FDA Delays Opioid REMS; Will Industry Snooze?

After much angst and turmoil, the U.S. Food and Drug Administration (FDA) is delaying for a year their mandate to the pharmaceutical industry to develop Risk Evaluation and Mitigation Strategies (REMS) for certain opioid analgesics. A question now is, having received a wake-up call that the FDA means business when it comes to safeguarding these products, will industry take constructive action on their own or merely press the snooze button for the coming year?

By way of background, last May the FDA convened a public meeting to gather input on developing REMS programs specifically for extended-release and long-acting opioid analgesic formulations, followed by a public comment period ending June 30, 2009. REMS would be intended to ensure that the benefits of these drugs continue to outweigh risks associated with: (1) their improper use in non-opioid-tolerant and inappropriately selected individuals; (2) abuse, (3) misuse, and (4) overdose. REMS would likely include elements to ensure that prescribers, dispensers, and patients are aware of and understand the risks and proper use of these products.

Now, the FDA has effectively delayed their final decisions regarding REMS by reopening and extending the comment period to October 19, 2010 “in light of continued public interest in this topic and to provide an opportunity for all interested parties to provide information and share views on the matter.” The actual reasons behind this extension — a reprieve of sorts — are not publicly known. The FDA had already received at least 1,255 comments from individuals and various stakeholder groups; mostly expressing concerns about placing severe restrictions on these vital analgesics, but many were constructive and wishing to comply with FDA directives in a rational manner. Perhaps, the FDA realized that they did not have adequate and accurate data to fully assess the situation or that there could be seriously negative unintended consequences of their mandates regarding opioid-REMS, but this is speculation.

Meanwhile, last July a new buccal-soluble fentanyl product (Onsolis®) to treat breakthrough cancer pain was approved with a REMS program that is so egregiously restrictive [see blogpost of 7/17/09] that, according to feedback we have received, it is questionable whether it will be prescribed. And, a recommended REMS program to accompany Exalgo® (a new extended-release hydromorphone product awaiting final approval) is only slightly less restrictive [see blogpost 9/26/09]. Both of these programs seem to belie the FDA stipulation and promise that appropriate REMS will “adequately manage the risks of these products without unduly burdening the health care system or reducing patient access to these medications.” Yet, last August, King Pharmaceuticals’ EMBEDA™ product (a tamper-resistant extended-release morphine sulfate and naltrexone hydrochloride combination product) was FDA-approved with a reasonable “interim REMS” consisting of a medication guide and special communications sent to prescribers [see blogpost 8/14/09]. So, what may happen during the coming year in terms of the fates of the existing opioid REMS, new opioid product approvals by the FDA, and the shape of “interim REMS” to come is anyone’s guess right now.

The added year could be a boon to the pharmaceutical industry if they use the time to seriously address issues surrounding opioid safety on their own, essentially making pressure coming from the FDA superfluous. Industry now has an idea of what an opioid-REMS program could consist of, albeit the two current examples are far from desirable from all perspectives. Various pharmaceutical firms and stakeholder organizations have already formed working groups to address the opioid-REMS mandate and, hopefully, they can come up with practical approaches that truly will manage risks while also preserving patient access to opioid analgesics. We encourage them to continue their work in earnest and arrive at concrete and rational plans during the coming months.

Interested persons have until October 19, 2010 to submit comments to the FDA:
Title: “Risk Evaluation and Mitigation Strategies for Certain Opioid Drugs; Notice of Public Meeting; Reopening of Comment Period.” Docket ID#: FDA-2009-N-0143.
> Submit written comments to: Division of Dockets Management (HFA-305); Food and Drug Administration; 5630 Fishers Lane, rm. 1061; Rockville, MD 20852.
> Submit electronic comments by going to regulations.gov and clicking on the “Submit Comment” tab.
> For further information call 301-796-3448; or e-mail: OpioidREMS@fda.hhs.gov.

Why Primary Care Providers Shun Opioid Therapy

Despite considerable research demonstrating that opioid analgesics can be valuable and effective therapy for many types of pain, and the recommendations of numerous guidelines, primary care providers often avoid prescribing these medications. Reasons for this run contrary to best medical practice.

