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LILY RECEIVES MARKETING EXCLUSIVITY EXTENSION FOR CYMBALTA

Eli Lilly & Company announced on July 6 that duloxetine (Cymbalta) will have an additional 6 months of U.S. marketing exclusivity, which now will run through December 2013. The drug is approved both as an antidepressant and analgesic. The FDA granted the extension because the company completed a study of duloxetine in children.

Lilly conducted two studies of the drug's effects on children and adolescents, but it does not plan to pursue approval for the drug in those age groups because there were no clear benefit over a placebo for pediatric depression.

FDA ANNOUNCES SAFETY MEASURES FOR EXTENDED-RELEASE AND LONG-ACTING OPIOIDS

The U.S. Food and Drug Administration (FDA) announced on July 9, 2012, approval of a risk evaluation and mitigation strategy (REMS) for extended-release (ER) and long-acting (LA) opioids, highly potent drugs approved for moderate to severe, persistent pain that requires treatment for an extended period. The REMS is part of a federal initiative to address the prescription drug abuse, misuse, and overdose epidemic. The REMS introduces new safety measures designed to reduce risks and improve the safe use of ER/LA opioids, while ensuring access to needed medications for patients in pain.

“Misprescribing, misuse, and abuse of extended-release and long-acting opioids are a critical and growing public health challenge,” said FDA Commissioner Margaret A. Hamburg, MD. “The FDA's goal with this REMS approval is to ensure that health care professionals are educated on how to safely prescribe opioids and that patients know how to safely use these drugs.”

The new ER/LA opioid REMS will affect more than 20 companies that manufacture these opioid analgesics. Under the new REMS, companies will be required to make education programs available to prescribers based on an FDA Blueprint. It is expected that companies will meet this obligation by providing educational grants to continuing education (CE) providers, who will develop and deliver the training. The REMS also will require companies to make available FDA-approved patient education materials on the safe use of these drugs. The companies will be required to perform periodic assessments of the implementation of the REMS and the success of the program in meeting its goals. The FDA will review these assessments and may require additional elements to achieve the goals of the program.

“We commend the FDA for taking action to save lives by increasing access to prescriber education,” said Gil Kerlikowske, Director of the Office of National Drug Control Policy. “Since day one, the Obama Administration has been laser focused on addressing the prescription drug abuse epidemic and today's action is an important contribution to this comprehensive effort.”

ER/LA opioid analgesics are widely prescribed medicines with an estimated 22.9 million prescriptions dispensed in 2011, according to IMS Health, which provides services and information to the health care and pharmaceutical industries. It is estimated that more than 320,000 prescribers registered with the Drug Enforcement Administration (DEA) wrote at least one prescription for these drugs in 2011. ER/LA opioid analgesics are associated with serious risks of overuse, abuse, misuse, and death and the numbers continue to rise. According to the Centers for Disease Control and Prevention, 14,800 Americans died from overdoses involving opioids in 2008. In 2009, there were 15,597 deaths involving these medications—nearly 4 times as many deaths compared with 1999.

“Misuse and abuse of prescription opioids is a complex problem and demands a holistic response,” said John Jenkins, MD, director of Center for Drug Evaluation and Research's (CDER's) Office of New Drugs. “The new REMS program is one component of a multi-agency, national strategy to address this important public health issue.”

Key components of the ER/LA opioid analgesics REMS include the following:

• Training for prescribers. Based on an FDA Blueprint, developed with input from stakeholders, educational programs for prescribers of ER/LA opioids will include information on weighing the risks and benefits of opioid therapy, choosing patients appropriately, managing and monitoring patients, and counseling patients on the safe use of these drugs. In addition, the education will include information on how to recognize evidence of, and the potential for, opioid misuse, abuse, and addiction, and general and specific drug information for ER/LA opioid analgesics.

• Updated Medication Guide and patient counseling document. These materials contain consumer-friendly information on the safe use, storage, and disposal of ER/ LA opioid analgesics. Included are instructions to consult one's physician or other prescribing health care professional before changing doses; signs of potential overdose and emergency contact instructions; and specific advice on safe storage to prevent accidental exposure to family members and household visitors.

• Assessment/auditing. Companies will be expected to achieve certain FDA-established goals for the percentage of prescribers of ER/ LA opioids who complete the training, as well as assess prescribers’ understanding of important risk information over time. The assessments also cover whether the REMS is adversely affecting patient access to necessary pain medications, which manufacturers must report to FDA as part of periodic required assessments.

It is expected that the first continuing education activities under the REMS will be offered to prescribers by March 1, 2013. There is no mandatory requirement that prescribers take the training and no precondition to prescribing ER/LA opioids to patients. However, the Obama Administration endorsed a mandatory training program on responsible opioid prescribing practices in April 2011 as part of its comprehensive plan to address the epidemic of prescription drug abuse. The program, which would be linked to DEA registration by providers, would require legislative changes that are being pursued by the Administration.

