total of 193 patients (48.9%) received ALO-02 for at least 181 days and 105 patients (26.6%) were treated with the drug for more than 361 days. Although the trial was not designed to show efficacy, the analgesic effects of oxycodone were evident over time. Pain scores improved over the course of the study, and withdrawal was not induced by the naltrexone component of the formulation. Dr. Sommerville said withdrawal occurred in one patient and that patient did not take the medication correctly. Adverse events (AEs) of the innovative drug were similar to those reported of other opioids. The most common treatment-emergent AEs were nausea (25.3%), constipation (21.3%), vomiting (13.9%)

a prescription for NSAIDs is made. This would allow the doctor to make a clinical decision based on the risk– benefit ratio of the prescription, Dr. Orr said. For patients with RA and other inflammatory diseases, the first priority is to control the underlying disease process, and not to rely on NSAIDs for symptom control, Dr. Orr commented. The investigators searched the electronic medical records of more than 10,000 patients from a large primary care practice facility attached to a major university in Dublin, to screen for NSAID prescription use in September and October 2012. Search parameters included patients aged more than 50 years prescribed diclofenac, ibuprofen, mefanamic acid, naproxen, etorocoxib and celecoxib (Celebrex, Pfizer). Patients’ records were analyzed for IHD risk factors, including hypertension, diabetes mellitus, known IHD, previous MI, and revascularization with stenting or surgery. The study cohort included 108 patients prescribed NSAIDs (63 women). The median age of the study participants was 47 years (range, 50-87 years). Thirty-nine of 108 patients (36%) had established IHD or risk factors for IHD, including hypertension (50%), diabetes (16%), hypertension and diabetes (16%), MI (5%), coronary artery bypass graft (3%) and known IHD (10%). NSAIDs were prescribed for the following conditions or diseases: RA (5%), osteoarthritis (19%), acute musculoskeletal pain (11%) and back pain (12%), as well as nonspecified pain (28%) and other miscellaneous conditions (25%). Analysis of 39 patients with IHD or

and headache (11.6%). The most commonly reported treatment-related AEs included constipation (18%), nausea (14.9%), somnolence (8.4%), fatigue (6.8%), dizziness (5.6%) and vomiting (5.1%). The most common treatment-emergent serious AEs, each seen in 0.5% of patients, were acute myocardial infarction, noncardiac chest pain, pneumonia, convulsion and nephrolithiasis. The treatment discontinuation rate was 60%, which is similar to other long-term opioid trials, according to Dr. Sommerville. The two most common AEs leading to discontinuation were nausea (4.6%) and constipation (2.5%). Efficacy data are not yet available from an ongoing double-blind, placebo-controlled trial of ALO-02. Commenting on this study, Nathaniel Katz, MD, president of Analgesic Solutions and adjunct assistant professor of anesthesia at Tufts University School of Medicine in Boston, said ALO-02 is an example of one of two approaches for abuse deterrents. The first approach is a physicochemical barrier,

cardiovascular risk factors showed that more than half (56%) were prescribed NSAIDs for one month or longer and six of 39 (15%) for a year or longer. The most widely prescribed NSAID in these at-risk patients was diclofenac (56% of all prescriptions), which, according to Dr. Orr, is the most widely prescribed NSAID in Ireland. Aafke Koffeman, MD, a researcher in the Department of General Practice at the Erasmus Medical Center in Rotterdam, The Netherlands, presented a separate study at EULAR showing that patients with a high risk for serious side effects continue to use OTC NSAIDs for longer than they safely should and at higher doses than recommended. In this study, more than one-third of high-risk patients (i.e., history of ulcer or complication, MI, stroke, heart failure, over age 70, or glomerular filtration rate <30 ml/L) or those with two or more specific risk factors (use of an anticoagulant, aspirin, corticosteroid, or selective serotonin reuptake inhibitor; age 60-70 years; or history of severe rheumatoid arthritis or diabetes mellitus) took an NSAID for longer than seven days, and 3% exceeded the maximum daily dosage. Speaking of the dangers of NSAIDs in high-risk patients in general, Dr. Koffeman said: “These data highlight the importance of health care professionals continuing to inform their patients of the risks of taking NSAIDs, particularly when a new diagnosis or prescription increases their individual risk. Highrisk patients with painful musculoskeletal complaints should be advised to take safer alternative painkillers.” —Alice Goodman

making it more difficult to crush or dissolve the pill or capsule. “All currently marketed abuse deterrents, including extended-release tapentadol [Nucynta, Johnson & Johnson] and reformulated OxyContin [Purdue Pharma], are based on this,” Dr. Katz said. The second approach is to combine an opioid with an antagonist that becomes active only when the drug is tampered with. One such drug, Embeda, a morphine/ naltrexone formulation, was on the market but was voluntarily recalled by Pfizer in 2011, due to insufficient product stability. (Pfizer currently is pursuing options for reintroducing it, according to Dr. Sommerville.) ALO-02 is the second drug based on this principle. “It is not clear which approach will work better or whether both approaches will be effective. The jury is out on approach No. 1; the second approach may work better. It is challenging to figure out how to defeat abuse. In general, my sense is abuse deterrents will reduce abuse, and the marketplace will tell us which approach works best,” Dr. Katz said. —Alice Goodman


SEPTEMBER 2013

PainMedicineNews.com I 27

SCIENCE & TECHNOLOGY

Recruiting Online for Clinical Trials Allows Access to Larger Cohort and B Fort Lauderdale, Fla.—Recruitment for clinical trials is poised to move into the electronic era because the overwhelming majority of Americans have Internet access and are computer literate. A multicenter research team reported at the annual meeting of the American Academy of Pain Medicine (abstract 105), that webbased tools provide more cost-effective and efficient ways to reach large populations for recruitment into clinical trials, and also provide an easy way for study participants to provide medical diary information. “In doing clinical trials, one of the options that our biomedical informatics department provided us with was an electronic data entry system,” said Candace Brown, MSN, PharmD, professor of pharmacy, obstetrics and gynecology at the University of Tennessee Health Science Center in Memphis. “It’s a really good idea in terms of compliance, as well as for reporting adverse events [AEs] and daily pain-rating scales. And most of our computer-literate patients love these systems; they find it very convenient.” Dr. Brown is one of three principal investigators in a randomized controlled trial on the efficacy of gabapentin [Neurontin, Pfizer] in the treatment of vulvodynia. The success of clinical trials is largely dependent on the recruitment and maintenance of adequate numbers of study participants, but pain trials often are characterized by low recruitment and high attrition rates. However, web-based recruiting allows researchers to access a wider pool of potential participants and to screen them before the first research visit. In an interview with Pain Medicine News, Dr. Brown said their biomedical informatics group developed a recruitment website that was launched simultaneously with the current investigation— a multicenter trial of women with vulvar pain. The website contains a series of prescreening questionnaires and informational videos, and also offers multiple methods for prospective study participants to interact with study coordinators. On the back end, the website is linked to a database that compiles applicant information and automatically emails it to coordinators. The researchers are provided with customized views on their own web interfaces; Google Analytics is used to collect data on keyword searches, geographic location, bounce rates and time spent on the page. This information allows developers to further refine the site, making it more appealing to the target population. Most institutions that conduct clinical trials should have the ability to build similar websites, according to Dr. Brown. “I would sure think they could do it,” Dr. Brown said. “As a matter of fact, I think most institutions should be doing it; these kinds of sites have tremendous potential.” Dr. Brown said the system has made her research responsibilities much more manageable. “If we didn’t have this system, we’d be doing all of this by hand, and that would have been extremely time-consuming,” she explained. “The system whips out the data seamlessly, so our statisticians can analyze it. It also gives nurses, on a daily basis, the opportunity to see if patients are completing their diaries and if they’re compliant.”

‘It’s a really good idea in terms of compliance, as well as for reporting adverse events and daily pain-rating scales. And most of our computerliterate patients love these systems; they find it very convenient.’ —Candace Brown, MSN, PharmD

One of the interesting observations the researchers made while using the web-based system was an apparently higher incidence of AEs being recorded by study participants. “It is unclear whether this finding may be due to this particular patient population; a higher incidence of AEs in females; or because maybe entering the information on a daily basis makes a difference,” Dr. Brown said. Christin Veasley, BS, executive director for the National Vulvodynia Association and cofounder of the Chronic Pain Research Alliance, said there is a significant advantage to web-based recruiting systems. “With respect to pain trials, I think it’s a universal experience that we’re not getting as many prospective subjects in the trials as we’d like to,” she said. “There are many reasons for this, and if we are going to meet our recruitment goals in a time- and cost-efficient manner, we really need to start thinking outside the box about novel ways to increase our potential participant pool.” Vulvodynia trials are even more challenging because half of the women with vulvar pain don’t seek medical care for their symptoms. “This greatly narrows our potential pool [of participants] and increases the time it takes to recruit adequate numbers,” Ms. Veasley said. “We also need to make sure we’re studying the spectrum of disease, not just clinic-based populations, so it’s really important that we reach a wide selection of women from the general population. Web-based recruiting sites like this one appear to be a promising new tool to accomplish this.” —Michael Vlessides

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large, 11-year study demonstrated that overweight and obesity are predisposing factors for chronic low back pain (LBP) in men and women who did not have LBP at the outset. In the population-based, prospective cohort study, conducted in Norway, obesity also increased the likelihood of a recurrence of chronic LBP (defined as pain persisting for at least three months continuously in the past year). “Our results show that we definitely can say that high body mass index [BMI] is a risk factor for LBP,” lead author Ingrid Heuch, MD, PhD, senior consultant, Department of Neurology, Oslo University Hospital, Oslo, Norway, wrote in an email. “We have then taken into account possible effects of other risk factors, and adjusted for them in the analysis.” see BMI page 15

ibromyalgia may be almost as common in men as it is in women, a new study shows. Using the most recent diagnostic criteria, researchers determined that the condition’s prevalence is 2.1% overall in the general population, affecting 2.4% of women and 1.8% of men. The research report was published online in Arthritis Care & Research (2013 Feb 19. doi: 10.1002/acr.21931. [Epub ahead of print]). The findings also support the validity of the American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity as a research tool because the overall prevalence falls in line with previous estimates, said the report’s lead author Frederick Wolfe, clinical professor of medicine at the University of Kansas School of Medicine and director of the National Data Bank for Rheumatic Diseases, both in Wichita. FIBRO SP FIB PECTRUM page 11

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SPECIAL EDITION 7th Annual Compendium of Clinical Reviews in Pain Management PainMedicineNews.com • DECEMBER 2012 • Volume 10 Number 12

Regional Anesthesia for Total Joint Arthroplasty

The Changing Role of Ultrasonography in Pain Medicine

David A. Provenzano, MD Eugene R. Viscusi, MD

Michael Gofeld, MD

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linicians who treat pain have noted that the response to opioids varies widely

among patients, with opioid dose

Fibromyalgia Diagnosis: Moving Beyond Tender Points

requirements varying in the clinical setting by as much as 40-fold.1

Pain sensitivity Spectrum of Pain Sensitivity Patient A

Patient B

The Role of Urine Drug Monitoring in Pain Management

Patient C

10

Chad S. Boomershine, MD, PhD

Pain Intensity

Most-read Most-read Mo o d Articles A tiic icles cles es From From m Siste Sis ist ister er Pu ub blic b l cation lic cati a ns

8

Lynn R. Webster, MD

6 4 2 0 Stimulus Intensity

Figure 1.

