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The IndependEnt Monthly Newspaper for pain management PainMedicineNews.com • October 2011 • Volume 9 Number 10

PRIMARY CARE

Study: Two-day Discharge After Arthroplasty Feasible Toronto—A multidisciplinary program implemented two years ago in an Ontario hospital allows patients to be discharged from an ambulatory hospital two days after primary hip- or kneereplacement surgery. Physicians at the Kingston General Hospital associated with Queen’s University implemented the fast-track arthroplasty program in 2009 at Hotel Dieu Hospital, the local ambulatory care center. They recently compared patients’ discharge times and outcomes before and after implementation of the program and found that patients’ average length of stay was reduced from 116 to 47 hours. Key components of the program include early patient education and discharge planning,

Landmark WHO Headache Report Finds Enormous Impact, Major Gaps In Understanding

ndividuals who experience migraine headaches lose 1.3% of their lives to disability, according to the World Health Organization’s (WHO) first global atlas on headaches. “Lifting the Burden: Atlas of Headache Disorders and Resources in the World 2011” is full of such details on the prevalence and impact of headache around the world, painstakingly chronicling its personal and societal effects. Yet, the report is also as detailed when it comes to documenting the worldwide failure to adequately diagnose, treat and manage headache. The WHO report is primarily based on survey responses received from neurologists, primary care physicians and patients from 101 countries between October 2006 and March 2009, epidemiologic data from published reports and population-based studies. Its exhaustive nature lends support to the authors’ ultimate assessment that

see WHO page 20

see Two-Day page 15

HMO Initiative Targets Opioid Overprescribing

Interventional Pain Medicine 12 | RF Neurotomy Possible Treatment for Degenerative Spondylolisthesis

A progressive approach to managing opioid misuse in noncancer patients

n the scramble to contain an epidemic of opioid misuse and overprescribing, one HMO is taking what a former federal prosecutor is calling a “highly progressive approach” to address the problem. Group Health, in Seattle, providing health care to more than 600,000 people in Washington and

Idaho, is asking its primary care physicians to closely track the expectations and outcomes of those patients receiving opioids for chronic noncancer pain. The objective is for physicians and patients to have empirical evidence of the benefits or failures of treatment. see HMO page 46

BOOK PAGE Essentials of Pain Management

Clinical Pain Medicine 28 | Williams’ Diagnosis Shines Light on Exhausting Rheumatic Disease 33 | Platelet-rich Plasma Confers Only Slightly More Pain Relief Than Autologous Whole Blood for Chronic Tennis Elbow Policy & Management 44 | What Can IT Do for Your Growing Pain Practice?

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THE INDEPENDENT MONTHLY NEWSPAPER FOR PAIN MANAGEMENT PainMedicineNews.com • OCTOBER 2011 • Volume 9 Number 10

PRIMARY CARE

Study: Two-day Discharge After Arthroplasty Feasible

Most-read Articles From Sister Publications

Toronto—A multidisciplinary program implemented two years ago in an Ontario hospital allows patients to be discharged from an ambulatory hospital two days after primary hip- or kneereplacement surgery. Physicians at the Kingston General Hospital associated with Queen’s University implemented the fast-track arthroplasty program in 2009 at Hotel Dieu Hospital, the local ambulatory care center. They recently compared patients’ discharge times and outcomes before and after implementation of the program and found that patients’ average length of stay was reduced from 116 to 47 hours. Key components of the program include early patient education and discharge planning,

Landmark WHO Headache Report Finds Enormous Impact, Major Gaps In Understanding

see WHO page 20

see TWO-DAY page 18

INTERVENTIONAL PAIN MEDICINE 12 | RF Neurotomy Possible Treatment for Degenerative Spondylolisthesis

HMO Initiative Targets Opioid Overprescribing A progressive approach to managing opioid misuse in noncancer patients

CLINICAL PAIN MEDICINE 28 | Williams’ Diagnosis Shines Light on Exhausting Rheumatic Disease 33 | Platelet-rich Plasma Confers Only Slightly More Pain Relief Than Autologous Whole Blood for Chronic Tennis Elbow POLICY & MANAGEMENT 44 | What Can IT Do for Your Growing Pain Practice? BOOK PAGE Essentials of Pain Management see page 43

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There is

concern

1. Switching Opioids: The Impact of Drug-Drug Interactions (Part 1 of a 4-Part From the Bench to the Bedside Series) 2. Pain Physicians Find Key to Successful Treatment of Chronic Pelvic Pain 3. In Tough Financial Times, Pain Clinic Reinvents Itself 4. Large Study: Frequent Nausea Worsens Migraine Severity 5. New IOM Report Lays Out Plan for Improving Pain Care

widespread about these

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expense.

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Pain Medicine News is an independent clinical newspaper that circulates to 48,134 physicians in the 12 specialties that most commonly treat patients in pain: pain manage ment, pain medicine, family practice, general practice, internal medicine, neurology, oncology, orthopedics, palliative care, physical medicine and rehabilitation and rheumatology. It is also distributed monthly to 44,832 anesthesiologists as a dedicated section within McMahon Publishing‘s No. 1–read clinical newspaper, Anesthesiology News. The editors of Pain Medicine News attend more than 15 conferences every year in these specialties and publish reports on the scientifically sound, clinically relevant findings presented there. Pain Medicine News includes reports on medications, devices and techniques for treating, managing and caring for patients in pain. It also includes CME activities, as well as educational articles on legal and compliance issues relating to the prescribing of medications and on business and money management relating to your practice.

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Physicians in the United States who treat pain as a major part of their practice may qualify to receive Pain Medicine News free of charge. If you would like to receive the publication,please email or fax a note requesting to be added to our circulation. To change your address, please include your old address—with your old mailing label if possible—along with the new address. Please sign and date your request (Post Office requirement), and send to: Circulation Coordinator, Pain Medicine News, 545 W. 45th St., 8th Floor, New York, NY 10036; fax: (212) 664-1242; email: circulation@mcmahonmed.com If you are not a physician who treats pain and would like to subscribe, please send a check payable to Pain Medicine News. Please allow 8-12 weeks for the first issue. Subscription, $70.00 per year (outside U.S., $90.00). Single copies, $7.00 (outside U.S., $10.00). McMahon Publishing, Sales, Production and Editorial Offices: 545 W. 45th St., 8th Floor, New York, NY 10036. Tel. (212) 957-5300 POSTMASTER: Please send address changes to Pain Medicine News, 545 W. 45th St., 8th Floor, New York, NY 10036 Copyright © 2011 McMahon Publishing, New York, NY. All rights reserved. Pain Medicine News, ISSN 1942-1419, is published monthly by McMahon Publishing, 545 W. 45th St., New York, NY 10036. Postmaster: send address changes to McMahon Publishing, 545 W. 45th St., 8th Floor, New York, NY 10036

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I n Brief

Utah—When it comes to fighting opioid abuse, all states can learn from Utah. The Utah Department of Health recently presented data showing a dramatic reduction in deaths from unintentional overdoses of prescription pain pills, from 326 in 2007 to 236 in 2010. The decline can be attributed to a campaign initiated by state health officials in 2007 that educates doctors and patients about the dangers of misusing pain pills. The statewide initiative included radio and TV spots urging the public to take their drugs as prescribed and physician training sessions on best prescribing practices, including starting patients on smaller doses and avoiding long-acting drugs for acute pain. About 50% of the 600 physicians who attended the session said they changed their practices based on the training. Currently, the Utah Pharmaceutical Drug Crime Project has about $1 million to continue the campaign through 2012. Additionally, recent bills passed in the state legislature tackle the problem using several tactics, including maintaining a database so physicians can determine which patients are at high risk for misusing pain medications.

Massachusetts—A statewide Department of Public Health program that distributes naloxone (Narcan) spray to drug addicts celebrated its 1,000 saved life in June. The program went statewide in 2007 after a test run in Boston saw opioid- and heroine-related deaths in the city drop 32% in one year. It is, according to state officials, in large part responsible for a drop in prescription drug deaths in Massachusetts. After jumping from 6.2 deaths per 100,000 people to 17.1 per 100,000 in 2007, the state has seen the rate of deaths related to opioids and heroine overdose fall back down to 11.6 per 100,000.

Dallas—Last year it was all about Chicago Bears’ quarterback Jay Cutler’s inability to handle pain, opting out of a game that decided who was going to the Super Bowl. This year, pain thresholds are once again an issue in the National Football League. Dallas Cowboys’ quarterback Tony Romo was heralded for playing with a broken rib and punctured lung while bringing his team back from behind to beat the San Francisco 49ers. Cowboy’s owner Jerry Jones said his QB’s status for the next game depended on a phrase seen often in the pages of this magazine, but rarely glimpsed in the sports section: pain management. “It has everything to do with just his ability to handle the pain,” said Mr. Jones, “ and we know he has a bunch of it.”

New Drug Application Filed for Qutenza 8% Patch To Treat HIV-PN

eurogesX, Inc., a biopharmaceutical company that develops novel pain management therapies, submitted a supplemental New Drug Application (sNDA) to the FDA last month, requesting to expand the label for Qutenza 8% patch to treat HIV-associated peripheral neuropathy (HIV-PN). HIV-PN is the most common neurologic complication of HIV infection; patients with HIV experience symptoms ranging from mild tingling to severe, excruciating pain. The sNDA seeks approval for a 30-minute application of Qutenza HIV-PN. Qutenza has already been approved by the FDA as a 60-minute application for the management of neuropathic pain associated with postherpetic neuralgia, as well as by the European Commission to treat peripheral neuropathic pain in nondiabetic adults alone or in combination with other medicinal products for pain.

As part of the new application, NeurogesX has requested a Priority Review designation. FDA Priority Review status is given to drug candidates that offer major advances in treatment or that provide a treatment option where no adequate therapy exists, and accelerates the standard review time from 10 to six months. “An approval for this indication would be particularly meaningful as the treatment of HIV-PN represents a significant unmet medical need in the HIV community,” Anthony DiTonno, president and CEO of NeurogesX, said in a statement. “Currently, no FDA approved drugs are available to treat this complication. Additionally, as Qutenza is a topical treatment with minimal systemic absorption, it is expected to have minimal risk of drug–drug interactions, a feature that is particularly important in this patient population.” —Based on a press release from NeurogesX

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I n Brief FDA Rejects Gout Pain Drug Application

he gout treatment armamentarium will not be gaining a new pain agent, following the FDA’s denial of canakinumab (Ilaris, Novartis), a monoclonal antibody that had been under consideration as a treatment for gouty arthritis in refractory patients. Novartis was informed by the FDA that in order for the drug to be considered as a gout therapy in the future, further data in refractory patients will be needed. Although canakinumab showed efficacy in its clinical trials, specifically by reducing gout attacks and curbing pain, the FDA ultimately was troubled by what it believed to be an unacceptably high rate of serious infections (1.9%). The company had initially sought a rheumatoid arthritis indication for canakinumab in addition to approval for gout, but dropped that indication following a negative vote by an FDA advisory committee early in the summer. The drug is already indicated for familial cold auto-inflammatory syndrome and cryoprinassociated period syndrome (i.e., MuckleWells syndrome).

It is not known when Novartis will provide the additional data to the FDA, or specifically what was being requested. In June, the FDA advisory committee

voted against approving the drug for gout pain due to the infection concerns, a problem not seen with other approved gout agents. In addition to the increased risk for serious infections seen in the trials, the committee also voiced concern that the drug was studied for only 12 weeks in its two largest trials. Despite the safety issues, the clinical studies showed canakinumab reduced gout pain in most patients, as well as the chances that they would experience another gout attack in the coming months. “We have not met the burden of proof showing that this is a safe drug for that patient population,” Kathleen O’Neil, MD, associate professor of pediatrics at the University of Oklahoma College of Medicine, Oklahoma City, and the panel’s chair, said at the time of the June committee vote. David Felson, MD, professor of medicine at Boston University and a member of the advisory panel, further noted in June that because Ilaris suppresses the immune system, patients may be at an even greater risk for infection as they take more doses. The researchers also did not test canakinumab in older patients or in those with renal failure. The studies further showed that the drug elevates uric acid and some forms of cholesterol. No drugs had been approved for gout for nearly 40 years until the FDA gave approval to two uric acid–lowering agents in the last few years, febuxostat (Uloric,Takeda) and Krystexxa (pegloticase, Savient). —PMN Staff

The following comments address the article “New IOM Report Lays Out Plan for Improving Pain Care (Pain Medicine News August 2011 page 1). he IOM [Ins T misguided and mistaken. The report fails to call for much needed accountability for medicine’s longstanding failure

American Pain Foundation Launches Social Media Campaign

he American Pain Foundation (APF) has announced the launch of the “If I Lived in a World with Less Pain, I Could…” social media campaign. The campaign will highlight the scope of the problem of managing pain, and the need for effective and timely pain care for all. APF encourages those who are affected by pain to virtually attend the online event on APF’s Facebook event page and submit a video, photo or written response to what they could do if they lived in a world with less pain.

“Pain is a horrible state of existence that we have a moral obligation to address,” said Will Rowe, chief executive officer of APF. “ ‘If I Lived in a World with Less Pain, I Could…’ is just one way APF stands committed to embracing the Institute of Medicine’s blueprint for action in relieving pain in America and taking an active role in ensuring that a cultural transformation on pain becomes a reality. The campaign not only unites people affected by pain, but provides a platform for our voices to be heard.” The campaign ends on Dec. 31 at midnight To learn more about the “If I Lived in a World with Less Pain, I Could…” campaign, visit www.painfoundation.org. —Based on a press release from American Pain Foundation

titute of Medicine] report to “transform” pain care is

SAID ON THE WEB

to adequately assess and treat pain. … his article is the first I have seen Comment on these and other articles online It is regrettable that the IOM doesn’t want its colthat had concrete suggestions @ PainMedicineNews.com. leagues in medicine to be held accountable for the pain toward better pain care. It is my care they provide. It is clear … that the IOM thinks sugbelief that education of our primary care gesting improvements in pain care will somehow make a difference. physicians is the most important issue. But, of course its previous report, “Crossing the Quality Chasm,”—which Most family physicians are not well versed in pain management and there[addressed] pain control—seemingly has done nothing to improve pain fore nearly always choose the side of caution when prescribing or intervencare. The IOM report is rife with underpowered suggestions that, for the ing in acute pain issues—therefore allowing many to become chronic pain most part, repeat the failed suggestions of the past. … Only when medi- issues. cine is required by law to deliver a high standard of pain care are we likely As far as other interventional treatments, the cost of most of these is outto see real improvement. Perhaps the IOM—like others in medicine—pre- rageous—not to mention that many insurance carriers will not approve fers to engage in wishful thinking rather than create … a new day for peo- most of the options now available. There needs to be much more research ple in pain. on the psychological issues that chronic pain patients face. bdavi...

hope@...

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I n Brief

Janssen Adds Online Tools to PrescribeResponsibly.com

o assist health care professionals in managing their patients’ pain, Janssen Pharmaceuticals has launched several new resources and tools on prescriberesponsibly.com, an online program designed to support appropriate and responsible treatment of pain. Introduced in early 2010, PrescribeResponsibly.com and its many educational materials have been viewed by thousands of physicians and pharmacists, both via its Web site and at medical conferences. “The tools and content offered on PrescribeResponsibly.com may help physicians better understand how to strike the challenging balance between safeguarding patients and ensuring they have the care they need,” said Steven Passik, PhD, professor of psychiatry and anesthesiology at Vanderbilt University Medical Center in Nashville, Tenn. “It is important to ensure that issues often associated with opioid pain medicines, including abuse, addiction, misuse and diversion, do not prevent patients who need relief from having access to appropriate pain treatment.”

Now you can follow Pain Medicine News on

@painmednews

Clinical materials newly added to the site include a variety of pain and risk assessments intended to help physicians evaluate pain, manage adverse events, identify aberrant drug-related behaviors, monitor long-term therapy, facilitate patient education and communication and document treatment

progress when using opioid therapies. Also featured is general education content authored by experts related to safe

and responsible opioid prescribing and pain management. —Based on a press release from Janssen. Dr. Passik is a consultant to Janssen Pharmaceuticals, and received compensation for his prior contributions to PrescribeResponsibly.com.

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I n Brief

FDA Rejects Zelrix Patch for Migraine

he FDA has issued a negative complete response letter to NuPathe Inc. for the company’s transdermal sumatriptan migraine patch (Zelrix). The rejection of the New Drug Application was based on the FDA’s belief that the company provided insufficient data to support a migraine indication. The concerns are believed to

be related to the safety of the singleuse patch, based on questions the FDA had regarding sumatriptan’s chemical make-up and manufacturing. NuPathe stated in a press release that it will soon be able to provide the FDA with the additional information it is requesting, and may conduct additional studies as well. Sumatriptan was developed and

initially marketed as Imitrex by GlaxoSmithKline, helping to usher in the triptan class of migraine treatments. Imitrex is now off patent. In addition to showing sumatriptan’s efficacy (50% of subjects were pain-free at two hours, with 24% of patients reporting no headache at study’s end) the Phase III trial supporting the transdermal patch’s FDA

approval application showed that 70% of subjects reported no nausea, a common adverse event seen with oral triptans. Long-term safety data (one year, with use of one to six patches in any 30-day period) also has been reported, with most adverse events being mild to moderate and transient in nature. —PMN Staff

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I n Brief

U.S. Physicians’ Offices Pay Dearly for Insurance Paperwork

hysicians in the United States spend an average of $61,000 more per year on administrative expenses involving health insurance than their Canadian counterparts, a new study has found. Researchers at Cornell University and the University of Toronto, in Ontario, Canada, and colleagues found that administrative costs—such as dealing with insurance companies on claims and payment issues—in the United States averaged nearly $83,000 per doctor, compared with $22,000 north of

the border. In all, such expenditures tally $27 billion per year more in the United States than in Canada, a result of that country’s more streamlined single-payer health care system, the researchers said. Although U.S. physicians spend money interacting with health insurers, their staffs bear the brunt of the time drain, according to the study. Nurses and medical practice staff in the United States spend an average of 20.6 hours each week per physician handling insurance issues. In Canada, the figure is 2.5 hours.

Canadians spend nearly half what Americans spend per capita on health care: $3,895 versus $7,290, respectively. A report on the findings appeared in the August issue of Health Affairs. —PMN Staff

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I n Brief FDA Approves First Drug-Releasing Implant for Chronic Sinusitis

he FDA has approved Intersect ENT’s Premarket Approval application for the Propel mometasone

furoate implant offering localized, controlled drug delivery for patients with chronic sinusitis. Chronic sinusitis is a condition in which patients’ sinuses become swollen and inflamed, leading to difficulty breathing, facial pain or headache and reduced sense of smell and taste. The condition is common, affecting one in seven adults in the United States. Inserted by a physician following endoscopic sinus

surgery, the springlike implant expands to prop open the sinus and gradually delivers an advanced corticosteroid with anti-inflammatory properties directly to the sinus lining to maintain sinus patency. For more information, go to www.intersectent.com.

—Based on a press release from

Intersect ENT.

Live Poll Results Below are the results of the

PainMedicineNews.com June Live Poll.

Log on to www.PainMedicineNews.com to answer this month’s question and find out the up-to-the-minute results instantly. Do you think the negative attention the state of Florida has gotten for its pain clinics is justified? Yes 62% No

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14%

Results do not reach statistical validity.

FDA Grants Nucynta New Indication

he FDA has approved an extended-release (ER) formulation of tapentadol, Nucynta ER (Janssen Pharmaceuticals), for moderate to severe chronic pain. This is the second indication given to the oral µ-opioid agonist. Nucynta, a centrally acting synthetic agent, was previously approved for the treatment of acute pain. The ER formulation is taken twice daily when 24-hour pain relief is needed for extended periods. A risk evaluation and mitigation strategy (REMS) was requested and subsequently developed by Janssen for Nucynta, which is a Schedule II drug. The most common adverse reactions that may occur in patients taking Nucynta are nausea, constipation, headache, dizziness and somnolence. Respiratory depression is a risk associated with the entire class of µ-opioid agonists. This class of drugs also can raise cerebrospinal fluid pressure, and thus should not be used in patients with head injuries or increased intracranial pressure. Nucynta is contraindicated within 14 days of use of monoamine oxidase inhibitors. Life-threatening serotonin syndrome has been reported in patients concomitantly taking Nucynta and serotoninergic drugs. For complete product information, go to www.nucynta.com.