The FDA continues to support this approach, but absent the needed legislation, intends to exercise its authority to require mandatory elements for companies and voluntary elements for prescribers—all of which are important and necessary steps to help curb the misuse and abuse of ER/ LA opioid analgesics, without being overly burdensome.

NATIONAL FIBROMYALGIA ASSOCIATION ONLINE CONTINUING EDUCATION

The mission of the National Fibromyalgia Association (NFA) is to develop and implement programs to improve the quality of life for people with fibromyalgia (FM). Founded in Southern California in 1997, the NFA works to build national awareness, provide patient assistance and support, educate the medical community, facilitate research, build collaboration between the patient and scientific communities, and develop cohesive and motivated patient advocacy. It is the world's largest FM nonprofit organization and has more than 85,000 registered constituents. The Association assists an estimated 1.5 million people annually through telephone inquiries, e-mail, and the Internet.

The NFA also represent patients; it is also actively involved in health care professional services and education, including

• Distribution of thousands of information packets each year at major national medical meetings.

• Continuing Medical Education programs, partnering with leading medical universities including Johns Hopkins, the University of Michigan, Albert Einstein College of Medicine, Duke University, Boston University, the University of Wisconsin, and others.

• Collaboration with the National Institutes of Arthritis, Musculoskeletal and Skin Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute of Women's Research regarding better scientific research and dissemination of related scientific discovery to the medical community.

• Development and distribution of the FM Pain Kit, a health care professional (HCP)-specific resource that offers tools to assist in making an FM diagnosis and treating the disorder, as well as patient resource materials to help them live a better quality of life.

• Creation and execution of patient and HCP surveys to help produce better CME programs and offer better outcomes for people living with FM.

Health care professionals who treat fibromyalgia are often faced with questions related to diagnosing, prescribing medications, and other treatment options available to help their patients. This section offers information on current continuing medical education (CME)/CE opportunities developed by the National Fibromyalgia Association in collaboration with partners, such as California State University, Fullerton, as well as other online and annual meeting events. Information on available continuing education can be found at: http:// www.fibromyalgiahcp.com/PageServer3e47.html? pagename = hcp_cmeCe.

CITALOPRAM REVISED SAFETY RECOMMENDATIONS BASED ON RISK OF CARDIAC ARRHYTHMIA

On March 28, the FDA posted a clarification on dosing and warning recommendations for the antidepressant citalopram hydrobromide (Celexa and generics). Previously in August 2011, the FDA issued a Drug Safety Communication stating that citalopram should no longer be used at doses greater than 40 mg per day because it could cause potentially dangerous abnormalities in the electrical activity of the heart. Citalopram use at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation, but because it may be important for some of those patients to use citalopram, the drug label has been changed to describe the particular caution that needs to be taken when citalopram is used in such patients. The revised drug label also describes lower doses that should be used in patients over 60 years of age. The August 24, 2011, the Drug Safety Communication warned that citalopram (Celexa®, Forest Laboratories, Inc., St. Louis, Missouri), also available as generics, should not be given in doses larger than 40 mg daily. Labeling will be revised to reflect this new maximum dose that was previously up to 60 mg daily. Higher-dose citalopram has been associated with QT interval prolongation; citalopram should not be used in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or predisposition to hypokalemia or hypomagnesemia are at higher risk for torsade de pointes. A maximum dose of 20 mg daily is recommended in the following situations: age greater than 60 years, hepatic impairment, cytochrome P450 (CYP) 2C19 poor metabolizers, and use of concomitant cimetidine. That original alert stated: “Citalopram should not be used in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or predisposition to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing Torsade de Pointes, a rare type of ventricular tachycardia,”

Citalopram is not recommended for use at doses greater than 40 mg per day because such doses cause too large an effect on the QT interval and confer no additional benefit. Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram use is also not recommended in patients who are taking other drugs that prolong the QT interval. The maximum recommended dose of citalopram is 20 mg per day for patients with hepatic impairment, patients who are older than 60 years of age, patients who are CYP 2C19 poor metabolizers, or patients who are taking concomitant cimetidine (Tagamet) or another CYP 2C19 inhibitor, because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and torsade de pointes.

FDA WARNS OF RISK OF DEATH FROM CODEINE USE IN SOME CHILDREN FOLLOWING SURGERY

The U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication on August 15 concerning three children who died and one child who experienced a nonfatal but life-threatening case of respiratory depression after taking the pain reliever codeine following surgery to remove tonsils (tonsillectomy) and/or adenoids (adenoidectomy). The surgeries were performed to treat obstructive sleep apnea syndrome, a condition that results in repeated episodes of complete or partial blockage of the upper airway during sleep. The children received doses of codeine that were within the typical dose range.

Health care professionals and parents should be aware of the risks of using codeine in children who have had their tonsils and/or adenoids removed to treat obstructive sleep apnea syndrome. When prescribing codeine-containing drugs, health care providers should use the lowest effective dose for the shortest time on an as-needed basis. If parents or caregivers notice signs of overdose in a child, such as unusual sleepiness, difficulty being aroused or awakened, confusion, or noisy and difficult breathing, they should stop giving the child codeine and seek medical attention immediately.