Paravertebral Blocks: The Evolution of a Standard of Care

The Use of Opioids in Chronic Pain: Complexity and Practice

Kevin King, DO Jaques E. Chelly, MD, PhD, MBA

John F. Peppin, DO, FACP

Regenerative Medicine in Pain Management Tory McJunkin, MD Paul Lynch, MD Timothy Deer, MD Jack Anderson, MD

Managing the Difficult Pain Case

Case Study 1: Timothy R. Deer, MD Jason Pope, MD

Case Study 2: Sanjay S. Sastry, MD Alyn L. Benezette, DO Kristina H. Berger, MD

Case Study 3: Christopher Gharibo, MD Prashanth Reddy, MD

12 | ÃÊ Ê,i>`ÞÊvœÀÊ*Àˆ“iÊ/ˆ“i¶ 12 Ê*Àœq œ˜Ê iL>Ìi POLICY PO P O L I C Y & MANAGEMENT 18 1 8 | ʘÛiÃ̈}>̈œ˜ÊœvÊ*>ˆ˜Ê œV̜ÀÊ,œVŽÃ *>ˆ˜Ê œ““Õ˜ˆÌÞ PRN PR P RN 2 0 | œÌV…i`Ê ÀÕ}Ã]Ê ÀœŽi˜Ê/ÀÕÃÌ 20


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Charles E. Argoff, MD Professor of Neurology Albany Medical College Director of the Comprehensive Pain Program Albany Medical Center Albany, New York

REPORT Delayed-Release Prednisone in Rheumatoid Arthritis

REPORT Postoperative Pain Management: A Critical Evaluation of the Investigational IONSYS System

Treatment Considerations levels of proinflammatory mediheumatoid arthritis (RA) is ators, such as interleukin (IL)-6 the most common chronic Faculty and tumor necrosis factor-Îą, inflammatory joint disease, Arthur L. Weaver, peak during the middle of the affecting approximately 2.8 milnight and early morning hours, lion adults in the United States MD, MS, FACP, MACR resulting in pronounced early alone.1 The symptoms of RA Clinical Professor of Medicine, Emeritus morning symptoms in patients include fatigue as well as swellSection of Rheumatology with RA,3,4 which can impact ing, pain, and stiffness of the University of Nebraska at Omaha joints 2 ; these manifestations patientsâ&#x20AC;&#x2122; ability to work or particOmaha, Nebraska ipate in normal activities.5 may vary in a predictable pattern throughout the day.3 In patients without RA, an Alvin F. Wells, MD, PhD, FACR increase in inflammatory cytoThis report will discuss the Director, Rheumatology and kine levels triggers a cascade pathophysiology of the diurnal Immunotherapy Center of hypothalamic corticotropinvariations of the manifestations Franklin, Wisconsin releasing hormone, pituitary of RA along with the potential production d ti off adrenocorticod ti utility tilit off a llow-dose, d d delayedl d tropic hormone, and glucocortirelease prednisone strategy to coid secretion by the adrenal cortex, which collectively treat the symptoms of RA, including morning symptoms. inhibit the production of inflammatory cytokines.6 This represents normal physiologic feedback control. In Diurnal Variations in Symptoms of patients with active RA, however, the cortisol response Rheumatoid Arthritis is impaired, which leads to a relative adrenal glucocorticoid insufficiency and unopposed cytokine-mediated Physiologic and pathophysiologic biologic circadian inflammation during the early morning hours.3,4,6 These rhythms can modulate the presentation and morbidity of various diseases. Similar diurnal variations have been observations may support a role for appropriately timed observed in the clinical manifestations of RA.3 The early exogenous glucocorticoid therapy to balance the pathologic circadian mismatch between cytokine and glucocormorning severity of RA symptoms coincides with the cirticoid production.4 cadian rhythm of cytokine release.3 Specifically, plasma

R

Despite advances in pain manAcute postoperative pain conChair agement technology, the advent tinues to be undertreated, with of acute pain services, and proup to 75% of patients in the Eugene R. Viscusi, MD fessional practice guidelines United States failing to receive Professor of Anesthesiology aimed at improving postoperative adequate postoperative pain Director, Acute Pain Management pain management, inadequacies relief.1,2 Postoperative pain manThomas Jefferson University and treatment gaps still exist, and agement was revolutionized with improvement remains a priority.7 the introduction of patient-conPhiladelphia, Pennsylvania trolled analgesia (PCA) using IV An analgesic intervention Faculty or epidural delivery routes more that might help to mitigate clinithan 20 years ago.3 Opioids are cian concern is the fentanyl ionJohn Fanikos, RPh, MBA tophoretic transdermal system the primary treatment for acute Director of Pharmacy Business (IONSYS), a credit cardâ&#x20AC;&#x201C;sized, pain management,4 either alone Brigham and Womenâ&#x20AC;&#x2122;s Hospital self-contained, and preproor increasingly as part of a multiBoston, Massachusetts grammed investigational product modal analgesic strategyâ&#x20AC;&#x201D;charcandidate intended to provide acterized by administration of 2 Michael H. Huo, MD pain i relief li f ffor adult d lt iinpatients ti t or more drugs d ((eg, opioid i id and d Professor requiring opioids following surnonopioid analgesics, used in Department of Orthopedic Surgery gery.8 It is a needle-free system combination) that act by different UT Southwestern Medical Center mechanisms, and along differthat is applied to the skin on the Dallas, Texas ent pain pathwaysâ&#x20AC;&#x201D;an approach upper arm or chest.8 A generally that is recommended by the imperceptible electrical current American Society of Anesthesithen delivers a small dose of fenologists (ASA) and the American Pain Society.5,6 However, tanyl directly through the skin and into the systemic circulation. The FDA approved IONSYS in 2006; however, it existing PCA modalities have limitations that include invawas never launched in the United States due to required sive access, challenges in titration of analgesic effect, changes in manufacturing. The enhanced design will be cumbersome pump technologies, impaired patient mobilreviewed by the FDA in the near future for use in patients ity, and limited drug preparations that have been associwith moderate to severe postoperative pain. ated with programming, medication, and dosing errors.

Supported by

Gregory L. Holmquist, PharmD, CPE Pain and Palliative Care Specialist Certified Pain Educator Palliative Care Strategies Seattle, Washington

Introduction )FSQFT [PTUFS BMTP LOPXO BT TIJOHMFT SFTVMUT GSPN SFBDUJWBUJPO PG FOEPHFOPVT MBUFOU WBSJDFMMB [PTUFS WJSVT JOGFDUJPO XJUIJO UIF TFOTPSZ HBOHMJB 5IJT DPOEJUJPO JT DIBSBDUFSJ[FE CZ B QBJOGVM VOJMBUFSBM WFTJDVMBS FSVQUJPO XIJDI UZQJDBMMZ PDDVST JO B SFTUSJDUFE EFSNBUPNBM EJTUSJCVUJPO Prodromal symptoms, such as headache and malaise, may PDDVS QSJPS UP SBTI POTFU XIJDI UZQJDBMMZ MBTUT  UP  EBZT Estimates suggest that one-third of the US population XJMM FYQFSJFODF BO FQJTPEF PG BDVUF IFSQFT [PTUFS EVSJOH UIFJS MJGFUJNF XJUI UIF JODJEFODF SJTL JODSFBTJOH XJUI BHF .PSF UIBO IBMG PG BMM DBTFT PG IFSQFT [PTUFS PDDVS JO JOEJWJEVBMT BHFE  ZFBST PS PMEFS In the majority of cases, IFSQFT [PTUFS FQJTPEFT SFTPMWF XJUIPVU GVSUIFS TFRVFMBF However, some patients, particularly the elderly, are at IJHIFS SJTL GPS EFWFMPQJOH QPTUIFSQFUJD OFVSBMHJB 1)/ a condition of severe, often debilitating neuropathic pain that persists for at least 3 months after the shingles rash IBT IFBMFE These symptoms can lead to impaired sleep and depression and may interfere with activities of daily MJWJOH "MMPEZOJBÂ&#x2030;QBJO FWPLFE CZ OPSNBMMZ OPOQBJOGVM TUJNVMJ TVDI BT MJHIU UPVDIÂ&#x2030;BMTP DBO PDDVS JO PS CFZPOE UIF PSJHJOBMMZ BGGFDUFE EFSNBUPNBM BSFBT Similar to the SFMBUJPOTIJQ CFUXFFO IFSQFT [PTUFS BOE BHF UIF SJTL GPS EFWFMPQJOH 1)/ BMTP DPSSFMBUFT XJUI JODSFBTJOH BHF #FHJOOJOH BU  JO UIPTF BHFE  ZFBST PS ZPVOHFS 1)/ SJTL SJTFT UP  JO UIPTF BHFE  UP  ZFBST BOE UP  JO JOEJWJEVBMT BHFE  ZFBST PS PMEFS3 Various medication classes, including antidepressants FH USJDZDMJD BOUJEFQSFTTBOUT <5$"T> BOUJDPOWVMTBOUT PQJPJET UPQJDBM BHFOUT FH DBQTBJDJO MJEPDBJOF BOE N-methyl-D-aspartate receptor antagonists, have been employed for the management of PHN, and the FDA has HSBOUFE TQFDJGJD BQQSPWBM UP BU MFBTU  BHFOUT HBCBQFOUJO QSFHBCBMJO UPQJDBM MJEPDBJOF UPQJDBM DBQTBJDJO GPS UIJT

JOEJDBUJPO   However, physicians continue to need UIFSBQFVUJD PQUJPOT GPS UIFJS QBUJFOUT Over the past decade, gabapentin has been used JODSFBTJOHMZ GPS UIF NBOBHFNFOU PG 1)/ )PXFWFS UIJT antiepileptic and antinociceptive agent requires dosing 3 times a day to maintain appropriate bioeffective plasma MFWFMT UIFSFCZ QPUFOUJBMMZ BGGFDUJOH BEIFSFODF  This article discusses the pharmacology and clinical data related to a once-daily gastroretentive formulation of HBCBQFOUJO (3"-*4&Â&#x2122; <HBCBQFOUJO> UBCMFUT %FQPNFE *OD '%"BQQSPWFE GPS UIF NBOBHFNFOU PG 1)/

Clinical Pharmacology of Gabapentin Gabapentin is absorbed by a saturable, neutral, L-amino transport system that is found primarily in the QSPYJNBM TNBMM JOUFTUJOF The rapid release of gabapentin CZ DPOWFOUJPOBM JNNFEJBUFSFMFBTF *3 GPSNVMBUJPOT DBO TBUVSBUF UIF VQUBLF TZTUFN SFTVMUJOH JO B QMBUFBV PG QMBTNB MFWFMT EFTQJUF IJHIFS EPTFT PG HBCBQFOUJO  Thus, NPSF GSFRVFOU TNBMMFS EPTFT  UJNFT EBJMZ BSF SFRVJSFE UP BDIJFWF FGGFDUJWF QMBTNB MFWFMT PWFS B IPVS QFSJPE Once-daily drug formulations are often developed with the intent of increasing convenience by decreasing the required dose frequency of the agent and to maintain NPSF DPOTUBOU QMBTNB ESVH MFWFMT "DIJFWJOH UIF MBUUFS goal can potentially produce a more uniform clinical effect

over time as well as reduce the incidence of adverse events "&T UIBU XPVME PUIFSXJTF PDDVS JO UIF DPOUFYU PG NVMUJQMF JOUSBEBZ QFBLT BOE USPVHIT JO QMBTNB ESVH MFWFMT

Placebo

15 10.9

10 4.5

5

2.2

Clinical Pharmacology of GRALISEâ&#x201E;˘ (3"-*4&Â&#x2122; JT B PODFEBJMZ GPSNVMBUJPO PG HBCBQFOUJO that incorporates polymer technology to promote gastric SFUFOUJPO PG UIF UBCMFU UIF (3"-*4&Â&#x2122; UBCMFU JT TVGGJDJFOUMZ small to enable swallowing, but once in contact with gastric GMVJE UIF UBCMFU TXFMMT UP B TJ[F UIBU QSPNPUFT SFUFOUJPO JO UIF GFE TUPNBDI (3"-*4&Â&#x2122; JT LOPXO UP CF TVCTUBOUJBMMZ FYDSFUFE CZ UIF LJEOFZ 3FEVDUJPOT JO (3"-*4&Â&#x2122; EPTF should be made in patients with age-related compromised SFOBM GVODUJPO (3"-*4&Â&#x2122; TIPVME OPU CF VTFE JO QBUJFOUT XJUI B DSFBUJOJOF DMFBSBODF SBUF PG MFTT UIBO  N- QFS NJOVUF PS JO QBUJFOUT PO IFNPEJBMZTJT 5IJT QSPMPOHFE retention allows gabapentin to be gradually released to the upper small intestine at a relatively constant rate over a MPOHFS QFSJPE PG UJNF 'JHVSF  SFMBUJWF UP *3 GPSNVMBUJPOT BOE QSFWFOUT TBUVSBUJPO PG UIF USBOTQPSUFS  Thus, this

Somnolence

8,000 6,000 4,000 2,000 0 0

6

12

24

Time, h Figure 1. Mean steady-state plasma concentrations for once-daily GRALISEâ&#x201E;˘ 1,800 mg in healthy subjects (day 8). "EBQUFE GSPN SFGFSFODF 

4.1

Headache

3.9

3.3

Peripheral edema

2.7

Diarrhea

2.8

1.4

Dry mouth

2.5

2.2

Nasopharyngitis

Figure 2. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with postherpetic neuralgia (events in at least 2% of all GRALISEâ&#x201E;˘-treated patients and more frequent than in the placebo group). *O DMJOJDBM USJBMT JO QBUJFOUT XJUI QPTUIFSQFUJD OFVSBMHJB  PG UIF  QBUJFOUT USFBUFE XJUI (3"-*4&Â&#x2122; BOE  PG UIF  QBUJFOUT USFBUFE XJUI QMBDFCP EJTDPOUJOVFE QSFNBUVSFMZ EVF UP BEWFSTF SFBDUJPOT "EBQUFE GSPN SFGFSFODF 

strategy provides prolonged absorption when compared with UIF EPTJOH PG *3 HBCBQFOUJO #BTFE PO UIJT HBTUSPSFUFOUJWF UFDIOPMPHZ (3"-*4&Â&#x2122; DBO CF EPTFE PODF EBJMZ XJUI TJNJMBS CJPBWBJMBCJMJUZ UP   NH *3 HBCBQFOUJO UBLFO PWFS  EJWJEFE EPTFT At steady-state levels, cumulative gabapentin exposure and gabapentin plasma levels over time BSF TJNJMBS XIFO DPNQBSJOH (3"-*4&Â&#x2122; XJUI *3 HBCBQFOUJO  UJNFT EBJMZ " EPTFFTDBMBUJPO QFSJPE JT SFDPNNFOEFE PWFS B XFFL QFSJPE UP SFBDI B UBSHFU EPTF PG   NH QFS EBZ this dose-escalation strategy may attenuate the incidence BOE TFWFSJUZ PG "&T (3"-*4&Â&#x2122;   NH UBLFO XJUI BO FWFOJOH NFBM EFMJWFST FGGFDUJWF IPVS QBJO DPOUSPM XJUI MPX SBUFT PG TJEF FGGFDUT BOE PODFEBJMZ EPTJOH 'JHVSF  