Writing in Medscape Neurology & Neurosurgery, Bill H. McCarberg, MD — Assistant Clinical Professor, University of California San Diego School of Medicine; Founder, Chronic Pain Management Program, Kaiser Permanente, San Diego, CA; and a well-respected writer/lecturer — addresses the question of why primary care providers often do not adequately meet the needs of patients with pain by providing opioid therapy. He concedes that pain is undertreated, especially in the primary care setting. Primary care providers are usually the point of entry into the American healthcare system, and include family physicians, internists, osteopaths, pediatricians, gynecologists, and physician assistants and nurse practitioners. Even though more than 1 in 4 Americans report episodes of pain each year, 70% of persons with acute pain simply do not seek medical attention and hope that they can manage the pain on their own. Still, moderate to severe pain is one of the most common reasons for primary care visits in the United States; however, inadequate training among healthcare professionals may prevent proper assessment of pain conditions, and deficiencies in pain management related to patient gender, race, and socioeconomic status have been reported, McCarberg observes.

For either acute or persistent pain, opioids can be a valuable and effective option, he continues. “The contribution of opioids to improved function, sleep, mood, and pain has been demonstrated in multiple trials.” State medical boards have developed intractable pain acts to encourage all providers to manage pain more effectively and guidelines have been established for the use of controlled substances for the treatment of pain. Despite these advances, primary care providers are increasingly hesitant to prescribe opioids, largely due to concerns about patient compliance with treatment, the possibility of adverse effects or opioid abuse, and the perceived scrutiny of opioid-prescribing practitioners by regulatory authorities.

Additionally, both clinicians and patients are concerned that opioid therapy will lead to addiction, although only a small percentage of patients with pain actually develop iatrogenic (therapy-induced) addiction, according to McCarberg. Some of the confusion may stem from inconsistent use of the terminology or misunderstandings associated with opioid misuse, abuse, tolerance, dependence, and addiction. “The public health is not best served by decreasing the medical use of opioids even with increases in prescription opioid misuse and abuse,” he states. The potential for inappropriate medication use should be considered as part of an individualized risk-benefit analysis conducted for every patient being considered for opioid therapy. “Risk for aberrant drug use depends more on genetic and psychosocial factors, including personal and family history of drug abuse, the presence of psychiatric disorders, and a potential patient agenda for euphoria and abuse, rather than the mere exposure to an opioid.”

Commentary: Our bias is that opioid risk assessments, while appropriate in many but not all cases, should not incur a “cops ‘n robbers” atmosphere whereby all patients are viewed as potential opioid abusers until proven otherwise. McCarberg observes that, “The majority of patients who present to their primary care provider will be considered low risk and can be managed routinely [on opioids] in this setting.” In cases where a patient with pain has a known history of substance abuse or a complicating psychiatric disorder, consultation or referral to an appropriate specialist may be advisable, he recommends. However, this may not be practical for all patients and in all communities; the solution, we believe, is for healthcare providers to take the time and make the effort to become better educated on opioid prescribing and its possible complications, and to also better educate patients (and their caregivers) on potential risks and the safe use of opioid analgesics. The alternative — merely not prescribing opioids for pain conditions that could benefit from such therapy — is bad medicine.

Reference: McCarberg BH. Chronic pain in primary care. Medscape Neurology & Neurosurgery. 2009(Oct) [article available here].

Chile Peppers Aid Neuropathic Pain – Somewhat

For patients with peripheral neuropathy, a new research review suggests that up to 4 of 10 sufferers could experience some pain relief from the active component of chili peppers — topical capsaicin cream. Peripheral neuropathies include nerve disorders that can cause burning pain, tingling, numbness, weakness, and other discomforts. However, there are some strong limitations of the research.

Oxford University researchers Sheena Derry and Andrew Moore led the Cochrane Collaboration systematic research review, which included 8 randomized, double blind, placebo-controlled trials involving more than 1,000 adult participants. The capsaicin formulations investigated were either mild creams that patients can apply themselves or a newer form, the high-dosage capsaicin patch, which a health care provider administers after applying a local anesthetic to the target area to minimize stinging and burning.

Six clinical studies (389 participants total) compared mild 0.075% capsaicin cream applied 3 to 4 times daily to painful sites with a placebo cream. Of participants who used the active cream, 41% experienced “some degree of pain relief,” compared with about 26% using placebo. The amount of pain relief varied among studies, from substantial (pain half gone or better) to undefined “improvement.” Two trials employed a single daily application of high-dose (8.0%) capsaicin cream via a patch that was left in place for 30 to 90 minutes. Of the 431 participants who received the high-dose capsaicin patch, 39% felt that it relieved their pain by at least one-third, compared with about 30% of the 278 participants administered placebo patches.