“The FDA is currently conducting a review of adverse event reports and other information to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as post-operative pain following other types of surgery or procedures,” said Bob Rappaport, MD, director of the Division of Anesthesia, Analgesia and Addiction Products in FDA's Center for Drug Evaluation and Research. “The FDA will update the public when more information is available.”

Codeine is an ingredient found in prescription medicines used to relieve pain or cough. Once in the body, codeine is converted to morphine in the liver by an enzyme called cytochrome P450 isoenyme 2D6 (CYP2D6).

Some people metabolize codeine much faster and more completely than others. These people, known as ultrarapid metabolizers, are likely to have higher-than-normal levels of morphine in their blood after taking codeine. These high levels can lead to overdose and death. The three children who died after taking codeine exhibited evidence of being ultrarapid metabolizers.

The estimated frequency of ultrarapid metabolizers is generally 1 to 7 out of every 100 people. However, in certain ethnic groups, the frequency may be as high as 28 out of every 100 people. The only way to know if someone is an ultrarapid metabolizer is to do a genetic test. There are FDA-cleared tests to check for ultrarapid metabolism. For more information, see the FDA Drug Safety Communication: “Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death,” accessible at: http://www. fda.gov/Drugs/DrugSafety/ucm313631.htm, and the FDA Consumer Update: “Is post-surgery codeine a risk for kids,” accessible at: http://www.fda.gov/ ForConsumers/ConsumerUpdates/ucm315497.htm.

EFFECTS OF ANTIDEPRESSANTS ON SUICIDAL AGE GROUP AND BEHAVIOR DIFFER BY THOUGHTS

The U.S. Food and Drug Administration (FDA) issued black box warnings on the use of antidepressants by children, adolescents, and young adults. These warnings were based on the occurrence of suicidal thoughts and attempts, not on actual suicides. A reanalysis of data from 41 previous studies that included 9185 patients has found no evidence of increased suicide risk in children and adolescents aged 7 to 18 receiving active medication. Relative to placebo, depression symptoms lessened among treated patients in this group. However, unlike the older population, there was no greater decrease of suicidal thoughts and behavior in treated versus control subjects.

It's unclear why some youths whose depressive symptoms are reduced continue to have suicidal ideation and behavior. The authors suggest that perhaps other psychopathology, such as aggressive impulsive traits in youths, plays a more important role in this. Nevertheless, the overall rate of suicidal thoughts and attempts was not significantly greater than that of youths randomized to placebo in the study. The findings were based on a synthesis of 41 adult, geriatric, and youth trials of the antidepressant drugs, fluoxetine and venlafaxine. Only fluoxetine was administered to youth. Despite a strong association between depression severity and suicide risk in youths, treatment with fluoxetine did not decrease suicide risk beyond that observed with placebo. By contrast, with older patients receiving either fluoxetine or venlafaxine treatment, there was a greater reduction in suicide risk relative to control patients receiving placebo. The effect of treatment on depression severity appears to be the mechanism whereby antidepressants lower suicide risk in adult and geriatric patients. This study was supported, in part, by the Agency for Healthcare Research and Quality (HS16973).

See “Suicidal thoughts and behavior with antidepressant treatment. Reanalyis of the randomized placebo-controlled studies of fluoxetine and venlafaxine,” by Robert Gibbons, PhD, Hendricks Brown, PhD, Kwan Hur, PhD, and others in the Archives of General Psychiatry published online February 6, 2012.

IASP INTERPROFESSIONAL PAIN MANAGEMENT CURRICULA ONLINE

Over the last 2 years, the International Association for the Study of Pain (IASP) Education Initiatives Working Group has been developing a new interprofessional pain curriculum. It is now available online at: www.iasp-pain.org/Content/ NavigationMenu/GeneralResourceLinks/Curricula/ Interprofessional/default.htm. The group shared its first draft with IASP members last year and received many comments and suggestions for changes. Judy Watt-Watson, who chaired the effort, stated: “An interprofessional pain curriculum provides a common basis for different professions to learn the same language, to gain a basic understanding of pain mechanisms, and to master major biopsychosocial concepts important to all.”

This new interprofessional curriculum supplements the professional curricula that the IASP has published for the following seven disciplines: dentistry, medical schools, nursing, pharmacy, psychology, physical therapy, and occupational therapy. Those are accessible online at: http://www.iasp- pain.org/Content/NavigationMenu/GeneralResource Links/Curricula/default.htm.