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I n ter v entional Pai n Medici n e

Cervical and Lumbar Medial Branch Radiofrequency Neurotomy Produced Pain Relief Chicago—More than half of patients treated with radiofrequency neur otomy (RFN) for back pain and more than two-thirds treated with RFN for neck pain experienced complete pain relief for at least six months, according to a study presented at the International Spine Intervention Society’s 2011 Annual Scientific Meeting. The series comprised 210 consecutive patients treated between June 2004 and December 2009 at two clinics in New Zealand. The clinicians used strict criteria for identifying pain relief: In addition to experiencing complete relief from pain, patients had to be able to complete all routine activities of daily living and return to work, and could not use analgesic medications or other health care. “The success criteria was overly strict, but the data corroborate what I see in my own clinic practice. It bolsters the fact that these procedures work in correctly selected patients and should be available for patients,” said Manoj Bobby Wunnava, MD, assistant professor of anesthesiology at the University of North Carolina School of Medicine, Chapel Hill. Lead investigator John MacVicar, MB ChB, said the outcomes are consistent with the results from benchmark studies on cervical and lumbar

RFN and the study used the same techniques. “Our results show what can be achieved if patients are correctly selected and the correct technique is assiduously followed,” said Dr. MacVicar, medical director of the Southern Rehabilitation Institute, Christchurch, New Zealand. “RF neurotomy is a precise technique and patients must first have complete relief from initial and confirmatory medialbranch blocks. Success is also dependent on the use of larger-gauge needles and placing the electrode in a correct anatomical position, parallel to the nerves being treated.” Dr. MacVicar added that “carrying out additional confirmatory diagnostic blocks does take extra time and performing radiofrequency neurotomy in an anatomically accurate fashion is more time-consuming than other methods that are used, but the extra effort is well worth it when the result is better outcomes for the patients.” In the study, Dr. MacVicar and his co-investigator James Borowczyk, MB ChB, compared patient outcomes from their two practices: practice A and practice B. Overall, the outcomes at the two practices were statistically similar. The investigators found that 56% of patients achieved complete relief of back pain and 68% had complete relief

of neck pain for at least six months. The vast majority of patients were treated at the L3/4, L4/5, C2/3 or C5/6 levels. The median numerical pain rating (scale, 0-100) prior to treatment was 60 in practice A and 50 to 55 in practice B. The median duration of relief from a first procedure for cervical pain was 17 months in practice A and 20 months in practice B. With respect to lumbar pain, the median duration of relief from the first procedure was 15 months in each practice. When adding repeat treatments, the median duration of relief was 15 months (cervical) and 13 months (lumbar) in both practices, with ongoing relief in more than 60% of patients. The bulk of patients who did not benefit from RFN experienced no relief, Dr. MacVicar reported. “This latter finding was the most remarkable to me, as I expected a larger number of patients in the ‘unsuccessful’ group to have at least partial results,” noted Dr. Wunnava. “Yet it seems that the nonresponders, for the most part, were true nonresponders in that they did not have any result from the radiofrequency procedure. This speaks to the effectiveness of the criteria for defining treatment success.” —Rosemary Frei, MSc Drs. MacVicar and Wunnava did not report any relevant conflicts of interest.

RF Neurotomy Possible Treatment For Degenerative Spondylolisthesis Chicago—A chart review of radiofrequency neurotomy (RFN) procedures performed on patients with low back pain associated with degenerative spondylolisthesis shows this approach may be useful as adjunctive therapy. Investigator Stephan Klessinger, MD, of the Nova Clinic, Biberach, Baden-Württemberg, Germany, looked at 67 patients with degenerative spondylolisthesis confirmed by magnetic resonance imaging (MRI), which he had treated with RFN. Patients had a mean follow-up time of 7.1 months, and the 67 consecutive patients ranged in age from 40 to 89 years. None had neurologic deficits or a history of lumbar surgery; 42 were Meyerding grade 1 and 25 were Meyerding grade 2. The level of the spondylolisthesis was L3/4 in eight patients, L4/5 in 38 and L5/S1 in 21. The results showed that 43 patients experienced an average pain reduction of more than 50% for at least three months; the mean duration of pain relief was 7.1 months (range, 2-42 months).

The results showed that 43 of 67 patients experienced an average pain reduction of more than 50% for at least three months; the mean duration of pain relief was 7.1 months.

‘The extra effort is well worth it when the result is better outcomes for the patients.’ —John MacVicar, MB ChB

Dr. Klessinger concluded that although the results are “not very good, they show that radiofrequency neurotomy might be useful as an additional therapy in patients with back pain and spondylolisthesis.” He noted, however, that not all patients would benefit from the technique. For example, a patient with spondylolisthesis and high-grade spinal canal stenosis “will have more problems because of the stenosis and is, therefore, not an ideal candidate for radiofrequency,” he said. Additionally, patients with mild degenerative spondylolisthesis and no spinal canal stenosis but Modic changes on MRI also are not good candidates for RFN because it may provide “an additional pain source,” explained Dr. Klessinger. To determine whether patients are suitable candidates for RFN, Dr. Klessinger performs a controlled medial branch block. The results were presented at the 2011 annual meeting of the International Spine Intervention Society. —Rosemary Frei, MSc Dr. Klessinger reported no relevant conflicts of interest.

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PainMedicineNews.com I 13

In ter ve n tio n al Pain Medici n e

Bioengineered Spinal Disk Implants Relieve Neck Pain and Backache

egenerating disks in the spine, which can cause intense pain, may soon be replaced by bioengineered disk implants, according to research published online Aug. 1 in the Proceedings of the National Academy of Sciences. Researchers from Cornell University in Ithaca, N.Y., and Weill Cornell Medical College in New York City, have created a biologically based spinal implant that allows as much movement as normal disks and could relieve the persistent pain from neck and backaches. “We’ve engineered disks that have the same structural components and behave just like real disks,” said Lawrence Bonassar, PhD, associate professor of biomedical engineering and mechanical engineering at Weill Cornell. However, the bioengineered spinal disks have been tested only in rats. “The hope is that this promising research will lead to engineered disks that we can implant into [human] patients with damaged disks,” he added.

Currently, patients with degenerative disks are treated with painkillers, physical therapy and steroid injections. Those diagnosed with severe degenerative disk disease often undergo a diskectomy, in which the affected spinal disk is removed and the vertebrate bones are fused. This treatment, however, limits patients’ flexibility.

The researchers found that the bioengineered disk provided as much cushioning space between spinal vertebrae as a natural disk. To provide better options for patients with degenerative disk disease, Dr. Bonassar’s team engineered artificial disks out of two polymers—collagen, which provides structural stability, and a hydrogel called alginate, which fills in the middle.

The researchers seeded the implants with cells from a rat’s spine to repopulate the structures with new tissue. For two weeks, they let the cells grow around the scaffold, creating a living disk, and then surgically replaced a spinal disk in a rat’s tail with the new implant. The researchers found that the bioengineered disk provided as much cushioning space between spinal vertebrae as a natural disk. As opposed to current artificial implants, which degrade over time, the new implants actually functioned better as they matured in the body over the six-month experimental period. “The implant allowed the spine to bear as much weight and move as freely as a normal disk,” the researchers noted. Additionally, over time, cells from the implant started growing outward into the rest of the spine, integrating into the normal tissue. From a biological perspective, the new disks could create a “huge advantage” over traditional implants because of the way in which they integrate and mature with the vertebrae. This major surgery would become less invasive and safer, and would come with fewer long-term side effects. —Victoria Stern

Epidural Placement Enhanced With Simple Equation, Ultrasound

simple equation that uses a patient’s height and weight to estimate the distance from the skin to the epidural space appears to work when applied to some of the most challenging patients, the morbidly obese. The study was presented at the 2011 annual meeting of the Society for Obstetric Anesthesia and Perinatology (abstract 30).

Manuel C. Vallejo, MD

Trainees used a combination of the technique plus ultrasound to estimate the epidural space in 56 morbidly obese women, and achieved good accuracy (Pearson correlation coefficient [CC], >0.85). The equation comes with a chart similar to that used to estimate body mass index (BMI); trainees simply plug in the height and weight of the patient, and the chart predicts the approximate distance from the skin to the epidural space.

“The equation works pretty well for our population,” said study author Manuel C. Vallejo, MD, professor and director of obstetric anesthesia at Magee-Womens Hospital of University of Pittsburgh Medical Center. He keeps an index card version of the chart and gives it to all residents when they are attempting to insert an epidural. “It gives you an estimation of where you want to be,” Dr. Vallejo said. “And, I feel a lot better when residents use it.” Ultrasound helps find the epidural space, he added, but in overweight and obese patients—who make up nearly 70% of the U.S. population— the image will reveal mostly fatty tissue. In these patients, it also is difficult to find normal anatomic landmarks, such as the hips and spinous processes. Indeed, research has shown that morbid obesity (BMI ≥40 kg/m2) is associated with an increased failure rate of up to 5% for epidurals. Previously, Dr. Vallejo and his colleagues tested the equation on normalweight women in labor and found that it predicted the distance from the skin to the epidural space with high accuracy (Pearson CC, 0.91). “Anything above 0.81 is considered a high correlation,” he said. His team also has shown that using ultrasound helps trainees reduce their rate of failed epidural placements.

Given the utility of both tools, the investigators decided to combine them into one technique. “If the ultrasound reveals a lot of fatty tissue, the equation helps trainees know where to look for the epidural space in that image,” Dr. Vallejo said. To investigate, he and his colleagues asked trainees to use the equation to calculate the distance from the skin to the epidural space in 56 morbidly obese women; the trainees then combined the technique with ultrasound for transverse and longitudinal views. An experienced anesthesiologist trained in using ultrasound then measured the actual distance to the epidural space. Dr. Vallejo found that the equation used in conjunction with ultrasound resulted in a Pearson CC greater than 0.85. The epidural distance equation used alone was less predictive (CC, 0.59). Trainees using the combined technique of equation and ultrasound located the space in morbidly obese patients after a median of two attempts, with no accidental dural punctures. It is not unusual that multiple attempts are necessary in a morbidly obese patient, Dr. Vallejo said, simply because it is so difficult to estimate the distance to the epidural space. “I think that the equation—especially if you’re just learning—in conjunction with ultrasound would be much

better than ultrasound, especially in the morbidly obese.” “I think this is a good study,” said Jose Carvalho, MD, PhD, director of obstetric anesthesia at Mount Sinai Hospital, in Toronto, Canada. At his facility, clinicians use ultrasound to measure the epidural space in all patients, especially obese women. “We never do it without ultrasound,” he said. However, Dr. Carvalho questioned whether the equation presented by Dr. Vallejo’s team adds much to the accuracy. A Pearson CC of 0.59 for the equation alone is not very impressive, he said. And, he added, a CC does not tell the whole story, such as the size of the limits of agreement. It is difficult to find a formula that works in obese women because fat distribution can vary, Dr. Carvalho said. Some patients with a high BMI may not have much back fat, and vice versa. So, an equation based solely on anthropometric variables, such as height and weight, will not be equally useful for all patients. He suggested that clinicians focus training on the most useful technique, ultrasound. “I think the only way to determine epidural depth is ultrasound,” Dr. Carvalho said. “That is the only method; equations will never be the answer.” —Alison McCook

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Adding Gabapentin Does Not Decrease Post-op Pain From Total Knee Replacement But other studies have shown the opposite Toronto—Gabapentin does not decrease pain perform more than 700 TKAs. before and after patients undergo primary total knee Patients were excluded if they arthroplasty (TKA), according to a new study. had a range of conditions, Results from the study showed no statistically sig- including chronic pain or nificant differences after surgery in postoperative allergy or intolerance to nonmorphine use, pain scores or hospital length of stay steroidal anti-inflammatory between patients randomized to gabapentin (Neuron- ‘If these patients are specifically tin, Pfizer) or placebo. studied, you’d probably see The results of the current study stand in contrast significantly better outcomes with to an earlier meta-analydrugs like gabapentin and pregabalin.’ sis conducted by the same —Naveen Elipe, MBBS, MD researchers, that looked at the effects of gabapentin after patients received a range of surgeries, from mastec- drugs, acetaminophen, morphine, tomy to laparoscopic cholecystectomy (Can J Anesth gabapentin or spinal anesthesia. 2006;53:461-469). In the meta-analysis, the invesPerioperatively, the patients tigators found gabapentin was associated with lower received the study medication postoperative pain scores and analgesia use. orally, either gabapentin 600 mg “Our new study shows that there is not a strong or placebo, as well as a standard indication for using gabapentin in total knee arthro- spinal anesthesia with hyperplasty, although it still may be useful in other patient baric bupivacaine combined populations,” said James E. Paul, MD, MSc, associate with fentanyl. Postoperatively, clinical professor and research chair in anesthesiol- the patients were given IV morogy, and director of the Acute Pain Service, McMas- phine for three days and gabapenter University, in Hamilton, Canada. “Perhaps in the tin 200 mg or placebo orally every context of multimodal analgesia, it has less incremen- eight hours. tal benefit.” The researchers found no sigIn the current study, 101 patients were randomized nificant differences between the to gabapentin (n=52) and placebo (n=49) before gabapentin and placebo groups in and after TKA. The study was conducted at Hender- morphine consumption after surgery. son General Hospital, in Hamilton, Canada, from They also did not find significant difMay 2008 to March 2010, where surgeons annually ferences in pain scores at rest, patient

satisfaction or hospital length of stay. The team reported a high incidence of nausea and vomiting in both treatment groups; however, the rate of mild to severe nausea or vomiting was significantly lower in the gabapentin group than in the placebo group (63% vs. 82%, respectively). The rate of moderate to severe pruritus also was significantly lower in the gabapentin group than the placebo group (0% vs. 12%, respectively). Naveen Eipe, MBBS, MD, who was not involved in the study, speculated that excluding chronic pain patients in the TKA study may have affected the results. “Gabapentinoids are very likely to improve pain management in patients undergoing surgery at a site of chronic pain,” said Dr. Eipe, staff anesthesiologist at The Ottawa Hospital and assistant professor at the University of Ottawa, Canada. “If these patients are specifically studied, you’d probably see significantly better outcomes with drugs like gabapentin and pregabalin [Lyrica, Pfizer].” —Rosemary Frei, MSc

Cervical Nucleoplasty Shines in Long-term Follow-up Of Radicular and Axial Pain Syndromes Chicago—The results of a new study indicate that cervical nucleoplasty significantly improves the long-term neurologic, symptomatic and disability characteristics of individuals with radicular and axial pain syndromes. A German team found that, at sixand eight-year follow-ups, disk decompression with cervical nucleoplasty yielded 72% good to excellent results among 460 patients, based on Neck Disability Index scores. Additionally, only 56 patients or 12% of the total, required reoperations; 29 occurred in the first year after the original procedure. “Nucleoplasty is a quick and safe

‘Data such as these should be carefully evaluated by thirdparty carriers like Wellpoint/Empire Blue Cross/Blue Shield and others that currently discriminate against percutaneous, minimally invasive spine procedures.’ —Lawrence Kamhi, MD

procedure of minimally invasive disk compression with excellent clinical results,” said lead investigator Sebastian Gitter, MD, of the Nova Clinic in Biberach, Germany. Lawrence Kamhi, MD, interventional pain physician at Beth Israel Hospital in New York City, noted that it is likely these results compare favorably with those of diskectomy and fusion, and that nucleoplasty has the additional advantage of being minimally invasive. “Postoperative recovery time should thus be shorter as well,” said Dr. Kamhi, who is actively pushing for more see Nucleoplasty page 18

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

Smallest Decline in Osteoporotic Hip Fracture Rates Seen in White Men London—For reasons that are not clear, the prevalence of hip fracture hospitalizations for individuals over age 55 years in a representative sample of U.S. community hospitals declined significantly in black and Hispanic men and women from 1998 to 2008. However, the decline was much less robust in whites, especially white men. These findings of a retrospective, population-based study were presented at the 2011 European Rheumatology Congress (EULAR). “The overall decline in osteoporotic hip fracture during the 10 years we studied may be due to better screening, education and early treatment of osteoporosis. But osteoporotic hip fractures are still a significant burden in the white population, with the prevalence in white men decreasing the least over the past 10 years,” said study co-author Gurkipal Singh, MD, professor of medicine, Stanford University, Palo Alto, Calif. “Further prevention methods are still needed to decrease the prevalence of hip fracture, especially in white men.” The authors previously published a study showing a significant decline in the prevalence of hip fractures in the United States from 1988 to 2005 (Ann Rheum Dis 2008;67:55). The present study sought to explore whether there were racial, ethnic or gender disparities in the decline in prevalence. The study sample included patients older than age 55 admitted

Two-Day continued from page 1

intraoperative local infiltrative analgesia and physiotherapy starting four to six hours after surgery. The clinicians select patients for the fast-track program based on criteria that have been shown in the literature to be associated with improved outcomes following lowerlimb total joint arthroplasty. “Our fast-track model is easily adoptable, requiring little investment in additional resources or the mastery of new technical skills,” said lead investigator Michael Raphael, fourth-year medical student at Queen’s University, during a poster presentation of the results at the Canadian Anesthesiologists’ Society’s 2011 annual meeting. “This will allow our program to be implemented outside of tertiary care specialty centers in almost any hospital setting.” “I will talk to my colleagues about this—I’m most interested because it reduces the length of stay and therefore can increase efficiency and the number of surgeries that are done,” said Michael Gallagher, MD, staff anesthesiologist with the Greater Niagara Hospital in Niagara Falls, Ontario, and former director of anesthesia for the Greater Niagara Health Authority, after viewing

