New Opioid, Exalgo, on Slippery Slope of REMS

[ADDENDUM: Exalgo was FDA-approved for marketing on March 1, 2010 with a risk evaluation and mitigation strategy (REMS) program that requires education for healthcare providers and a patient medication guide. However, the previously proposed program requiring the registration of prescribers and patients was not part of the REMS. -- SBL]

On September 23, 2009 an FDA expert panel endorsed manufacturer plans to introduce Exalgo™, a new extended-release formulation of hydromorphone. Final FDA approval of the analgesic, possibly in November, would include a REMS (Risk Evaluation and Mitigation Strategy) program that may portend the future of regulatory burdens on opioids and have serious negative consequences for both healthcare providers and patients.

Developed by Neuromed (Vancouver, BC) and licensed to Covidien (St. Louis, MO) for United States distribution, Exalgo is a once-daily formulation of hydromorphone intended for the treatment of moderate to severe pain. Currently, only an immediate-release hydromorphone (eg, Dilaudid® and others), dosed every 4 to 6 hours, is available as an oral formulation in the U.S. The new extended-release version uses a novel bilayer tablet system, the OROS® Push-Pull™ technology, to release hydromorphone at a relatively constant rate during a 24-hour period. As with all other opioids, the primary risks of Exalgo are overdose, abuse, and diversion, which can be associated with inappropriate prescribing, dispensing, use, and handling. Therefore, to help win FDA approval, Neuromed proposes a REMS program called the “Exalgo Alliance (The Alliance for Responsible Exalgo Prescribing and Use),” which is a controlled access program including the following elements [also see Neuromed Briefing Material]:

• Exalgo will be available exclusively through the Alliance program and practitioners can only prescribe the product after they have demonstrated their understanding of the drug’s risks and enrolled in the program.


• Exalgo can only be used to treat patients who are enrolled in the Alliance program and have signed an agreement with their prescriber acknowledging that they understand the risks and will adhere to responsible drug use and handling.


• The product can only be dispensed by pharmacies and in other healthcare settings that have demonstrated an understanding of Exalgo risks and are enrolled in the Alliance program.


• Wholesalers and distributors must agree to sell Exalgo only to enrolled pharmacies and healthcare settings.


• Pharmacists must verify that both the prescriber and the patient presenting a prescription are enrolled in the Exalgo Alliance and that they are adhering to program requirements, including safe-use conditions being followed by the patient.

Upon FDA approval of Exalgo, implementation of the REMS and program monitoring will be handled by Covidien. Details of enrollment procedures (including education) and the various paperwork that may be required on a continuing basis are unspecified at this time. However, it is clear that Exalgo will incur a considerable burden of time and effort throughout the distribution chain, involving prescribers, distributors, dispensers, and patients — and, no doubt, this would entail added expense.

Commentary: According to a Reuters news report, the FDA’s experts largely agreed that Exalgo could be beneficial and was more convenient but they said the manufacturer needed to closely watch how the drug was used. According to panel chairman, Jeffrey Kirsch, MD, the panel felt Exalgo was "…very prone to crushing and other methods of abuse. On the spectrum of abuse, I think it's toward the top." Yet, the FDA Briefing Material for the meeting [available here] provides no data indicating exceptional abuse liability for hydromorphone. For example, one of the FDA’s citations in their briefing document refers to a clinical study conducted in only 9 subjects that found hydromorphone was no different in abuse potential than hydrocodone or oxycodone [Walsh et al. 2008].

The FDA briefing also mentioned the government’s DAWN report as a data source [SAMHSA 2008]; however, the most recent data, for 2006, indicates hydromorphone products accounted for less than 1% of nonmedical use of all pharmaceuticals, less than 3% of such cases involving opioid agents, and it was implicated in less than 1% of all drug-related suicide attempts. Data provided by the manufacturer covering 12 clinical trials specifically of Exalgo indicated there were only 44 cases of *possible* misuse/abuse among 2811 patients treated [see Neuromed briefing material, p 82]. Furthermore, according to FDA data in its briefing document, hydromorphone has not been a frequently prescribed analgesic; in 2008 there were 1.9 million prescriptions dispensed for IR-hydromorphone but this represented merely 1% of the total market for all IR-opioid analgesics. And, the total market for extended-release opioids was small; less than 9% of the overall opioid-analgesic market. So, looking at all available data, one must question why a new extended-release version of hydromorphone would merit such an extensive and restrictive REMS program.