Clinical Trials of GRALISEâ&#x201E;˘

10,000

4.2

0.3

Dizziness

(3"-*4&Â&#x2122; JT JOEJDBUFE GPS UIF NBOBHFNFOU PG QPTUIFSQFUJD OFVSBMHJB 1)/  (3"-*4&Â&#x2122; JT OPU JOUFSDIBOHFBCMF XJUI PUIFS HBCBQFOUJO QSPEVDUT CFDBVTF PG EJGGFSJOH QIBSNBDPLJOFUJD QSPGJMFT UIBU BGGFDU UIF GSFRVFODZ PG BENJOJTUSBUJPO

2.7

0

Indication and Usage of GRALISEâ&#x201E;˘

" XFFL QMBDFCPDPOUSPMMFE 1IBTF *** TUVEZ XIJDI VTFE POMZ UIF   NH EPTF PG (3"-*4&Â&#x2122; JODMVEFE  QBUJFOUT XJUI 1)/ The reduction in pain scores observed was HSFBUFS GPS (3"-*4&Â&#x2122; UIBO GPS QMBDFCP P  (3"-*4&Â&#x2122; QSPWJEFE B  PS HSFBUFS JNQSPWFNFOU JO QBJO TDPSF JO OFBSMZ POFUIJSE PG QBUJFOUT BOE B  PS HSFBUFS JNQSPWFNFOU JO QBJO TDPSF JO BQQSPYJNBUFMZ  PG BMM QBUJFOUT The most DPNNPO "&T JO UIF (3"-*4&Â&#x2122; BSN JODMVEFE EJ[[JOFTT  IFBEBDIF  TPNOPMFODF  BOE QFSJQIFSBM FEFNB   5IF EJTDPOUJOVBUJPO SBUFT EVF UP "&T XFSF  XJUI (3"-*4&Â&#x2122; BOE  XJUI QMBDFCP 'JHVSF   Furthermore, the type and incidence of AEs were similar across age groups except for peripheral edema, which tended to increase with age, suggesting that this GPSNVMBUJPO NBZ CF TVJUFE GPS VTF JO UIF FMEFSMZ  

Conclusion PHN is associated with a considerable decrement in RVBMJUZ PG MJGF BOE EJTQSPQPSUJPOBUFMZ BGGFDUT UIF FMEFSMZ Gabapentin is an effective agent for the management of 1)/ SFRVJSJOH EPTJOH  UJNFT QFS EBZ " OPWFM PODFEBJMZ HBTUSPSFUFOUJWF GPSNVMBUJPO PG HBCBQFOUJO (3"-*4&Â&#x2122; IBT been FDA-approved for the management of PHN, offering

DPOWFOJFOU EPTJOH BOE B GBWPSBCMF UPMFSBCJMJUZ QSPGJMF  (3"-*4&Â&#x2122; IBT TIPXO QBUJFOUT DBO SFBDI B   NH PODF EBJMZ EPTF JO  XFFLT UIF UIFSBQFVUJD MFWFM OFFEFE UP QSPWJEF FGGFDUJWF QBJO SFMJFG XJUI MPX SBUFT PG TJEF FGGFDUT

Indication and Usage (3"-*4&Â&#x2122; JT JOEJDBUFE GPS UIF NBOBHFNFOU PG QPTUIFSQFUJD OFVSBMHJB 1)/  (3"-*4&Â&#x2122; JT OPU JOUFSDIBOHFBCMF XJUI PUIFS HBCBQFOUJO QSPEVDUT CFDBVTF PG EJGGFSJOH QIBSNBDPLJOFUJD QSPGJMFT UIBU BGGFDU UIF GSFRVFODZ PG BENJOJTUSBUJPO

Important Safety Information (3"-*4&Â&#x2122; JT DPOUSBJOEJDBUFE JO QBUJFOUT XIP IBWF EFNPOTUSBUFE IZQFSTFOTJUJWJUZ UP UIF ESVH PS JUT JOHSFEJFOUT 5IF NPTU DPNNPO BEWFSTF SFBDUJPO UP (3"-*4&Â&#x2122; É&#x2039; BOE UXJDF QMBDFCP JT EJ[[JOFTT "DSPTT BMM (3"-*4&Â&#x2122; DMJOJDBM USJBMT UIF PUIFS NPTU DPNNPO BEWFSTF SFBDUJPOT É&#x2039; WFSTVT QMBDFCP BSF TPNOPMFODF headache, peripheral edema, diarrhea, dry mouth, and OBTPQIBSZOHJUJT 5IF UZQFT BOE JODJEFODF PG BEWFSTF FWFOUT were similar across age groups except for peripheral edema, XIJDI UFOEFE UP JODSFBTF JO JODJEFODF XJUI BHF "OUJFQJMFQUJD ESVHT "&%T JODMVEJOH HBCBQFOUJO UIF BDUJWF JOHSFEJFOU JO (3"-*4&Â&#x2122; JODSFBTF UIF SJTL PG TVJDJEBM UIPVHIUT PS CFIBWJPS JO QBUJFOUT UBLJOH UIFTF ESVHT GPS BOZ JOEJDBUJPO 1BUJFOUT USFBUFE XJUI BOZ "&% GPS BOZ JOEJDBUJPO should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any VOVTVBM DIBOHFT JO NPPE PS CFIBWJPS 'PS BEEJUJPOBM TBGFUZ JOGPSNBUJPO QMFBTF TFF UIF (3"-*4&Â&#x2122; GVMM QSFTDSJCJOH JOGPSNBUJPO

References  4BNQBUILVNBS 1 %SBHF -" .BSUJO %1 )FSQFT [PTUFS TIJOHMFT

BOE QPTUIFSQFUJD OFVSBMHJB Mayo Clin Proc     )BSQB[ 3 0SUFHB4BODIF[ *3 4FXBSE +' BOE UIF "EWJTPSZ $PNNJUUFF PO *NNVOJ[BUJPO 1SBDUJDFT "$*1 $FOUFST GPS %JTFBTF $POUSPM BOE 1SFWFOUJPO $%$  1SFWFOUJPO PG IFSQFT [PTUFS SFDPNNFOEBUJPOT PG UIF

"EWJTPSZ $PNNJUUFF PO *NNVOJ[BUJPO 1SBDUJDFT "$*1  MMWR Recomm Rep  33   :BXO #1 4BEEJFS 1 8PMMBO 1$ 4U 4BVWFS +- ,VSMBOE .+ 4Z -4 " population-based study of the incidence and complication rates PG IFSQFT [PTUFS CFGPSF [PTUFS WBDDJOF JOUSPEVDUJPO Mayo Clin Proc     &JEF , 4UVCIBVH " 0ZF * #SFJWJL ) $POUJOVPVT TVCDVUBOFPVT BENJOJTUSBUJPO PG UIF /NFUIZM%BTQBSUJD BDJE /.%" SFDFQUPS BOUBHPOJTU LFUBNJOF JO UIF USFBUNFOU PG QPTUIFSQFUJD OFVSBMHJB Pain      $MBYUPO "+ $SBNFS + 1JFSDF $ " TZTUFNBUJD SFWJFX PG UIF BTTPDJBUJPOT CFUXFFO EPTF SFHJNFOT BOE NFEJDBUJPO DPNQMJBODF Clin Ther      4UFXBSU #) ,VHMFS "3 5IPNQTPO 13 #PDLCSBEFS )/ " TBUVSBCMF USBOTport mechanism in the intestinal absorption of gabapentin is the underMZJOH DBVTF PG UIF MBDL PG QSPQPSUJPOBMJUZ CFUXFFO JODSFBTJOH EPTF BOE ESVH MFWFMT JO QMBTNB Pharm Res     .D-FBO .+ $MJOJDBM QIBSNBDPLJOFUJDT PG HBCBQFOUJO Neurology    TVQQM  44  $IFO $ $PXMFT 7& )PV & 1IBSNBDPLJOFUJDT PG HBCBQFOUJO JO B OPWFM HBTUSJDSFUFOUJWF FYUFOEFESFMFBTF GPSNVMBUJPO DPNQBSJTPO XJUI BO JNNFEJBUFSFMFBTF GPSNVMBUJPO BOE FGGFDU PG EPTF FTDBMBUJPO BOE GPPE J Clin Pharmacol     3PXCPUIBN . )BSEFO / 4UBDFZ # #FSOTUFJO 1 .BHOVT.JMMFS - (BCBQFOUJO GPS UIF USFBUNFOU PG QPTUIFSQFUJD OFVSBMHJB B SBOEPNJ[FE DPOUSPMMFE USJBM JAMA     (3"-*4&Â&#x2122; <QSFTDSJCJOH JOGPSNBUJPO> .FOMP 1BSL $" %FQPNFE *OD   (PSEJ 5 )PV & ,BTJDIBZBOVMB 4 #FSOFS # 1IBSNBDPLJOFUJDT PG HBCBQFOtin after a single day and at steady state following the administration PG HBTUSJDSFUFOUJWF FYUFOEFESFMFBTF BOE JNNFEJBUFSFMFBTF UBCMFUT B SBOEPNJ[FE PQFOMBCFM NVMUJQMFEPTF UISFFXBZ DSPTTPWFS FYQMPSBUPSZ TUVEZ JO IFBMUIZ TVCKFDUT Clin Ther     4BOH $/ 4BUIZBOBSBZBOB 3 $BSUFS '+ 4XFFOFZ . (BCBQFOUJO FYUFOEFE SFMFBTF GPS UIF PODFEBJMZ USFBUNFOU PG QPTU IFSQFUJD OFVSBMHJB 1PTUFS QSFTFOUFE BU UIF *OUFSOBUJPOBM "TTPDJBUJPO GPS UIF 4UVEZ PG 1BJO UI 8PSME $POHSFTT PG 1BJOÂĽ "VHVTU 4FQUFNCFS   .POUSFBM $BOBEB  *SWJOH ( 4POEBH & 4XFFOFZ . 5PMFSBCJMJUZ BOE TBGFUZ PG PODFEBJMZ HBCBQFOUJO JO UIF USFBUNFOU PG QPTUIFSQFUJD OFVSBMHJB 1PTUFS QSFTFOUFE BU UIF UI "OOVBM .FFUJOH PG UIF "NFSJDBO "DBEFNZ PG 1BJO .FEJDJOF .BSDI   /BUJPOBM )BSCPS .%  3JDF "4 .BUPO 4 1PTUIFSQFUJD /FVSBMHJB 4UVEZ (SPVQ (BCBQFOUJO JO QPTUIFSQFUJD OFVSBMHJB B SBOEPNJTFE EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEZ Pain   

Supported and Funded by: Horizon Pharma, Inc.