2008, compared with women in other races, and white men had much higher prevalence rates compared with black and Hispanic men,” said Dr. Singh. “In fact, even after recent declines, the prevalence of hip fractures in white men was still higher in 2008 than that in both to the hospital with a primary diagnosis of hip frac- black and Hispanic men in 1998. White men also had ture entered in the Nationwide Inpatient Sample the lowest percentage decline over the 10 years com(NIS), which is a stratified random sample of U.S. pared with other races and ethnicities.” community hospitals. The study focused on 12 states “Clearly the significant decline in people over age in the NIS database that 55 of osteopoincluded race and ethnicity ‘The overall decline in osteoporotic hip rotic hip fracture information from 1998 to fracture during the 10 years we studied hospitalizations 2008. Population data were in the 10 years obtained from the U.S. may be due to better screening, education studied between Census Bureau. 1998 and 2008 and early treatment of osteoporosis. In the 12 states studis heartening, ied, 191,024 hospitaliza- But osteoporotic hip fractures are still a but osteoporotic tions for osteoporotic hip significant burden in the white population.’ fractures remain fracture were recorded in a source of sig—Gurkipal Singh, MD nificant morbidpeople aged 55 and older, for a prevalence of 750 per ity and mortality 100,000. In 2008, the number of these hospitaliza- in the United States,” said R. Elaine Lambert, MD, tions declined to 130,599—a prevalence of 414 per adjunct clinical professor of medicine, Stanford Uni100,000. The prevalence of hip fracture hospitaliza- versity School of Medicine. Dr. Lambert was not tions declined in blacks, Hispanics and whites, but involved in Dr. Singh’s study. the decline was less in white women, and even less “Additional study is needed to help identify the in white men. The percentage declines from 1998 to causes of the differences in rates of osteoporotic hip 2008 were as follows: black females 47%; black males fractures by gender and ethnicity,” Dr. Lambert said. 51%; Hispanic females 51%; Hispanic males 46%; “This data reflects the ongoing need for vigilance in white females 42%; white males 37%. screening and treating patients, both [white] men “In spite of significant declines, white women had and women, to prevent fracture complications.” significantly higher prevalence rates in 1998 and in —Alice Goodman

the research. “However, while it seems simple, there is a lot of work involved, including using people from many different health disciplines.” The eligibility criteria for the fasttrack program include age up to 85 years; an American Society of Anesthesiologists score no greater than 3 with no functional limitation due to cardiac or respiratory disease; a body mass index of 45 kg/m2 or less; independent mobility, a normal hematocrit; no history of rheumatoid arthritis; no history of pulmonary embolism or deep vein thrombosis within the previous six months, an absence of warfarin therapy unless atrial fibrillation is present; and having functional strength in the upper extremities. Patients also need to have stairs-free access to their home bedroom and bathroom, and have adult assistance available on return from the hospital. Eligible patients are provided with information about the program, including the details of the analgesia regimen, the rapid start of postoperative physiotherapy and the possibility of postoperative nausea and vomiting. Upon arrival at the hospital they are given 975 mg oral acetaminophen and, if they do not have any contraindications, 200 mg oral

celecoxib (Celebrex, Pfizer) and 25 mg oral pregabalin (Lyrica, Pfizer). The intraoperative analgesia is spinal anesthetic (9-13 mg bupivacaine and 100 mcg intrathecal morphine) and a periarticular injection mixed in 120 mL saline (300 mg ropivacaine [Naropin, APP] for most patients or 200 mg for those over age 80 or under 60 kg), 300 mcg epinephrine, 5 to 10 mg morphine in the absence of an allergy or sensitivity to it and 15 to 30 mg ketorolac in the absence of renal dysfunction. Incisions are infiltrated with a dilute solution of local anesthetic at the end of the operation. The first postoperative night patients receive IV patient-controlled anesthesia and then are transitioned to oral medications. They are started on physiotherapy within four to six hours of surgery. Patients also receive 650 mg oral acetaminophen every four hours for 24 hours, 200 mg oral celecoxib every 12 hours for 24 hours and 25 mg oral pregabalin every eight hours for 24 hours if opioids were used preoperatively, as well as 5,000 units of subcutaneous low-molecular-weight heparin for 14 to 28 days. One week postsurgery, the patients are contacted by phone; six weeks postsurgery, they have a follow-up

visit at the orthopedic clinic. Raphael and two physicians compared data from 100 patients treated at Hotel Dieu Hospital before program implementation with 100 patients treated with the fast-track program. The fast-track patients experienced significantly lower median rest and active pain scores and used significantly lower amounts of opioids. The fast-track patients also had a significantly shorter average length of stay, at 47 hours versus 116 hours, after adjustment for age, sex, body mass index, smoking, comorbidities and surgical procedure (P<0.05). The groups also had a similar number of postoperative emergency department visits (14 and 13, respectively). In the fast-track group, there was one readmission for postoperative hematoma and another for infection; in the standarddischarge group, there was one readmission for inadequate pain control. Seventy-nine of 82 patients (96%) contacted one week postoperatively said they had good overall surgical and hospital experiences Three reported moderate to severe pain; two of these patients were using low-dose oral opioids and the other was taking only nonsteroidal anti-inflammatory drugs. —Rosemary Frei, MSc

With LIDODERM® is indicated for relief of pain associated with post-herpetic neuralgia. Apply only to intact skin.

Start With LIDODERM® (lidocaine patch 5%) alone or with oral analgesics for your patients with PHN pain During a 2-week enriched-enrollment study, 84% of PHN patients had moderate to complete pain relief*1 t It is important to know that LIDODERM may take up to 2 weeks to achieve the best outcome2,3 LIDODERM can be used as a first-line therapy for PHN, either alone or with oral analgesics2

LIDODERM Started Working With One Dose LIDODERM demonstrated effective PHN pain relief with the first dose†4

During a 2-Week Study* (N=32) 84% of patients reported moderate to complete relief vs 28% for placebo (P<0.001)

84%

FELT MODERATE TO COMPLETE RELIEF OVER 2 WEEKS

During a 12-Hour Study† (N=35)

1 DOSE (up to 3 patches)

PROVIDED SIGNIFICANT RELIEF

OVER YEARS of USE

AT 30 MINUTES

AT 4-12 HOURS

Patients felt significant pain relief after first dose vs observation cohort (P=0.0001)

Significant reduction in pain intensity vs placebo (P<0.001 to P=0.038)

Choose LIDODERM With the Safety Profile in Mind LIDODERM has a favorable safety profile in PHN patients, when used appropriately1,2,4 Low risk of drug-drug interactions; in these clinical trials, patients used concomitant analgesics as needed (which included opiates, acetaminophen, NSAIDs, and tricyclic antidepressants)1,2,4 t Nonnarcotic, nonsedating, nonscheduled t May be used in patients who have comorbidities or are taking concomitant medications t During or immediately after LIDODERM treatment, the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritis, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours. Other reactions include dizziness, headache, and nausea References: 1. Galer BS, et al. Pain. 1999;80(3):533-538. 2. Lidoderm Prescribing Information. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2010. 3. Data on file, DOF-LD-02, Endo Pharmaceuticals Inc. 4. Rowbotham MC, et al. Pain. 1996;65(1):39-44.

Important Safety Information t LIDODERM is contraindicated in patients with a history of sensitivity to local anesthetics (amide type) or any product component. t Even a used LIDODERM (lidocaine patch 5%) patch contains a large amount of lidocaine (at least 665 mg). The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used LIDODERM patch, although the risk with this formulation has not been evaluated. It is important to store and dispose of LIDODERM out of the reach of children, pets, and others. t Excessive dosing, such as applying LIDODERM to larger areas or for longer than the recommended wearing time, could result in increased absorption of lidocaine and high blood concentrations leading to serious adverse effects. t Avoid contact of LIDODERM with the eye. If contact occurs, immediately wash the eye with water or saline and protect it until sensation returns. Avoid the use of external heat sources as this has not been evaluated and may increase plasma lidocaine levels. t Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine, because of their inability to metabolize lidocaine normally. LIDODERM should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic. LIDODERM should also be used with caution in pregnant (including labor and delivery) or nursing mothers. t Allergic reactions, although rare, can occur. t When LIDODERM is used concomitantly with local anesthetic products, the amount absorbed from all formulations must be considered. t Immediately discard used patches or remaining unused portions of cut patches in household trash in a manner that prevents accidental application or ingestion by children, pets, or others. Before prescribing LIDODERM, please refer to the accompanying brief summary of full Prescribing Information.

*Demonstrated over 14 days in a post hoc analysis of a randomized, enriched-enrollment, double-blind, placebo-controlled, crossover trial. Patients enrolled in the study had been using LIDODERM for ≥1 month (ie, enriched enrollment); mean age of 77.4 years and mean PHN duration of 7.3 years. Pain relief was measured using a 6-item verbal scale: 0 (worse), 1 (no relief), 2 (slight relief), 3 (moderate relief), 4 (a lot of relief), and 5 (complete relief). Patients exited the study if their verbal pain relief rating decreased >2 categories for any 2 consecutive days from baseline. *Results of enriched-enrollment studies can’t be generalized to the entire population; subjects in such studies may be able to distinguish the active drug from placebo based on nontherapeutic features of the treatments. A randomized, double-blind, placebo-controlled, 4-way crossover trial (N=35) assessed safety and efficacy of LIDODERM. Patients were allodynic with a mean age of 75 years and mean PHN duration of 48 months. Pain intensity was measured with a horizontal 100-mm Visual Analogue Scale: 0=no pain and 100=worst pain imaginable. Measurements were recorded before patch application, at 30 minutes, and at hours 1, 2, 4, 6, 9, and 12. Least-squares means were used as the best unbiased estimate of the patients’ mean values.

†

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I n ter v entional Pai n Medici n e Nucleoplasty continued from page 14

coverage of interventional pain procedures by insurance companies. “Data such as these should be carefully evaluated by third-party carriers like Wellpoint/Empire Blue Cross/Blue Shield and others that currently discriminate against percutaneous, minimally invasive spine procedures.” Cervical nucleoplasty is one of a small number of procedures for

cervical radiculopathies or chronic neck pain that constitute a middle ground between cervical epidural injection and open anterior diskectomy and fusion surgery, according to Dr. Kamhi. A team led by Dr. Gitter treated its first patient with cervical nucleoplasty in July 2000; approximately 90,000 patients worldwide have been treated with the procedure to date. The German group uses the technique on patients with radicular or

axial pain with central focal and lateral herniation. The group selects individuals whose arm pain is greater than their cervical-axial neck pain, with magnetic resonance imaging evidence of contained disk protrusion, disk height at least 50% and at least one failed selective nerve root block. The group does not treat patients with severe degenerative disk disease, spinal fracture or tumor, severe spinal stenosis or degenerative instability. Of the 460 cervical nucleoplasty

Nursing Mothers LIDODERM has not been studied in nursing mothers. Lidocaine is excreted in human milk, and the milk: plasma ratio of lidocaine is 0.4. Caution should be exercised when LIDODERM is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established.

LIDODERM® (Lidocaine Patch 5%) Brief Summary (For full Prescribing Information refer to package insert.) INDICATIONS AND USAGE LIDODERM is indicated for relief of pain associated with post-herpetic neuralgia. It should be applied only to intact skin. CONTRAINDICATIONS LIDODERM is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product. WARNINGS Accidental Exposure in Children Even a used LIDODERM patch contains a large amount of lidocaine (at least 665 mg). The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used LIDODERM patch, although the risk with this formulation has not been evaluated. It is important for patients to store and dispose of LIDODERM out of the reach of children, pets, and others. (See HANDLING AND DISPOSAL) Excessive Dosing Excessive dosing by applying LIDODERM to larger areas or for longer than the recommended wearing time could result in increased absorption of lidocaine and high blood concentrations, leading to serious adverse effects (see ADVERSE REACTIONS, Systemic Reactions). Lidocaine toxicity could be expected at lidocaine blood concentrations above 5 μg/mL. The blood concentration of lidocaine is determined by the rate of systemic absorption and elimination. Longer duration of application, application of more than the recommended number of patches, smaller patients, or impaired elimination may all contribute to increasing the blood concentration of lidocaine. With recommended dosing of LIDODERM, the average peak blood concentration is about 0.13 μg/mL, but concentrations higher than 0.25 μg/mL have been observed in some individuals. PRECAUTIONS General Hepatic Disease: Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine, because of their inability to metabolize lidocaine normally. Allergic Reactions: Patients allergic to para aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine. However, LIDODERM should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain. Non-intact Skin: Application to broken or inflamed skin, although not tested, may result in higher blood concentrations of lidocaine from increased absorption. LIDODERM is only recommended for use on intact skin. External Heat Sources: Placement of external heat sources, such as heating pads or electric blankets, over LIDODERM patches is not recommended as this has not been evaluated and may increase plasma lidocaine levels. Eye Exposure: The contact of LIDODERM with eyes, although not studied, should be avoided based on the findings of severe eye irritation with the use of similar products in animals. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns. Drug Interactions Antiarrhythmic Drugs: LIDODERM should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic. Local Anesthetics: When LIDODERM is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: A minor metabolite, 2, 6-xylidine, has been found to be carcinogenic in rats. The blood concentration of this metabolite is negligible following application of LIDODERM. Mutagenesis: Lidocaine HCl is not mutagenic in Salmonella/mammalian microsome test nor clastogenic in chromosome aberration assay with human lymphocytes and mouse micronucleus test. Impairment of Fertility: The effect of LIDODERM on fertility has not been studied. Pregnancy Teratogenic Effects: Pregnancy Category B. LIDODERM (lidocaine patch 5%) has not been studied in pregnancy. Reproduction studies with lidocaine have been performed in rats at doses up to 30 mg/kg subcutaneously and have revealed no evidence of harm to the fetus due to lidocaine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, LIDODERM should be used during pregnancy only if clearly needed. Labor and Delivery LIDODERM has not been studied in labor and delivery. Lidocaine is not contraindicated in labor and delivery. Should LIDODERM be used concomitantly with other products containing lidocaine, total doses contributed by all formulations must be considered.

ADVERSE REACTIONS Application Site Reactions During or immediately after treatment with LIDODERM (lidocaine patch 5%), the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours. Allergic Reactions Allergic and anaphylactoid reactions associated with lidocaine, although rare, can occur. They are characterized by angioedema, bronchospasm, dermatitis, dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria. If they occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. Other Adverse Events Due to the nature and limitation of spontaneous reports in postmarketing surveillance, causality has not been established for additional reported adverse events including: Asthenia, confusion, disorientation, dizziness, headache, hyperesthesia, hypoesthesia, lightheadedness, metallic taste, nausea, nervousness, pain exacerbated, paresthesia, somnolence, taste alteration, vomiting, visual disturbances such as blurred vision, flushing, tinnitus, and tremor. Systemic (Dose-Related) Reactions Systemic adverse reactions following appropriate use of LIDODERM are unlikely, due to the small dose absorbed (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Systemic adverse effects of lidocaine are similar in nature to those observed with other amide local anesthetic agents, including CNS excitation and/or depression (light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold, or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression, and arrest). Excitatory CNS reactions may be brief or not occur at all, in which case the first manifestation may be drowsiness merging into unconsciousness. Cardiovascular manifestations may include bradycardia, hypotension, and cardiovascular collapse leading to arrest. OVERDOSAGE Lidocaine overdose from cutaneous absorption is rare, but could occur. If there is any suspicion of lidocaine overdose (see ADVERSE REACTIONS, Systemic Reactions), drug blood concentration should be checked. The management of overdose includes close monitoring, supportive care, and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdose with lidocaine. In the absence of massive topical overdose or oral ingestion, evaluation of symptoms of toxicity should include consideration of other etiologies for the clinical effects, or overdosage from other sources of lidocaine or other local anesthetics. The oral LD50 of lidocaine HCl is 459 (346-773) mg/kg (as the salt) in nonfasted female rats and 214 (159-324) mg/kg (as the salt) in fasted female rats,which are equivalent to roughly 4000 mg and 2000 mg, respectively, in a 60 to 70 kg man based on the equivalent surface area dosage conversion factors between species. DOSAGE AND ADMINISTRATION Apply LIDODERM to intact skin to cover the most painful area. Apply up to three patches, only once for up to 12 hours within a 24-hour period. Patches may be cut into smaller sizes with scissors prior to removal of the release liner. (See HANDLING AND DISPOSAL) Clothing may be worn over the area of application. Smaller areas of treatment are recommended in a debilitated patient, or a patient with impaired elimination. If irritation or a burning sensation occurs during application, remove the patch (es) and do not reapply until the irritation subsides. When LIDODERM is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered. HANDLING AND DISPOSAL Hands should be washed after the handling of LIDODERM, and eye contact with LIDODERM should be avoided. Do not store patch outside the sealed envelope. Apply immediately after removal from the protective envelope. Fold used patches so that the adhesive side sticks to itself and safely discard used patches or pieces of cut patches where children and pets cannot get to them. LIDODERM should be kept out of the reach of children. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature]. Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 LIDODERM® is a Registered Trademark of Hind Health Care, Inc. © Endo Pharmaceuticals 2011 Rev. March 2010 6524-12 E1

procedures the group performed between July 2000 and July 2008, 317 were single-level and 143 were double-level. Forty-eight percent were at C5/6 levels, 44% were C6/7, 6% were C4/5 and 2% were C3/4. Overall, 58% of the patients were women, although 53% of patients aged 30 to 40 years were men. Of the patients, 162 (35%) had lowgrade weakness preoperatively. Of these cases, 76% experienced increased muscle strength within two months. Forty-eight patients (10%) had middlegrade weakness preoperatively; 51% of had increased muscle strength postprocedure. Seven patients (1.5%) had high-grade weakness; in none of the cases did the muscle strength increase postprocedure. Of the patients, 285 (62%) underwent a decrease in visual analog scale (VAS; 10 being the worst possible pain) score from 8 or 9 presurgery to 1 or 2 within three weeks of surgery. Seventy-five percent were completely pain-free immediately postoperatively, Dr. Gitter reported, and the remainder were pain-free within three weeks of the procedure. VAS scores of another 87 patients (19%) dropped from between 7 and 9 to 4 and 5 within 4 weeks of having the procedure, and to 1 and 2 within eight weeks. Many patients had occasional neck pain during heavy lifting and intermittent radicular paresthesias, although Dr. Gitter noted that the paresthesias were lower grade than preoperatively. Only 41 (9%) reported no significant decrease in preoperative axial and/or radicular pain. Twenty-nine (6%) of the patients required a reoperation within one year of the index procedure. Another 10 (2%) required a reoperation after 18 months, three (0.6%) after 24 months, six (1.3%) after four years, five (1%) after six years and three (0.6%) after eight years. At eight years, 72% of the patients had good to excellent outcomes based on their Neck Disability Index scores, 18% had acceptable outcomes and 10% had poor outcomes, according to Dr. Gitter. The study results were presented at the 2011 annual meeting of the International Spine Intervention Society, held recently in Chicago. —Rosemary Frei, MSc

LD-1664R/March 2010

Dr. Kamhi does not have any financial or other conflicts of interest to disclose. Dr. Gitter could not be reached to determine whether he has any relevant conflicts of interest.

LIDODERM® is a registered trademark of Hind Health Care, Inc.

CHADDS FORD, PENNSYLVANIA 19317

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C lin ical Pain Medici n e

Abnormal Scar Mapping May Predict Post-Cesarean Pain Risk

esarean deliveries continue to rise as reflected by the number of women undergoing the procedure, as well as the average number of procedures women undergo. Women with scar hyperalgesia before a repeat cesarean delivery may be at risk for persistent postoperative pain. The authors of a preliminary analysis presented at the 2011 annual meeting of the Society for Obstetric Anesthesia and Perinatology suggested that detection tools such as scar mapping may lead to detours around unnecessary pain (abstract 1). “The idea that pain processing can change after injury is not new, but no one had ever evaluated surgical incisions or scars before a patient undergoes a second surgical procedure,” said lead author Clemens M. Ortner, MD, fellow in obstetric anesthesiology at the University of Washington School of Medicine, in Seattle. Approximately 1.4 million cesarean deliveries are performed in the United States every year; nearly one-third are elective repeat procedures. As part of a multicenter project at the University of Washington led by Ruth Landau, MD, that sought to identify preoperatively women at risk for both severe acute and chronic postcesarean pain, Drs. Ortner, Landau and colleagues assessed 165 women scheduled for repeat cesarean deliveries. Before the procedure, the investigators evaluated pain mechanisms involving the ascending excitatory pathways using mechanical temporal summation (mTS). The scar from a previous cesarean delivery also was mapped to determine the level of hyperalgesia. Each woman received standardized spinal anesthesia during delivery: 12 mg of bupivacaine, 25 mcg of fentanyl and 100 mcg of morphine. Two days later, the team recorded postoperative pain scores and mapped the wound to evaluate postoperative hyperalgesia. Preoperative scar hyperalgesia was found in 67 women (41%); however, only 13 women (8%) recalled having persistent pain after the previous delivery. Women with preoperative hyperalgesia had higher pain scores at 12, 24 and 48 hours after delivery. The extent of hyperalgesia correlated with pain severity (P<0.001), 48-hour postoperative hyperalgesia (P<0.001) and preoperative mTS (P<0.05). “The study is one of the first to

make a relationship between hyperalgesia surrounding a previous surgical scar, a persistent state of central nervous system hyperexcitability and increased acute postoperative pain,” said Patricia Lavand’homme, MD, PhD, an anesthesiologist at Catholic University of Louvain Medical School, in Belgium, who was not involved in the study. “By using quantitative

sensory testing to assess mechanical hypersensitivity surrounding the scar after surgery, and by evaluating excitatory pain processes, we might have an idea of the preoperative status of the patient.” Central sensitization participates in the acute postoperative pain commonly experienced by the patient and plays a role in the risk for developing

persistent postsurgical pain in some patients. “Looking at my clinical practice, around 30% of the patients present with an abnormal temporal summation, and they are at higher risk for both severe acute pain and persistent pain,” Dr. Lavand’homme said. “Those patients really deserve a targeted perioperative management.” —Lynne Peeples

20 I PainMedicineNews.com

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Clinical Pai n Medicine WHO continued from page 1

headache sufferers have been let down by the health care industry and their own governments. “The first global inquiry into these matters illuminates the worldwide neglect of a major public health problem,” wrote the authors of the report, “and reveals the inadequacies of responses to it in countries throughout the world.”