Last July we expressed concerns about the highly restrictive and costly REMS program associated with Onsolis®, a new, rapid-acting, buccal-soluble fentanyl product for acute breakthrough pain [see blogpost 7/17/09]. At the time, the FDA claimed that this was an exceptional case and not typical of what might be required for extended-release opioid analgesics. Now, along comes the REMS for Exalgo, specifically described as a “controlled access” program and seeming to impose onerous obstacles remarkably similar to many of those for Onsolis. And, all of this appears like an “end run” that circumvents and undermines efforts by opioid manufacturers and other groups who have been working for many weeks under an FDA mandate to develop a rational class-wide REMS covering all extended-release and long-acting opioids.

Some very serious and disturbing questions need answers: Is the restrictive Exalgo REMS a harbinger of what lies ahead for all opioid analgesics? Will there eventually be separate REMS programs for every opioid analgesic, each with its own registration requirements and prescribing procedures? How will healthcare providers cope with this? How many patients with chronic pain might ultimately suffer from reduced access to opioid analgesics as a result?

Resources:
> Briefing Information for the September 23, 2009 Joint Meeting of the Anesthetic Life Support Drugs Advisory Committee with the Drug Safety and Risk Management Advisory Committee Meeting Announcement. FDA Briefing Material — PDF available here. Neuromed Briefing Material — PDF available here.
> SAMHSA (Substance Abuse and Mental Health Services Administration), Office of Applied Studies. Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-30, DHHS Publication No. (SMA) 08-4339, Rockville, MD, 2008 [report available here].
> Walsh SL, Nuzzo PA, Lofwall MR, Holtman Jr JR. The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug Alcohol Depend. 2008;98(3):191-202 [see abstract].

Why Size DOES Matter in Pain Research Trials

Understanding Evidence-Based Pain Management (EBPM)

Published research literature in the pain management field is inundated with reports of clinical trials having both positive and negative outcomes that enroll too few subjects to yield valid results. This wrongly depicts the therapies under investigation and biases the base of evidence for guiding clinical practice. Two recently-published studies exemplify some of the problems with small trials.

Study of PIRFT for Lower Back Pain Aborted Prematurely
Investigators in Norway conducted a randomized, sham-procedure controlled trial to examine an interventional treatment for chronic low back pain due to intervertebral disc degeneration [Kvarstein et al. 2009]. The treatment involved insertion of a probe (called the discTRODE™) into the outer part of an affected disc, the annulus, and applying radiofrequency (RF) current to heat and expectedly heal the disrupted area. In general, the procedure is known as percutaneous intradiscal radiofrequency thermocoagulation (PIRFT).

Twenty eligible patients were randomized to either intra-annular PIRFT or a sham treatment, which followed identical procedures except no heat was applied via the probe. At 6 months, an interim analysis did not reveal any significant differences between active and sham treatments for the primary endpoint — change in pain intensity (on a 0–10 scale) — and the further inclusion of patients in the trial was discontinued. After 12 months, overall reductions in pain from baseline levels reached statistical significance; however, there were no differences between the two groups and 20% of patients in each group actually fared worse. Based on these results, the authors concluded that they would not recommend intra-annular PIRFT using the discTRODE probe.

There are some concerns about the size of this study that raise questions about its validity. For one thing, patient inclusion was extremely selective: only 74 patients were recruited for the study out of 700 referrals, and merely 20 were treated (10 in each group). Yet, the authors had determined in advance that they would need at least 25 subjects in each group to have an 80% probability of detecting a 2-point statistically significant (at p=0.05) improvement in pain scores. The 80% number is called “statistical power,” which researchers can calculate in advance, and it is the likelihood that a significant difference between groups will be found if such a difference does exist. Even with 80% power, there is a 20% chance that important differences will be overlooked. Since this study did not enroll sufficient numbers of patients there was no power to detect significant differences and we cannot conclude that the outcomes were reliable evidence of PIRFT failure.

In an editorial accompanying the study, van Kleef and Kessels [2009] suggest that stopping the study after the inclusion of only 20 patients was unacceptable. They observe that all outcomes did show positive trends for PIRFT, although these were not statistically significant with so few subjects. It is understandable that the researchers were reluctant to continue the study — which administered to half the patients an invasive sham treatment with inherent risks — when favorable results seemed doubtful. However, there might be ethical questions regarding involving patients receiving either active and sham treatments in a study that is underpowered to produce valid outcomes and therefore provides little of value for the pain management field on the subject.