20  1"*/ .&%*$*/& /&84 t "13*- 

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lease advise as to how a person with no diagnostic training—having not ir, your lack of knowledge pertaining to pharmacy education and of our done an examination, not having evaluated a possibly very complex battraining is evident in your response and paints every pharmacist with the tery of laboratory tests, not having sorted through the complex interplay of same stroke. By your logic then, every physician can do surgery and manage a physical, physiologic and psychosocial factors and potential comorbidities— hospital. It is odd that one to two pharmacology classes is all that is required to could improve on the decision-making process of someone who has, at least prescribe once medical school is done. Med school and residency training is priin theory, met these qualifications? Is the pharmacist going to spend an hour, marily focused on getting the diagnosis right and that’s all that matters it seems, often with models and diagrams, explaining to the patient what his or her almost to the detriment of everything including prescribing, which is often an medical problem appears to be and what the most appropriate potential treatafterthought. While the right diagnosis is a major part of a health care provider, ments, pharmacologic or otherwise, might be? If that is what is proposed, it is not the only thing; after all what’s the point if you can diagnose but can’t then the pharmacist is really a physician and should simply be reclassified as properly manage/treat a patient? Some never do master prescribing, and it is such. How the pharmacy profession presumes to rectify the very real problems the field of pharmacy and nursing with their checks and balances that keeps the of overprescribing and woeful patient compliance in the face of the above, health care system functioning and the patient demands explanation. One cannot help but be reminded off the safe. That is exactly why phardangers of the combining of arrogance and ignorance. Gen-maacists are an untapped Comment on these erating broadsides at the medical profession, simplistiresource, because cally painting all physicians with the same paintbrush, we can expertly and other articles online @ then proposing themselves as a solution, appears disinmanage and treat genuous at the very least. We really do appreciate pharpatients who are comPainMedicineNews.com. macists’ help where they have expertise. This effort to pplex. You do not need a tread into waters where they are unqualified is not helpful. If pharm macist to manage treatpharmacists really want to treat patients, why not simply goo to ment for the simple s straightforward medical school? After all, they say there is a shortage of physipatients, but you may still need the pharmacist to counsel them on how to take cians. Shouldn’t be that hard to get into med school. And if it is, does that not their medications safely and properly. … I as the pharmacist round with variunderscore the concept that maybe making all these complex decisions does ous medical teams and multidisciplinary teams for six hours a day and see more demand more awareness than is obtainable by pharmacy training alone? patients than my physician friends. When they get a complex patient, guess who wch74... also gets a consult? Me, the pharmacist. I have saved lives and prevented thousands of patients from harm by physicians and patients themselves. In health care, I have met many brilliant people who are not physicians, who make a huge Comment on difference in the delivery of health and patient care. All of them, if they wanted, “Marijuana Usage in Chronic Pain Patients: were smart enough to be admitted to med school but chose not to for various personal and professional reasons. Be it health care or our government, everyone Driving and Work Guidelines for Clinicians” should check everyone: The pharmacist checks the physician and nurse; the phy(June 2013) sician checks the pharmacist and nurse; and the nurse checks the physician and pharmacist; all for one common goal: to protect the patient and do no harm. ery informative article and I appreciate the attempt to use past 1pant... data to form an opinion that is overall against medical marijuana. However, scientifically the argument is very flawed and should be viewed more as opinion than evidence-based. Randomized controlled trials are the ONLY way we can ensure provComment on able truth. Observational studies only find “Walgreens’ Florida Pain Pill Woes Mounting” (March 2013) associations, most of which are misleading. So readers beware ... this article should as anyone considered that our general population is getting older as a whole, and with age comes pain not prove or disprove the efficacy of medinever experienced before? Also, isn’t Florida one of the largest populations of older folks? With comcal marijuana. We need more information passion and concern from the medical community—it all adds up as an explanation for their increase. Are before we can draw that conclusion. As a records or scripts on file to account for the increase in demand? Why not check this out first; if no scripts, physician myself, I would be careful passetc., level sanctions—but only if it’s clearly not a case of elder population increase. … Our government ing judgment on a topic that is becoming could be hurting the folks who are suffering the most by cutting off their ability to fill scripts—where will overwhelmingly more popular to the pubthey go now? And what will happen to that pharmacy when they increase lic and may possibly have enormous benetheir ordering norms … and so it goes … fits once it can be adequately studied. susan... —rober...

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32 I PainMedicineNews.com

SEPTEMBER 2013

COMM ENTARY

‘The Answer Certainly Does Not Lie With Current Opioids’: An Interview With Lynn Webster, MD Part 3 of 3

The first and second parts of Dr. Webster’s interview can be found at www.painmedicinenews.com

In this issue, Pain Medicine News completes its three-part series with Lynn R. Webster, MD. In this Q&A, he addresses the third goal for his presidency of the American Academy of Pain Medicine: investigating new treatments that are more effective and safer than current options. Pain Medicine News: Why is this goal so important, and what new therapies do you see with potential to improve safety and effectiveness? Dr. Webster: The need for safer pain therapies is an imperative. Over the past year, we have seen how epidural steroids can cause dozens of deaths and permanent neurologic deficits due to meningitis. And the challenges of safely and effectively prescribing opioids continue to daunt the best efforts of pain specialists and primary care clinicians. Some patients do well on opioids, but opioids bring risks to individual patients

and to society that must be addressed. Over-thecounter medications also can cause harm. The FDA has cited acetaminophen as the leading cause of acute liver failure in the United States, and deaths from gastrointestinal bleeding linked to nonsteroidal antiinflammatory drugs (NSAIDs) rival deaths from opioids, according to some estimates. The cardiovascular effects of NSAIDs must also be considered. Less frequently but no less significantly, spinal injections and neuromodulator systems have caused paralysis and other severe complications. A patient seeking relief from unremitting, severe pain shouldn’t have to pay such a terrible price, but the fact is all therapies have

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Acute Pain Management

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Cancer Pain

Magdi Hanna; Ben Zylicz August 31, 2013 Cancer Pain provides a comprehensive, practical guide to the management of pain in cancer patients. Beginning with a discussion of current issues in the control of cancer pain, the initial chapters provide a clear, concise explanation of cancer pain syndromes, an up-to-date understanding of the pathophysiologic mechanism and recent developments in creating preclinical cancer pain models.

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Clinical Pain Management: A Practical Guide

Mary E. Lynch; Kenneth D. Craig; Philip W. H. Peng December 7, 2010 This book takes a practical, interdisciplinary approach to the assessment and management of pain. Concise chapters, tables, bullets, algorithms and guidelines serve as a quick reference to physicians, anesthetists, neurologists, other specialists, generalists and trainees managing pain.

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Complications in Regional Anesthesia and Pain Medicine: Second Edition

Joseph Neal; James P. Rathmell July 18, 2012 The second edition of Complications in Regional Anesthesia and Pain Medicine e continues to build on the goal of creating a single-source reference that addresses complications related to the practice of regional a est es a and anesthesia a d pain pa medicine. ed c e

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Controversies in the Anesthetic Management of the Obese Surgical Patient

Yigal Leykin; Jay B. Brodsky August 4, 2012 This book considers a wide range of important practical issues and controversies. Key questions in preoperative, intraoperative and postoperr ative management are carefully addressed, and different approaches are evaluated, casting light on their effectiveness and limitations. Written by world leaders in the field, this book will be an invaluable aid for anesthesiologists.

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Evidence-Based Chronic Pain Management

Cathy Stannard; Eija Kalso; Jane Ballantyne April 5, 2010 A genuine evidence-based text for optimum pain relief in various chronic conditions.

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Practical Treatment Options for Chronic Pain in Children and Adolescents: An Interdisciplinary Therapy Manual

Michael Dobe; Boris Zernikow July 26, 2013 Pain is an increasingly common symptom in children and adolescents, and nearly 5% of the pediatric population now suffers from severe chronic pain conditions. This manual describes the inpatient treatment program of one of the world’s largest treatment facilities for chronic pain in children, and the guidance provided is also applicable to outpatient pain management.

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Understanding Low Back Pain Anatomical Chart

Anatomical Chart Company October 1, 2008 Using the latest low back pain guidelines from the American Pain Society and the American College of Physicians, this visual and textual overr view explains the types, causes and risk factors, signs and symptoms, treatment and management, g , and p prevention of low back p pain. PMN0913


34 I PainMedicineNews.com

SEPTEMBER 2013

COMM ENTARY WEBSTER continued from page 32

pain field now believe pain is a disease that requires disease-modifying therapies. We need breakthrough therapies with a new focus on the mechanisms of pain, which are most complex. We need to find ways to heal injured nerves, reverse central sensitization and abolish inflammatory disorders, whether they are central or peripheral. These needs are only the beginning. PMN: Given the reality that opioids will continue to be a necessary part of the arsenal of pain therapies, what message do you see in recent actions from the FDA, which approved Purdue’s Citizens’ Petition, while rejecting Endo’s? How will this affect the development of abuse-deterrent formulations going forward? Dr. Webster: Abuse-deterrent formulations are a small step toward safer therapies, but let’s be clear: Opioids are fraught with problems, even if they have abuse-deterrent properties, so we need more than safer reformulations. This is not to say that this step is not important in making extended-release formulations safer. As for the petitions, I do not have access to the data that led to the FDA decision allowing Purdue to claim the reformulated OxyContin has abuse-deterrent properties while refusing to block generic forms of the Endo product. My understanding is that the FDA saw differences between the safety advantages offered by one product versus the other. My hope is that eventually all opioids, both extended-release and immediate-release formulations, will have abusedeterrent properties. But until there are replacements for opioids as strong analgesics and the will to offer patients these replacements at prices they can afford, we will continue to see problems with opioids. PMN:: Some patients do achieve greater control of pain and improved function from opioids while never misusing their medications. How much should those people be asked to compromise in order to introduce less abusable formulations to market? For example, you mentioned price. Are the newer formulations going to cost patients more out of pocket? Dr. Webster: Of course, this is the big question. We have a serious public health problem with opioids, so there may need to be a public health solution where only opioids with abuse-deterrent properties are allowed on the market. Think of a comparison to the safety belts in a car that are now mandatory, regardless of the driving record of the driver. All purchasers of cars are paying for this safety measure, regardless of the amount they drive and their risk in driving. In the same vein, it may cost patients a bit more for abuse-deterrent formulations, but there may be overall less cost to the system if we see less diversion and nonmedical abuse of medications. Part of the solution would require insurers to rethink their coverage options for abuse-deterrent opioids and also for alternatives to opioids. The Centers for Disease Control

and Prevention (CDC) reports that nonmedical use of prescription opioids costs health insurers about $73 billion every year, so there is obviously enormous will to do something about the problem [[MMWR 2011;60;1487-1492]. We must make sure that the voices of patients who suffer every day with terrible pain are not lost as these changes occur. Those patients who have done nothing wrong should not be made to suffer while solutions to the prescription drug crisis are found. PMN:: A recent movement has sought to limit the FDA-approved labeling for opioids for dosage, duration and indications related to chronic, noncancer pain. Is this likely to improve safety, or do you see problems?

of Medicine report, “Relieving Pain in America” (National Academies Press), the spending on painrelated research pales in comparison to the need. Despite the low investment, some very promising research is being done. Recent discoveries drawn from central nervous system imaging are very exciting. Research into the genetic and molecular levels promises a wealth of new understanding. Yet these studies are complex, and it is still too early for the development of therapies from such studies to have much impact on the worst types of pain. PMN:: Is the goal to replace opioids altogether or to replace them with safer versions?

Dr. Webster: I think the goal should be to find safer but also effective therapies that are not addicDr. Webster: If the proposed changes were imple- tive and do not cause serious side effects like respimented, I suspect far fewer opioids would be pre- ratory depression, but that are highly effective both scribed; therefore, fewer for short-term and longwould be diverted and, in term pain. Most opioids time, we would see fewer are classified as μ-agonists. ‘A patient seeking relief from It may be possible for a people being treated for opioid abuse and addiction. μ-agonist to meet these unremitting, severe pain shouldn’t However, the changes also criteria, but that dream would make it more diffi- have to pay such a terrible price, but has long eluded investigacult for people in pain to the fact is all therapies have risks. tors. The answer certainly receive their medications, does not lie with current Not treating the pain is also risky.’ opioids. So eventually we whereas people with addicneed to replace the opioids tion or the desire to abuse —Lynn Webster, MD substances would likely shift we have today by discovtheir drug-seeking activities ering new μ-agonists that elsewhere—perhaps to illegal street opioids. This is don’t cause the same problems or non–μ-agonists already happening in some areas, including New Eng- that are as effective as opioids. What we also need— land as reported in The New York Times. Many who and right away—are new health care delivery modhave been abusing prescription opioids are moving to els that incorporate the best evidence from multiple heroin. specialties, including psychosocial, biobehavioral, pharmacologic and nonpharmacologic treatments. PMN:: When you talk about safety with This will involve cooperation at the research level opioids, the conversation always turns to and at the delivery-of-care level. methadone. What needs to change in the PMN: What public and patient health mesdelivery of methadone for the treatment of sage is the most important for everyone to chronic pain? hear, in your opinion? Dr. Webster: According to the CDC, one-third Dr. Webster: If I could use my platform as AAPM of unintentional opioid-related overdose deaths are president to disseminate one message, it would be associated with methadone, but methadone repre- that government and private payors must not list sents only about 2% of all opioids prescribed (http:// methadone as a preferred analgesic. Methadone www.cdc.gov/vitalsigns/MethadoneOverdoses). This should be second- or third-line only, and all prodemonstrates that methadone is more risky than any viders must demonstrate that they know how to other opioid, and that there must be more caution use it before prescribing. Methadone has been with prescribing it and consuming it. part of my public message since at least 2004, One thing that needs to change is the casual copre- and I have spoken and published extensively on scribing of benzodiazepines with methadone and this subject, trying to raise awareness of the need other opioids. The recent CDC report on women for caution. Maybe there should even be licensand overdose [[MMWR 62;537-542] revealed a high ing to prescribe methadone for pain in the same involvement of benzodiazepines in many deaths. Sec- way practitioners are licensed to provide medicaond, too often payors will place methadone as a pre- tion-assisted addiction treatment. My hope is that ferred opioid because it is inexpensive. Methadone AAPM will offer such a course by year’s end, so should never be a first-line or preferred option for that providers can earn continuing education credchronic pain. If payors wish to list methadone as a its and a certificate of training. The methadone preferred drug, they should pay to educate physicians issue is that important and AAPM can save lives and other providers on how to safely prescribe it. with such a training program. PMN: What about pain-related research that does not involve opioids? Dr. Webster: According to the 2012 Institute

In addition to serving as AAPM president, Dr. Webster is medical director of CRI Lifetree Research, Salt Lake City, Utah.