FILE SLUG

STATUS & HISTORY

Current file: PMNeNewsAd_LetterCS5 1ST PROOF LAYOUT APPROVED PROOF 1: 10/11 PICKED UP FROM: Underappreciated Societal alone, 190 million workdays FINAL are OK lost headache in their country. Only 12% of INITIALS AND DATE INITIALS AND DATE APPLIED TO: REV 1: 10/14 Burden annually due to migraine. those countries have a reporting system REV 2: Full name of project Senior editor AD LAYOUT EXPT’D: Migraine and other headache disorItEditor is seemingly hard to conceive then, for headache and expenditures surveys REV 3: AD LAYOUT RECEIVED: REV 4: ders have a significant impact on phys- the Copy report’s assertion that headache dis- are conducted in only 7%. Project no. editor EDIT LAYOUT EXPT’D: REV 5: ical and emotional health, orders “Headache disorders are ubiquitous, Revision # Rev 1 as well as Sales receive relatively little attention EDIT LAYOUT RECEIVED: REV 6: healthLayout insurance productivfrom the health care community. The prevalent, disabling and largely treatdate/time costs and September 27, 2011 10:55 AM Production REV 7: EDITOR: ity. ToEditorial wit,date/time the WHO report states WHO report maintains that a minor- able,REVbut under-recognized, under8: MAX sign-off ART DIRECTOR: that 50% to 70% of adults in the world ity of individuals worldwide who expe- diagnosed and under-treated,” the Trim size COMMENTS: KEYWORDS: reportColor at specs least one headache per year. rience headache are diagnosed, let alone report stated. “Illness that could be The chronic nature of headache is elu- treated to appropriate therapeutic lev- relieved is not, and burdens, both indiFile path Max: Server Data:Data:Magazines:PAINMED:PMN House Ads:2011:enews ad:PMNeNewsAd_LetterCS5.indd cidated by the fact that it affects up to els. Amazingly, only 18% of countries vidual and societal, persist.” 4% of all adults on 15 or more days of responding in the WHO report even Indeed, according to the National each month. In the European Union have data on the societal impact of Headache Foundation, the National

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THE INDEPENDENT MONTHLY NEWSPAPER FOR PAIN MANAGEMENT PainMedicineNews.com • OCTOBER 2011 • Volume 9 Number 10

PRIMARY CARE

Landmark WHO Headache Report Finds Enormous Impact, Major Gaps In Understanding

see WHO page 20

see TWO-DAY page 18

Each installment contains articles from the current month’s issue ahead of print, as well as links to other web-exclusive content

INTERVENTIONAL PAIN MEDICINE 12 | RF Neurotomy Possible Treatment for Degenerative Spondylolisthesis

HMO Initiative Targets Opioid Overprescribing A progressive approach to managing opioid misuse in noncancer patients

surf watch The Top 5 Articles on PainMedicineNews.com, see page 3.

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PainMedicineNews.com I 21

C lin ical Pain Medici n e Institutes of Health (NIH) spends just $13 million per year on migrainerelated research—about 0.05% of its total budget. “Headache is the Rodney Dangerfield of medicine,” said Steven Herzog, MD, medical director of the Headache Institute at Texas Neurology in Dallas, in commenting on the WHO report. “It gets no respect.” However, he added, “if you’re paralyzed by a migraine attack, you can’t get out of bed, turn the lights on, go to work,

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go to school, do chores—you’re ‘paralyzed’ in bed.” Education, Proper Diagnosis Lacking The WHO issued a report 10 years ago (“Headache Disorders and Public Health”) that emphasized the importance of migraine education. Since then, there’s been little effort to train physicians on the nuances of migraines and other headache disorders, said Brad Klein, MD, medical director of

the Abington Headache Center at Abington Memorial Hospital, near Philadelphia. “On average, about four hours is spent on migraine in undergraduate medical education,” said Dr. Klein. “During neurology residency, [headache training] is about 10 hours total. But for most neurologists, patients with migraine and headache disorders will represent about 20% of their patients, and even for primary care doctors, they’ll see six times more patients

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THE INDEPENDENT MONTHLY NEWSPAPER FOR PAIN MANAGEMENT PainMedicineNews.com • OCTOBER 2011 • Volume 9 Number 10

PRIMARY CARE

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Landmark WHO Headache Report Finds Enormous Impact, Major Gaps In Understanding

see WHO page 20

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INTERVENTIONAL PAIN MEDICINE 12 | RF Neurotomy Possible Treatment for Degenerative Spondylolisthesis

HMO Initiative Targets Opioid Overprescribing A progressive approach to managing opioid misuse in noncancer patients

surf watch The Top 5 Articles on PainMedicineNews.com, see page 3.

with migraine than tension headache. But many major academic medical centers across the country don’t even have a headache center or headache specialist. It’s amazing to me how many physicians are uninformed and lack a basic understanding of how to manage headaches.” Even with exhaustive diagnostic criteria now available, like that developed by the International Headache Society, they are only used in 56% of the WHO report’s responding countries. see WHO page 23

http://video.webcasts.com/events/apce001/39551 There are no prerequisites

Current and Emerging Therapies in Chronic Pain This fall, join national experts in chronic pain management for a series of live, complimentary, interactive webinars

Supported by educational grants from Covidien, Millennium Laboratories, and Pfizer Presented by the Johns Hopkins School of Medicine, in collaboration with Applied Clinical Education

Course Director Michael R. Clark, MD, MPH, MbA Associate Professor and Director Chronic Pain Treatment Programs Department of Psychiatry and Behavioral Sciences The Johns Hopkins Medical Institutions Baltimore, Maryland

Statement of need Four key areas in which clinicians have significant knowledge gaps are: • The knowledge of pain mechanisms and of the mechanisms of action of therapies • Recently approved therapies for chronic pain • Recently published or revised chronic pain treatment guidelines • Novel pain therapies in late-stage development that may be available soon

Schedule

All Sessions 2:00

Sponsorship Statement Presented by the Johns Hopkins University School of Medicine

Statement of Responsibility The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

Faculty Presenter Charles E. Argoff, MD

Professor of Neurology Albany Medical College Director, Comprehensive Pain Center Albany Medical Center Albany, New York

Accreditation Statement The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation Statement The Johns Hopkins University School of Medicine designates this live activity for a maximum of 7 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Policy on Faculty and Provider Disclosure It is the policy of the Johns Hopkins University School of Medicine that the faculty and provider disclose real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/ unapproved uses of drugs or devices during their presentations. The Johns Hopkins University School of Medicine Office of Continuing Medical Education has established policies in place that will identify and resolve all conflicts of interest prior to this educational activity. Detailed disclosure will be made in the course handout materials.

EST

Article

Multimodal Analgesia for Chronic Pain: Rationale and Future Directions Argoff CE, Albrecht P, Irving G, Rice F. Pain Med. 2009;10(suppl 2):S53-S66.

October 12, 2011 • Psychosocial comorbidities Faculty Presenter Dennis Turk, PhD

John and Emma Bonica Professor of Anesthesiology and Pain Research University of Washington School of Medicine Seattle, Washington

Article

Assessment and Treatment of Psychosocial Comorbidities in Patients With Neuropathic Pain Turk DC, Audette J, Levy RM, et al. Mayo Clin Proc. 2010;85(3 suppl):S42-S50.

October 19, 2011 • Pain management in older patients Faculty Presenter Perry G. Fine, MD

Professor of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah

Article

Pharmacological Management of Persistent Pain in Older Persons: American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons Ferrell B, Argoff CE, Epplin J, et al. Pain Med. 2009;10(6):1062-1083.

October 26, 2011 • Interventional therapies Faculty Presenter Richard Rosenquist, MD

Clinical Professor Director, Center for Pain Medicine and Regional Anesthesia University of Iowa Carver College of Medicine Iowa City, Iowa

Article

Interventional Therapies, Surgery, and Interdisciplinary Rehabilitation for Low Back Pain: An Evidence-Based Clinical Practice Guideline From the American Pain Society Chou R, Loeser JD, Owens DK, et al. Spine (Phila Pa 1976). 2009;34(10):1066-1077.

November 2, 2011 • Topical analgesics Faculty Presenter TbD

Article

Topical therapies for osteoarthritis. Altman RD, Barthel HR. Drugs. 2011;71(10): 1259-1279.

Intended Audiences Primary care physicians, physician pain specialists, neurologists, and other health care professionals with an interest in improving their professional skills relative to the treatment and management of chronic pain. The audience also may include nurses, nurse practitioners, physician assistants, and pharmacists.

- 3:00

October 5, 2011 • Multimodal therapy

Learning Objectives After completing this activity, the participant will demonstrate the ability to: • Elucidate the pathophysiology of chronic pain and how treatment approaches can target chronic pain appropriately by mechanism of action. • Review currently available therapies, particularly recently approved treatments, for common chronic pain conditions (eg, rheumatologic disorders such as osteoarthritis and other musculoskeletal conditions; neuropathic pain and fibromyalgia; chronic low back pain; and chronic pain associated with other medical conditions). • Apply recommendations from recent evidence-based guidelines to inform the treatment of chronic pain. • Describe emerging therapies for chronic pain that are in late-stage development.

November 9, 2011 • Neuropathic pain Faculty Presenter vera bril, MD

Professor of Medicine Department of Neurology University Health Network Toronto General Hospital Toronto, Ontario, Canada

Article

Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy Bril V, England J, Franklin GM, et al. Neurology. 2011;76(20):1758-1765.

November 16, 2011 • Opioid therapy Faculty Presenter David A. Fishbain, MD

Professor, Department of Psychiatry & Behavioral Sciences Adjunct Professor, Neurological Surgery and Anesthesiology Miller School of Medicine Miami, Florida

Article Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. Chou R, Fanciullo GJ, Fine RG, et al. J Pain. 2009; 10(2):113-130.

O ctober 2 0 1 1

PainMedicineNews.com I 23

Cli n ical Pain M edici n e WHO continued from page 21

Usage of diagnostic criteria is even lower in low- and middle-income countries in Africa, the Eastern Mediterranean and Southeast Asia. This, too, is the case with assessment tools for headache impact, which the WHO reports are used in less then 25% of responding countries. “Health care for headache must be improved, and education is required at multiple levels to achieve this,” according to the WHO report. “Most importantly, health care providers need better knowledge of how to diagnose and treat the small number of headache disorders that contribute substantially to public ill health.” Dr. Herzog noted that many patients with migraine and other headache disorders remain undiagnosed for years. “By the time the patient has gotten to see a headache specialist, years and years of mismanagement have taken place—using the wrong medications, not being aggressive enough,” he said. “Literally every day, I see patients who have had headaches for 10 or 20 years and were never asked the right

questions or given the right diagnosis. There’s no disorder that’s more misdiagnosed and misunderstood than migraine.” Global Problems With Treatment, Access The WHO report portrays undertreated headache as a global problem, citing many disparities in treatment and its access between wealthier Western countries and the rest of the world. It points out that although headache treatment guidelines are used in 55% of countries worldwide, “usage is much less common in low-income countries.” Triptans, a migraine-specific class of headache medications that generally have strong efficacy and safety profiles than other treatments, are used less often in underdeveloped countries than the more widely available ergotamine. (Indeed, the report stresses that access to appropriate medications is a barrier to effective treatment worldwide, regardless of income status.)

Headache is self-treated by nearly half of sufferers worldwide and in most cases there are no health care professionals managing their care. Reimbursement rates globally also show great disparity, with headache agents fully reimbursed in only half of

responding countries—this despite the fact that headache is a very treatable disorder with countless options for effective, individualized treatment. The years of misdiagnosis and inappropriate treatment make it harder for someone with headache to be treated effectively once they are diagnosed. “The longer you’re chronic, the harder it is to break the cycle,” Dr. Herzog said. “Once the brain sets up pathways where pain is normal, it’s very hard to reboot the system and alter that chemistry to get it back to normal.” Dr. Klein hopes that the WHO report will help bring more substantive change to migraine care by altering people’s attitudes about the importance of treating headaches, stating: “I hope people that matter—decision makers in the NIH, educators in medical schools—have read it and are saying, ‘We need to work harder.’” —Gina Shaw and Donald M. Pizzi

Comparison of Somatic and Physical Pain Symptoms Looks To Determine If Clusters Are Key National Harbor, Md.—The presence and level of severity of pain symptom clusters in patients with chronic pain may have long-term treatment implications, according to the lead researcher of a new study. “Most chronic pain patients have multiple symptoms, such as pain, sleep disorders, fatigue, anxiety [and] depression,” explained David A. Fishbain, MD, professor (tenured) of psychiatry and behavioral sciences, and adjunct professor, Department of Neurological Surgery and Department of Anesthesiology, University of Miami Leonard M. Miller School of Medicine, as well as a Pain Medicine News editorial board member. “We usually find a multiplicity of symptoms, both psychiatric and pain related. This is important because research has shown it is harder to treat pain when there is depression and vice versa. Comorbid symptoms affect the treatment of initial symptoms. The more symptoms you have, the harder [pain] is to treat.” In a multisite trial (the community as well as several rehabilitation centers), Dr. Fishbain and his co-investigators looked to gauge by chi-square the frequency of 15 somatic symptoms, as well as analyze and compare somatic symptom clusters, in four groups: community patients with pain (n=158), acute pain patients (n=326), chronic pain patients (n=324) and non–pain patients in the community (n=129). Each group was administered a large number of items

that included the symptoms being studied, and were then compared based on which items were endorsed. A cluster analysis was then performed in patients with moderate to severe pain (score of 5-7 and 8-10, respectively, on a 10-point scale). Dr. Fishbain used a similar methodology in a recent study on anger in chronic pain patients (Pain Med 2011;12:127-137; Pain Medicine News July 2011, page 1). The researchers defined a cluster as two or more related symptoms that have the potential to impact each other if one is treated (Oncol Nurs 2007;34:971980; J Pallative Med 2008;11:591-600). Although research exists for comorbid symptom groups in nonmalignant pain (Pain Med 2003;4:51-62; Pain Practice 2009;9:449-467; Pain Med 2010;11:158-179; J Pain Palliat Care Pharmacother 2008;22:221-225), Dr. Fishbain said this is the first somatic symptom cluster study in pain. “Symptom clusters affect function,” he said. “Even in well-treated cancer, patient function is impaired.” Dr. Fishbain and his colleagues identified five clusters in community pain patients, four in acute pain patients and five in chronic pain patients. “It is very possible that these clusters respond as a group to treatment,” said Dr. Fishbain. “We may be able to target the clusters.” Patients with chronic pain had significantly greater frequency of nine symptoms (numbness, dizziness,

muscle weakness, difficulty staying asleep, muscle tightness, irritability, falling, concentration and headaches) than chronic pain patients in the community. They also had significantly greater frequency than acute pain patients for these nine symptoms, in addition to fatigue, depression, memory and nausea. All three treatment groups had statistically significantly greater frequency of 14 symptoms than non–pain patients. Patients with chronic pain in the community had a similar cluster makeup to those of acute pain patients, in terms of acuteness and frequency of all 15 symptoms, the researchers reported. Chronic pain patients with moderate pain showed four distinct clusters, whereas those with severe pain had five. “So, the more pain you have the more difficult whatever symptoms clusters you have are to treat,” said Dr. Fishbain. The researchers concluded that somatic pain symptoms form five distinct cluster patterns (memory, neurologic, behavior, somatic and autonomic) and are looking to further study which combination of symptoms respond as a group to different treatments. “We do believe that they will respond as a group,” said Dr. Fishbain. The poster (161) was presented at the recent annual meeting of the American Academy of Pain Medicine. —Donald M. Pizzi

For moderate to severe pain when a continuous, around-the-clock (ATC) opioid analgesic is needed for an extended period of time

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80 mg

Tablets are actual size.

WARNING: IMPORTANCE OF PROPER PATIENT SELECTION AND POTENTIAL FOR ABUSE OxyContin contains oxycodone which is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine. (9) OxyContin can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing OxyContin in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. (9.2) OxyContin is a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. (1) OxyContin is not intended for use on an as-needed basis. (1) Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. OxyContin 60 mg and 80 mg tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in opioid-tolerant patients, as they may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory-depressant or sedating effects of opioids. (2.7) Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. (2.2) OxyContin must be swallowed whole and must not be cut, broken, chewed, crushed, or dissolved. Taking cut, broken, chewed, crushed or dissolved OxyContin tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone. (2.1) The concomitant use of OxyContin with all cytochrome P450 3A4 inhibitors such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. Patients receiving OxyContin and a CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. (7.2)

Please read Brief Summary of Full Prescribing Information on the following pages and Contraindications on adjacent page.

Learn more about OxyContin® at www.PurdueHCP.com/ OxyContin

Because different patients with pain have different treatment needs

Q12h dosing with as few as 2 tablets per day When converting from other opioids, the 7 OxyContin® Tablet strengths enable you to more closely approximate the calculated conversion dose OxyContin® is a single-entity opioid Because steady-state plasma concentrations are approximated within 24 to 36 hours, dosage adjustment may be carried out every 1 to 2 days

Indications and Usage OxyContin® is a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Usage OxyContin® is not intended for use on an as-needed basis. As used here, “moderate” and “moderate to severe” pain do not include commonplace and ordinary aches and pains, pulled muscles, cramps, sprains, or similar discomfort. OxyContin® is not indicated for the management of pain in the immediate postoperative period (the ﬁrst 12-24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. OxyContin® is indicated for postoperative use following the immediate postoperative period only if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (See American Pain Society guidelines.) OxyContin® is not indicated for preemptive analgesia (preoperative administration for the management of postoperative pain). OxyContin® is not indicated for rectal administration.

OxyContin® is contraindicated in • Patients who have signiﬁcant respiratory depression • Patients who have or are suspected of having paralytic ileus • Patients who have acute or severe bronchial asthma • Patients with known hypersensitivity to any of its components or the active ingredient, oxycodone

Purdue is ﬁrmly committed to maintaining the highest standards of sales and marketing practices in the industry while continuing to advance the proper treatment of patients. If Purdue’s sales and marketing practices fail to meet this standard, we urge you to contact us at 1-888-726-7535.