Conclusions & Commentary: The investigators concede that estimates of benefit and harm for capsaicin formulations are not robust due to limited amounts of data for different neuropathic conditions and inconsistent outcome definitions. Furthermore, true double blinding was a significant problem in the research trials, because capsaicin stings and burns while a placebo does not; trials attempted to overcome this by including other stinging ingredients in the placebos and there were noteworthy beneficial placebo effects reported. Although both active capsaicin formulations provided some pain relief, the numbers needed to treat (NNT) are not impressive: roughly 1 in 7 patients (NNT 95% CI; 4.1-17) may benefit from low dose capsaicin during 6 to 8 weeks, while only about 1 in 11 (6.4-70) benefit from the high-dose patch during 12 weeks. The wide confidence intervals reflect the different neuropathies examined and the relatively small numbers of subjects with each condition. At the same time, with the low-dose cream about 1 of every 2 patients experienced local skin reactions — burning, stinging, or redness — which can incur therapy discontinuation. There are few data examining the benefit-to-risk ratio of high-dose capsaicin, plus patients receiving the high-dose formulation require pretreatment with a local anesthetic. A further limitation of the trials was that there were no comparisons of capsaicin creams with counterirritants, such as Ben Gay® or Icy Hot®, available over-the-counter. The warm or cool sensations of these products distract from pain and they can be used on an as-needed basis, while capsaicin must be applied on a regular schedule.

Overall, the authors of this review suggests that, for patients suffering daily neuropathic pain, capsaicin therapy may provide some additional relief if they have failed to respond well or have proven intolerant of other treatments. For those patients, they wrote, “even a small degree of pain relief may be considered worthwhile.” Although, the reviewers still suggest that it might be best to consider capsaicin creams as an adjunctive or a secondary pain-relief measure, since there are oral medications for neuropathic pain with clear research evidence of effectiveness and tolerable side effects.

Reference: Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews. 2009(Oct);4(CD007393) [abstract here].

Magnets, Copper Bracelets Useless for Pain Relief

New research indicates that copper bracelets and magnetic wrist straps are ineffective in relieving arthritis pain. The investigators claim that reported pain-relieving benefits of such devices are most likely due only to placebo effects; however, maybe that is a worthwhile reason for using them?

The study conducted in the United Kingdom and appearing in the British journal Complementary Therapies in Medicine [Richmond et al. 2009] enrolled 45 patients aged 50 or over and diagnosed with osteoarthritis. Each participant wore 4 devices in random order during a 16-week period: two wrist straps with differing levels of magnetism, a copper bracelet, and a demagnetized wrist strap (placebo control). Outcome assessments were done using the WOMAC Osteoarthritis Index, the McGill Pain Questionnaire, a pain visual analogue scale (VAS), and medication use.

No differences were observed between devices in terms of their effects on pain, stiffness, physical function, or medication use as measured by any of the assessments. The investigators conclude that magnets and copper bracelets are generally ineffective, and any reported therapeutic benefits are most likely attributable to non-specific placebo effects. On the other hand, they do concede that such devices have no major adverse effects and may provide hope of relief for some patients. According to lead investigator Stewart Richmond, a Research Fellow in the Department of Health Sciences at the University of York, magnet therapy for arthritis is a rapidly growing industry, with annual worldwide sales of devices incorporating permanent magnets worth up to $4 billion USD. “Although their use is generally harmless, people with osteoarthritis should be especially cautious about spending large sums of money on these devices,” he said.

Clinical Comment: It should be noted that this sort of research trial design — with the same subjects crossing over to participate in all 4 therapies — has limitations in terms of producing robust and valid results. Also, the researchers enrolled insufficient numbers of subjects to significantly detect less than at least a 25% therapeutic difference between groups [see our blogpost of 9/25/09 discussing why size matters in research trials]. While the conclusion of this trial is that copper bracelets and magnetic wrist straps exert at best only placebo analgesic effects, we have noted in recent blogposts that placebo effects appear to engender significant pain relief for some persons [see 10/16/09 and 10/7/09]. So, perhaps these devices are not necessarily a bad idea if patients want to wear them — provided only modest cost is involved and the individuals truly believe that the devices could be of benefit. Practitioners, themselves, may be reasonably reluctant to recommend such devices for treating painful arthritis until valid evidence of their effectiveness becomes available. What do you think? (Comment below.)