IMPROVEMENT IN POSTOPERATIVE PAIN OUTCOMES

The European Union–funded international project PAIN OUT has established an acute pain registry with more than 30,000 data sets and is currently developing an Electronic Knowledge Library and a Clinical Decision Support System. Launched in January 2009, with 4-year funding from the European Commission's 7th Framework Program, PAIN OUT includes 17 clinical and research partners in nine European countries. Due to the vast interest, 60 additional hospitals from all over the world are taking part in PAIN OUT's international extension, PAIN OUT International. The registry and benchmarking tool involves collecting patient-reported pain outcomes and process data on surgery, anesthesia, and postoperative pain management in a highly standardized procedure, using the validated International Pain Outcomes Questionnaire (IPO). Participating sites subsequently receive online feedback about their results and benchmarking on regional and international levels. Longitudinal records will allow follow-up of changes over time.

The second tool, a Case-Based Clinical Decision Support System, allows a clinician faced with a complex patient to query the registry for similar cases. The clinician then receives point-of-care, real-time, patient-specific advice about appropriate management, to determine which interventions are likely to be most effective for this patient. The third tool, the Electronic Knowledge Library, summarizes current evidence-based guidelines for treating postoperative pain and delivers the information in a user-friendly electronic format. As the registry grows to comprise many cases, it will mirror real-life situations, permitting powerful data analyses and hypothesis testing that should advance research in the field of acute pain.

PAIN OUT relies on 10 years of experience gained from the German Post-operative Pain Registry (QUIPS), which tracks postoperative outcomes and related data in over 150 German hospitals, with over 230,000 records. From 2013 on, PAIN OUT desires to cooperate closely with QUIPS, with comparability or even merging of the two databases as possibilities for the future.

ONDCP ADVOCATES WIDER AVAILABILITY OF NALOXONE FOR OPIOID OVERDOSES

Last April, Gil Kerlikowske, White House Director of the Office of National Drug Control Policy (ONDCP), released the following statement:

“On behalf of the White House Office of National Drug Control Policy, I would like to thank everyone working on the important issue of overdose fatality prevention. In 2010, the Obama Administration released its inaugural National Drug Control Strategy, which recognizes the important role naloxone can play in reversing drug overdoses. With more people dying from unintentional drug overdoses than car accidents, it is vitally important that we do what is necessary to prevent drug abuse, while also preventing drug overdoses and getting people the treatment they need. I look forward to continuing this important conversation and continuing to support evidenced-based ways to protect public health and safety and prevent overdoses.”

On August 22, Mr. Kerlikowske called for increased action to prevent drug overdose deaths, urging wider distribution of a naloxone for use as an antidote to overdoses of opioid drugs, including prescription pain relievers and heroin, saying that “naloxone can be expanded beyond public health officials.”

Because naloxone is available only by prescription, it is accessed easily only by health professionals and some law enforcement officers. Kerlikowske now advocates broadening access to naloxone by addicted people, pain patients, and their families. He was speaking at Project Lazarus, a North Carolina program that pioneered wider distribution of the medication and is seen as a model prevention program for its comprehensive approach to fighting overdose and prescription drug misuse.

“As valuable as naloxone is, it's only a small piece of the broad spectrum of drug use prevention,” Kerlikowske stressed, adding, “We're very serious about removing the legal impediments that can mean the difference between life and death. The odds of surviving an overdose, much like the odds of surviving a heart attack, really depend on how quickly the victim receives treatment.”

Kerlikowske recounted the story of a young woman who survived an overdose with rapid administration of naloxone. Her brother who was participating in Project Lazarus used a naloxone kit he had received from his treatment provider to save his 26-year-old sister's life, when he found her “unresponsive and not breathing and her face was blue”. The brother called his counselor who told him to hang up, dial 911, and use the naloxone. Within about a minute or two of receiving the drug, his sister woke up. Four days after “her near death experience,” Kerlikowske said, “she entered treatment. Without naloxone, she wouldn't have had that choice.”

This spring, the FDA held a meeting to discuss making naloxone available over the counter, but such a move would require a manufacturer to seek approval to do so, which would in turn require expensive drug testing—that does not appear to be forthcoming. There are other regulatory paths to over-the-counter status that would bypass this hurdle, but it is not clear whether Obama administration officials will pursue them; neither Kerlikowske nor his office provided further specifics.

Dr. Nora Volkow, Director of the National Institute on Drug Abuse, also supports broader distribution of the overdose antidote. Early in August a bill to provide federal grants to expand naloxone programs like Project Lazarus, known as the Stop Overdose Stat (SOS) Act, was introduced in the House by Rep. Mary Bono Mack (R-Calif.) and Rep. Donna Edwards (D-Md.), with bipartisan support from two dozen other members, but its chances of passage and the amount of funding it would receive are also not known.

“I welcome Director Kerlikowske's announcement today to expand the availability of naloxone, proven to be an effective treatment in reversing drug overdose,” Rep. Edwards said in an e-mail. “This is a critical component of H.R. 6311, the Stop Overdose Stat (SOS) Act.”