B8284-K

12/10

4 CONTRAINDICATIONS OxyContin is contraindicated in: 10 mg l 15 mg l 20 mg l 30 mg 40 mg l 60 mg* l 80 mg*

*60 mg and 80 mg tablets for use in opioid-tolerant patients only

BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the full prescribing information and Medication Guide.) WARNING: IMPORTANCE OF PROPER PATIENT SELECTION AND POTENTIAL FOR ABUSE OxyContin contains oxycodone which is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine. (9) OxyContin can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing OxyContin in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. (9.2) OxyContin is a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. (1) OxyContin is not intended for use on an as-needed basis. (1) Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. OxyContin 60 mg and 80 mg tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in opioid-tolerant patients, as they may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory-depressant or sedating effects of opioids. (2.7) Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. (2.2) OxyContin must be swallowed whole and must not be cut, broken, chewed, crushed, or dissolved. Taking cut, broken, chewed, crushed or dissolved OxyContin tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone. (2.1) The concomitant use of OxyContin with all cytochrome P450 3A4 inhibitors such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. Patients receiving OxyContin and a CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. (7.2) 1 INDICATIONS AND USAGE OxyContin is a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. Limitations of Usage OxyContin is not intended for use on an as-needed basis. OxyContin is not indicated for the management of pain in the immediate postoperative period (the first 12-24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. OxyContin is indicated for postoperative use following the immediate post-operative period only if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (See American Pain Society guidelines.) OxyContin is not indicated for pre-emptive analgesia (preoperative administration for the management of postoperative pain). OxyContin is not indicated for rectal administration.

ileus components or the active ingredient, oxycodone. 5 WARNINGS AND PRECAUTIONS 5.1 Information Essential for Safe Administration OxyContin tablets must be swallowed whole and must not be cut, broken, chewed, crushed, or dissolved. Taking cut, broken, chewed, crushed or dissolved OxyContin tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone. OxyContin 60 mg and 80 mg Tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in opioid-tolerant patients. Use of these doses in patients who are not opioid tolerant may cause fatal respiratory depression. Instruct patients against use by individuals other than the patient for whom OxyContin was prescribed, as such inappropriate use may have severe medical consequences, including death. Opioid analgesics have a narrow therapeutic index in certain patient populations, especially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. 5.2 CNS Depression OxyContin may cause somnolence, dizziness, alterations in judgment and alterations in levels of consciousness, including coma. 5.3 Interactions with Alcohol, CNS Depressants and Illicit Drugs Hypotension, profound sedation, coma or respiratory depression may result if OxyContin is added to a regimen that includes other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). Therefore, use caution when deciding to initiate therapy with OxyContin in patients who are taking other CNS depressants. Take into account the types of other medications being taken, the duration of therapy with them, and the patient’s response to those medicines, including the degree of tolerance that has developed to CNS depression. Consider the patient’s use, if any, of alcohol and/ or illicit drugs that cause CNS depression. If the decision to begin OxyContin is made, start with a lower OxyContin dose than usual. [see Drug Interactions (7.3)] Consider using a lower initial dose of a CNS depressant when given to a patient currently taking OxyContin due to the potential of additive CNS depressant effects. 5.4 Respiratory Depression Decreased respiratory drive resulting in respiratory depression is the chief hazard from the use or abuse of opioid agonists, including OxyContin. The risk of opioid-induced respiratory depression is increased, for example, in elderly [see Use In Specific Populations (8.5)] or debilitated patients; following large initial doses in any patient who is not tolerant to the respiratory-depressant or sedating effects of opioids; or when opioids are given in conjunction with other agents that either depress respiratory drive or consciousness. Use OxyContin with extreme caution in patients with any of the following: pulmonale

Respiratory depression induced by opioids typically follows a pattern entailing first a shift in CO2 responsiveness of the CNS respiratory drive center, which results in a decrease in the urge to breathe, despite the presence of hypercapnia. The increase in brain CO2 can result in sedation that can accentuate the sedation from the opioid itself. Profound sedation, unresponsiveness, infrequent deep (“sighing”) breaths or atypical snoring frequently accompany opioid-induced respiratory depression. Eventually, hypoxia ensues. In addition to further decreasing consciousness, hypoxia, along with hypercapnia, can predispose to life-threatening cardiac arrhythmias. 5.5 Seizures Oxycodone, as with other opioids, may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Use OxyContin with caution in patients with a history of seizure disorders. 5.6 Head Injury The respiratory depressant effects of opioids include carbon dioxide retention, which can lead to an elevation of cerebrospinal fluid pressure. This effect may be exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Oxycodone may produce miosis that is independent of ambient light, and altered consciousness, either of which may obscure neurologic signs

associated with increased intracranial pressure in persons with head injuries. 5.7 Hypotensive Effect OxyContin may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Oxycodone may produce orthostatic hypotension in ambulatory patients. Administer OxyContin with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. 5.8 Cytochrome P450 3A4 Inhibitors and Inducers Since the CYP3A4 isoenzyme plays a major role in the metabolism of OxyContin, drugs that alter CYP3A4 activity may cause changes in clearance of oxycodone which could lead to changes in oxycodone plasma concentrations. The expected clinical results with CYP3A4 inhibitors would be an increase in oxycodone plasma concentrations and possibly increased or prolonged opioid effects. The expected clinical results with CYP3A4 inducers would be a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If co-administration is necessary, caution is advised when initiating OxyContin treatment in patients currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. [see Drug Interactions (7.2) and Clinical Pharmacology (12)] 5.9 Interactions with Mixed Agonist/Antagonist Opioid Analgesics It is generally not advisable to administer mixed agonist/ antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) to a patient receiving OxyContin. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect and may precipitate withdrawal symptoms in these patients. 5.10 Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids may cause increases in the serum amylase. The administration of OxyContin may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use OxyContin with caution in patients who are at risk of developing ileus. 5.11 Tolerance Tolerance to opioids is demonstrated by the need for increasing doses to maintain adequate analgesic effect (in the absence of disease progression or other external factors). If tolerance develops, or if pain severity increases, a gradual increase in dose may be required. The first sign of tolerance is usually a reduced duration of effect. Tolerance to different effects of opioids may develop to varying degrees and at varying rates in a given individual. There is also inter-patient variability in the rate and extent of tolerance that develops to various opioid effects, whether the effect is desirable (e.g., analgesia) or undesirable (e.g., nausea). 5.12 Special Risk Groups Use OxyContin with caution in the following conditions, due to increased risk of adverse reactions: alcoholism; delirium tremens; adrenocortical insufficiency; CNS depression; debilitation; kyphoscoliosis associated with respiratory compromise; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis. 5.13 Driving and Operating Machinery OxyContin may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. 5.14 Use in Addiction Treatment OxyContin has no approved use in the treatment of addiction. Its proper usage in individuals with drug or alcohol addiction (substance dependence), either active or in remission, is for the management of pain requiring opioid analgesia. 5.15 Laboratory Monitoring Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative”. Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and use caution in interpreting results. 6 ADVERSE REACTIONS The following adverse reactions described elsewhere in the labeling include: [see Boxed Warning, Warnings and Precautions (5.1, 5.4) and Overdosage (10)] [see Warnings and Precautions (5.1, 5.2) and Overdosage (10)] [see Warning and Precautions (5.7)

and Overdosage (10)] [see Drug Abuse and Dependence (9.2, 9.3)] [see Warnings and Precautions (5.10)] [see Warnings and Precautions (5.5)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OxyContin was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received OxyContin in total daily doses ranging from 20 mg to 640 mg per day. The average total daily dose was approximately 105 mg per day. OxyContin may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)]. The most common adverse reactions (>5%) reported by patients in clinical trials comparing OxyContin with placebo are shown in Table 2 below: TABLE 2: Common Adverse Reactions (>5%) Adverse OxyContin Placebo Reaction (n=227) (n=45) (%) (%) Constipation Nausea Somnolence Dizziness Pruritus Vomiting Headache Dry Mouth Asthenia Sweating

(23) (23) (23) (13) (13) (12) (7) (6) (6) (5)

(7) (11) (4) (9) (2) (7) (7) (2) — (2)

In clinical trials, the following adverse reactions were reported in patients treated with OxyContin with an incidence between 1% and 5%: Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, gastritis, hiccups General disorders and administration site conditions: chills, fever Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: twitching Psychiatric disorders: abnormal dreams, anxiety, confusion, dysphoria, euphoria, insomnia, nervousness, thought abnormalities Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups Skin and subcutaneous tissue disorders: rash Vascular disorders: postural hypotension The following adverse reactions occurred in less than 1% of patients involved in clinical trials: Blood and lymphatic system disorders: lymphadenopathy Ear and labyrinth disorders: tinnitus Eye disorders: abnormal vision Gastrointestinal disorders: dysphagia, eructation, flatulence, gastrointestinal disorder, increased appetite, stomatitis General disorders and administration site conditions: withdrawal syndrome (with and without seizures), edema, peripheral edema, thirst, malaise, chest pain, facial edema Injury, poisoning and procedural complications: accidental injury Investigations: ST depression Metabolism and nutrition disorders: dehydration Nervous system disorders: syncope, migraine, abnormal gait, amnesia, hyperkinesia, hypesthesia, hypotonia, paresthesia, speech disorder, stupor, tremor, vertigo, taste perversion Psychiatric disorders: depression, agitation, depersonalization, emotional lability, hallucination Renal and urinary disorders: dysuria, hematuria, polyuria, urinary retention Reproductive system and breast disorders: impotence Respiratory, thoracic and mediastinal disorders: cough increased, voice alteration Skin and subcutaneous tissue disorders: dry skin, exfoliative dermatitis 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of controlled-release oxycodone. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: abuse, addiction, overdose, death, amenorrhea, symptoms associated with an anaphylactic or anaphylactoid

reaction, cholestasis, dental caries, increased hepatic enzymes, muscular hypertonia, hyponatremia, ileus, palpitations (in the context of withdrawal), seizures, syndrome of inappropriate antidiuretic hormone secretion, and urticaria. In addition to the events listed above, the following have also been reported, potentially due to the swelling and hydrogelling property of the tablet: choking, gagging, regurgitation, tablets stuck in the throat and difficulty swallowing the tablet. 7 DRUG INTERACTIONS 7.1 Neuromuscular Junction Blocking Agents OxyContin may enhance the neuromuscular blocking action of true skeletal muscle relaxants (such as pancuronium) and produce an increased degree and/or duration of respiratory depression. 7.2 Agents Affecting Cytochrome P450 Isoenzymes Inhibitors of CYP3A4: Since the CYP3A4 isoenzyme plays a major role in the metabolism of OxyContin, drugs that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. A published study showed that the co-administration of the antifungal drug, voriconazole, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. Although clinical studies have not been conducted with other CYP3A4 inhibitors, the expected clinical results would be increased or prolonged opioid effects. If co-administration with OxyContin is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP450 inhibitors. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. [see Clinical Pharmacology (12.3)] Inducers of CYP3A4: CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone (oral) AUC and Cmax by 86% and 63%, respectively. If co-administration with OxyContin is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. Inhibitors of CYP2D6: Oxycodone is metabolized in part to oxymorphone via cytochrome CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic antidepressants), such blockade has not been shown to be of clinical significance during oxycodone treatment. 7.3 CNS Depressants Start OxyContin at 1/3 to 1/2 of the usual dosage in patients who are concurrently receiving other CNS depressants including sedatives or hypnotics, general anesthetics, phenothiazines, centrally acting anti-emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result. No specific interaction between oxycodone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate. [see Warnings and Precautions (5.2 )] 7.4 Interactions with Mixed Agonist/Antagonist Opioid Analgesics Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should generally not be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as OxyContin. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and may precipitate withdrawal symptoms in these patients. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category B: There are no adequate and well-controlled studies of oxycodone use during pregnancy. Based on limited human data in the literature, oxycodone does not appear to increase the risk of congenital malformations. In animal reproduction and developmental toxicology studies, no evidence of fetal harm was observed. Because animal reproduction studies are not always predictive of human response, oxycodone should be used during pregnancy only if clearly needed. Teratogenic Effects The effect of oxycodone in human reproduction has not been adequately studied. Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 0.5 and 15 times an adult human dose of 160 mg/day, respectively on a mg/m2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no long-term developmental or reproductive effects in the pups. [see Nonclinical Toxicology (13)]

Non-Teratogenic Effects Oxycodone hydrochloride was administered orally to female rats during gestation and lactation in a pre- and postnatal toxicity study. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by mothers given the highest dose used (6 mg/kg/day, equivalent to approximately 0.4-times an adult human dose of 160 mg/day, on a mg/m2 basis). However, body weight of these pups recovered. 8.2 Labor and Delivery Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. OxyContin is not recommended for use in women immediately prior to and during labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. Have a specific opioid antagonist, such as naloxone or nalmefene, available for reversal of opioid-induced respiratory depression in the neonate. Neonates whose mothers have been taking opioids chronically may also exhibit withdrawal signs, either at birth and/or in the nursery, because they have developed physical dependence. This is not, however, synonymous with addiction [see Drug Abuse and Dependence (9.3)]. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts. 8.3 Nursing Mothers Oxycodone has been detected in breast milk. Instruct patients not to undertake nursing while receiving OxyContin. Do not initiate OxyContin therapy while nursing because of the possibility of sedation or respiratory depression in the infant. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.4 Pediatric Use Safety and effectiveness of OxyContin in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3)]. Of the total number of subjects (445) in clinical studies of oxycodone hydrochloride controlled-release tablets, 148 (33.3%) were age 65 and older (including those age 75 and older) while 40 (9.0%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received oxycodone hydrochloride controlled-release tablets. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. However, reduce the starting dose to 1/3 to 1/2 the usual dosage in debilitated, non-opioid-tolerant patients. Respiratory depression is the chief risk in elderly or debilitated patients, usually the result of large initial doses in patients who are not tolerant to opioids, or when opioids are given in conjunction with other agents that depress respiration. Titrate the dose of OxyContin cautiously in these patients. 8.6 Hepatic Impairment A study of OxyContin in patients with hepatic impairment demonstrated greater plasma concentrations than those seen at equivalent doses in persons with normal hepatic function. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Follow a conservative approach to dose initiation and adjust according to the clinical situation [see Clinical Pharmacology (12.3)]. 8.8 Gender Differences In pharmacokinetic studies with OxyContin, opioid-naive females demonstrate up to 25% higher average plasma concentrations and greater frequency of typical opioid adverse events than males, even after adjustment for body weight. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages, and there was no male/female difference detected for efficacy or adverse events in clinical trials. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance OxyContin contains oxycodone, which is a Schedule II controlled substance with an abuse liability similar to morphine. OxyContin, like morphine and other opioids used for analgesia, can be abused and is subject to criminal diversion.

9.2 Abuse Abuse of OxyContin poses a hazard of overdose and death. This risk is increased with compromising the tablet and with concurrent abuse of alcohol or other substances. With parenteral abuse, the tablet excipients can result in death, local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV. Opioid drugs are sought by people with substance use disorders (abuse or addiction, the latter of which is also called “substance dependence”) and criminals who supply them by diverting medicines out of legitimate distribution channels. OxyContin is a target for theft and diversion. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, altering or forging of prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among people with untreated substance use disorders, and criminals who divert controlled substances. The risks of misuse and abuse should be considered when prescribing or dispensing OxyContin. Concerns about abuse and addiction, should not prevent the proper management of pain, however. Treatment of pain should be individualized, balancing the potential benefits and risks for each patient. Compromising an extended or controlled-release delivery system will result in the uncontrolled delivery of oxycodone and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)]. The risk of fatal overdose is further increased when oxycodone is abused concurrently with alcohol or other CNS depressants, including other opioids [see Warnings and Precautions ( 5.3)]. Abuse may occur by taking intact tablets without legitimate purpose, by crushing and chewing or snorting the crushed formulation, or by injecting a solution made from the crushed formulation. Drug addiction is characterized by compulsive abuse, repeated use for non-medical purposes, loss of control over intake, craving of psychic effects and continued abuse despite harm or risk of harm in medical, social, legal or occupational domains. There is a potential for drug addiction to develop following exposure to opioids, including oxycodone. Drug addiction is a treatable disease, but relapse is common. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by intentional misuse for non-medical purposes, often in combination with other psychoactive substances. OxyContin has been diverted for non-medical use. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, proper dispensing and correct storage and handling are appropriate measures that help to limit misuse and abuse of opioid drugs. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. 9.3 Dependence Physical dependence to an opioid is manifested by characteristic withdrawal signs and symptoms after abrupt discontinuation of a drug, significant dose reduction or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome in adults is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. [See Use In Specific Populations (8.2)] In general, opioids should not be abruptly discontinued [see Dosage and Administration (2.9)]. 10 OVERDOSAGE Acute overdosage with OxyContin can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. It is important to take the pharmacokinetic profile of OxyContin into account when treating overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as opioid continues to be absorbed from ingested tablets. Deaths due to overdose have been reported with abuse and misuse of whole OxyContin tablets, and with abuse and misuse by ingesting, inhaling, or injecting crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when OxyContin is abused concurrently with alcohol or other CNS depressants, including other opioids.

In the treatment of OxyContin overdosage, primary attention should be given to the maintenance of a patent airway, and of effective ventilation (clearance of CO2) and oxygenation, whether by spontaneous, assisted or controlled respiration. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The pure opioid antagonists such as naloxone or nalmefene are specific antidotes against respiratory depression from opioid overdose. Since the duration of action of OxyContin may exceed that of the antagonist, especially when the overdose involves intact tablets, keep the patient under continued surveillance and administer repeated doses of the antagonist according to the antagonist labeling as needed to maintain adequate respiration. Do not administer opioid antagonists in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. In patients who are physically dependent on any opioid agonist including OxyContin, an abrupt partial or complete reversal of opioid effects may precipitate an acute abstinence (or withdrawal) syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. See the prescribing information for the specific opioid antagonist for details of its proper use. 17 PATIENT COUNSELING INFORMATION See MEDICATION GUIDE as appended at the end of the full prescribing information 17.1 Information for Patients and Caregivers Provide the following information to patients receiving OxyContin or their caregivers: is a morphine-like substance. only if swallowed whole. Taking cut, broken, chewed, crushed, or dissolved OxyContin Tablets can result in a fatal overdose. tablet at a time. tablet prior to placing in the mouth. ensure complete swallowing immediately after placing in the mouth. of increased or incident pain occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. consulting the prescribing professional. physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). other central nervous system depressants (e.g. sedatives, hypnotics) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death. are planning to become, pregnant to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child. potential. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. with OxyContin for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the OxyContin dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. If tapering is appropriate, their prescriber can provide a dose schedule to gradually discontinue the medication. the reach of children. When OxyContin is no longer needed, the unused tablets should be destroyed by flushing down the toilet. Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product. CAUTION DEA Order Form Required. ©2010, Purdue Pharma L.P. Purdue Pharma L.P. Stamford, CT 06901-3431 U.S. Patent Numbers 5,508,042; 6,488,963; 7,129,248; 7,674,799; 7,674,800 and 7,683,072 302483-0B

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Clinical Pai n Medicine

Williams’ Diagnosis Shines Light On Exhausting Rheumatic Disease

ny time a star professional athlete declines due to injury to participate in what could likely be the beginning of yet another championship run, it makes national headlines. Such was the case when tennis superstar Venus Williams withdrew from the U.S. Open on Aug. 31 before facing the 22nd seed Sabine Lisicki in the second round. It was a little less shocking in the case of Ms. Williams, who had already missed most of the 2011 professional tennis season due to hip, foot and abdominal injuries, and then a virus. Yet when the 21-time Grand Slam champion revealed she had been diagnosed with Sjögren’s syndrome—a little-known autoimmune disease that is marked by fatigue, joint pain, dry eyes and mouth, numbness and swelling (Figures 1 and 2)—she suddenly became the new face of the disorder. “I’m really disappointed to have to withdraw from this year’s U.S. Open,” said Ms. Williams in a statement. “I have recently been diagnosed with Sjögren’s syndrome, an autoimmune disease which is an ongoing medical condition that affects my energy level,” Ms. Williams said. “I enjoyed playing my first match here and I wish I could continue but right now I am unable to.” Ms. Williams said the disease had caused her to lose a great deal of energy over the summer, making it difficult to continue in the competition. In the statement she said, “[the disease] was just energy-sucking, and I just couldn’t play pro tennis.” For individuals with the disease, there is now hope that having such a high-profile person sharing their diagnosis—Ms. Williams is by far the most wellknown person to announce she has Sjögren’s syndrome—will lead to a better understanding of the condition. Steven Taylor, CEO of the Sjögren’s Syndrome Foundation, said, “We applaud Venus for publicly stepping forward and shedding light on this serious autoimmune disease. Her courage gives hope to the many who live silently with Sjögren’s because of the lack of awareness around this disease.” According to the Sjögren’s Syndrome Foundation, approximately 1 to 4 million people in the United States have the disorder, making it the second most common autoimmune rheumatic disease. Most people with Sjögren’s will only have inflammation in the tear ducts and salivary glands, but some will experience a more severe multiorgan system disease that behaves like lupus. There is also an elevated risk for lymphoma associated with Sjögren’s. It is most commonly diagnosed in women between the ages of 40 and 60, although it can occur at any age. Ms. Williams is 31. Milder cases can be controlled with topical medications, whereas more severe symptoms require treatment with immune-suppressing medications such as steroids or methotrexate. Depending on the severity of her condition,

Mild

Moderate

Severe

Figure 1. Dry eyes of Sjögren’s syndrome patient. Source: Johns Hopkins Wilmer Eye Institute

Neurologic problems, concentration/memory loss (brain fog)

Dry eyes, corneal ulcerations and infections

Dry nose, recurrent sinusitis, nose bleeds

Difficulty swallowing, heartburn, reflux, esophagitis

Dry mouth, mouth sores, dental decay; difficulty with chewing, speech, taste and dentures

Recurrent bronchitis, pneumonia, interstitial lung disease

Arthritis, muscle pain

Dry skin, vasculitis, Raynaud’s phenomenon

Abnormal liver function tests, chronic active autoimmune hepatitis, primary biliary cirrhosis

Stomach upset, gastroparesis, autoimmune pancreatitis

Vaginal dryness, painful intercourse

Peripheral neuropathy (numbness and tingling in the extremities)

Figure. Ways Sjögren’s syndrome affects the body. Source: Sjögren’s Syndrome Foundatioon

Ms. Williams should be able to return to the game after a period of treatment and rehabilitation. “I am thankful I finally have a diagnosis,” she said in her

statement, “and am now focused on getting better and returning to the court soon,” she said. —Donald M. Pizzi and Victoria Stern

http://video.webcasts.com/events/apce001/39551 There are no prerequisites

Current and Emerging Therapies in Chronic Pain This fall, join national experts in chronic pain management for a series of live, complimentary, interactive webinars

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Multimodal Analgesia for Chronic Pain: Rationale and Future Directions Argoff CE, Albrecht P, Irving G, Rice F. Pain Med. 2009;10(suppl 2):S53-S66.