Reference: Richmond SJ, Brown SR, Campion PD, et al. Therapeutic effects of magnetic and copper bracelets in osteoarthritis: A randomised placebo-controlled crossover trial. Compl Ther Med. Article in Press, October 2009 [abstract here].

FDA Clarifies How to Dispose of Opioids

The U.S. Food and Drug Administration (FDA) has launched a new Web page for consumers [available here] on how to dispose of opioid analgesics and other controlled substances. Quite simply, the FDA recommends that opioids should be flushed down the sink or toilet.

The goal is to keep unused opioids away from children and others who could be severely harmed by taking them accidentally or illegitimately. However, despite the safety reasons for flushing certain drugs, some people have questioned the practice because of concerns about trace levels of drug residues found in surface water, such as rivers and lakes, and in some community drinking water supplies. Yet, according to Raanan Bloom, PhD, an Environmental Assessment Expert in the FDA's Center for Drug Evaluation and Research, most drugs are not completely absorbed or metabolized by the body, so the main way drug residues enter water systems is by people ingesting medications and then naturally passing them into waste water via their urine or feces. The FDA believes that any potential risk to people and the environment from flushing opioids is outweighed by the real possibility of life-threatening risks from the unauthorized ingestion of these medicines.

There has been some confusion because not all medicines should be flushed down the sink or toilet. The FDA recommends that most nonopioid drugs can be disposed of in household trash after mixing them with an unpalatable substance (eg, coffee grounds) and sealing them in a container. Another disposal option is through drug take-back programs, as federal and state laws permit; however, such programs may not be readily available in some communities.

All opioids have disposal instructions in their professional prescribing information but this information often does not get passed along to consumers. The FDA Web page has a specific list of narcotic Schedule-CII opioids as recommended for flushing; however, since all opioids can be hazardous if they fall into the wrong hands, it seems a simple matter for practitioners to instruct patients as they hand them prescriptions for any opioid products, “As soon you are done using this medication, be sure to flush any remaining portion down the sink or toilet.” Giving such advice takes practically no time and could save a life.

Study Finds Analgesic Placebo Effects in Spine

Benefits of placebo effects for aiding pain relief are appearing more frequently in the medical news these days. Most recently, a study by German researchers appearing in the journal Science describes how analgesic placebo effects inhibit pain perception directly in the spinal cord, which may have implications for enhancing pain therapies.

Falk Eippert and colleagues at Germany's University Medical Center Hamburg-Eppendorf enrolled 15 healthy young men in their experiment [Eippert et al. 2009]. First, the researchers gauged subjects’ pain thresholds by applying heat to their arms. Next, two identical but inactive creams were applied to the subjects’ arms, with instructions that one was a powerful “pain reliever cream” and the other was a latent "control cream." When heat was applied to the treated areas to stimulate pain, the fake pain-reliever cream reduced pain sensations (placebo effect); whereas, the control cream offered no pain relief. MRI scans performed during the tests showed that when heat was applied to the arms treated with the fake pain-reliever cream there was less activity in the dorsal horns of the subjects’ spinal cords.

Commentary: The researchers note that the analgesic placebo effects demonstrate the impact that psychological factors can have on pain perception; however, their study does not help to explain the mind-body connections between the men's beliefs about the creams and how they responded to pain from the heat. Importantly, however, in this small study (more like a case series) there was a direct reduction of nociception in the spinal cord as a result of placebo effects, suggesting that psychological factors can act on the earliest and most elemental stages of pain processing in the central nervous system. The power of analgesic placebo effects should not be dismissed or ignored; as we noted recently, such effects have been found to play important roles in the treatment of gastrointestinal pain disorders in children (see webpost 10/7/09). While the psychological dynamics at work in children may be different, this study by Eippert and colleagues recommends that mind-body influences on pain relief also may be worthy of consideration in adults. Further research is necessary to clarify how placebo effects might be invoked clinically to enhance therapies for pain.

Reference: Eippert F, Finsterbusch J, Bingel U, Büchel C. Direct evidence for spinal cord involvement in placebo analgesia. Science. 2009 (Oct 16);326(5951):404 [see abstract here].