FREQUENT ACETAMINOPHEN AND IBUPROFEN USE LINKED TO REDUCED HEARING

Frequent nonprescription analgesic use has been linked with hearing loss by investigators at Brigham and Women's Hospital. Women taking ibuprofen or acetaminophen 2 or more days per week experienced increased risk of hearing loss and the effect increased with more frequent medication use. The link between these medicines and hearing loss appeared greater in women less than 50 years old, especially for those who took ibuprofen 6 or more days per week.

There was no association between aspirin use and hearing loss. The study appeared in the September 15, 2012, issue of the American Journal of Epidemiology. This study examined the relationship between frequency of aspirin, ibuprofen, and acetaminophen use and risk of hearing loss among women in the Nurses’ Health Study II. Data from 62,261 women ages 31 to 48 years at baseline were reviewed in women who were followed for 14 years, from 1995 to 2009. Ten thousand and twelve women self-reported hearing loss. Women who used ibuprofen 2 to 3 days weekly had a 13% increased risk for hearing loss, whereas women who used the medication 4 to 5 days per week had a 21% increased risk. For those who used ibuprofen 6 or more days per week, the increased risk was 24%. Women who used acetaminophen 2 to 3 days per week had an 11% increased risk for hearing loss as compared with those who took it 1 day a week or less, and women taking the medicine 4 to 5 days per week had a 21% increased risk. A possible mechanism is reduced cochlear blood flow.

PharmaNet SYSTEM REDUCED INAPPROPRIATE PRESCRIPTIONS OF POTENTIALLY ADDICTIVE DRUGS

A centralized prescription information network provides real-time information to pharmacists in British Columbia (BC), Canada. The system, called PharmNet, significantly reduced inappropriate prescriptions for opioids and benzodiazepines according to a report in CMAJ (Canadian Medical Association Journal). The system, implemented in BC pharmacies in July 1995, reduced potentially inappropriate prescriptions for opioids and benzodiazepines in patients receiving social assistance and seniors. The reductions ranged from about one-third (33%) to one-half (49%) depending on the drug and patient group. The system allows BC pharmacists to view the most recent 14 months of a patient's medication use regardless of which physician prescribed the drugs or which pharmacy dispensed them. The system enables pharmacists to identify potentially harmful drug interactions, accidental duplications in therapy, or potential prescription drug misuse. In the study, the investigators monitored “potentially inappropriate” prescriptions for opioids and benzodiazepines in BC, which they defined as a second prescription for the same drug from a different prescriber and filled at a different pharmacy within 7 days of a previous prescription for at least 30 tablets. Most Canadian provinces have now adopted a system that permits pharmacists to see their patients’ current medication history at the time of dispensing a medication or a real-time monitoring program specifically aimed at monitoring prescription drugs prone to misuse. Ontario adopted the latter approach in establishing its Monitoring System earlier this year.

UNITED KINGDOM NATIONAL HEALTH SERVICE GUIDANCE ON PALLIATIVE USE OF OPIOIDS

On May 29, the United Kingdom National Health Service (NHS) National Institute for Health and Clinical Excellence (NICE) announced new guidelines to help ensure safe and consistent prescribing of opioids as a first-line treatment option to relieve pain for patients receiving palliative care for chronic or incurable illnesses. NICE reports that evidence suggests that pain caused by advanced disease remains undertreated despite a range of opioids being recommended for use in the NHS. Many patients also worry about the long-term use of opioids, their side effects, and the possibility of becoming addicted.

The guideline recommends asking patients about their concerns when first prescribing, frequently reviewing pain control and side effects, and notifying the patient who to contact after hours. Patients with advanced or progressive disease should be offered regular oral sustained-release or immediate-release preparations with rescue oral immediate-release preparations for breakthrough pain. And patients with advanced and progressive disease requiring strong opioids should be offered oral sustained-release morphine as first-line maintenance therapy.

“Many people with chronic or advanced conditions will experience a high level of pain which can only be treated by opioids such as morphine, as weaker forms of pain relief will no longer be effective,” said Mark Baker, Centre for Clinical Practice, NICE, London, United Kingdom.

“However, we understand that patients can be anxious about using these medicines for a number of reasons,” he said. “Likewise, healthcare professionals may not always be sure about when to prescribe certain types of opioids. The new guideline aims to address all those fears and provide clear advice to the NHS to ensure a consistent approach to treatment and ultimately help to drive up standards of care.”

The guideline makes recommendations in a number of key areas, including:

• Communication: When offering a patient pain treatment with strong opioids, ask them about concerns such as: addiction, tolerance, side effects, fears that treatment implies the final stages of life. Offer patients access to frequent review of pain control and side effects and information on who to contact out of hours, particularly during initiation of treatment.

• Starting treatment: When starting treatment with strong opioids, offer patients with advanced and progressive disease regular oral sustained-release or immediate-release preparations (depending on patient preference and clinical presentation), with rescue doses of oral immediate-release preparations for breakthrough pain.

• First-line maintenance therapy: Offer oral sustained-release morphine as first-line maintenance therapy to patients with advanced and progressive disease who require strong opioids. If pain remains uncontrolled despite optimising first-line therapy, review analgesic strategy and consider seeking specialist advice.