October 12, 2011 • Psychosocial comorbidities Faculty Presenter Dennis Turk, PhD

John and Emma Bonica Professor of Anesthesiology and Pain Research University of Washington School of Medicine Seattle, Washington

Article

Assessment and Treatment of Psychosocial Comorbidities in Patients With Neuropathic Pain Turk DC, Audette J, Levy RM, et al. Mayo Clin Proc. 2010;85(3 suppl):S42-S50.

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Professor of Anesthesiology University of Utah School of Medicine Salt Lake City, Utah

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October 26, 2011 • Interventional therapies Faculty Presenter Richard Rosenquist, MD

Clinical Professor Director, Center for Pain Medicine and Regional Anesthesia University of Iowa Carver College of Medicine Iowa City, Iowa

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November 2, 2011 • Topical analgesics Faculty Presenter TbD

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Topical therapies for osteoarthritis. Altman RD, Barthel HR. Drugs. 2011;71(10): 1259-1279.

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October 5, 2011 • Multimodal therapy

November 9, 2011 • Neuropathic pain Faculty Presenter vera bril, MD

Professor of Medicine Department of Neurology University Health Network Toronto General Hospital Toronto, Ontario, Canada

Article

Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy Bril V, England J, Franklin GM, et al. Neurology. 2011;76(20):1758-1765.

November 16, 2011 • Opioid therapy Faculty Presenter David A. Fishbain, MD

Professor, Department of Psychiatry & Behavioral Sciences Adjunct Professor, Neurological Surgery and Anesthesiology Miller School of Medicine Miami, Florida

Article Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. Chou R, Fanciullo GJ, Fine RG, et al. J Pain. 2009; 10(2):113-130.

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Disparities in Quality of Life Found Following Workers’ Compensation Claims St. Louis—Pain can prove costly for individuals already dealing with financial woes and problems at home, a new study has found. According to research published in the August issue of Spine (2011;26:1402-1409), blacks, the working poor and people younger than 35 years old are more likely to suffer from financial problems and domestic issues after settling workers’ compensation claims for painful, on-the-job back injuries. The authors reached these conclusions after reviewing the court records of nearly 1,500 blacks and nonHispanic whites who settled workers’ compensation claims in the St. Louis and Kansas City, Mo., areas. “Patients with residual pain at the time that litigation concludes are at risk for long-term decline in function, lost earning potential and marital discord,” Raymond Tait, PhD, the study’s lead author and professor of psychiatry at

Saint Louis University, told Pain Medicine News. “These findings are incompatible with long-held notions that claim settlement is curative. The pattern suggests that it represents a point from which patients continue to decline.” Dr. Tait and his colleague John Chibnall, PhD, also a professor of psychiatry at Saint Louis University, examined the court records of 580 black and 892 non-Hispanic workers’ compensation claimants over 10 years—comparing the five-year period before their settlements with the five-year period after— to determine the frequency of cases involving general financial matters (e.g., bankruptcy), domestic financial matters (e.g., child support), residential financial matters (e.g., eviction) and domestic behavior (e.g., divorce). Blacks who settled workers’ compensation claims were consistently more likely to be involved in general and domestic financial cases than non-Hispanic whites, and these

legal issues mounted. By the fifth postsettlement year, for example, levels of general and domestic financial cases for the black workers increased by approximately 10% above baseline, compared with 3% for white workers. Similarly, younger workers were more likely to experience financial difficulties. Those younger than 35 years old demonstrated a nearly 14% increase in general financial legal actions over baseline, a rate that was three times higher than that of the 35- to 54-year-old cohort and five times higher than that of the 55-andolder cohort. “We believe that societal factors drive many of the differences that we have found in treatment and intermediate treatment outcomes,” Dr. Tait said. “Over the long term, racial and ethnic effects are augmented if not exceeded by socioeconomic status factors, especially the resources available to the patient in pain.”

Dr. Tait and his team focused much of their recent research on disparities in pain treatment along racial and economic lines. Like the Spine study, much of their work was partly supported by funding from the Agency for Healthcare Research and Quality. However, although Dr. Tait draws troubling conclusions from his findings, not everyone in the pain community agrees. “The problem with this study is that it identifies these differences but can offer no insight into causation; any conclusions on the part of the reader are purely speculative,” said Mark Lema, MD, professor and chair of anesthesiology at the State University of New York at Buffalo, who was not involved in Dr. Tait’s research. “Do the number of children have an impact on these differences? Is one group of injured workers engaged in extremely hard labor? It’s almost impossible to answer the questions based on this article without offering my personal biases, but I don’t see this report as an issue regarding the availability of pain care between the groups.” —Brian P. Dunleavy

‘4-D’ Ultrasound May Help Guide Central Lines

new tool that allows real-time, three-dimensional ultrasound may help cut down on errors while placing central lines, without adding precious time to the procedure, researchers have found. When anesthesiologists attempted the technique on a sample of 10 patients undergoing heart surgery, they cannulated the internal jugular vein in every patient—and, in nine of the 10 patients, with the first needle pass (Figure). No back wall passes or inadvertent punctures of the carotid artery occurred. The cases required an average of 15 seconds to scan the blood vessels, and the average time to insert the needle into the internal jugular vein was 14

Figure. Screen view of internal jugular vein cannulation with “4-D” ultrasound. The needle appears hyperechoic in all planes (X, Y and Z) and in volumetric image (arrows).

seconds, according to the study, which the researchers presented at the 2011 annual meeting of the Society of Cardiovascular Anesthesiologists, in Savannah, Ga. (abstract 63). Traditional ultrasound techniques take approximately the same amount of time to find the vein, said David Auyong, MD, of Virginia Mason Medical Center in Seattle. The new technique “didn’t take longer, and it potentially showed that we could follow the needle better, by avoiding the back wall passes and arterial punctures.” However, one patient required six needle passes, likely because the internal jugular vein was relatively deep, Dr. Auyong said. Many anesthesiologists now rely on ultrasound when inserting a central line, but the traditional technique cannot always rigorously track the tip of the needle, as evidenced by the lingering risk for complications such as pneumothorax and inadvertent arterial puncture. The new “4-D” technique uses a probe that wobbles slightly (roughly four times per second) over a three-dimensional area such as the internal jugular vein, creating a three-dimensional image in real time—with time representing the fourth dimension, Dr. Auyong explained. “The ultimate goal here is a way to track the needle more reliably,” he said. Dr. Auyong, who has lectured for SonoSite, which supplied the ultrasound equipment used in the study, said that the biggest hurdle for uptake of the technology is learning how to use it. When he demonstrates it to other anesthesiologists, he said they

often struggle with having to follow four images simultaneously in order to track the needle. “It is not something that is necessarily intuitive the second you pick it up.” Dr. Auyong said he, too, struggled at first, but grew more comfortable after an estimated 10 practice insertions of a needle. Cost is another barrier, said Paul Barash, MD, professor of anesthesiology at Yale University School of Medicine, in New Haven, Conn. Ultrasound helps reduce the risk for complications associated with vascular catheterization, Dr. Barash said, but the physicians who do not use it often attribute their hesitation to the expense of the equipment. Another technology, even if useful, might not make much difference if it is even more expensive, said Dr. Barash, who was not involved in the Virginia Mason research. “Anything that improves the technique of ultrasound will be helpful. But the question is, how much is it going to cost to improve the technique?” Dr. Auyong acknowledged that 4-D ultrasound probes are two to four times more expensive than standard probes, which themselves cost roughly $10,000. Because the 4-D probes are relatively new, they also are somewhat larger and bulkier than conventional probes. “However, 4-D can be used in other applications, not just vascular access,” Dr. Auyong added. Clinicians are using the new technology in cardiology and obstetrics, he said, but not many yet in anesthesia. “There are just pockets of people who use it in any kind of application in anesthesia.” —Alison McCook

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Incorporating Scans To Identify Vertebral Fracture Improves Risk Assessment

Once VFA was integrated into FRAS, only 53 patients required another clinic review, Dr. Kuet explained.

“By incorporating VFA into risk assessment, we identified [clinically silent] vertebral fractures. More than one-fourth of these patients would not otherwise have been treated,” said presenting author Kar-Ping Kuet, MD, Sheffield Teaching Hospitals, National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom. “We also found important underlying causes of vertebral fractures in 46 patients. We believe the cost of adding VFA into our one-stop fracture risk assessment service [FRAS] is offset by a reduction in the need for further outpatient appointments.” Vertebral fractures are common in clinical practice and are a strong independent predictor of fracture risk, Dr. Kuet explained. “Despite this, only approximately one-third of all vertebral fractures come to clinical attention, leaving many patients undiagnosed and untreated. Knowledge of the presence of asymptomatic vertebral fractures enhances assessment of an individual’s future fracture risk,” he said. VFA scans use low-dose ionizing radiation to obtain an image of the spine, and can be performed concurrently with DXA. VFA was incorporated into FRAS for high-risk individuals in Sheffield Hospital in 2008. High-risk was defined as women over age 65 years, men over age 70 years, individuals over age 50 years taking corticosteroids for more than three

PROOF 1: 10/11 REV 1: 10/14 REV 2: REV 3: REV 4: REV 5: REV 6: REV 7: REV 8:

PICKED UP FROM: APPLIED TO:

previously undiagnosed and new vertebral fractures wereAD identified LAYOUT EXPT’D:in 29 Editor LAYOUT RECEIVED: patients with existingADvertebral fractures. Project no. Copy editor Vertebral fractures were present accordEDIT LAYOUT EXPT’D: Revision # Rev 1 Sales EDIT LAYOUT RECEIVED: ing to prior imaging in 36 patients. Layout date/time 27, 2011 10:55 AM Production In the 202 cases of confirmed vertemonths, height loss and September appearance on October 2008 to March 2009. EDITOR: Editorial date/time MAX sign-off ART DIRECTOR: were found to DXA suggestive of vertebral fractures. Of these, 83% were women and 17% bral fracture, 46 patients Trim size KEYWORDS: previously unknown causes. These The study presented in poster form at menCOMMENTS: with a mean age of 62 years; 1,833 have Color specs the 2011 annual meeting of the Euro- underwent VFA, and 360 were sus- causes included vitamin D deficiency/ File path Against Rheumatism, Max: Server Data:Data:Magazines:PAINMED:PMN House Ads:2011:enews pean League was pected of having a vertebralad:PMNeNewsAd_LetterCS5.indd fracture insufficiency (n=28), abnormal serum based on a systematic retrospective case and underwent subsequent spinal x-ray. or urine electrophoresis (n=6), primary review of 3,524 patients who attended Vertebral fractures were confirmed in hyperparathyroidism (n=4), secondary see fractures page 46 FRAS over a six-month period from 202 of 360 patients; of these, 137 were Full name of project

London—Incorporating vertebral fracture assessment (VFA) scans along with dual-energy x-ray absorptiometry (DXA) scans when assessing fracture risk in high-risk patients enhances the ability to identify clinically silent vertebral fractures for treatment, as well as underlying causes of vertebral fracture, according to new research. Using this new approach led to a substantial reduction in the need for further clinic visits.

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Each installment contains articles from the current month’s issue ahead of print, as well as links to other web-exclusive content

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NIH-funded Research Seeks To Establish New ‘Ontology’ for Pain

rom his days as a resident in neuropsychiatry, Werner Ceusters, MD, had an issue with language and the barriers it can create. He wasn’t bothered so much by how an English-speaking physician would communicate with a Spanish-speaking patient, for example (although that was an issue); rather, he was troubled by how health care practitioners’ choice of words and patients’ frequent inability to articulate their symptoms ultimately affected treatment outcomes. He also was concerned about how physicians and patients often failed to use the same terminology recognized by computer technology in patient care and research. “I felt very uncomfortable with the imprecise language that was used by health care workers and patients to express their feelings,” said Dr. Ceusters, now professor of psychiatry and director of the ontology research group at the University of Buffalo’s New York State Center of Excellence in Bioinformatics and Life Sciences. “There was, and still is, a huge gap between the way clinicians and patients express themselves and what computers are able to understand.” According to Dr. Ceusters, the diagnosis and management of pain is made more difficult by this language gap because physicians cannot “see” patients’ pain as they might perceive other symptoms. Dr. Ceusters and his team recently received a $794,000 research grant from the National Institutes of Health to develop and study an ontology—or uniform system of meaning—to describe pain and related disability as well as mental health and quality-of-life issues associated with pain. The researchers’ hope is that this new ontology will help clinicians distinguish between the categories of pain and ultimately produce more precise definitions of pain.

“The current focus on pain is due to interest in my work by a group of international pain experts who came to realize that traditional terminology‘There was, and still is, a huge gap between the way clinicians and patients express themselves and what computers are able to understand.’

—Werner Ceusters, MD

based approaches [are] a dead end,” Dr. Ceusters told Pain Medicine News. “And it builds further on our research on the application of my work in psychiatry.”

Dr. Ceusters and his team will design an ontology for pain based on the principles of the Open Biological and Biomedical Ontology Foundry, using basic formal ontology and referent tracking as “generic semantic technologies.” The Foundry is an organization supporting the development and use of controlled vocabularies in the biomedical field. They will test the efficacy of this language by applying it to five distinct patient groups, or data sets, in five different countries (the United States, United Kingdom, Sweden, Israel and Germany). The investigators will attempt to build a “realismbased ontology” to describe the data sets in a uniform and formal way that is general enough to include other information as it becomes available. By doing so, the researchers believe they can create a better means of assessing pain sufferers’ quality of life and degree of disability, and identify better methods and tools for unambiguous diagnostic and treatment annotation and classification. The goal is to build a software program that can represent pain in clear terms, with a symptom checklist that can be universally understood by both patients and practitioners as well as computers. “I think only time will tell if this approach will help,” said Charles Argoff, MD, professor of neurology and director of Albany Medical Center’s pain management program, in Albany, N.Y., who was not involved in the ontology project. “Much depends on how that vocabulary is disseminated and if it can become standard language. Given the regional variations and tremendous overall diversity of the population, this could be a daunting task to accomplish. However, it seems worth the effort to explore further.” —Brian P. Dunleavy

Platelet-rich Plasma Confers Only Slightly More Pain Relief Than Autologous Whole Blood for Chronic Tennis Elbow

reek investigators claim to have shown in a randomized controlled trial that platelet-rich plasma (PRP) is superior to autologous whole blood in the short term for the treatment of chronic lateral elbow epicondylitis. In their study, published in The American Journal of Sports Medicine (2011 Aug. 2 [Epub ahead of print]), the team found that at six weeks posttreatment there was a statistically significant reduction in pain with PRP compared with autologous whole blood. “Our findings were statistically significant at the six-week interval regarding pain, which is the major complaint of these patients,” lead researcher Christos Thanasas, MD, orthopedic

surgeon at the Henry Dunant Hospital in Athens, told Pain Medicine News. “So we can support the superiority of PRP treatment at this time frame. For its part, whole-blood treatment had a similar outcome in the next follow-up evaluations. Our message is that both treatments are promising.” Peter McCann, MD, chairman, Department of Orthopedic Surgery, Beth Israel Medical Center, New York City, said the study was well performed but does not show any clinically meaningful benefit from PRP. “There was no difference in elbow function at any time, and all results at six months were equivalent. As with the vast majority of PRP studies, there is no clinical benefit proven for PRP

to hasten tendon healing over current treatments—that is, rest, cortisone injections and rehab[ilitation],” observed Dr. McCann in an email. “The authors are correct that future studies are required to determine if there is any role for PRP in clinical practice, despite the hope (and hype) from lab studies that it may have a theoretical benefit.” Dr. Thanasas and his co-investigators randomized 28 consecutive patients with chronic lateral epicondylitis to a single injection of either autologous peripheral whole blood or autologous PRP. The injections were each 3 mL in volume. The study was single blind because it was difficult to mask the injection process.

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Prefilled Syringes Cut Waste—and Bottom Line on Drugs

witching from vials to prefilled syringes may save hospitals thousands of dollars each year by reducing drug waste, according to new findings presented at the 2011 annual meeting of the International Anesthesia Research Society. Researchers at the Medical University of South Carolina, in Charleston, compared the amount of unused drugs before and after clinicians began using prefilled syringes in a 10-room operating room (OR) suite. They found that the switch cut both the likelihood for and the volume of unused drug drawn into a syringe that would need to be discarded after the procedure. Comparing two time periods covering fewer than 200 surgeries each, the researchers found that this reduction in waste saved $126 per day (abstract S-124). Prefilled syringes likely reduce waste because they are sealed containers, ready to be used and able to be returned to the shelves if unused, explained study author Christopher Fortier, PharmD, manager of pharmacy support and OR services and clinical assistant professor at the institution. Often, anesthesiologists will draw up medications into vials in the OR “just in case they may need it,” Dr. Fortier noted. But if that medication is not used, it must be discarded. In contrast, if a prefilled syringe is not used, clinicians can return it, unopened, he said. “In that way, you’re only using the product you need, when you need it.” The system also cuts waste by reducing the amount of leftover medication in syringes, he added. For instance, an anesthesiologist may prepare 10 mL of a medication but use only 5 mL during surgery; the rest is discarded. But a 5-mL, prefilled syringe would obviate the waste, Dr. Fortier said. Prefilled syringes are more expensive upfront, Dr. Fortier said. However, the actual cost difference in

materials alone is hard to estimate, as clinicians who draw their own must purchase the syringes, labels and needles—and add overhead costs by asking technicians or doctors to draw up medications out of vials prior to surgery.

Prefilled syringes from PharMEDium, which sponsored the research.

To investigate whether prefilled syringes cut back specifically on drug costs by curbing waste, Dr. Fortier and his team measured the amount of discarded drugs—either unused or left over in used containers—from 154 surgeries (Phase I). They then compared that amount with what was wasted from 171 surgeries (Phase II) in which doctors used prefilled syringes.

“Even though we could have simulated the process of PRP extraction, the color of the liquids is different and keeping the injection away from the patients’ notice was not feasible,” explained Dr. Thanasas.