Placebo Power in Pediatric Gastrointestinal Pain

Chronic abdominal pain is a common and challenging complaint in childhood, largely due to pain-predominant functional gastrointestinal disorders (FGIDs) that include irritable bowel syndrome (IBS), functional dyspepsia, functional abdominal pain, and abdominal migraine. According to a new study reported in the journal Gastroenterology, both placebo and the tricyclic antidepressant amitriptyline work equally well in treating these disorders in children — a result that may have important implications for how practitioners can maximize placebo effects in children.

Investigators from multiple centers in the United States conducted a prospective, randomized placebo-controlled trial in which children, ages 8 to 17, with irritable bowel syndrome, functional abdominal pain, or functional dyspepsia were administered either 4 weeks of placebo or amitriptyline [Saps et al. 2009]. Of the 83 children (78% girls) completing the study, 63% reported feeling better and 5% feeling worse taking amitriptyline compared with 57.5% feeling better and 2.5% feeling worse in the placebo group. Pain relief was excellent or good in 45% of children receiving placebo compared with 50% of those treated with amitriptyline. Essentially, there were no significant differences between amitriptyline and placebo after 4 weeks of treatment; both groups had generally good therapeutic response. There also were no differences found between groups regarding psychologic variables, such as depression and somatization; however, amitriptyline did significantly reduce anxiety (p<.0001).

Clinical Concepts: Past investigations in adults have found significant beneficial effects of antidepressants, including amitriptyline, for IBS; so, the extraordinary placebo response in this study of children was unexpected. Therefore, a companion editorial in the journal focuses on a better understanding of the benefits of placebo effects in children with IBS and other FGIDs [Benninga and Mayer 2009]. Significant progress has been made in the identification of brain networks and signaling systems underlying placebo responses. For example, several studies have shown that painful stimuli engage prefrontal cortex regions associated with the expectation of symptom relief, which results in the inhibition of limbic regions (reducing anxiety and excitatory arousal) and the increased activity of endogenous pain inhibition systems (involving opioid and dopamine channels). It is possible that a “healing context” — eg, comforting advice of a trusted practitioner and/or sugar pills — may stimulate these naturally occurring pain-relieving systems. Furthermore, research indicates that mind-based therapies for IBS, such as cognitive behavioral therapy (CBT) and hypnotherapy, activate similar brain networks, which in turn reduces pain perception and presumably clinical symptoms. Therefore, hypnotherapy or CBT might be considered as options for treatment prior to pharmacologic interventions in some cases.

Additionally, prior investigations of therapies for IBS have demonstrated robust positive influences of practitioner-patient relationships for producing clinically significant outcomes, Benninga and Mayer note. An intriguing explanation for placebo effects in children may relate to the fact that, in contrast to straightforward physician-patient interactions in the adult, the healthcare provider exerts a dual effect on the pediatric patient: one directly on the child, the other on the parent–child “dyad” — that is, the child's response to therapy is influenced by changing parents' attitudes and expectations. There apparently can be a close correlation between parental anxiety and pain sensitivity in the child; in brief, if the parents believe in a treatment and/or practitioner, and act less anxious about the child’s symptoms, it can increase placebo effects in the child.

Benninga and Mayer observe that most children with functional abdominal pain have mild symptoms that are usually of short duration and are easily managed in primary care. Current practice typically involves support and empathy for the family with assurances that no serious disease is present and that the child will likely outgrow it — all of which might enhance the placebo power of the practitioner-family-patient interaction. The primary goal is not complete eradication of pain, but resumption of a normal lifestyle with regular school attendance, participation in desired extracurricular activities, and a normal sleep pattern. With this approach, approximately 40%–70% of the children may have complete resolution of their complaints. The study by Saps et al. might be viewed as an important contribution to the pediatric literature, emphasizing the vital importance of supportive practitioner-family-patient interactions and perhaps inspiring new studies of placebo effects in children with other GI disorders, such as gastroesophageal reflux disease and constipation.

References:
> Benninga MA, Mayer EA. The power of placebo in pediatric functional gastrointestinal disease. Gastroenterology. 2009(Oct);137(4):1207-1210 [see full article here].
> Saps M, Youssef N, Miranda A, et al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children With functional gastrointestinal disorders. Gastroenterology. 2009(Oct);137(4):1261-1269 [see abstract].