TENS Trial for Neuropathic Pain Fails to Show Significant Benefits
Another recently-published trial assessed the short-term benefits of high-frequency (HF) versus low-frequency (LF) transcutaneous electrical nerve stimulation (TENS) for neuropathic pain following spinal cord injury [Norrbrink 2009]. A total of 24 patients participated in a crossover trial design, with half of the patients randomly assigned to 2 weeks of 3-times-daily HF (80 Hz) TENS therapy and the other half to an identical regimen but using LF (burst of 2 Hz) TENS. After a 2-week wash-out period, patients switched stimulation frequencies and repeated the 2-week treatment procedure. On a group level, no significant changes were found from baseline or between HF and LF on pain intensity ratings (the primary outcome), or on ratings of mood, coping with pain, life satisfaction, sleep quality, or psychosocial consequences of pain. However, on a subjective 5-category global pain-relief scale a favorable effect was reported by 29% of individual patients for HF stimulation and by 38% for LF stimulation; this seems promising but statistically significant differences were not reported and there was no control group for comparison.

The author of this study did not indicate having done a statistical power analysis; however, according to our calculations, with only 24 subjects enrolled (48 in each group with the cross-over design), the trial was underpowered to detect less than a 22% difference between HR and LF treatment effects as being statistically significant. Another problem with small studies is that any dropouts greatly weaken the pool of available data for proper analysis, and 9 of the patients (38%) did not complete this study. Still, the researcher concluded that TENS merits consideration as a complementary treatment in patients with spinal chord injuries and neuropathic pain.

Underpowered Trials: More Harm Than Good?
The accurate reporting of clinical trials of experimental therapies — whether the outcomes are favorable or unfavorable — can be critical for establishing a valid and trustworthy base of evidence. However, the value of conducting and reporting small, underpowered studies must be questioned. Although such investigations, as pilot studies, might be helpful for designing more extensive future research, reporting them in the literature may prematurely skew or bias perceptions of the treatments in question. This is especially concerning when such studies end up eventually being included in review articles, meta-analyses, or guidelines.

Based on their small study, Kvarstein and colleagues disclaim any benefits of PIRFT using the discTRODE probe when a much larger study might have shown just the opposite. And, while Norrbrink proposes that TENS merits consideration for treating neuropathic pain following spinal cord injury, the data she presents from only 15 trial completers do not significantly support such a conclusion. Meanwhile, based on these studies healthcare insurance plans are likely to deny reimbursement for either therapy, and any future research in support of these therapies will need to overcome the negative perceptions to qualify the treatments for payment. Granted, larger and adequately powered trials may be more costly and take longer to do, but at least their outcomes can be trusted as being of some significant consequence.

References:
> Kvarstein G, Mawe L, Indahl A, et al. A randomized double-blind controlled trial of intra-annular radiofrequency thermal disc therapy – a 12-month follow-up. Pain. 2009(Oct);145(3):279-286 [See abstract].
> Norrbrink C. Transcutaneous electrical nerve stimulation for treatment of spinal cord injury neuropathic pain. J Rehab Res Dev (JRRD). 2009;46(1):85-94. [Article PDF available here.]
> van Kleef M, Kessels AGH. Underpowered clinical trials: time for a change. Pain. 2009(Oct);145(3):265-266.

Ultra-High Opioids: When “Too Much” is Just Right

Controversy still exists about the long-term prescribing of opioids for chronic noncancer pain (CNCP) conditions, and particularly regarding the safety and effectiveness of higher opioid doses. Yet, there appears to be a subset of patients with CNCP who require and thrive on ultra-high doses exceeding morphine-equivalent opioid doses of 1,000 mg/day — demonstrating that what some practitioners might consider as being way too much opioid is just the right amount for certain patients. However, careful patient management is necessary according to a recent journal article.

Read more »

Can Pain Research Be Trusted? Caveat Lector!