The research was funded by an educational grant from PharMEDium, which sells prefilled syringes. Fewer cases in Phase II had drug waste (38%) than did Phase I cases, in which 71% had discarded medications. When there were drugs to discard, the total volume decreased by 61%, going from 3,284 mL in Phase I to 1,266 mL in Phase II. As a result, the cost of drug waste fell from $3,106 in Phase I to $1,849 in Phase II, according to the researchers. The drugs that had the greatest decreases in waste included lidocaine (90%), followed by succinylcholine and glycopyrrolate. The current study did not look at safety with prefilled syringes, Dr. Fortier noted, but they have some important advantages over conventional syringes. Prefilled syringes are color-coded and have the name of the drug noted in different locations and angles on the syringe. They also contain bar codes that clinicians can scan to ensure they have the right drug. When clinicians draw up medications from vials, they also must label the syringe, and mistakes can happen, Dr. Fortier said. By using prefilled syringes, “you’re improving safety in how it’s labeled. There’s no question what you’re picking up.” Indeed, the Anesthesia Patient Safety Foundation has recommended that clinicians rely on prefilled or premixed solutions whenever possible, said Robert Stoelting, MD, president of the group, which has received support from PharMEDium. The increased upfront cost may cause some clinicians to hesitate before adopting prefilled syringes, Dr. Stoelting said. “This research addresses this issue and thus will be helpful to other institutions when they consider cost versus benefit—considering safety, less risk for contamination and the ability of an anesthesia professional to do other tasks,” he said. —Alison McCook

The clinician-researchers did not prescribe cortisone or nonsteroidal anti-inflammatory drugs during follow-up; the patients used oral acetaminophen and ice therapy for pain relief. They were all told to refrain from heavy physical activity for a week postprocedure. Patients also were reassessed one week after injection and given a simple program of stretching and eccentric-loading exercises to be performed twice a day for five weeks. At the one-week follow-up, 64% (9 of 14) of the PRP-treated patients and 28.6% (4 of 14) of autologous whole blood–treated subjects reported local pain and discomfort that started on the day of injection and gradually subsided (P<0.05). No other adverse events were reported. PRP treatment was associated with statistically significantly more improvement from baseline of visual

analog scale (VAS) scores compared with autologous blood treatment at six weeks, at 3.8 and 2.5 points, respectively (P<0.05). Both groups continued to experience slight improvements in VAS scores at threeand six-month follow-up, but the differences between the two groups’ improvements were not statistically significant. There also were no statistically significant differences between the two groups’ improvement on the Liverpool elbow score. “The Liverpool elbow score is only slightly affected by this disease and this fact, we believe, led to no important change after treatment, and this led in turn to no difference between the groups,” commented Dr. Thanasas. “Perhaps another more-suitable functional score for tennis elbow must be created and used.” —Rosemary Frei, MSc

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Mounting Board Demands Foster Growing Unease

any physicians are becoming increasingly concerned that conditions for maintaining board certification may also become unofficial requirements for maintaining state licensure, turning what has been voluntary into something that is mandatory to practice medicine. Many physicians also worry that they may have to duplicate the expensive and time-consuming board maintenance of certification (MOC) requirements to retain their medical licenses. Physicians who became board-certified during the past decade must pass a closed-book written examination and provide medical practice performance evaluations in addition to obtaining traditional continuing medical education (CME) credits in order to maintain certification, generally every seven to 10 years. The enhanced requirements, enacted in 2000 by the 24 medical and surgical specialty boards belonging to the American Board of Medical Specialties (ABMS), have garnered mixed reviews, ranging from grudging acceptance to vehement opposition. Supporters claim the process keeps physicians up to date in knowledge and practice and improves patient safety. Critics complain that the testing methodology does not represent current practice because it prohibits access to reference materials and forces doctors to spend unnecessary time and money cramming for tests in specialty areas in which they do not practice and have no intention of doing so. “The last thing we need is to have our primary care physicians retire rather than take on the board recertifications that are being forced on them,” said Stanley H. Block, MD, medical director of Providence Community Health Centers, in Rhode Island. Critics also say there is no objective evidence to support claims of improved patient outcomes. “I’m a champion test-taker. I’ve taken all kinds of tests throughout my medical career and I can tell you that a test does not measure whether you are any good or not. It merely tells you whether you are good at taking a test,” said Jane Orient, MD, an internist in Tucson, Ariz., and executive director of the Association of American Physicians and Surgeons, which represents doctors in private practice. “Maintenance of certification is a waste of time and money,” she said.

University of New York, Syracuse, according to American Medical News.

From MOC to MOL In April 2010, the Federation of State Medical Boards (FSMB), which represents the approximately 70 medical and osteopathic boards in the United States and its territories, enacted a new framework for maintenance of licensure (MOL). Currently, most state boards require renewing doctors to merely update information about their certifications, training and malpractice claims, provide proof of their CMEs and pay a fee. The new framework would require physicians to also pass periodic knowledge and skills tests, and to demonstrate performance standards using patient data from their own practices. Their results might then be compared with local and national statistics. Early next year, the FSMB will initiate pilot projects with 11 state medical boards to test various approaches to MOL, said Drew Carlson, communications director for the group. New standards would be enacted sometime after that.

The MOL framework tracks so closely to the MOC requirements that FSMB “strongly supports having physicians who are already engaged in maintenance of certification [be] recognized as being in compliance with any state’s MOL program,” said Humayun J. Chaudhry, DO, president and chief executive, in a statement posted on the organization’s Web site. Although the American Medical Association (AMA) supports lifelong learning, delegates at the AMA’s annual meeting in June expressed concern that new rules for MOL would force them to duplicate CME and other MOC requirements. The delegates voted to ask the ABMS not to require physicians to pass numerous examinations in order to maintain their certifications. “There is widespread concern about these multiple certifications and licensure examinations that are starting to chew up more and more expense,” said Gregory Threatte, MD, professor and chair of pathology at the State

Show Them the Money Some physicians believe MOC has less to do with improving quality of care than with collecting additional fees for examination and other services on the part of specialty medical boards and their related societies and associations. Contributing to this perception is the fact that some of the larger boards collect millions of dollars in annual testing fees, have assets totaling tens of millions of dollars and pay their officers and executives high salaries. Individual physicians can expect to pay several thousand dollars to complete the MOC process. The medical boards, all not-forprofit corporations, deny having a profit motive and maintain that the new requirements encourage lifelong learning, support physician competence, and improve clinical outcomes and patient safety. In addition to the AMA, many organizations including the Joint Commission and the Accreditation Council for Continuing Medical Education, endorse professional assessment, continuous learning and lifelong practice improvement. Nevertheless, financial conflicts of interest, or at least their appearance, can arise because medical boards and their affiliated societies are financially intertwined in the recertification process. “For some of the other boards, a significant amount of their revenue comes from maintenance of certification because they’ve created products that fit some of those requirements,” said David L. Brown, MD, secretary of the American Board of Anesthesiology (ABA). “Unlike some of the boards that have developed products to sell to their physicians, we made a very conscious decision not to do that so it wouldn’t be perceived that we were somehow trying to increase revenues with products,” Dr. Brown said. “We purposely tried to stay away from having that conflict.” The ABA last year collected $912,000 in MOC fees, less than 10% of the organization’s $9.5 million annual revenue, he said. Mark A. Warner, MD, president of the American Society of Anesthesiologists (ASA), said the ASA is not the exclusive provider of educational materials and activities for the maintenance of certification in anesthesiology (MOCA) process. see Board page 42

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“Any other organization may develop materials and activities for the MOCA process, presumably working with the ABA to ensure that these meet their guidelines,” Dr. Warner said. Thus far, however, only the ASA has sought approval to supply these materials. “It seems likely that this will change in coming years, as I know of at least one anesthesiology subspecialty organization that is discussing the possibility of doing so,” said ABA President Glenn P. Gravlee, MD. The ABA has been implementing MOCA over the past decade. Anesthesiologists who were originally certified prior to 2000 are “grandfathered” or exempted from the process, but they are encouraged to participate in it. In addition to CMEs, diplomates must submit a four-step case evaluation and complete an anesthesia simulation course at an ASA-certified simulation center. The “cognitive examination” consists of 200 multiple-choice questions, 150 of which are general and the remaining 50 are specific to pediatrics, cardiothoracic medicine, neuroanesthesia, critical care, obstetrics/gynecology and pain medicine. Forcing all anesthesiologists to study for these subspecialties is wasteful, said Paul Kempen, MD, PhD, a general anesthesiologist at the Cleveland Clinic, in Ohio. “They want us to test every 10 years in all areas of anesthesia, including chronic pain management, which is a whole new specialty in itself. It’s a waste of time and money,” he said. The ABA’s Dr. Brown explained preparing separate specialty examinations would have been too costly. “So we’re trying to bridge it to make it pretty commonsense stuff that actually has applicability for most people,” he said. But so far, it appears that nearly all anesthesiologists who are required to undergo MOCA are in the process of doing so. According to Dr. Brown, 99.6% of the 2000 cohort of ABA diplomates is expected to complete the MOCA program by 2013. Dr. Warner added, “The ASA is not aware of any information on anesthesiologists who are critics of the MOCA process. Some individuals have expressed concern to ASA that the MOCA process is either not clear to them or is an activity that they do not wish to pursue. However, there see board page 47

Simulation Centers Get Boost From MOCA

ne of the requirements of MOCA is to attend an approved anesthesia simulation course. The ASA has endorsed 27 simulation centers nationwide, including at such major institutions as Mount Sinai, Stanford University and Vanderbilt University. ASA President Mark Warner, MD, said the centers were selected based on their educational programs, facilities and instructor experience. Participants work as part of a small team but take turns being the primary anesthesiologist. Scenarios recreate challenging clinical cases, including “the management of hypoxemia and hemodynamic derangement and to emphasize teamwork skills in resolving such events,” Dr. Warner said. Each participant’s performance is videotaped and reviewed afterward, but is neither graded nor scored. “This is not a pass/fail exam, but an experiential learning opportunity that is designed to stimulate

practice improvement,” the ASA said. According to David Brown, MD, president of the ABA, past participants viewed the experience as positive, with 92% indicating it would change their practice. Paul Kempen, MD, PhD, general anesthesiologist at the Cleveland Clinic, in Ohio, remains critical. “The installation of simulators in university settings requires the investment of tremendous amounts of money. Now they want to create repeat and paying customers to use this equipment at preferred sites and finance it,” he said. “There is no protocol (yet) as to what should be simulated in terms of recertification, nor validation that it is effective in this setting,” Dr. Kempen added. “There are no tests required for simulation. It’s almost as if they are saying, ‘Just come, pay for it, and you’ll have a good time.’” —T.A.

15 16

21 14

13 18

5 12 23

26 4

9 19

Cooper Simulation Laboratory, Cooper University Hospital, Camden, N.J.

Center for Medical Simulation, Cambridge, Mass.

Duke University Human Simulation and Patient Safety Center, Duke University Medical Center, Durham, N.C.

Texas Tech University Health Sciences Center, Lubbock, Texas

Stanford School of Medicine Center for Immersive and Simulation-based Learning, Stanford, Calif.

6. 7.

Stony Brook University Medical Center Clinical Skills Center ,Stony Brook, N.Y. University of Utah Anesthesiology Department Center for Patient Simulation, Salt Lake City, Utah

The Mount Sinai School of Medicine Human Emulation, Evaluation, and Education Lab for Patient Safety, New York City

Patient Simulation Center, University of Texas

Medical Branch at Galveston

18. University of Chicago Center for Simulation

10. University of Virginia Health System Medical Simulation Center, Charlottesville

19. University of Miami–Jackson Memorial Hospital Center for Patient Safety

11. Howard and Joyce Wood Simulation Center, Washington University in St. Louis School of Medicine

20. UCLA Simulation Center, Los Angeles

12. Anesthesia Simulation Center, San Francisco General Hospital, University of California, San Francisco Department of Anesthesia and Perioperative Care 13. Northwestern Center for Clinical Simulation, Northwestern University Feinberg School of Medicine, Chicago

21. Mayo Clinic Multidisciplinary Simulation Center, Rochester, Minn. 22. Vanderbilt University Simulation Technologies Program, Nashville, Tenn. 23. University of New Mexico School of Medicine, Anesthesiology Simulation Education Program, Albuquerque

14. Peter M. Winter Institute For Simulation Education and Research, University of Pittsburgh

24. Wake Forest University Baptist Medical Center Patient Simulation Laboratory, Winston Salem, N.C.

15. Institute for Simulation and Interprofessional Studies, University of Washington, Seattle

25. Beth Israel Deaconess Medical Center, Simulation and Skills Center, Boston

16. Oregon Health & Science University Anesthesia Simulation Services Attention, Portland

26. Medical University of South Carolina Healthcare Simulation Center, Charleston

17. Penn State Hershey Clinical Simulation Center, Hershey

27. University of Kentucky Department of Anesthesiology, Lexington

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Atlas of Image-Guided Intervention in Regional Anesthesia and Pain Medicine

James P. Rathmell Thoroughly illustrated with state-of-the-art CT and fluoroscopic scans and original drawings, this atlas offers step-by-step instructions for imageguided block techniques in regional anesthesia and pain medicine. For each procedure, Dr. Rathmell provides details on patient selection, patient positioning, technique and potential complications, with special attention to the use of radiographs to guide needle or catheter placement.

Atlas of Pain Management Injection Techniques: Second Edition

Steven D. Waldman, MD, JD

ORDER OnLInE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

This resource conveniently places at your fingertips every essential pain management injection technique used today—in a straightforward, beautifully illustrated manner that lends itself to ready implementation in any clinical setting. From head and neck to foot and ankle, this reference equips you to perform a complete range of clinical injection techniques.

Beyond Pain: A Comprehensive Pain Board Review for the Pain Management Physician

Thomas Moshiri, MD A detailed and intensive review of the core knowledge needed to pass the pain boards. Containing the essential information you must know and condensing complex subjects into easy-to-understand topics. No other book contains all the information you need in an easy-to-understand manner in one single location.

Chronic Pain Management: Guidelines for Multidisciplinary Program Development

Michael E. Schatman; Alexandra A. Campbell The only source to offer these strategies, backed by the American Academy of Pain Management, this reference will help readers understand the benefits of multidisciplinary chronic pain management and help them apply these techniques to their clinic for effective, consistent and financially viable patient care.

Essentials of Pain Management

Evidence-Based Chronic Pain Management

For Doctors Only: A Guide to Working Less & Building More, Third Edition

Nalini Vadivelu; Richard D. Urman; Roberta L. Hines

This concise, evidence-based text contains essential topics important for every pain management student, trainee and practitioner. Both acute and chronic pain management principles and techniques are discussed, while numerous case vignettes help reinforce basic concepts and improve clinical decision making. Throughout, a multidisciplinary approach to pain is stressed. Behavioral and physical therapies, plus ethical considerations, are also discussed in this indispensable guide for anyone involved in the management of pain.

Cathy Stannard; Eija Kalso; Jane Ballantyne

Evidence-Based Chronic Pain Management contributes an important advance in the practice of pain management providing the information on which to build more coherent and standardized strategies for relief of patient suffering. It answers questions about the most effective methods, and those that are not effective yet continue to be used. The volume also includes discussion of the positive and the negative evidence, and addresses the grey areas where evidence is ambivalent.

Christopher R. Jarvis; David B. Mandell; Jason M. O’Dell This volume helps physicians move beyond theory and into practice by outlining how to find quality advisors and construct a collaborative, multidisciplinary planning team.

McGraw-Hill Specialty Board Review: Pain Medicine Salahadin Abdi, Howard Smith; Pradeep Chopra

McGraw-Hill Specialty Board Review: Pain Medicine is the perfect way to prepare for the American Board of Anesthesiology exam as well as exams given by the American Board of Pain Medicine and the American Academy of Pain Medicine. It’s also great for recertification! You’ll find everything you need in one comprehensive review…questions, answers, explanations, practice tests and references. PMN1011

44 I PainMedicineNews.com

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Policy & Manageme nt

What Can IT Do for Your Growing Pain Practice? Dear Arizona Pain Specialists,

My IT [information technology] manager has submitted several proposals for purchasing new software and hardware to supplement our current systems. All of our systems are working now, so I can’t help but think most of these updates are unnecessary. Should I approve these purchases? Is it normal for a company to have large dollar technology purchases even when there is nothing wrong? Thank you, Sticker Shocked Dear Sticker Shocked,

ithout knowing the details of such proposals, it’s difficult to say if your practice has a sufficient technology infrastructure. That said, it is not outside the realm of possibility to spend a large amount of money improving your existing infrastructure. When considering tech upgrades, several big-picture questions need to be asked and evaluated. You should start with the most important part of the process, a needs assessment.

1. Total Cost of Ownership: Is there an annual subscription fee? Do you need to host this application on your own in-house server and, if so, will you need to purchase this server? Remember that less initial cost is not always better. The cost should be weighed against a list of pros and cons about the software. Assign a dollar amount to each feature to help make decisions. Neglecting this step could mean a greater overall cost in the long run, even though the initial cost appears much cheaper. For example, an email system that does not include outof-office replies, forwarding or distribution groups may cost half as much as a competing application that includes all of these features, but it would not satisfy the needs assessments of most pain practices. 2. Upgrades and Patches: Is the device or software updated regularly with new bug fixes and features? Does the manufacturer still release new products or is this an old, outdated support product?

The Needs Assessment The needs assessment goes directly to your point, “All of our systems are working now, so I can’t help but think most of these updates are unnecessary.” Your IT manager should be able to explain to you why you “need” this new software or hardware and how it will improve daily workflow. Success must be defined All projects, small and large, by your organization’s needs. must start with a needs assessand can vary from faster Internet, ment to properly execute. The scope of the assessment can vary better electronic health records experience, greatly depending on the project, less network downtime, better phone routing but the goals are the same: To garner commitment from all parsystem or any other IT solution. ties who will be affected by the project, and to ensure that those who use the final product have a chance to provide You don’t want a dead product. Companies that feedback before purchasing. Those influenced by the have infrequent updates may take months or years purchase should be able to provide a list of software/ to resolve bugs with their software or devices, which hardware features needed, as well as rationale for could lead to a loss of productivity when issues with how the purchase would improve workflow. As proj- the software arise, incompatibility with newer prodect size increases, the needs assessment and employee ucts and security vulnerabilities. feedback required for appropriate decision making become more important. 3. Support: How many local support options are there? Is there a spare unit on hand if there is a Research and Testing hardware failure? Can the system administrator After completing the needs assessment, the system troubleshoot the common issues with the device? administrator (IT manager) should research hardYou should always have multiple support paths for ware and software options to meet the established your final solution. A local consultant should be at objectives. The following criteria should be taken the top of your list, but remote support options are into consideration: also acceptable.

4. Scalability: Scalability refers to the ability of a system or network to either assimilate growing amounts of work into the existing system, or for the system to expand to accommodate the increasing workload. You may have 10 to 15 employees now, but will this option work when there are 40 to 50 employees? 100 employees? How soon will you need to worry about having sufficient technology for that many employees? A general rule of thumb is to consider how a system will expand with an additional 50 users. It’s important to know if there are costs associated with user licensing and if your server hardware is capable of supporting more than your current user load. 5. Implementation Time: How long will it take to apply this software or hardware solution? Will an outside consultant be necessary to complete the steps? Can your system administrator handle the installation and configuration? It is always advisable to implement a robust, easy to manage system. It takes manpower to administrate systems, so the less complex the administration task, the more time your staff has to handle other responsibilities.

6. Workflow: This is perhaps the most important piece of the research process. How does this application or hardware fit into your existing workflow? Is it difficult for employees to use the system while they’re working or does it help them do their job more efficiently? The objective of any piece of software or hardware is either to increase security or to improve functionality. A system shouldn’t be implemented when it doesn’t achieve one of these objectives. If a system is not improving your security or your usability, there is no reason to implement it.

7. Security: In the medical industry, every application must be scrutinized for security. Does the vendor store patient information on its servers? When sending patient information, is the application encrypting that data or, at the very least, de-identifying the data? Are the users monitored and logged by the system? Can you differentiate between employees? Business owners often skimp on security for a variety of reasons, including cost, inconvenience or they underestimate its importance. This is a big mistake. Security should be taken very seriously and you should avoid any application that does not provide you with some basic features, such as unique user logins, an audit trail and user/group-level permissions.