U.S. Seniors Want OTC Acetaminophen Saved, Survey

According to a new survey of U.S. senior citizens, mild-to-severe pain is a common occurrence and most of them rely on over-the-counter acetaminophen for relief. They believe that education, not government regulation that would limit access, is the best solution for addressing any safety concerns regarding this analgesic.

The survey was commissioned by The Alliance for Aging Research to better understand U.S. seniors’ attitudes, perceptions, and concerns regarding age-related pain management and changes to over-the-counter (OTC) acetaminophen availability being considered by the Food and Drug Administration (FDA). We have previously discussed how the FDA is considering making higher-dose OTC acetaminophen products (eg, 500 mg. or more) available only by prescription and possibly banning all Rx acetaminophen-opioid combination products. In our blogpost (see 7/8/09) we described how available data does not support such actions.

According to the just-released survey, nearly half (46%) of U.S. seniors suffer pain — from headaches, arthritis, joint/muscle problems, backache, or colds — at least several times a week, with a third of them (34%) reporting pain every day. In most cases, the pain is moderate (46%), with 31% suffering mild pain and 17% experiencing severe pain. More than two-thirds (68%) rely on OTC pain relievers; only about 1-in-5 also sometimes use prescription analgesics. Acetaminophen-containing products are by far the most popular OTC analgesics, with most persons using extra-strength formulations. Here are some conclusions from the survey:

• Most seniors interviewed were unaware of the FDA’s considering changing the rules on the availability of OTC pain relievers, and 78% expressed opposition to such restrictions.


• By more than an 8-to-1 margin, seniors believe consumer education is a much better way to protect people from abusing or overdosing on pain relievers than government restrictions.


• Most seniors believe that changing the availability of 500 mg. acetaminophen pain relievers would make it harder and more expensive to get safe and effective pain relief. Respondents were generally uncertain about what they would do, but half (52%) said they would use more of the lower dose formulation to make up the difference.


• By very wide margins, seniors believe it would be a bad idea if the FDA required a doctor’s prescription to buy extra-strength acetaminophen products. They do not believe it is necessary or practical to make such a change —preferring individual responsibility over government regulation — and fear the added cost and inconvenience that could result.

Comment: In fair balance, roughly 1-in-5 respondents thought it would be a good idea for the FDA to require prescriptions for extra-strength acetaminophen products, with most saying it would help keep people from abusing the drug and that doctors should determine what people take for pain. However, even after being informed of the potential for liver damage due to excessive use of acetaminophen, more than three-quarters (76%) of survey respondents believed it should continue to be readily available OTC. Therefore, the message from senior citizens to government seems clear: We would welcome education on safe drug use, but leave our acetaminophen alone!

The nationwide survey was conducted via telephone by the Clarus Research Group during September 14-18, 2009, on behalf of the Alliance for Aging Research (http://agingresearch.org/). This private, non-profit organization was founded in 1986 to promote medical and behavioral research into the aging process, and to advocate for improving the health and independence of Americans as they age. The survey included a random sample of 801 U.S. adults aged 65 and older; however, the accuracy of such surveys in truly representing the entire population of interest must be cautiously considered. Support for the survey was provided by McNeil Consumer Healthcare, Division of McNeil-PPC, Inc., makers of Tylenol®.

Reference: Nationwide Survey of U.S. Seniors: Pain Management and the FDA. Alliance for Aging Research. September 2009. PDF document available here.

The DEA & Opioid REMS – An Intimidating Future?

Involvement of the U.S. Drug Enforcement Administration (DEA) in the FDA’s plans for an opioid-REMS (Risk Evaluation and Mitigation Strategy) initiative is still unknown. However, if what is happening with the prescribing of buprenorphine is any example, practitioners prescribing opioids for pain may be headed for considerable aggravation in the name of “regulatory responsibility.”

During the past several years, practitioners in the U.S. have been strongly encouraged to acquire the necessary training — usually a one-day course, often conducted at conferences in the pain field — to become authorized by the DEA to prescribe buprenorphine (Subutex® or Suboxone®) for treating opioid addiction, including dependence on opioid analgesics. About 18,000 physicians currently have obtained authorization, called a “waiver.” Now, according to a news feature from Join Together [Curley 2009], a letter from the DEA sent to these physicians has sparked concerns about intimidation and a perceived attempt to suppress the number of practitioners prescribing the medication. The letter sent late last July from DEA diversion manager Barbara A. McGrath said that the agency was developing plans to inspect buprenorphine-waiver recipients.