“Because opioids are powerful medicines people worry they can become addicted, particularly if opioids are prescribed over an extended period of time,” said Damien Longson, MD, NICE, London, United Kingdom. “This guideline puts a strong emphasis on good communication between healthcare professionals and patients, which is key to ensuring any worries or uncertainties are addressed with timely and accurate information. This will help the patient to feel content in following what has been prescribed and therefore potentially improving their pain control and reducing any associated side effects.”

The new guideline is available at: http://www.nice. org.uk/CG140.

HYDROMORPHONE EXTENDED-RELEASE 32-mg TABLETS APPROVED

The U.S. Food and Drug Administration (FDA) approved a new 32-mg tablet strength of EXALGO (hydromorphone HCI) extended-release tablets (CII) for opioid-tolerant patients with moderate-to-severe chronic pain requiring continuous around-the-clock opioid analgesia for an extended period of time. The FDA approved the 8-, 12-, and 16-mg tablets of EXALGO in March 2010 and the Supplemental New Drug Application for the 32-mg tablet was submitted in January 2012 with postmarketing data to support the original application's compendium of clinical trials demonstrating efficacy and tolerability.

“We believe that the new 32 mg tablet—delivered by the same extended-release OROS® technology used with the 8, 12, and 16 mg tablets—will provide an established pharmacologic profile and analgesic potency of once-daily hydromorphone. This new EXALGO 32 mg tablet represents an important milestone as 32 mg was the median effective dose upon which patients were stabilized during the pivotal trial,” said Thomas Smith, MD, Chief Medical Officer at Mallinckrodt. “By providing a variety of tablet strengths, we hope that physicians and opioid-tolerant patients can work together to develop and tailor a treatment regimen that adequately and appropriately controls their chronic pain.”

“Physicians may try as many as five types of opioids before finding a treatment plan that provides pain relief to patients,” said Dr. Joseph Shurman, Chairman, Pain Management, at Scripps Memorial Hospital. “Sustained release treatments like EXALGO help patients avoid fluctuations in blood plasma levels and a new tablet strength provides more options for physicians to use with their opioid-tolerant patients.”

All EXALGO dosage strengths, including the new 32-mg tablet, are subject to the recently approved Risk Evaluation and Mitigation Strategy (REMS) program for all long-acting and extended-release opioids. The three primary components of this REMS program are: training for prescribers in the form of continuing medical education (CME) initiatives, which will be available by March 2013; updated medication guides for each opioid and a patient counseling document; and assessment and auditing to ensure the reach and effectiveness of prescriber training. Mallinckrodt will maintain the current EXALGO REMS program Web site at: www.exalgorems.com and continue to provide important EXALGO prescribing information, with a focus on appropriate patient selection and dosing, to new prescribers. In addition, Mallinckrodt continues to provide to health care professionals, patients, and caregivers more than 60 educational tools, at no cost, on the safe and appropriate prescribing, dispensing and use of opioids at: www.caresalliance.org.

FDA WARNS OF RARE SERIOUS BURNS WITH OTC TOPICAL MUSCLE AND JOINT PAIN RELIEVERS

On September 13, 2912, the U.S. Food and Drug Administration (FDA) alerted the public that certain over-the-counter (OTC) products that are applied to the skin for the relief of mild muscle and joint pain have been reported to cause rare cases of serious skin injuries, ranging from first- to third-degree chemical burns, where the products were applied. These OTC topical muscle and joint pain relievers are available as single- or combination-ingredient products that contain menthol, methyl salicylate, or capsaicin. The various formulations include creams, lotions, ointments, and patches. When applied to the skin, the products produce a local sensation of warmth or coolness; they should not cause pain or skin damage. However, there have been rare cases of serious burns following their use as described below. Some of the burns had serious complications requiring hospitalization. In many cases, the burns occurred after only one application of the OTC topical muscle and joint pain reliever, with severe burning or blistering occurring within 24 hours of the first application. Based on the reported cases, the majority of second- and third-degree burns occurred with the use of products containing menthol as the single active ingredient, and products containing both menthol and methyl salicylate, in concentrations greater than 3% menthol and 10% methyl salicylate. Few cases reported using a capsaicin-containing product.

Consumers using an OTC topical muscle and joint pain reliever who experience signs of skin injury where the product was applied, such as pain, swelling, or blistering of the skin, should stop using the product and seek medical attention immediately.

Additional Information for Consumers

• Rare cases of serious burns have been reported to occur on the skin where over-the-counter (OTC) topical muscle and joint pain relievers were applied. These products contain the active ingredients menthol, methyl salicylate, or capsaicin.

• Of the burns that have been reported, the majority of second- and third-degree burns occurred with products containing menthol as the single active ingredient and products containing both menthol and methyl salicylate, at concentrations greater than 3% menthol and 10% methyl salicylate. Few cases reported using a capsaicin-containing product. Some of the burns had serious complications requiring hospitalization.