Understanding Evidence-Based Pain Management (EBPM)

The prime ingredient of evidence-based pain management practices is, obviously, good and reliable evidence. Yet, as discussed below, several recent investigations have described disturbing examples of data falsification, deceptive authorship practices, improprieties in clinical trial reporting, and misrepresentations of research results. The simple truth appears to be that published research reports in the pain management field cannot always be trusted and the best advice is caveat lector — reader beware.

Data Fraud Stuns Pain Care Community
Consumers of medical research literature rarely question the veracity of reported data. So, it is not surprising that the pain-management community was stunned to learn last winter that at least 21 published research studies (maybe more) dating back to 1996 involved the use of falsified data. The research had been conducted by pain specialist Scott S. Reuben, MD, according to articles in Anesthesiology News [Marcus 2009] and the Journal of Pain & Palliative Care Pharmacotherapy [Lipman 2009]. Reuben had conducted clinical trials demonstrating the benefits of various agents for perioperative analgesia, and the fake data was discovered during an internal investigation by Baystate Medical Center in Springfield, Massachusetts, where he had worked.

Motivations behind Reuben’s deception were not reported and coauthors of the various papers have not been implicated in the fraud. The offending articles have been retracted by the journals in which they appeared — such as Anesthesiology, Anesthesia and Analgesia, and others — however, the articles had already become an enduring part of the pain literature and there is a question of whether future writers or investigators will be aware that the articles were subsequently withdrawn. Additionally, through the years Reuben had published at least 72 articles and every research article, review paper, or meta-analysis that has included references to or data from his work could be tainted and/or biased to some degree by his dishonesty.

Authorship Deceptions
A more common form of academic misconduct involves false attribution of authorship in journal articles. A recent report notes that at least a fifth (20%) of articles published in medical journals may have “guest” authors — persons having little or nothing to do with developing the papers but named on an honorary basis [Godlee 2009]. For example, in the above case, Reuben also was found to have committed publishing forgery by naming Evan Ekman, MD, as a coauthor on at least two of the papers even though Eckman claims he had no role in developing the manuscripts [Marcus 2009]. Additionally, as many as 8% of articles may have at least one “ghost” author; someone who had written or substantially contributed to the article but is not acknowledged at all [Godlee 2009]. Both “guest” and “ghost” authorship were found to be more common in clinical research articles than in reviews or editorials, and it also is believed that the above estimates are an understatement of the problem. While such practices may not repudiate the validity of reported study outcomes, the fact is that readers are being lied to by such deceit.

Hidden Clinical Trials
Two recent investigations looked at problems with the registration and reporting of clinical trials. In the first study [Ross et al. 2009], researchers found that fewer than half (46%) of trials registered with the U.S. National Institutes of Heath (at ClinicalTrials.gov) were ever published. This means that only about half of the potential evidence for guiding evidence-based medicine practices, whether positive or negative, is ever publicly available. To make matters worse, research results that are published may not reflect the clinical trials as they were designed. A second study [Mathieu et al. 2009] found that nearly a third (31%) of randomized, controlled, clinical trials (RCTs) had discrepancies between outcomes that had been registered and those that were eventually reported in the published accounts; in 8 out of 10 cases the inconsistencies favored reporting only outcomes that were statistically significant. Going even further, while accurate trial registration helps ensure transparency and accountability, Mathieu and colleagues found that more than a quarter of published trials had never been registered at all, 14% were not registered until after trial completion, and 11% were registered with no descriptions or only vague indications of the primary outcomes. All of this leads to a publication bias, whereby trials demonstrating statistically significant and positive results tend to appear in journals much more frequently than others, and the public is left with distorted depictions of investigations involving particular therapies or interventions.

Researchers “Spinning” Research
Just as publicists may “spin” the news in favor of their clients, medical researchers sometimes try to present results of lackluster studies in a more attractive light. An investigation noted recently in the British Medical Journal [Chew 2009] examined a sampling of 72 published RCTs containing essentially unremarkable results and found that 40% of them conveyed “spin,” defined as reporting results in such a way as to convince readers that an experimental treatment was beneficial despite poor or non-significant outcomes. Examples of linguistic “spin” included: “[The treatment] is expected to be a very important modality in the treatment strategy of [the disorder]”, “[The treatment effect] approached conventional statistical significance.” Another tactic in the various articles examined was to focus on interesting secondary or subgroup analyses, rather than on the statistically non-significant primary outcomes. A second investigation looked at how benefit claims in RCT articles are sometimes “spun” without any supporting evidence. Of 35 RCTs examined, which made 695 favorable efficacy statements in total about the experimental treatments in question, nearly half (338 or 49%) of the remarks did not specify the statistical significance (if any) of the claimed benefits. And, of the 96 safety claims that were made, only 2 included the term “significant” and only 1 of these was supported by a statistical result.