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Use of Topical Analgesics in Treating Neuropathic and Musculoskeletal Pain WILLIAM ZEMPSKY, MD Head, Divison of Pain and Palliative Medicine Connecticut Childrenâ&#x20AC;&#x2122;s Medical Center Professor of Pediatrics University of Connecticut School of Medicine Storrs, Connecticut Disclosure: Dr. Zempsky serves on the Scientific Advisory Board of Vapogenicx, Inc.

T

opical administration of anesthetics and analgesics can allow for the efficient, painless delivery of medications that may reduce systemic side effects associated with the medication while providing clinical advantages over

injected or oral administration for the same clinical situation. Topical administration of nonsteroidal anti-inflammatory drugs (NSAIDs), lidocaine, capsaicin, and other agents is useful for a range of conditions including acute and chronic musculoskeletal pain.

Background Topical medications target the site of application and ideally produce effective drug concentrations locally with minimal systemic absorption. Topical anesthetics and analgesics target the peripheral nerves and soft tissue at that site.1 A number of topical medications are beneficial for chronic musculoskeletal pain. In contrast, transdermal medications do not have to be applied over an involved site and attempt to reach systemic drug concentrations to achieve therapeutic results.2 This review will focus on topical medications (Table). Benefits of topical drug delivery include the potential for local therapeutic drug levels with reduced side effects, painless drug delivery, improved patient adherence and acceptance, ease of dose termination, avoidance of first-pass metabolism, and direct access to the target site. The skin is a barrier to drug delivery, its primary role being to prevent the ingress or egress of compounds across it.3 The stratum corneum, the upper most layer of the skin, is a thin layer of cornified nonviable keratinocytes that is an effective barrier to water-soluble

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

substances, which typically include anesthetics. Topical medications must traverse the stratum corneum to reach their site of action, which may be the peripheral transducing terminals of cutaneous sensory fibers located in the dermis and epidermis,4 or the local soft tissues including synovial fluid, synovial tissue, and cartilaginous structures.5 Three delivery methods have been used to bypass the stratum corneum barrier.6 1. Injection of local anesthetics or other medications, usually via a small-gauge hypodermic syringe, is the oldest of the methodologies. 2. Passive diffusion from creams, gels, or patches comprises the second general class of methodologies. Passive diffusion of topical agents require that they have a molecular weight under 500 DA, with a hydrophobic component to allow it to transverse the stratum corneum but also some hydrophilic features to penetrate the epidermis.7 3. Active drug delivery methods that enhance the rate of drug passage through the skin and shorten the time to onset of action. There are a diverse group of

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Table. Common Topical Anesthetics and Analgesics for Chronic Pain Brand or Other Names

Drug Arnica

Use MSK pain

Formulation Gel, cream

Capsaicin

Zostrix, Qutenza, Neuropathic others pain, MSK pain

Patch, gel, cream

Lidocaine

Lidoderm

Neuropathic pain, MSK pain

Patch

MSK pain

Oinment, liniment cream

Menthol and Many methyl salicylates Topical NSAIDs

Flector, Voltaren, MSK pain Pennsaid, others

Patch, gel, cream

NSAID, nonsteroidal anti-inflammatory drug; MSK, musculoskeletal

technologies that facilitate the drug delivery process. These include heat-enhanced diffusion, iontophoresis, sonophoresis, laser-assisted transdermal passage, or pressurized gas delivery of powdered drug particles.6 Microporation, a newer technology, uses tiny microneedles to penetrate the stratum corneum and are directly placed within the epidermis. Topical as well as transdermal drug delivery is a rapidly expanding field. Most of the drugs and technologies used for procedural topical anesthesia have been well studied; however, this is not universally the case for topical medications used for musculoskeletal pain, which will be discussed in this review. Additionally, most of these topical agents have been studied exclusively in adults. The extrapolation of use of the these agents in children seems reasonable given several factors, the pharmacodynamic response to most medications including local anesthetics, opioids, and NSAIDs are substantially mature by the age of 2 years, the degree of systemic absorption of these topical medications is low, and the local skin effects are, for the most part, minimal and short-lived.8

Topical Medications for Treatment of Musculoskeletal Pain LIDOCAINE Although indicated for the treatment of postherpetic neuralgia (PHN) in the United States, lidocaine 5% topical anesthetic patch (Lidoderm, Endo) has gained usage in a variety of neuropathic and musculoskeletal clinical conditions. The 5% lidocaine patch is composed of an adhesive material containing lidocaine, which is applied to a nonwoven polyester felt backing that allows for slow medication release. The patch provides analgesic action, reducing pain with some decrease in sensory function but without the complete loss of sensation; thus, it is not effective for procedural pain.9, 10 The size of the patch is 10-14 cm.11 In addition to treatment of PHN, the 5% lidocaine patch has been used with efficacy in a variety

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of neuropathic pain conditions, such as post-thoracotomy pain, complex regional pain syndrome, and postamputation pain.12 The lidocaine patch also is effective for musculoskeletal conditions. The 5% lidocaine patch is effective in adults with osteoarthritis (OA)13,14 lower back pain.15,16 It also has shown efficacy for myofascial pain syndrome.17 The lack of significant side effects makes topical 5% lidocaine an appropriate option for any focal neuropathic pain with allodynia or hyperalgesia.18 The patch must be placed at the site of pain in order to be effective. Although it has not been studied specifically in children, we have used the 5% lidocaine patch successfully in many of the conditions described above, especially low back pain and focal neuropathic pains. Lidocaine absorption in adult usage amounts to only 3% to 5 % of the total dose available in the patch and systemic levels do not increase with daily use. Systemic toxicity in adults is not considered a significant risk.19,20 For children under 50 kg, we limit the treatment to 1 to 2 patches for 12 hours per day to ensure safety. For children weighing more than 50 kg the adult dose of 3 patches for 12 hours per day is recommended. Often, 7 to 10 days of treatment is necessary before efficacy is noted. Side effects usually are limited to redness or other signs of skin irritation.

NSAIDS Topical NSAIDS can provide local relief without the risks of an orally or parenterally delivered NSAID. Primarily, they have been evaluated for OA and acute musculoskeletal injury. These drugs are applied over the injured or painful body part and penetrate into the subcutaneous tissues, musculature, and tendons, where they exert their therapeutic action.21 After administration of topical NSAIDs, peak plasma concentrations are 0.2% to 8% of concentrations achieved with appropriate oral dosing.22 However, levels of NSAID in the meniscus and cartilaginous structures as well as in muscular tissues are 4 to 7 times greater after topical administration than oral administration.5,23 Concentrations in the tendon sheath are several hundred times greater than plasma concentration after topical administration. Length of time to peak concentration (Cmax) is about 10 times longer in topically rather than orally administered NSAIDs with Cmax for topical preparations ranging from 2.2 to 23 hours.22 Unlike orally administered NSAIDs, topical NSAIDs have not been associated with increased risk for bleeding, and the risk for any gastrointestinal side effects for topical administration is considerably lower.5 Adverse events with topical NSAIDs are predominately local cutaneous reactions. Photosensitivity is a rare adverse reaction to topical NSAIDs.5 Although there a fewer comparative trials, in general, topical NSAIDs appear as effective and have a better safety profile in adults than oral NSAIDs, although onset of action is slower.22,24 There are a variety of topical NSAID preparations including creams, gels, patches, and plasters. NSAIDS


delivered topically include diclofenac, ketoprofen, and ibuprofen. Superiority of topical NSAIDs compared with placebo has been demonstrated for both diclofenac (Flector Patch, Pfizer) and ketoprofen patches (various)for acute musculoskeletal conditions.25 Based on a large meta-analysis, ketoprofen may be the most effective of the topical NSAIDs for acute pain.26 Diclofenac topical solution (Pennsaid, Mallinckrodt) was superior to placebo and as effective as 3 times-a-day oral diclofenac for knee OA.28 Diclofenac gel (Voltaren, Endo, Novartis) was superior to placebo in a 12-week study of knee OA, with decreased pain and improved function seen.29 There are no randomized trials of topical NSAIDs in the pediatric age group. Given the excellent safety profile and low systemic absorption, use of topical NSAID treatment in children and adolescents with acute or chronic musculoskeletal pain is a reasonable option.

CAPSAICIN Capsaicin, the active compound in chili peppers, is a counter-irritant (a substance applied to the skin that, by acting as an irritant on a painful zone, attenuates the sensation of pain) that provides some relief in neuropathic pain conditions. Capsaicin is a TRPV1 agonist that first activates nociceptive nerve fibers in the skin and causes the release of substance P, which results in neurogenic inflammation. This is followed by reversible defunctionalization of nerve endings resulting in the inhibition of pain transmission.30-32 Low-concentration (0.025% and 0.075%) capsaicin creams have shown mild efficacy in a variety of neuropathic conditions, including PHN, diabetic neuropathy polyneuropathy, and postsurgical neuropathic pain. These creams must be applied several times a day and can take several weeks of application to have effect.32 More recently, an 8% capsaicin patch (Qutenza, Acorda Therapeutics) has been developed for one-time use and has shown efficacy in PHN and HIV neuropathic pain.30 In patients with musculoskeletal pain, capsaicin was superior to placebo in 154 patients with chronic low back pain. A systematic review of topical capsaicin for musculoskeletal pain demonstrates superiority over placebo.33 Another meta-analysis showed superiority of placebo of capsaicin for OA pain.34 A recent nonblinded, comparative, 6-week trial of topical capsaicin plus routine treatment versus routine treatment alone in 130 adults with fibromyalgia demonstrated decreased myalgic score and global subjective improvements in the capsaicin group. The experimental group showed continued improvements in symptoms 6 weeks after the end of treatment.35 Local skin irritation with capsaicin cream use is common with burning and erythema and itching being the predominant side effects. These effects usually diminish after 1 to 2 weeks of use. Pretreatment of the skin with topical anesthetic is necessary before the use of the capsaicin 8% patch to improve tolerability.

Use of capsaicin in pediatrics is limited to case reports. Given the rare incidence of systemic side effects, use of capsaicin for chronic pain in children and adolescents could be considered and will be limited by tolerance to the application. Other counter-irritants such as methyl salicylates and menthol also have been used for musculoskeletal pain. Methyl salicyiate may have direct analgesic effects but also provides tissue warming by its vasodilatory effects.36 Mentholâ&#x20AC;&#x2122;s mode of action is likely the cooling effect it has on the skin. There is limited evidence for the efficacy of these compounds; however, a recent study of a 10% methyl salicylate 3% menthol patch demonstrated greater pain relief than placebo in 208 adults with muscle strains.36

DEXAMETHASONE Dexamethasone, a steroid, can be delivered iontophoretically for a variety of inflammatory conditions such as knee OA, medical and lateral epicondylitis, Achilles tendonitis, and plantar fasciitis.37-39 The data supporting the efficacy of dexamethasone iontophoresis is variable. The largest study that evaluated dexamethasone iontophoresis for epicondylitis demonstrated reduced pain in the active drug group versus placebo; however, the results of several other smaller trials including one for epicondylitis were mixed. It is likely that dexamethasone iontophoresis provides short-term benefits including pain relief in acute musculoskeletal injuries.40 One pediatric study of dexamethasone iontophoresis demonstrated efficacy in a case series of 28 patients with juvenile idiopathic arthritis treated for temporomandibular joint involvement.41

ARNICA Arnica is a perennial herb indigenous to central Europe. It has been used topically to reduce inflammation, soothe muscle aches, and decrease swelling and bruising associated with injuries.42 Two studies have evaluated arnica gel for topical treatment of OA. Knuesel evaluated arnica gel in an open-label trial of 79 patients with mild to moderate OA, demonstrating improved function and decreased pain.43 A subsequent doubleblind randomized trial of 204 patients with radiologically confirmed active hand OA compared arnica gel with 5% ibuprofen gel and demonstrated no difference between the groups with decreased pain intensity and improved function in both treatment arms.44 Adverse reactions associated with arnica use are limited to mild local skin reactions.

Conclusions There are a variety of effective topical medications for musculoskeletal pain. Given the excellent safety profile, including lack of systemic absorption and minimal local side effects, the more extensive use of these medications in treating chronic musculoskeletal conditions should be considered.

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References 1.