The letter noted, "…we are attempting to discern whether the DATA-waived portion of your medical practice will need to be inspected." Recipients of the letter choosing to discontinue prescribing the drug could exit the program simply by filling out an attached form. Continuing physicians were informed to complete a questionnaire and to prepare for an inspection visit by having a variety of documents on hand, including DEA forms, licenses, treatment documentation, and waiver certificates. While the Join Together article concedes that the letter could be viewed as a simple administrative procedure, it observes that “… given DEA's reputation among some doctors for choosing heavy-handed enforcement over patient needs — along with a perceived hostility toward buprenorphine and other opiate-replacement therapies — the letter resulted in an immediate outcry from recipients.”

More from Join Together: According to Richard Saitz, MD, at the Boston University School of Medicine, the letters may have led some doctors to conclude that "it is the last straw and not worth it to them to put up with all of the challenges one needs to surmount to prescribe buprenorphine." Charles O'Keeffe a professor at Virginia Commonwealth University School of Medicine noted that the majority of letter recipients were family practitioners and internal-medicine specialists who "went to the trouble to take the courses and get certified to prescribe" — in other words, just the kind of providers that buprenorphine proponents were hoping would embrace the drug as a way to treat addiction in office-based practices. "Overall, the feeling was that it was inappropriate to single out these physicians," who may be especially vulnerable to feeling pressured by the DEA, O'Keeffe said.

Tom McLellan, deputy director of the U.S. Office of National Drug Control Policy (ONDCP), acknowledged to Join Together, "The problem is if you get a letter from the IRS or the DEA, it evokes strong emotional reactions." He said that the administration is working on a followup response to belay fears and that acting DEA administrator Michelle Leonhardt understood how the letter could have been misinterpreted. "They [the DEA] are merely trying to carry out their regulatory responsibilities," McLellan noted.

Followup comment: While the vast majority of buprenorphine prescribers would probably have nothing to fear from DEA inspections, healthcare providers are understandably loathe to have government agencies scrutinizing their practices for any reason. Many will no doubt opt out of the buprenorphine program. Is this what the future might hold in store for opioid analgesics under REMS initiatives?

Already, there are some otherwise qualified practitioners who do not prescribe opioid analgesics, rather than risk any possibility of running afoul of regulatory agencies. Also, we have previously noted that recently announced REMS programs for Onsolis® (see blogpost 7/17/09) and Exalgo™ (see 9/26/09) involve special prescriber registration and education (of unknown extent), but the ultimate enforcement of adherence to REMS requirements and restrictions is still largely undetermined; especially, what role the DEA may play. This is worthy of consideration, because if the mandated requirements and perceived regulatory risks of prescribing opioids become overbearing many healthcare providers will simply not do so. And, unknown numbers of patients will suffer as a result. Do you think all of this is of concern, or are we overreacting? (You can comment below.)

Reference: Curley B. DEA letter sparks fears about intimidation of buprenorphine docs. Join Together (online from the National Center on Addiction & Substance Abuse [CASA] at Columbia University). October 1, 2009 [article available here].

Drug Combo Helps Relieve Neuropathic Pain

Pharmacotherapy for neuropathic pain may have incomplete efficacy and dose-limiting side effects when given as monotherapy. A new study by Canadian researchers found that combination treatment using the anticonvulsant gabapentin and the tricyclic antidepressant nortriptyline was significantly more effective and better tolerated than treatment with either drug alone.

The study, reported in The Lancet, enrolled 56 patients with postherpetic neuralgia or diabetic polyneuropathy who had a daily pain score of at least 4 on a 0 to 10 scale [Gilron et al. 2009]. They were randomly selected to be given gabapentin alone, nortriptyline alone, or both drugs. In a cross-over design, all subjects received each type of treatment for a period of 6 weeks (during which time drugs were titrated toward maximum tolerated doses). At the start of the study, the average daily pain level among participants was 5.4.