In sum, except for instances of data fraud, which are rare, the other practices appear to be more commonplace than is warranted or acceptable. Of course, there also is the possibility that investigations of bias in research articles are themselves biased in some fashion. The most reasonable response seems to be for consumers of medical research literature to develop a healthy skepticism about everything they read in the journals and very cautiously accepting research conclusions as guides for patient care.

References:
> Chew M. Researchers, like politicians, use “spin” in presenting their results, conference hears. BMJ. 2009(Sep 15);339:b3779.
> Godlee F. More than 20% of articles have a “guest” author, study shows. BMJ. 2009(Sep 15);339:b3783.
> Lipman AG. The pain drug fraud scandal: implications for clinicians, investigators, and journals. J Pain Pall Care Pharmacother. 2009;23(3):216-218.
> Marcus A. Fraud case rocks anesthesiology community: Mass. researcher implicated in falsification of data, other misdeeds. Anesthesiology News. 2009(Mar):35(3). [Article available here, free registration required.]
> Mathieu S, Boutron I, Moher D, et al. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA. 2009;302:977-984.
> Ross JS, Mulvey GK, Hines EM, et al. Trial publication after registration in ClinicalTrials.gov: A cross-sectional analysis. PLoS Med. 2009. [Article available here.]

Yoga Relieves Low Back Pain, But Use Caution

Posting contributed by Winnie Dawson, MA, RN, BSN

Chronic low back pain (CLBP), a common complaint among adults, has been shown to improve with a program of regular exercise after the acute pain phase has passed. However, choosing an appropriate exercise regimen can be confusing for many people. A study funded by the National Institutes of Health — published in the September 2009 issue of the journal Spine — reported results showing that a series of twice-weekly yoga classes with home practice relieved pain and improved mood [Williams et al. 2009]. Ninety patients with mild to moderate chronic low back pain that persisted for more than 3 months, without evidence of serious pathology, were randomly assigned to a yoga practice group or a control group. Members of the yoga group participated in 24 weeks of twice-weekly, 90-minute yoga classes specifically designed for people with CLBP. The yoga participants were also asked to practice for 30 minutes on non-class days and received yoga props and instructional materials. Control group members received standard medical care.

The outcomes were based on participant questionnaires used to self-report levels of pain, disability, and depression, as well as the amount of medication usage. At 24 weeks, the results showed a statistically significant reduction in functional disability, pain intensity, and depression for the yoga group as compared with the control group. These improvements remained significant for the yoga participants at the 6-month follow-up after the study’s end. An additional benefit reported by study authors was a “clinically important trend” for reduced analgesic use by the yoga group compared with the control group. There were no adverse events reported in the yoga group. The authors concluded that this study provided a more rigorous evaluation (than previous studies) of yoga in this population and resulted in clinically effective symptom relief for people with CLBP.

Commentary: While the participants in this study ranged in age from 23 to 66, study outcomes showed no differences between age and symptom improvement. Yoga can be practiced by persons of any age when cautious consideration is given to personal levels of strength, flexibility, and balance. The yoga classes in this study were led by certified Iyengar yoga instructors but it is important to note that there are many forms of yoga, each with variations in postures and intensity. All styles of yoga focus on flexibility, balance, and breathing, but Hatha yoga and Iyengar yoga may be most appropriate for beginning students with CLBP. Hatha yoga uses a more gentle approach to posture flow and Iyengar yoga is a form that uses props to aid alignment. Some yoga instructors offer a special class — oftentimes called ‘Gentle Yoga’—for people with health concerns. Since some yoga routines may be too challenging for a person with CLBP, it is always appropriate to discuss chronic back conditions with a certified yoga instructor in advance. Patients also should be cautioned to advise their healthcare providers of their participation in any exercise program.

References:
> Williams K, Abildso C, Steinberg L, et al. Evaluation of the effectiveness and efficacy of Iyengar yoga therapy on chronic low back pain. Spine. 2009(Sep 1);34(19):2066-2076. PMID: 19701112 [PubMed citation.]
> Additional information on yoga and health is available at the U.S. National Center for Complementary and Alternative Medicine (NCCAM-Yoga).