Galer BS. Topical medications. In: Loeser JD, ed, Bonicaâ&#x20AC;&#x2122;s Management of Pain. Philadelphia: Lippincott-Williams & Wilkins; 2001;1736-1741.

concentrations after oral and topical ibupfofen administration. Clin Pharmacol Ther. 1999;65(4):357-368.

2. Argoff CE. Topical treatments for pain. Curr Pain Headache Rep. 20;8(4):261-267.

24. Underwood M, Ashby D, Carnes D, et al. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study. Health Technol Assess. 2008:12(22):iii-iv, ix-155.

3. Tadicherla S, Berman, B. Percutaneous dermal drug delivery for local pain control. Ther Clin Risk Manag. 2006;2(1):99-113.

25. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med. 2010(4);11:535-549.

4. Lumpkin EA, Caterina MJ. Mechanisms of sensory transduction in the skin. Nature. 2007;445(7130):858-865.

26. Mason L, Moore RA, Edwards JE, et al. Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis. BMC Musculoskelet Disord. 2004;5:28.

5. Bandolier. Bandolier extra, topical analgesics: a review of reviews and a bit of perspective. http://www .medicine.ox .ac.uk/bandolier/ Extraforbando /Topextra3.pdf. Accessed February 1, 2012. 6. Zempsky WT. Pharmacologic approaches for reducing venous access pain. Pediatrics. 2008;122(suppl 3):S140-S253. 7. Stamos SP. . Topical agents for the management of musculoskeletal pain. J Pain Symptom Manage. 2007;33(3):342-355. 8. Berde CB, Walco GA, Krane EJ, et al. Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop. Pediatrics. 2012:129(2):354-364. 9. Krumova EK, Zeller M, Westermann A, Maier C. Lidocaine patch (5%) produces a selective, but incomplete block of Aδ and C fibers. Pain. 201;153(2):273-280. 10. Wehrfritz A, Namer B, Ihmsen H, et al. Differential effects on sensory functions and measures of epidermal nerve fiber density after application of a lidocaine patch (5%) on healthy human skin. Eur J Pain. 2011;15(9):907-912. 11. Galer BS, Rowbotham MC, Perander J, et al. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain. 1999;80(3), 533-538. 12. Devers A, Galer, BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open label study. Clin J Pain. 2000;16(3):205-208. 13. Galer BS, Sahaler E, Patel, N. Topical lidocaine patch 5% may target a novel underlying pain mechanism in osteoarthritis. Curr Med Res Opin. 2004;20,1455-1458 14. Gammaaitoni AR, Galer BS, Onwala R, et al. Lidocaine patch 5% and its positive impact on pain qualities in osteoarthritis: results of a pilot 2-week, open label study using the neuropathic pain scale. Curr Res Med Opin. 2004;20(suppl 2):S13-S19. 15. Gimbel J, Linn R, Hale M, et al. Lidocaine patch treatment in patients with low back pain: results of an open-label, non-randomized pilot study. 2005. Am J Ther. 2005;12(4):311-319. 16. Galer BS, Gammaitoni AR, Oleka N, et al. Use of the lidocaine 5% patch in reducing intensity of various pain qualities reported by patients with low-back pain. Curr Res Med Opin. 2004;220(suppl 20):S5-S12. 17. Affaitati G, Fabrizio A, Savini A, et al. A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. Clin Ther. 2009;31:705-720. 18. Jensen TS, Madesen CS, Finnerup NB. Pharmacology and treatment of neuropathic pains. Curr Opin Neurol. 2009;22(5):467-474. 19. Lidoderm. Package insert. Endo pharmaceuticals, Chadds Ford, PA, 2010. 20. Campbell BJ, Rowbotham M, Davies PS, et al. Systemic absorption of topical lidocaine in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. J Pharm Sci. 2002;91(5):1343-1350. 21. Esparza F, Cobian C, Jiminez JF, et al. Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries. Br J Sports Med. 2007;41(3):134-139. 22. Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic disease: a comparison. Drugs. 2000;60(3):555-574. 23. Tegeder I, Muth-Selbach U, Lotsch J, et al. Application of microdialysis for the determination of muscle and subcutaneous tissue

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27. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of topical diclonfenac solution (Pennsaid) compared with oral diclonfenac in symptomatic treatment of osteoarthritis of the knee: a randomized control trial. J Rheumatol. 2004;31(10):2002-2012. 28. Roth SH, Shainhouse JZ. Efficacy of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle controlled trial. Arch Intern Med. 2004;164(18):2017-2023. 29. Barthel HR, Haselwood D, Longley S, et al. Randomized control trial of diclonfenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009;39(3):203-212. 30. Irving GA, Backonja MM, Dunteman E, et al. A multicenter, randomized, double-blind controlled study of NGX-4010, a highconcentration capsaicin patch, for the treatment of post herpetic neuralgia. Pain Medicine. 2011;12(1):99-109. 31. Derry S, Lloyd R, Moore RA, et al. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009;7(4):CD007393. 32. Knoktova H, Pappagallo M, Szallasi A. Capsaicin (TRPV1 agonist) the pay for pain relief. Farewell or revival? Clin J Pain. 2008;24(2):142-154. 33. Mason L, Moore, RA, Edwards JE, et al. Systematic review of topical capsaicin for the treatment of chronic pain. Br Med J. 2004;328(7446):991. 34. Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin. A meta-analysis. Eur J Clin Pharmacol. 1994;46:9(6):517-522. 35. Casanueva B , Rodero B, Quintial C et al. Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients. Rheumatol Int. 2012 Jul 28. [Epub ahead of print] 36. Higashi Y, Kiuchi T, Furuta, K. Efficacy and safety profile of a topical methyl salicylate and menthol patch in adult patients with mild to moderate muscle strain: a randomized double-blind, parallelgroup, placebo-controlled, multicenter study. Clin Therap. 2009; 32;34-43. 37. Gudeman SD, Eisele SA, Heidt RS Jr., et al. Treatment of plantar fasciitis by iontophoresis of 0.4% dexamethasone. A randomized, double-blind, placebo-controlled study. Am J Sports Med. 1997;25(3):312-316. 38. Neeter C, Thomee R, Silbernagel KG, et al. Iontophoresis with or without dexamethasone in the treatment of acute Achilles tendon pain. Scand J Med Sci Sports. 2003;13(6):376-382. 39. Nirschl RP, Rodin DM, Ochiai DH, et al. Iontophoretic administration of dexamethasone sodium phosphate for acute epicondylitis. A randomized, double-blinded, placebo-controlled study. Am J Sports Med. 2003;31(3):189-195. 40. Turro J, Bruneti L, Patel M. Ionotphoretic adminstration of dexamethasone for musculoskeletal pain. J Musculoskel Med 2011;228:410-421. 41. Mina R, Melson P, Powell S, et al. Effectiveness of dexamethsone iontophoresis for temporomandibular joint involvement in juvenile idiopathic arthritis. Arthritis Care Research. 2011;63:1511-1516. 42. Ross reference TK 43. Knuesel O, Weber M, Suter A. Arnica montana gel in osteoarthritis of the knee: an open, multicenter clinical trial. Adv Ther. 2002;19(5):209-218. 44. Widrig R, Suter A, Saller R, Melzer, J. Choosing between nsaid and arnica for topical treatment of hand osteoarthritis in a randomized, double-blind study. Rheumatol Int. 2007;27(6):585-591.


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SEPTEMBER 2013

REPORT Management of Opioid-Induced Constipation in Patients With Advanced Illness of pain related to tumor enlargeoderate to severe pain is a ment, metastasis or, as another common clinical problem Faculty example, neuropathic pain in the among patients with advanced illsetting of diabetes mellitus. Other ness, particularly in the palliative Darren Brenner, MD times, the pain may be iatrogenic care setting. Although cancer pain Assistant Professor of Gastroenterology in etiology, such as complicahas historically received the most and Hepatology tions related to radiation therapy attention, patients with AIDS, Northwestern University Feinberg for the treatment of cancers, or advanced congestive heart failure, School of Medicine neuropathy induced by antiretroand advanced lung disease also Chicago, Illinois viral or chemotherapeutic agents. commonly experience pain.1 Unfortunately, the prevalence of “When we look at patients with Joseph Pergolizzi, MD pain is quite high in the palliative advanced illness, pain is one of Adjunct Associate Professor of care setting.” the most prevalent symptoms Pharmacology In fact, a meta-analysis of that patients report,” said Joseph Temple University School of Medicine studies published during the Pergolizzi, MD, adjunct associate Philadelphia, Pennsylvania past 40 years found that 64% professor of pharmacology, Temof patients with advanced-stage ple University School of Medicine cancer reported significant pain in Philadelphia, Pennsylvania. in their daily lives.2 Another review, which included patients “This pain can arise due to the illness itself, such as in cases

M

Indication ®

RELISTOR is indicated for the treatment of opioidinduced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.

Contraindications RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstructions. Please see Important Safety Information throughout and brief summary of Prescribing Information on page 12.

Supported by


REPORT

with advanced illnesses such as cancer, AIDS, heart disease, chronic obstructive pulmonary disease (COPD), and renal disease reported that the prevalence of pain across 28 studies ranged between 34% and 96%.3 Moreover, the prevalence of pain among patients receiving hospice care may be as high as 90%.4 “The severity of pain has an important influence in the choice of treatment strategy,” Dr. Pergolizzi explained. “When patients report moderate to severe pain, that’s where we really rely on the opioids. In fact, escalating doses of opioids are oftentimes the only effective option for pain control in advanced disease.” This notion is endorsed by guidelines from several major societies in the United States, such as the American College of Physicians and the National Comprehensive Cancer Network, which recommend that opioids should be used for the treatment of moderate to severe pain in patients with advanced illness.5,6 Opioids, however, are associated with numerous adverse events (AEs), including nausea, sedation, pruritus, and respiratory depression.5,7 Perhaps the most common opioid AEs are those affecting the gastrointestinal (GI) tract, including opioidinduced constipation (OIC).8-10 The following report provides an overview of OIC, including a review of its epidemiology, risk factors, and how its pathophysiology and management differ from that of primary constipation, as well as a review of data for recently approved options for the management of this condition.

Pathophysiology of OIC Darren Brenner, MD, assistant professor of gastroenterology and hepatology, Northwestern University Feinberg School of Medicine in Chicago, Illinois, noted that, “in terms of pathophysiology, OIC is quite distinct from other forms of constipation.” For example, physiologic constipation results from extrinsic, non–disease-related factors that affect bowel function, such as decreased physical activity and inadequate dietary fiber and fluid intake. These factors may cause decreased bowel motility and increased transit time, which allows more time for fluid resorption in the intestinal lumen, leading to hard and dry stools.9 In other cases, constipation may result from pathologic conditions in the setting of underlying GI, nervous system, or metabolic disorders that interfere with GI motility or fluid absorption/secretion.9,11

“In contrast, OIC is mediated by the effect of opioids on opioid receptors that are located throughout the GI tract and the enteric nervous system,” said Dr. Brenner. The 3 major opioid receptors in the enteric nervous system are the μ-, γ-, and κ-subtypes.12 The μ-receptors are widely distributed in the GI tract submucosa as well as the ileal mucosa, where they influence ion transport changes.12 The primary mediator involved in the development of OIC is the μ-opioid receptor; inhibition of excitatory and inhibitory neurotransmitters occurs when opioid agonists bind to this receptor, causing multiple effects that contribute to OIC.7,13,14 These include inhibition of gastric emptying, reduction of mucosal secretions, and a decrease in peristalsis throughout the GI tract, thereby delaying transit.14,15 Furthermore, opioids stimulate non-propulsive motility, intestinal segmentation and tone, and increased pyloric and ileocecal sphincter tone. Opioids also result in increased absorption of fluids, mainly by delayed transit—increasing contact time for absorption—and by stimulating mucosal sensory receptors that activate a reflex arc that facilitates further fluid absorption.14 All of these pathophysiologic processes conspire to result in hard, dense stools and decreased motility, resulting in significant constipation14 that may be refractory to traditional strategies used to alleviate constipation.15 “Patients with advanced illness also may have autonomic dysfunction leading to GI motility disorders. For example, HIV affects local humoral immunity and causes motility disturbances via its influence on autonomic nerves,” said Dr. Pergolizzi. “Using opioids for any treatment [in patients with advanced illness] is going to be detrimental to the GI tract given the plethora of μ-opioid receptors located across the entire intestinal lining,” said Dr. Brenner. “However, treatment guidelines still rely on opioids for the treatment of moderate to severe pain, and I don’t see that changing any time soon. So the best thing we can do is develop strategies to overcome adverse GI events related to their use.” Nonselective opioid-receptor antagonists such as naloxone and naltrexone target the μ-, γ-, and κ-opioid receptors, which led to interest in their use for opioid therapy.15 However, both agents can cross the blood–brain barrier and antagonize receptors that mediate the analgesic effect of opioids.12,16

Important Safety Information RELISTOR ® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been

2

reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR


REPORT

“The last thing that we want to do in the palliative care setting is to reduce the analgesic effects of our opioids, because our primary goal is to reduce pain in these patients,” said Dr. Pergolizzi.