At study completion, 47 patients were analyzed for the primary outcome of mean daily pain relief. At maximum tolerated medication doses, average daily pain levels were 3.2 while patients were taking gabapentin, 2.9 while taking nortriptyline, and 2.3 while taking the combination treatment. Pain levels with combination treatment were significantly lower than with gabapentin (p=0.001) or nortriptyline alone (p=0.02). At maximum tolerated dose, the most common side effect was dry mouth, which was significantly less frequent with gabapentin than nortriptyline or combination treatment. No serious adverse events were recorded for any patients during the trial. Finally, in a Eureka Alert news report, lead investigator Ian Gilron, MD, observes, "It was also exciting to discover the effect of this combination on sleep interference"; patients rated sleep interference with the combined drugs as 1.0 on a scale of 10, compared with 2.2 when they took each drug individually. "That's a very important issue for this group of patients, whose debilitating, unrelenting pain often interferes with normal sleep."

Commentary: This study, funded by the Canadian Institutes of Health Research, suggests that combination therapies may be preferred over monotherapies for neuropathic pain. For example, an industry-sponsored meta-analysis of monotherapies for diabetic peripheral neuropathic pain reported last winter found gabapentin, pregabalin, and duloxetine were all comparable in effectiveness and superior to placebo [Quilici et al. 2009]; however, the magnitudes of effectiveness were less than combination therapy in the present study by Gilron and colleagues. Also of interest, average baseline pain scores among participants in the Gilron et al. study were moderate, which usually makes it more difficult to show dramatic improvements with pharmacotherapies; therefore, the 57% pain-score reduction with combination therapy was noteworthy, and the study was well-powered to demonstrate such effects. The researchers state, "Although development of more effective and better-tolerated monotherapies is much anticipated, our findings suggest that drug combinations represent the most effective strategy for many patients with neuropathic pain.” And, while this investigation focuses on diabetic neuropathy and postherpetic neuralgia, Gilron suggests that the methodology could also be applied to the study of other chronic conditions such as cancer-related pain, spinal disk disease, and the pain experienced after chemotherapy and mastectomies.

References:
> Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. The Lancet. Early Online Publication, September 30, 2009 [abstract here].
> Quilici S, Chancellor J, Lothgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurology. 2009;9(6). [Full article available here.]

Alcohol Misuse for Pain, a Commonplace Hazard

Healthcare providers should be concerned about alcohol misused by their patients to self-manage pain and caution them about the hazards of mixing alcohol with pain medications, according to a study recently published in the Journal of Pain [Riley and King 2009]. One in four patients may abuse alcohol as an analgesic, which appears to be most problematic among young white males and is exacerbated by greater pain frequency and depression.

It is well known that serious adverse reactions may occur when alcohol is mixed with analgesics for self-medication, and alcohol also is often misused to manage the added stress of chronic pain. Researchers from the University of Florida College of Dentistry conducted an extensive telephone-interview study to examine the use of alcohol to relieve pain in more than 4,300 adults with tooth pain (n=1,767), jaw or face pain (n=1,199), or arthritis pain (n=1,355). Results showed that more than a quarter of those interviewed (28%) misused alcohol as a pain management strategy. Such use was more frequent in men than women, in non-Hispanic whites, and among those at higher income levels. Additionally, alcohol use for pain was greatest in younger adults and in those with higher education, greater pain frequency, and/or experiencing depression. Only one factor, being married, seemed somewhat protective against the misuse of alcohol to manage pain.

The authors of this research funded by the U.S. National Institutes of Health recommend that the possible misuse of alcohol for self-managing pain should be assessed during treatment evaluation. Physicians and other health care providers need to be aware of their patients’ concomitant use of alcohol and pain medication, assess patients for psychosocial impairment due to alcohol, and when appropriate make adjustments to treatment or referrals to outside support services.

Comment: This study did not assess what proportion of those interviewed had pre-existing problems with alcohol use. As we have previously noted [see blogpost 9/16/09], 15.2 million Americans abuse or are addicted to alcohol, plus 3.1 million have abuse or addiction involving both alcohol and illicit drugs, according to U.S. government survey data. These figures, combined with the 58 million persons who are binge drinkers and 17.3 million reporting heavy drinking (according to the data), amounts to about 94 million persons with alcohol-use problems. This, alone, presents a very large population at high risk for adverse reactions, including potential overdose and death, when treated with prescription or OTC analgesics. Still unknown is the number of social drinkers who increase their alcohol use to cope with the discomfort and stress of pain, thereby risking adverse consequences when alcohol is combined with analgesic drugs.

Reference: Riley III JL, King C. Self-report of alcohol use for pain in a multi-ethnic community sample. J Pain. 2009(Sep);10(9):944-952 [see abstract].