Pain-Reliever Abuse/Addiction Stabilized in U.S.

No doubt about it — the United States has illicit-drug-use problems. However, according to the latest government data, news headlines and public outcries about mushrooming increases in pain-reliever misuse, abuse, and addiction are misleading. In fact, trends have remained stable for a number of years and pain relievers are a relatively small part of the problems.

The U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) just released the first data from their 2008 National Survey on Drug Use and Health (NSDUH). [See full document here.] In 2008, an estimated 20.1 million Americans aged 12 or older (8% of the population) were illicit-drug users, which was identical to the rate in 2007. Illicit drugs broadly include marijuana/hashish, cocaine (including crack), heroin, hallucinogens, inhalants, and the nonmedical use of prescription-type pain relievers, tranquilizers, stimulants, and sedatives. Marijuana was the most commonly used illicit drug in 2008 (15.2 million past month users) in the age 12+ population. There were 6.2 million persons who used prescription-type drugs nonmedically, which was lower than in 2007 (6.9 million), and an estimated 4.7 million of those persons used pain relievers nonmedically in 2008.

Widespread concerns have focused on drug abuse and addiction. In 2008, an estimated 22.2 million persons (8.9% of the population aged 12 or older) were classified with either substance abuse or dependence (that is, addiction) based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Of these, the majority, 15.2 million, had abuse or addiction solely to alcohol, in 3.1 million both alcohol and illicit drugs were involved, and 3.9 million had abuse or addiction to illicit drugs only. There had been only a slight and non-significant increase in these numbers from 2002 to 2008.

As the graph shows, of the 7.0 million persons aged 12 or older with abuse or addiction involving illicit drugs with or without alcohol in 2008, the greatest levels were for marijuana (4.2 million), followed by pain relievers (1.7 million) and cocaine (1.4 million). The rate of pain reliever abuse and addiction has remained essentially stable during the past 4 years. For the other categories — illicit drugs overall, cocaine, and marijuana — the trends have been stable since 2002.

IMPORTANT FLAWS/CONCERNS: The annual NSDUH survey generates an impressive array of data, often used by government agencies and civic organizations to justify their antidrug programs and research. However, there are a number of potential flaws and concerns that need to be recognized.

• Approximately 67,500 persons are interviewed face-to-face for the survey each year; an impressive number but still less than 0.03% of the population in question. Even with statistical adjustments, it is risky to assume that the results are completely accurate in representing all of America.


• The survey estimates that 4.7 million persons used pain relievers nonmedically in 2008. HOWEVER, the "nonmedical" use of these drugs is defined by the NSDUH as “use without a prescription of the individual's own or simply for the experience or feeling the drugs caused.” It does not account for the unauthorized use of analgesics to relieve pain, which we have called “medical misuse.” Proper attribution of motivations in this regard could make important differences in our understanding of problems with pain relievers.


• For example, in a prior post [see 8/12/09] we noted research that found about 1 in 8 U.S. high-school seniors have misused prescription opioid drugs for “nonmedical” purposes, but nearly half of them were illicitly using the medications for self-treating physical pain. So the “hidden problem” here could be untreated or mistreated pain in this population of young persons. And, while the research has not looked at this, it could be important as well to know how much marijuana use is for pain relief rather than recreational purposes.


• In the NSDUH survey, 56% of respondents got pain relievers they misused from a friend or relative for free and 18% reported they got the drug from one doctor. Only about 5% got the drugs from a drug dealer or other stranger, or on the Internet. Among those who reported getting the pain relievers from a friend or relative, nearly 82% reported that the friend or relative had obtained the drugs from just one doctor. Therefore, a large proportion of “nonmedical” use actually may be the sharing of legitimately prescribed analgesics for unauthorized pain-relief purposes. This is a different sort of problem than the survey data seem to convey.


• The accuracy of the NSDUH survey in clinically diagnosing substance abuse or addiction following DSM IV criteria should be questioned. However, an even greater concern than the 1.7 million persons revealed to have pain-reliever abuse or addiction could be the 15.2 million with alcohol abuse or addiction, plus the 3.1 million with abuse or addiction involving both alcohol and illicit drugs. These figures, combined with the 58 million persons who are binge drinkers and 17.3 million reporting heavy drinking (according to the survey), amounts to about 94 million Americans with alcohol-use problems. Combining alcohol with analgesics, as is commonly done, has a very high risk potential for overdose and death; so, unless alcohol-related problems are addressed there is little hope of reducing the hazards of analgesic misuse.