• The skin injuries described were recently assessed by FDA. Existing Tentative Final Monograph does not at this time require labels of OTC topical muscle and joint pain relievers to carry a warning that use of the products could result in serious burns.

• If you experience pain, swelling, or blistering of the skin where an OTC topical muscle and joint pain reliever was applied, stop using the product and seek medical attention immediately. These products should not cause pain or skin damage. These products produce local warmth or coolness.

• When applying OTC topical muscle and joint pain relievers to the skin, do not bandage the area tightly and do not apply local heat (heating pads, lamps, hot water in bags or bottles) because doing so can increase the risk of serious burns.

• Do not apply OTC topical muscle and joint pain relievers to wounds or damaged, broken, or irritated skin. Also do not allow contact with eyes and mucous membranes (such as the skin inside your nose, mouth, or genitals).

• Talk to a health care professional if you have any questions or concerns about using OTC topical muscle and joint pain relievers.

• Report side effects from the use of OTC topical muscle and joint pain relievers to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

Additional Information for Health Care Professionals

• Rare cases of serious burns have been reported to occur on the skin where over-the-counter (OTC) topical muscle and joint pain relievers were applied. These products contain the active ingredients menthol, methyl salicylate, or capsaicin.

• Of the burns that have been reported, the majority of second- and third-degree burns occurred with the use of products containing menthol as the single active ingredient and products containing both menthol and methyl salicylate, in concentrations greater than 3% menthol and 10% methyl salicylate. Few cases reported using a capsaicin-containing product.

• When recommending OTC topical muscle and joint pain relievers to patients, counsel them about how to use the products appropriately and inform them about the risk of serious burns. The skin injuries described were recently assessed by FDA. Existing Tentative Final Monograph does not at this time require labels of OTC topical muscle and joint topical pain relievers to carry a warning that use of the products could result in serious burns.

• If a patient experiences pain, swelling, or blistering of the skin where an OTC topical muscle and joint pain reliever was applied, advise the patient to discontinue using the product.

• Report adverse events involving OTC topical muscle and joint pain relievers to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of this page.

A search of FDA's Adverse Event Reporting System (AERS) database (from 1969 through April 21, 2011), the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance (NEISS-CADES) database (from 2004 to 2010), and the medical literature¹ identified 43 cases of burns on the application site associated with the use of over-the-counter (OTC) topical muscle and joint pain relievers containing the active ingredients menthol, methyl salicylate, or capsaicin. The products associated with these cases include patches, balms, and creams. All cases in this series include burns that were confirmed by a health care professional. In the case series, there were reports of burns ranging from first-degree to third-degree, but many cases did not specify the degree of the burn. Many cases occurred following one application of the OTC topical muscle and joint pain reliever, with severe burning or blistering occurring within 24 hours of the first application of the product. A majority of the second- and third-degree burns were reported with the use of products containing menthol as the single active ingredient or products containing both menthol and methyl salicylate, where the concentration of the ingredients was greater than 3% menthol and 10% methyl salicylate. Few cases reported using a capsaicin-containing product.

CALL FOR PROACTIVE ANALYSIS OF PRESCRIPTION MONITORING PROGRAM DATA

The Prescription Drug Monitoring Program (PDMP) Center of Excellence at Brandeis University's Heller School for Social Policy and Management recently assessed prescription drug monitoring programs and found inconsistency in approaches to the problem of prescription drug abuse. Center investigators reported on best practices that all states and territories could use to improve their effectiveness. Among their conclusions: prescription drug monitoring programs should shift from a reactive to a proactive approach. Peter Kreiner, Principal Investigator at the PDMP called for outreach to prescribers, pharmacists, insurers, law enforcement agents, and others who can prevent opioids from getting to inappropriate persons. By 2001, 16 states had authorized prescription drug monitoring programs. Today, 41 states have programs in operation.

The paper identified several practices with demonstrated effectiveness. States that collected prescribing data for all controlled substances reported lower rates of doctor-shopping (visiting multiple doctors to obtain prescriptions) than other states. The rates of fatal opioid overdoses grew more slowly in three states using state-issued prescription forms with uniquely configured page numbers, a practice designed to curb fraud. Proactively sending of alerts about possible abuse to physicians and pharmacists was associated with decreased prescription sales and lower rates of doctor-shopping. Analyzing trend data helped law enforcement agencies identify “pill mills” that were illicitly distributing prescription painkillers. Boosting doctors’ participation in and utilization of prescription drug monitoring programs was associated with reduced fatal prescription painkiller overdoses. The Pew Health Group, a division of The Pew Charitable Trusts, provided funding for the research.

CALIFORNIA STATE UNIVERSITY OPENS INSTITUTE FOR PALLIATIVE CARE

California State University–San Marcos (CSUSM) opened a statewide educational and workforce development initiative dedicated to palliative care today, the first in the United States. The CSU Institute for Palliative Care addresses “the critical shortage of nursing, social work, spiritual and other professionals with palliative care skills and training. It will also educate the public about the value of palliative care and how to access it.”