Epidemiology and Consequences of OIC OIC is an anticipated side effect of opioid therapy. Its overall relevance to the clinical community continues to increase, mainly because of the rising therapeutic use of opioids.17 For example, OIC rates in patients receiving cancer treatment and opioids can range from 69% to 90%,18,19 and studies of patients with advanced cancer who are receiving hospice care report rates as high as 87%.20 Additionally, among individuals with advanced illnesses other than cancer who are receiving opioid therapy, the prevalence of opioid-induced GI AEs approaches 90%.21 “In the palliative care patient with advanced disease, we are more aggressive in the use of opioids to reduce pain with the goal of comfort,” said Dr. Pergolizzi. “Although we try to balance the role of analgesic-related side effects, oftentimes, relief of pain is more important for these patients. As such, we typically use higher dose of opioids, which results in more adverse effects.” Risk factors for OIC include advanced age, opioid type/ strength, and advanced illness (eg, cancer, AIDS, or cardiovascular disease).18,20,21 Furthermore, the risk for OIC increases with relative immobility, dehydration, and altered nutritional intake, all of which are common in patients with advanced illnesses, particularly in the palliative care setting.21 Although patients may slowly acquire a tolerance to opioid-related side effects such as nausea or sedation, OIC may continue unabated throughout treatment.21 Dr. Pergolizzi said that there are several notable consequences of OIC. “First, OIC can result in other GI symptoms, including nausea and vomiting and a decreased ability to take in oral medications and nutrients. Second, if patients have no remedy to relieve the symptoms and complications of OIC as an outpatient, they really have no other option than to come to the emergency department to be evaluated. In some cases, the symptomatology and consequences of OIC are sufficiently severe to warrant hospitalization for more aggressive

interventions,” he said. “When you consider the patient with advanced illness, especially those in the palliative care setting, they would really rather not be hospitalized provided they have some option to adequately relieve OIC at home.” The consequences of OIC are diverse and significant. Clinical manifestations include abdominal pain, distension, and nausea and vomiting.9 When left untreated, OIC may lead to inadequate absorption of oral medications, fecal impaction, hemorrhoids, bowel obstruction, and intestinal perforation.9 “There is a vicious circle that exists between opioid use for the relief of pain and the subsequent pain and discomfort that can result from the development of secondary constipation,” said Dr. Pergolizzi. “Specifically, patients are given opioids to relieve the primary pain related to their advanced illness but end up developing OIC, which can, itself, be a painful condition. [When laxative agents provide insufficient relief,] patients are then faced with the choice of either refraining from further opioid therapy to relieve OIC, in which case the pain from their primary condition is not adequately treated, or taking larger doses of opioids and potentially worsening the pain associated with OIC.”

Treatment of OIC in Advanced Illness Physiologic constipation is typically managed through a combination of behavioral strategies and the use of agents designed to increase stool bulk, improve intestinal motility, and/ or aid the passage of stools through softening agents.9 Supportive strategies include increased hydration and improved patient mobilization—which can be difficult for patients with advanced illness—along with addressing the etiologic triggers of constipation.9 Laxatives are the first-line therapeutic option for OIC, and the various classes of laxative agents used to relieve physiologic mechanisms of constipation are summarized in Table 1.22,23 However, data from clinical trials suggest that conventional laxatives (eg, over-the-counter laxatives, polyethylene glycol, lactulose, magnesium citrate) may not offer adequate symptom relief for some patients.15,21 As reviewed in the section on the pathophysiology of different types of constipation, OIC in advanced illness is unique from other forms of constipation. “When we look at laxatives

Important Safety Information (continued) and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Use of RELISTOR has not been studied in patients with peritoneal catheters. Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients.

The most common adverse reactions reported with RELISTOR compared with placebo in clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%). Please see Important Safety Information throughout and brief summary of Prescribing Information on page 12.

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Table 1. Conventional Laxative Options for Opioid-Induced Constipation in Advanced Illness Type

Attributes

Examples

Side Effects/Complications

Bulk laxatives

Dietary fiber; causes water retention in the colon and increases stool bulk

Psyllium husk, methylcellulose

Increased gas; risk for bowel obstruction in patients with strictures

Osmotic laxatives

Salt content retains fluid retention and increased intestinal secretions

Sorbitol, lactulose, polyethylene glycol, magnesium citrate

Electrolyte imbalances; increased gas, nausea, and dehydration

Stool softeners

Decrease surface tension to lubricate and soften fecal matter

Dioctyl sodium, calcium sulfosuccinate

Require adequate fluid intake, useless in patients with compromised bowel motility

Stimulants

Increase colonic motility and electrolyte transport; stimulate fluid secretion

Senna, cascara, bisacodyl

Electrolyte imbalances; abdominal pain, nausea, and colonic dysmotility

From references 22 and 23.

and stool softeners, we see dramatic variability in terms of the response to such agents across our patient populations. A lot of that has to do with the specific mechanisms of constipation, particularly in patients with OIC,” said Dr. Pergolizzi. Another strategy that has been recommended to relieve AEs while maintaining analgesia is that of opioid rotation.5,24 This tactic is predicated on the fact that patients react differently to various types of opioids, which implies both incomplete crosstolerance and distinct variations in their pharmacodynamics and opioid-receptor binding affinities.24,25 However, this strategy has shown only moderate benefits in the reduction of OIC

and other related AEs. Narabayashi and colleagues investigated the safety of an opioid rotation in cancer patients and found that side effects commonly recurred after switching from one agent to another.26 There also are therapeutic equivalence concerns when switching from one opioid to another. Current recommendations are based on studies conducted within different patient populations that analyzed dose equivalency, not pain management.24,25 The relative ineffectiveness of traditional strategies for OIC has prompted research and development of targeted therapies, as some patients require additional therapeutic options.

Important Safety Information RELISTOR ® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been

4

reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR


REPORT

Blood-Brain Barrier Opioid

RELISTOR

Mu-opioid μ-opioid receptor receptor

Figure 1. Relistor inhibits opioids from m binding with μ-receptors in tissues such as the gastrointes gastrointestinal tract.

“Until recently, the only agents available were ere those being used to treat the more typical types of constipation—bulknstipation—bulking agents, osmotic and stimulant laxatives,” said Dr. Brenner. “Now we’re moving into an era where we’re developing [second-line] agents that focus on the precise pathophysiologic mechanisms of OIC to provide specific and effective antidotes.”

Peripheral Opioid-Receptor Antagonists The limitations of nonselective opioid antagonists have prompted the development of agents that do not cross the blood–brain barrier. These agents ideally would avoid the

analgesic-dampening and opioid-withdrawal effects ef of opioidreceptor antagonists while maintaining therape therapeutic efficacy for the alleviation of OIC.15 N-methylation of naltrexone results in a charged derivative, methylnaltrexone (Relistor, Salix Pharmaceuticals), which has restricted ability to cross the blood–brain barrier in humans because of its polarity and low lipid solubility.27 Relistor antagonizes μ-opioid receptors, which reverses opioid-induced delays on GI motility in a dose-dependent manner.27 Figure 1 shows Relistor blocking opioids from binding to μ-receptors within the GI tract.

Important Safety Information (continued) and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Use of RELISTOR has not been studied in patients with peritoneal catheters. Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients.

The most common adverse reactions reported with RELISTOR compared with placebo in clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%). Please see Important Safety Information throughout and brief summary of Prescribing Information on page 12.

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Placebo

80

RELISTOR 0.15 mg/kg

70

62%

a

58% a

Patients, %

60

RELISTOR 0.30 mg/kg 48% a

50 40 30 20

16% 14%

10 0 (n=52)

(n=47)

(n=55)

Study 1

(n=71)

(n=62)

Study 2

Figure 2. Laxation response rates within 4 hours of the first dose during clinical trials of Relistor in patients with advanced illness. a

P<0.0001 vs placebo

From reference 27.

The efficacy and safety of Relistor for OIC in patients with advanced illness were investigated in 2 clinical trials (Figure 2).27 Slatkin and colleagues conducted a randomized double-blind, placebo-controlled trial that compared a single subcutaneous injection of Relistor (0.15 mg/kg or 0.30 mg/kg) with placebo for OIC.21 The study included 154 patients with advanced illness such as cancer or other end-stage conditions (eg, cardiovascular disease, HIV/AIDS) who were receiving palliative care.21 Participants had received opioid therapy for at least 3 days before study randomization and had not experienced a bowel movement within 48 hours of the first dose.21

Within 4 hours of treatment, laxation response rates for Relistor doses of 0.15 mg/kg (n=47) and 0.30 mg/kg (n=55) were 61.7% and 58.2%, respectively, compared with 14% for placebo (P<0.0001). In fact, roughly half of the Relistor responders defecated within 30 minutes of receiving the agent.21 Within 24 hours, laxation rates remained steady for 0.15 mg/kg Relistor (68.1%) and 0.30 mg/kg Relistor (63.6%) compared with placebo (26.9%).21 The investigators reported comparable efficacy between both doses of Relistor, but patients in the 0.30 mg/kg treatment arm had higher rates of abdominal pain (38.2% vs 27.7%).21

Important Safety Information RELISTOR ÂŽ (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been

6

reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvieâ&#x20AC;&#x2122;s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR


REPORT

Table 2. Common Adverse Reactions Associated With Relistor During Clinical Trials in Patients With Advanced Illness RELISTOR a (n=165)

Placebo (n=123)

Pts (%)

Pts (%)

Abdominal pain

47 (28.5)

12 (9.8)

Flatulence

22 (13.3)

7 (5.7)

Nausea

19 (11.5)

6 (4.9)

Dizziness

12 (7.3)

3 (2.4)

Diarrhea

9 (5.5)

3 (2.4)

Hyperhidrosis

11 (6.7)

8 (6.5)

Adverse Reaction

a

Includes doses of 0.075, 0.15, and 0.30 mg/kg

From reference 27.

Other common AEs related to Relistor during this trial in the 0.15 mg/kg and 0.30 mg/kg treatment arms were flatulence (12.8% and 14.5%), nausea (4.3% and 14.5%), and dizziness (4.3% and 9.1%).21 In a similar study by Thomas and colleagues, 133 patients who had received opioids for at least 2 weeks and developed OIC that was refractory to the use of laxatives were randomly assigned to receive subcutaneous Relistor (0.15 mg/kg; n=63) or placebo (n=71) every other day for 2 weeks.28 Participants were recruited from palliative care settings and had advanced illness such as cancer, cardiovascular disease, COPD, emphysema,

Alzheimerâ&#x20AC;&#x2122;s disease, or dementia.28 The proportion of patients who experienced laxation within 4 hours was significantly higher in the Relistor group than in the placebo group (48% vs 15%, respectively; P<0.0001).28 Additionally, the median time to laxation after the first dose was significantly shorter in the Relistor group than in the placebo group (6.3 vs 48 hours, respectively; P<0.002).28 The most common AEs related to Relistor during this trial were abdominal pain (17%), flatulence (13%), nausea (11%), increased body temperature (8%), and dizziness (8%).28 The study by Thomas and colleagues also included an open-label extension in which patients received Relistor as

Important Safety Information (continued) and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Use of RELISTOR has not been studied in patients with peritoneal catheters. Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients.

The most common adverse reactions reported with RELISTOR compared with placebo in clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%). Please see Important Safety Information throughout and brief summary of Prescribing Information on page 12.