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IT Project Implementation Analogy Any new IT implementation has a basic goal of providing solid solutions to enhance quality for the user. Success must be defined by your organization’s needs and can vary from faster Internet, better electronic health records experience, less network downtime, better phone routing system or any other IT solution. Think of a successfully implemented IT project as a pitcher of water. When the rim of pitcher is brimming with water, your organization has reached success for a particular project. You can fill the pitcher with two things: time and money. If you need a project implemented successfully within a week, you don’t have much time and it will cost you more money. If, on the other hand, you have a long-term project, you may be able to budget less money toward this endeavor and still reach the same level of success. The size of the pitcher is determined by the needs assessment. If your practice has a long list of requirements and specifications for a piece of software, your needs list will be longer. If your list contains more flexible, less-specific requirements, you will have fewer needs. Implementation time represents the period you have to start up the project. A project that must be executed within one week would be represented by a small amount of human capital. Essentially, greater implementation time means you can pour more time into the success of the project. And the bigger the budget, the more money you can pour into the success of the project. You should start by determining what constitutes success for a particular IT project. What you want to accomplish will dictate the implementation time and size of the budget. The goal is to set realistic expectations for both and to acknowledge that an improperly funded or constrained project will not be as successful as one that is properly supported. Piecemeal Implementation: A Developmental Paradigm Normally, software and hardware are not binary systems. You can, for example, purchase certain

components that will fulfill the immediate needs of the company and also allow you to improve on them later. When working with a piecemeal development and implementation process, you must be careful to use a system that provides flexibility to alter and improve at a later time. A good idea is to purchase software and hardware that either allow for future growth or is inexpensive enough that it can easily be replaced when you want to finish the full implementation. When deciding what system to choose for an incremental, à la carte, implementation, ask what features will be missing during the initial deployment. You need to plan for the changes in workflow that will come with new features, and you need to plan the entire rollout so there are no surprises halfway through the implementation. For instance, a small pain practice with only a few employees doesn’t necessarily need an email system that includes distribution groups. However, the physicians might want to buy a system that includes a distribution group’s feature to not hinder future growth. As with any implementation, communication is the key to success. It should be clearly outlined when features will be implemented, which departments will be affected and who will take responsibility for ensuring that employees are following new processes. Remember that it costs money to fail at implementation. Not only do you lose the cost of the software or hardware, but you also lose labor costs and time spent researching the product. Your employees will also suffer if their workflow is being changed or if they have to work around, and not through, the system you implemented. What Can You Do? It is common to have high expenses during the growth phase of a company, especially for technology and infrastructure development. Remember, technology is here to make workflow better, not worse. It is sometimes easy to forget that employees will be using the systems you’re implementing and this is when many of the issues mentioned above can interfere with your company’s workflow.

In summary, clearly define objectives for the project and stick to them. Changing objectives mid-project will cause major delays in all phases and may require the system administrator to begin anew. If you find that your projects frequently need major revision throughout the implementation process, then you should reexamine your needs assessments process. Provide your system administrator with a reasonable budget and implementation timeframe. You will exhaust him or her if you keep projects under extreme time constraints or without proper funding. Have your system administrator develop a return on investment analysis after you’ve proposed the budget. It’s possible that it may cost more than you expect but have better returns in the long-term. Understand that technology, although not revenue generating, is about loss prevention and efficiency. Leverage IT resources to streamline workflow and to increase the stability of systems. Trust those you’ve hired to run your IT department, and ask these staff members to show you how and why increased technology purchases will benefit your practice. If they produce a strong needs assessment with sufficient staff feedback, make the recommended changes. A smart, effective practice uses the best technology available, including human capital, such as an intellectual IT department that can provide appropriate advice. —Paul Lynch, MD, Tory McJunkin, MD, and Randy Braunm Drs. Lynch and McJunkin founded Arizona Pain Specialists, a comprehensive pain management practice with three locations, seven pain physicians, ten midlevel providers, three chiropractors, on-site research and behavioral therapy. They teach nationally and are consultants for St. Jude Medical and Stryker Interventional Spine. Through their partner company, Boost Medical, they provide practice management and consulting services (including IT) to other pain doctors throughout the country. For more information, visit ArizonaPain.com and BoostMedical.com.

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The approach is strikingly conciliatory in contrast to litigious and punitive attempts to tackle the problem, said Ronald Friedman, JD, a private practice attorney who also serves on the Washington state attorney general’s prescription drug task force. “I see lots of misdirected prosecution that targets alleged overprescribing, accuses physicians of Medic-

‘I see lots of misdirected prosecution that targets alleged overprescribing, accuses physicians of Medicaid fraud and creates an atmosphere of paranoia and fear.’

Michael Von Korff, ScD, helped develop the initiative, and co-authored a paper outlining its components, which was published in Health Affairs (2011;30:1420-1424). Dr. Von Korff said primary care physicians have varying degrees of knowledge when it comes to appropriate opioid treatment and often are unaware that long-term opioid treatment typically is only “modestly effective” for treating chronic noncancer pain. He said professional society guidelines often are vague and leave the door open to wide variability in treatment. “There’s a disconnect between specialists and primary care physicians who dispense the overwhelming majority of opioid prescriptions,” Dr. Von Korff said. “Primary care physicians want practical and

—Ronald Friedman, JD

aid fraud and creates an atmosphere of paranoia and fear,” Mr. Friedman said. “Rather than spending public dollars converting the matter into a criminal justice issue, the best answer for this health care issue is to treat it as a health care issue and address it through initiatives such as those established at Group Health.” The Group Health initiative, rolled out in September 2010, is aimed specifically at changing the way primary care physicians prescribe opioids to patients who have chronic noncancer pain. Physicians are now asked to electronically document treatment expectations that have been agreed on by both the physician and the patient; to agree on a medication regimen; to develop a schedule for treatment monitoring visits; and to conduct urine drug screens when appropriate. Clinicians also are encouraged to seek out specialist consultations for complex cases and cases in which the patient does not respond to opioid-based treatment. Furthermore, patients with chronic, noncancer pain receiving long-term opioids are now managed by a single physician who assumes overall responsibility for opioid prescribing.

fractures continued from page 31

hyperparathyroidism due to renal disease (n=4), hypogonadism (n=3) and thyrotoxicosis (n=1). Identification of vertebral fracture led to treatment initiation for osteoporosis in 53 patients who would not have been treated on the basis of bone

is an important element of a multipronged approach to the problem of misuse and overdose, Dr. Von Korff said. Alex Cahana, MD, chief of the Division of Pain Medicine in the Department of Anesthesiology and Pain Medicine at the University of Washington School of Medicine, in Seattle, helped develop Washington state House bill 2876, which is aimed at reducing opioid misuse and overdose. He agreed that measuring pain, mood and function in every clinical encounter is a critical piece in addressing the issue. Dr. Cahana said the University of Washington has implemented an initiative similar to Group Health’s and most of the participating clinicians have responded positively. However, he said there were some initial concerns that closer scrutiny of prescribing practices would deter physicians from prescribing opioids to patients who need them.

‘We’re simply asking clinicians to take a look at whether the treatments they’re prescribing are, in fact, leading to the results they were meant to achieve. If they aren’t, they need to look at other approaches like exercise, alternative medicine and sleep hygiene, which are not used often enough.’ —Alex Cahana, MD

specific guidelines; but, guideline recommendations are broad and subject to differing interpretations about what constitutes appropriate care.” Dr. Von Korff is a senior investigator at Group Health’s research institute. To address these issues, Group Health clinicians developed a set of more specific treatment guidelines for their primary care physicians to follow. Adding structure to patient care by implementing specific guidelines and clinical and administrative protocols

mineral density alone and led to treatment alterations in an additional six patients. In the past, all patients with vertebral fractures required another clinic visit, but once VFA was integrated into FRAS, only 53 patients required another clinic review, Dr. Kuet explained. Rachelle Buchbinder, MD,

“We’re simply asking clinicians to take a look at whether the treatments they’re prescribing are, in fact, leading to the results they were meant to achieve,” Dr. Cahana said. “If they aren’t, they need to look at other approaches like exercise, alternative medicine and sleep hygiene, which are not used often enough.” Dr. Von Korff said that between September 2010 and September 2011, Group Health’s primary care physicians developed plans for 6,000 patients with chronic noncancer pain receiving opioids. He said it is too early to tell whether the initiative is decreasing rates of misuse and overdose, but initial feedback is promising. “Anecdotally, the initiative seems to have improved coordination of care and physicians are more aware of who among their patients is receiving opioids and whether they are improving,” he said. —David Wild

director of the Monash Department of Clinical Epidemiology at Cabrini Hospital in Malvern, Australia, said that this study suggests that the imaging technique is worthwhile. “Any imaging technique that improves identification of silent vertebral fractures leading to appropriate investigation and management would be clinically important,” she

wrote in an email. Dr. Buchbinder has published a number of articles on vertebroplasty, including a randomized controlled clinical trial comparing vertebroplasty to a sham procedure published in The New England Journal of Medicine in 2009 (361:557-568). —Alice Goodman

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are no survey data, to our knowledge, on the interest or disinterest of anesthesiologists in the MOCA process.” Widespread Criticism Yet, although some physicians say MOC is worthwhile, this sentiment does not appear to be widespread. In March 2010, The New England Journal of Medicine asked readers to vote on whether they thought a physician who holds certificates of unlimited duration from the American Board of Internal Medicine (ABIM) should voluntarily enroll in maintenance of certification (N Engl J Med 2010;362:948-952). The results were overwhelming: 63% of more than 2,500 respondents recommended against enrolling. Strikingly, more than 80% of the respondents were themselves boardcertified physicians (N Engl J Med 2010;362:e54-e55). Many of them commented that the cost outweighed the benefit, and that the program was a money-generating activity for ABIM. Many respondents who reported having gone through the process said it was only marginally beneficial and took time away from caring for patients and other learning activities. Others argued for keeping the requirement but revising the process to make it less burdensome. Martin S. Dubravec, MD, an allergist in Cadillac, Mich., completed his MOC with the American Board of Allergy and Immunology in 2008. “The material did not reflect my practice,” Dr. Dubravec said. “It was unduly burdensome and made it harder for me to provide high-quality care to patients, since I had to spend many hours and thousands of dollars preparing for clinically irrelevant tests.” Ron Benbassat, MD, an internist in Beverly Hills, Calif., said he is hoping to be a catalyst for change. “We are all for staying current with medical changes, but the onerous [MOC] program is no way to achieve this,” he said. Dr. Benbassat runs a Web site (www. changeboardrecert.com) in an effort to mobilize physicians to petition their boards, hospitals and state medical organizations to reform or abolish MOC requirements. “Doctors are collectively apathetic and afraid to make waves,” he said. “Doctors need to take their heads out of the sand, unify and take control back of our profession.” The controversy over MOC is not limited to physicians. The National

Board on Certification and Recertification of Nurse Anesthetists (NBCRNA), in August, announced proposed new rules for continued certification, including a standardized examination every eight years. The response has been vocal and about evenly split, said Wanda Wilson, PhD, CRNA, executive director of the American Association of

Nurse Anesthetists. Karen Plaus, PhD, CRNA, executive director of the NBCRNA, said her organization will consider the feedback and comments before making a final recommendation to its board. When it comes to anesthesiologists, Dr. Brown said the ABA has tried to make MOCA “the least onerous we can for our docs, with as much clarity

and transparency as we can for society.” “It’s a balance to try to get it right,” Dr. Brown continued. “Do we get it right for everybody? I would guess that we don’t. But the worst thing would be to have some group that doesn’t know anything about medicine trying to make these rules instead of us.” —Ted Agres

(naproxen sodium)

BRIEF SUMMARY NAPRELAN® (naproxen sodium) CONTROLLED-RELEASE TABLETS NAPRELAN® Controlled-Release Tablets, 375mg, 500mg and 750mg Equivalent to 375mg, 500mg and 750mg naproxen Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS). • Naproxen as NAPRELAN® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (See WARNINGS). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly people are at greater risk for serous gastrointestinal events. (See WARNINGS). DESCRIPTION NAPRELAN®* Tablets contain naproxen sodium, an arylacetic acid nonsteroidal antiinflammatory drug (NSAIDs). NAPRELAN® Tablets use the proprietary IPDAS®** (Intestinal Protective Drug Absorption System) technology. It is a rapidly disintegrating tablet system combining an immediate release component and a sustained release component of microparticles that are widely dispersed, allowing absorption of the active ingredient throughout the gastrointestinal (GI) tract, maintaining blood levels over 24 hours. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of NAPRELAN® Tablets and other treatment options before deciding to use NAPRELAN® Tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). NAPRELAN® Tablets are indicated for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis and acute gout. It is also indicated in the relief of mild to moderate pain and the treatment of primary dysmenorrhea. CONTRAINDICATIONS NAPRELAN® is contraindicated in patients: • with known hypersensitivity to naproxen. • who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS-Anaphylactoid Reactions, and PRECAUTIONS-Preexisting Asthma). • for peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of COX-2 selective and nonselective NSAIDs, given for up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see GI Effects – Risk of Ulceration, Bleeding, and Perforation). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS). Hypertension NSAIDs, including NAPRELAN® can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including NAPRELAN®, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. NAPRELAN® should be used with caution in patients with fluid retention or heart failure. GASTROINTESTINAL EFFECTS – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including NAPRELAN®, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and, therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. RENAL EFFECTS Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, NSAID administration may cause a dose-dependent reduction in

prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of NAPRELAN® in patients with advanced renal disease. Therefore, treatment with NAPRELAN® is not recommended in those patients with advanced renal disease. If NAPRELAN® therapy must be initiated, close monitoring of renal function is advisable. ANAPHYLACTOID REACTIONS As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to NAPRELAN®. NAPRELAN® should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS-Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. SKIN REACTIONS NSAIDs, including NAPRELAN®, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. PREGNANCY In late pregnancy, as with other NSAIDs, NAPRELAN® should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General NAPRELAN® cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of NAPRELAN® in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including NAPRELAN®. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with NAPRELAN®. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), NAPRELAN® should be discontinued. Hematological Effects Anemia has been seen in patients receiving NSAIDs, including NAPRELAN®. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term NSAID treatment, including NAPRELAN®, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving NAPRELAN® who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, NAPRELAN® should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. INFORMATION FOR PATIENTS See full Prescribing Information (PI) for suggested patient information that should be discussed prior to initiating therapy. Patients should also be encouraged to read the Medication Guide For NSAIDs (accompanies the PI) before taking NAPRELAN®. DRUG and LABORATORY TEST INTERACTIONS ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin: When NAPRELAN® is administered with aspirin, its protein binding is reduced, although the clearance of free NAPRELAN® is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics: Clinical studies, as well as post-marketing observations, have shown that NAPRELAN® can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Laboratory Test Interactions Serious GI tract ulcerations and bleeding can occur without warning symptoms; physicians should monitor for signs or symptoms of GI bleeding. Patients on longterm NSAIDs treatment should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, NAPRELAN® should be discontinued. Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. It is also suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed (Porter-Silber test). Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).

(naproxen sodium) CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY A two-year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses as high as 0.28 times the systemic exposure to the recommended human dose resulted in no evidence of tumorigenicity. PREGNANCY(Category C) There are no adequate, well-controlled studies with NAPRELAN® Tablets in pregnant women. NAPRELAN® Tablets should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Some evidence suggests when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during third trimester should be avoided. LABOR AND DELIVERY Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of NAPRELAN® on labor and delivery in pregnant women are unknown. NURSING MOTHERS The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided. PEDIATRIC USE No pediatric studies have been performed with NAPRELAN® Tablets, thus safety of NAPRELAN® Tablets in pediatric populations has not been established. GERIATRIC USE Clinical studies of NAPRELAN® Tablets did not include a sufficient number of subjects ≥ 65 years of age, prohibiting comparison between response in elderly and younger subjects. In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. Elderly or debilitated patients seem to tolerate GI ulcerations and bleeding less well than other individuals taking NSAIDs (see WARNINGS, RISK of GI Ulceration, Bleeding And Perforation With NSAID Therapy). Additionally, elderly patients may be more sensitive to dosedependent reduction in renal prostaglandin formation while taking NSAIDs (see WARNINGS, Renal Effects). ADVERSE REACTIONS The adverse reactions reported were based on the results from two double-blind controlled clinical trials of three months duration with an additional nine month open-label extension. A total of 542 patients received NAPRELAN® Tablets either in the double-blind period or in the nine month open-label extension. The most frequent adverse events from the double-blind and open-label clinical trials were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). INCIDENCE >1% BY BODY SYSTEM (Probable Causal Relationship) Incidence: ≤10% (number provided), 9-3%= asterisk, >3% unmarked Body as a Whole—Pain (back)*, pain*, infection*, fever, injury (accident), asthenia, pain chest, headache (15%), flu syndrome (10%). Gastrointestinal—Nausea*, diarrhea*, constipation*, abdominal pain*, flatulence, gastritis, vomiting, dysphagia, dyspepsia (14%), heartburn*, stomatitis. Hematologic—Anemia, ecchymosis. Respiratory—Pharyngitis*, rhinitis*, sinusitis*, bronchitis, cough increased. Renal—Urinary tract infection*, cystitis. Dermatologic—Skin rash*, skin eruptions*, ecchymoses*, purpura. Metabolic and Nutrition—Peripheral edema, hyperglycemia. Central Nervous System—Dizziness, paresthesia, insomnia, drowsiness*, lightheadedness. Cardiovascular—Hypertension, edema*, dyspnea*, palpitations. Musculoskeletal—Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder. Special Senses—Tinnitus*, hearing disturbances, visual disturbances. General—Thirst. OVERDOSAGE Significant naproxen overdosage may be characterized by drowsiness, heartburn, indigestion, nausea or vomiting. A few patients have experienced seizures, but it is not clear whether or not these were drug-related. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic carthartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding. DOSAGE AND ADMINISTRATION Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). RHEUMATOID ARTHRITIS, OSTEOARTHRITIS, AND ANKYLOSING SPONDYLITIS The recommended starting dose of NAPRELAN® Tablets in adults is 750-1000 mg once daily. During long-term administration, the dose of NAPRELAN® Tablets may be adjusted up or down depending on the clinical response of the patient. The lowest effective dose should be sought and used in every patient. In patients who tolerate lower doses of NAPRELAN® Tablets and need additional anti-inflammatory/ analgesic activity, the dose may be increased to 1500 mg once daily for limited periods. The physician should observe sufficient increased clinical benefit to offset the potential increased risk (see CLINICAL PHARMACOLOGY). A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see PRECAUTIONS). Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. MANAGEMENT OF PAIN, PRIMARY DYSMENORRHEA, AND ACUTE TENDINITIS AND BURSITIS The recommended starting and maintenance dose is 1000 mg once daily. For patients requiring greater analgesic benefit, 1500 mg may be used for a limited period. The NAPRELAN® DOSE CARD provides a 10-day tapered dose regimen contained in a single blister dose pack that provides 1500 mg given once daily (two NAPRELAN® 750 mg tablets) for 3 days, with a taper to 1000 mg given once daily (two NAPRELAN® 500 mg tablets) for the remaining 7 days. ACUTE GOUT The recommended dose of NAPRELAN® Tablets on the first day is 1000 - 1500 mg (given once daily), followed by 1000 mg given once daily, until the attack subsides. HOW SUPPLIED NDC 68453-375-10: NAPRELAN® 375 tablets in bottles of 100 NDC 68453-850-75: NAPRELAN® 500 tablets in bottles of 75 NDC 68453-777-03: NAPRELAN® 750 tablets in bottles of 30 NDC 68453-900-02: NAPRELAN® DOSE CARD: single blister card Rx Only: US Patent 5,637,320 Store at controlled room temperature, 20°-25°C (68° - 77°F). * NAPRELAN® is a registered trademark of Elan Corporation plc ** IPDAS is Registered Trademark of Elan Pharma Int. Ltd. Manufactured by: Elan Pharma International Ltd., Athlone, Ireland Manufactured for: Victory Pharma, Inc., San Diego, CA 92130 PI375011a Rev 07/10

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