“Palliative care reduces suffering and has been shown to significantly improve quality of life, patient satisfaction and health outcomes for people facing serious illnesses,” said CSUSM President, Karen Haynes. “We are very pleased to be giving this important Institute its start here at Cal State San Marcos and to begin addressing this critical workforce need in not only our region but the state and nation as well.”

“More people than ever before are living with one or more chronic conditions, and while palliative care can do so much to help, its role and benefits are not well understood. The CSU Institute for Palliative Care will educate people and make them aware of their options and the resources available to them through our community partners,” said CSU Institute for Palliative Care Executive Director, Helen McNeal.

The Institute has received initial grant funding of a combined $1.2 million over three years from the Archstone Foundation and the California HealthCare Foundation. See: www.csupalliativecare.org to learn more about the initiative.

OPIOID PRESCRIPTIONS FOR CHRONIC ABDOMINAL PAIN DOUBLED BETWEEN 1997 AND 2008

Although the number of outpatient visits for chronic abdominal pain (CAP) declined by almost a fifth from 1997–1998 to 2006–2008, visits during which an opioid was prescribed more than doubled, according to a new study. CAP is a common reason for outpatient visits, and its management is often a challenge for clinicians. Nevertheless, opioid analgesics have not been proven effective for treating CAP and have been linked to drug misuse and gastrointestinal symptoms, including worsening pain.

Based on two national surveys, each conducted a decade apart (the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey), the researchers estimated that there were 14.8 million outpatient visits (2464 per 100,000 population) for CAP from 1997 through 1999, which decreased by 17.6% (to 12.2 million outpatients visits, or l 863 per l 00,000 population) for 2006 through 2008. Over the same period, the proportion of visits for CAP in which the patient received at least one opioid prescription increased from 5.9% during 1997–1999 to 12.2% during 2006–2008.

The likelihood of receiving an opioid prescription was highest for patients 25 to 50 years old (4.8 times more likely than for ages 18 to 24 years). In contrast, opioid prescriptions were least commonly given to uninsured patients (12% of the rate for privately insured patients) and blacks (34% of the rate for whites). The researchers call for more studies to better understand the reasons for and consequences of these trends.

More details are in “Increasing frequency of opioid prescriptions for CAP in US outpatient clinics,” by Spencer D. Dorn, MD, MPH, Patrick D. Meek, DPharm, MSPH, and Nilay D. Shah, PhD, in the December 2011 Issue of Clinical Gastroenterology and Hepatology, 9(12), pp. 1078–1085.

SUBOXONE (BUPRENORPHINE AND NALOXONE SUBLINGUAL TABLETS) TO BE DISCONTINUED

Reckitt Benckiser Pharmaceuticals Inc. notified the U.S. Food and Drug Administration (FDA) on September 18, 2012, that the company is voluntarily discontinuing the supply of Suboxone Tablets in the United States (buprenorphine and naloxone sublingual tablets [CIII]) due to increasing concerns with pediatric exposure. The company received an analysis of data from U.S. Poison Control Centers on September 15, 2012, that found consistently and significantly higher rates of accidental unsupervised pediatric exposure with Suboxone® Tablets (buprenorphine and naloxone sublingual tablets [CIII]) than seen with Suboxone® Film (buprenorphine and naloxone sublingual film [CIII]). The rates for Suboxone Tablets were 7.8 to 8.5 times greater depending on the study period.

Although the data do not isolate the root cause of these findings, the unique child resistant, unit-dose packaging of the next generation Suboxone Film is believed to be one of the key contributing factors to the decrease in exposure rates compared with Suboxone Tablets, which are distributed in a multidose bottle containing 30 tablets, since the active ingredients of both products are the same. Other factors may include Reckitt Benckiser Pharmaceuticals’ community and health care professional educational initiatives in addition to the company's Risk Evaluation and Mitigation Strategy program.

Reckitt Benckiser Pharmaceuticals is working closely with the FDA and the broader health care community to ensure patients currently taking Suboxone Tablets have sufficient time and notification to appropriately transition to the same effective active ingredient with Suboxone Film to minimize any risk to the continuity of their treatment. We anticipate that distribution of Suboxone Tablets will be discontinued within the next six months, possibly sooner depending on discussions with the FDA.

The pediatric exposure safety issue is not related to the active ingredients found in both Suboxone Tablets and Suboxone Film. The company encourages patients currently taking Suboxone Tablets to continue with their treatment and consult their physician about how to transition to Suboxone Film. Suboxone Film is covered by the majority of insurance plans, and Medicare and Medicaid. Additionally, patients can access a savings program at Suboxone.com or from their physician to offset out-of-pocket costs associated with their medication. Since the U.S. launch of Suboxone in 2003, it is estimated that over 3 million Americans with opioid dependence have been treated with the safe and effective active ingredients in Suboxone Tablets and Suboxone Film buprenorphine and naloxone.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.