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REPORT

needed each day for 3 months. A total of 89 patients entered this phase of the trial (47 from the Relistor group, 42 from the placebo group).28 By the end of the 3-month extension, patients from the placebo group improved their rescuefree response rates from 11% to 52%; patients from the initial Relistor group improved their response rates from 45% to 57%.28 Median time to laxation for all patients was less than 45 minutes.28 The most common AEs during this phase were abdominal pain (30%), progression of malignant neoplasm (24%), nausea (21%), and vomiting (20%). Serious AEs related to Relistor were muscle spasms (1 patient) and exacerbated pain (1 patient); 32 deaths occurred, with all attributed to underlying disease.28 In both the Slatkin and Thomas studies, participants were permitted to continue their previously initiated laxative therapy, just not within 4 hours of study treatments. Figure 2 provides laxation rates from the 2 clinical trials of Relistor within 4 hours of the first dose.27 “In the 2 pivotal trials, the clinical benefit associated with the fact that methylnaltrexone does not cross the blood–brain barrier was confirmed by observations showing there was no analgesic-stealing effect,” said Dr. Pergolizzi. Indeed, in both trials there was no change in pain scores or evidence of central-opioid withdrawal in response to Relistor.21,28 Abdominal pain and flatulence were the most common AEs attributed to Relistor during the 2 clinical trials (Table 2).27 A post hoc analysis of abdominal pain rates during these studies found that it consisted primarily of abdominal cramping and did not affect patients’ overall evaluation of pain.29 These AEs were mostly mild to moderate in severity and did not affect patients’ global evaluation of pain. The incidence of abdominal pain in Relistor-treated patients was highest following the first dose and it decreased with subsequent doses.29 Of note, rare postmarketing cases of GI perforation have been reported in association with Relistor, particularly in patients with abnormal structural integrity in the walls of the GI tract, such as those with cancer, peptic ulcer, or Ogilvie’s syndrome. As a result, the prescribing information includes a warning that Relistor should be used with caution in patients with a known or suspected GI tract lesions.27 On the basis of these trials, in 2008 the FDA approved the use of Relistor for the treatment of OIC in patients with

advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. 27 Relistor is administered as a subcutaneous injection, and a typical schedule is 1 dose every other day as needed, but not to exceed more than 1 dose in a 24-hour period.27 Use of Relistor beyond 4 months has not been studied. The recommended dose of Relistor is 8 mg for patients who weigh between 38 and 61 kg; 12 mg for patients who weigh between 62 and 114 kg; and 0.15 mg/kg for patients who fall outside of these weight ranges.27 Only patients who require an 8- or 12-mg dose should be prescribed prefilled syringes. No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), dose reductions of Relistor by one half are recommended.27 If severe or persistent diarrhea occurs during treatment, patients should discontinue therapy with Relistor and consult their physician. If patients develop severe, persistent, and/or worsening abdominal symptoms, they should discontinue therapy with Relistor and promptly notify their physician. Use of Relistor has not been studied in patients with peritoneal catheters. Dr. Pergolizzi views subcutaneous Relistor administration as one of several unique advantages. “The fact that we can administer this agent via the subcutaneous route in patients undergoing palliative care is important, as many of these patients are unable to take in medications by mouth due to nausea, dysphagia, or decreased levels of consciousness. OIC itself can also cause significant nausea and may preclude oral medication intake for some patients,” he said.

Treatment Algorithm for Opioid-Induced Constipation in Advanced Illness With the approval of Relistor for the treatment of OIC in patients with advanced illness who are receiving palliative care when laxative therapy has not been sufficient, Drs. Brenner and Pergolizzi discussed the current landscape and clinical management of OIC in patients with advanced illness, including a potential treatment algorithm (Figure 3). “According to the FDA-approved labeling, methylnaltrexone is indicated for the second-line treatment of OIC. Therefore, the first step for patients with OIC will still be a trial of

Important Safety Information RELISTOR ® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been

8

reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR


REPORT

OIC in a patient with advanced illness undergoing palliative care

ª Trial of oral first-line laxative agent

ª Nonresponse or insufficient response

ª Relistor Trial Subcutaneous injection every other day, as needed, but no more frequently than 1 dose in a 24-h period Approved doses: • 8 mg for patients weighing 38-61 kg • 12 mg for patients weighing 62-114 kg • 0.15 mg/kg for patients whose weight falls outside of these ranges

ª

the traditional laxative therapies. For patients who fail to have a response to the traditional agents, you would proceed to methylnaltrexone. The mechanism of action for methylnaltrexone is well-suited for the treatment of OIC, so if the patient describes a clinical history in which they had regular bowel movements then developed constipation after initiation of opioid therapy, I would use methylnaltrexone,” said Dr. Pergolizzi. “Methylnaltrexone is indicated to be used when other laxatives have failed. But if a patient has a clear history of OIC [and hasn’t responded to first-line therapies], I wouldn’t spend a great deal of time switching from one laxative to another before prescribing methylnaltrexone,” said Dr. Brenner. According to Dr. Pergolizzi, determining the success of laxative therapy is, thankfully, not all that difficult. “When prescribing medications for the treatment of OIC, you have an easy, objective end point to follow: Has the patient had symptomatic relief in terms of a bowel movement or not? Methylnaltrexone offers a predictable and rapid response in the majority of patients with OIC,” he said.

Conclusion OIC is a highly prevalent side effect of opioid therapy. The pathophysiology of OIC is unique from that of physiologic constipation or constipation due to primary GI, neurologic, or metabolic conditions. Conventional therapies may be ineffective in restoring normal bowel function in patients with OIC. Relistor is an effective second-line therapy and initial prescription option for the treatment of OIC in patients with advanced illness who are receiving palliative care.

Nonresponse or insufficient response

ª Rescue therapy (ie, enemas, manual disimpaction)

Figure 3. Faculty-proposed treatment algorithm for OIC in advanced illness. OIC, opioid-induced constipation

Important Safety Information about RELISTOR RELISTOR ® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been reported in advanced illness patients with conditions that may

Important Safety Information (continued) and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Use of RELISTOR has not been studied in patients with peritoneal catheters. Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients.

The most common adverse reactions reported with RELISTOR compared with placebo in clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%). Please see Important Safety Information throughout and brief summary of Prescribing Information on page 12.

9


REPORT

be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Use of RELISTOR has not been studied in patients with peritoneal catheters.

Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients. The most common adverse reactions reported with RELISTOR compared with placebo in clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%).

References

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Glare P, Walsh D, Sheehan D. The adverse effects of morphine: a prospective survey of common symptoms during repeated dosing for chronic cancer pain. Am J Hosp Palliat Med. 2006;23(3):229-235.

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Mancini I, Bruera E. Constipation in advanced cancer patients. Support Care Cancer. 1998;6(4):356-364.

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van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007;18(9):1437-1449.

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Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disorder, and renal disease. J Pain Symptom Manage. 2006;31(1):58-69.

4.

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Fine PG, Portenoy RK. Opioid therapy in advanced medical illness. In: William Roberts, Colleen Sauber, eds. A Clinical Guide to Opioid Analgesia. New York, NY: McGraw-Hill; 2004:115-120.

Kutner JS, Kassner CT, Nowels DE. Symptom prevalence at the end of life: hospice providers’ perceptions. J Pain Symptom Manage. 2001;21(6):473-480. Swarm R, Abernethy AP, Anghelescu DL, et al; NCCN Adult Cancer Pain. Adult cancer pain. J Natl Compr Canc Netw. 2010;8(9):1046-1086. Qaseem A, Snow V, Shekelle P, et al; Clinical Assessment Subcommittee of the American College of Physicians. Evidence-based interventions to improve the palliative care of pain, dyspnea, and depression at the end of life: a clinical practice guidelines from the American College of Physicians. Ann Intern Med. 2008;148(2):141-146. Bader S, Jaroslawski K, Blum HE, Becker G. Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide. Clin Med Insights Oncol. 2011;5:201-211.

Please see brief summary of Prescribing Information on page 12.

10. Clemens KE, Klaschik EK. Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone bromide. Ther Clin Risk Manage. 2010;6:77-82. 11. Wingate D, Hongo M, Kellow J, et al. Disorders of gastrointestinal motility: towards a new classification. J Gastroenterol Hepatol. 2002;(17 suppl):S1-S14. 12. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106(5): 835-842. 13. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63(7):649-671. 14. De Schepper HU, Cremonini F, Park MI, Camilleri M. Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol Motil. 2004;16(4):383-394. 15. Thomas JR, Cooney GA, Slatkin NE. Palliative care and pain: new strategies for managing opioid bowel dysfunction. J Palliat Med. 2008;(11 suppl 1):S1-S19. 16. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther. 1996;59(4): 469-475.


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17. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and non-medical use of opioids. Pain Physician. 2008;11(2 suppl):S63-S88.

24. Mercandante S, Casuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol. 2001;19(11):2898-2904.

18. Rosti G, Gatti A, Costantini A, et al. Opioid-related bowel dysfunction: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol Sci. 2010;14(12):1045-1050.

25. Vissers KP, Besse K, Hans G, et al. Opioid rotation in the management of chronic pain: where is the evidence? Pain Pract. 2010;10(2):85-93.

19. Quigley C. The role of opioids in cancer pain. BMJ. 2005; 331(7520):825-829. 20. Sykes NP. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med. 1998;12(5):375-382. 21. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol. 2009;7(1):39-46. 22. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 suppl): S105-S120. 23. Schaefer DC, Cheskin LJ. Constipation in the elderly. Am Fam Physician. 1998;58(4):907-914.

26. Narabayashi M, Saijo Y, Takenoshita S, et al; Advisory Committee for Oxycodone Study. Opioid rotation from oral morphine to oral oxycodone in cancer patients with intolerable adverse effects: an open-label trial. Jpn J Clin Oncol. 2008;38(4):296-304. 27. Relistor (methylnaltrexone bromide) subcutaneous injection [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc; 2012. 28. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332-2343. 29. Slatkin NE, Lynn R, Su C, et al. Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials. J Pain Symptom Manage. 2011;42(5):754-760.

Disclosures: Dr. Brenner reported that he has served as a consultant for Perrigo and has served as a consultant for and on the speakers’ bureau of Salix Pharmaceuticals. Dr. Pergolizzi reported that he has served as a consultant for, on the speakers’ bureau of, and received honorarium from Endo Pharmaceuticals, Johnson & Johnson, Purdue Pharma, and Salix Pharmaceuticals. He has also served as a consultant for and received honorarium from Kirax Corporation.

Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. REL 13/22

SR1317

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Salix, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

11


Adverse Reactions from all Doses in DoubleBlind, Placebo-Controlled Clinical Studies of RELISTOR*

The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE RELISTOR is indicated for the treatment of opioidinduced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied. CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. WARNINGS AND PRECAUTIONS Severe or Persistent Diarrhea If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Intestinal Perforation Rare cases of gastrointestinal (GI) perforation have been reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (i.e., cancer, peptic ulcer, Ogilvieâ&#x20AC;&#x2122;s syndrome). Perforations have involved varying regions of the GI tract (e.g., stomach, duodenum, or colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Peritoneal Catheters The use of RELISTOR has not been studied in patients with peritoneal catheters. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in clinical practice. The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in patients with advanced illness receiving palliative care: Study 1 included a single dose, double blind, placebo-controlled period, whereas Study 2 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common adverse reactions (>5%) in patients receiving RELISTOR are shown in the table above.

Adverse Reaction

RELISTOR N = 165

Placebo N = 123

Abdominal Pain

47 (28.5%)

12 (9.8%)

Flatulence

22 (13.3%)

7 (5.7%)

Nausea

19 (11.5%)

6 (4.9%)

Dizziness

12 (7.3%)

3 (2.4%)

Diarrhea

9 (5.5%)

3 (2.4%)

Hyperhidrosis

11 (6.7%)

8 (6.5%)

* Doses: 0.075, 0.15, and 0.30 mg/kg/dose The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1.2%) and placebo (2.4%). Postmarketing Experience In addition to adverse events reported from clinical trials, the following adverse events have been identified during post-approval use of RELISTOR. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to RELISTOR, or a combination of these factors. Gastrointestinal Cramping, perforation, vomiting General Disorders and Administrative Site Disorders Diaphoresis, flushing, malaise, pain DRUG INTERACTIONS Drugs Metabolized by Cytochrome P450 Isozymes

In in vitro drug metabolism studies methylnaltrexone bromide did not significantly inhibit the activity of cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 or CYP3A4, while it is a weak inhibitor of CYP2D6. In a clinical drug interaction study in healthy adult male subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone bromide did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. Drugs Renally Excreted The potential for drug interactions between methylnaltrexone bromide and drugs that are actively secreted by the kidney has not been investigated in humans. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies have been performed in pregnant rats at intravenous doses up to about 14 times the recommended maximum human subcutaneous dose of 0.3 mg/kg based on the body

surface area and in pregnant rabbits at intravenous doses up to about 17 times the recommended maximum human subcutaneous dose based on the body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to methylnaltrexone bromide. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, methylnaltrexone bromide should be used during pregnancy only if clearly needed. Labor and Delivery Effects of RELISTOR on mother, fetus, duration of labor, and delivery are unknown. There were no effects on the mother, labor, delivery, or on offspring survival and growth in rats following subcutaneous injection of methylnaltrexone bromide at dosages up to 25 mg/kg/day. Nursing Mothers Results from an animal study using [3H]-labeled methylnaltrexone bromide indicate that methylnaltrexone bromide is excreted via the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELISTOR is administered to a nursing woman. Pediatric Use Safety and efficacy have not been established in pediatric patients. Geriatric Use In the phase 2 and 3 double-blind studies, a total of 77 (24%) patients aged 65-74 years (54 methylnaltrexone bromide, 23 placebo) and a total of 100 (31.2%) patients aged 75 years or older (61 methylnaltrexone bromide, 39 placebo) were enrolled. There was no difference in the efficacy or safety profile of these elderly patients when compared to younger patients. Therefore, no dose adjustment is recommended based on age. Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault). No studies were performed in patients with end-stage renal impairment requiring dialysis. Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of methylnaltrexone bromide has not been studied.

www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1 800-508-0024 Š2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. REL REL 13/22 13/02


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