In sum, while there are important problems with pain-reliever misuse, abuse, and addiction in America these are only one part of the larger picture. And, as we’ve noted before [see blogpost 8/19/09], there already are a number of U.S. government agencies or research institutes concerned with alcohol and illicit drugs but there are virtually none specifically addressing pain and problems associated with the analgesics used to treat pain conditions. That should be corrected, don't you think? Add your comments below.

Probability Blindness & Fallacies of FDA REMS

While much speculation and angst continue to surround the U.S. FDA’s planned Risk Evaluation and Mitigation Strategies (REMS) for increasing the safety of opioids and other analgesics, it is possible that the initiative is being driven to begin with by misconstrued data and faulty reasoning. We need to take a closer look at how analgesic-related risk probabilities might be calculated and viewed. In the final analysis, risk-avoidance regulations may incur unintended consequences of making relatively minuscule but manageable problems pertaining to analgesics into major obstacles to patient care.

When it comes to risks of adverse events with medications, there is a tendency to think in black or white terms — a drug is either safe or unsafe — when risk actually is a shades-of-gray concept [Gardner 2008]. Such risk can be calculated as a probability, which is the ratio of the number of particular drug-related adverse events (the numerator) divided by the total number of potential risk-event exposures (eg, number of people taking the drug, total drug doses administered; the denominator) occurring during a period of time. What is an optimally low probability of risk? How high a risk demands remedial action? Answers to these questions are often subjective, and may involve a degree of what Harvard professor Cass Sunstein calls “probability blindness” [Sunstein 2007] whereby judgments are guided more by public sentiment and/or political pressures than by compelling objective evidence of risks overpowering benefits. This is what may be happening with recent initiatives by the FDA to mandate REMS programs for an array of analgesic products.

Analgesic Safety Clearly Established
Incidents of overdose poisonings and deaths associated with analgesics have garnered a great deal of public notice and governmental concern. Yet, when considering the millions of doses administered each year (the denominator in a risk-probability calculation) currently approved analgesic products have remarkably favorable safety records. For example, in a previous blogpost we calculated that propoxyphene-containing products have been used without fatality 99.999% of the time, and many of the deaths that did occur were related to suicides or multiple-drug misuse [see post 7/12/09]. Similarly, using a worst-case scenario, acetaminophen-containing products have been used without liver injury or death 99.86% of the time, and most of the harmful events were due to carelessness in exceeding recommended maximum daily doses [see 7/8/09]. Despite the diminutive severe adverse event probability rates of 0.001% and 0.14% for propoxyphene and acetaminophen products, respectively, both have been denigrated as threats to public health and the FDA (as of this writing) is considering rigorously restricting their future availability.

Methadone provides a further example. A recent concern has been alleged cardiotoxicity of methadone and there is serious consideration being given to requiring ECG monitoring in all patients prescribed the drug for pain or for addiction therapy [see prior posting 8/8/09]. However, in a recent report describing 7 years of observation in methadone maintenance treatment (MMT) programs, encompassing 6,450 patient years of treatment, no deaths were attributed to cardiac arrhythmia [Anchersen et al. 2009]. Still, 4 deaths were of unknown causes that might have been cardiac related; so, a possible rate of fatal arrhythmia per patient year was 0.06% (4/6450 x 100). However, the denominator is actually much larger: assuming it would take only one dose of methadone to trigger a fatal cardiac event and patients are dosed at least once daily, the hypothetical probability becomes a negligible 0.0002% (4/[6450 x 365] x 100). Such a low and speculative risk does not seem to justify routine ECG monitoring in ALL patients.

As with other analgesics, methadone-associated mortality has been a special concern. A recent and credible U.S. government report examining this issue noted that methadone overdose deaths increased roughly 5-fold (from 786 to 4,462) between 1999 and 2005 [GAO 2009], which sounds menacing. Yet, during approximately that same time period there was an 8-fold increase in methadone prescriptions for pain alone (from 531,000 to 4.1 million). Proportionately, it appears that deaths (the numerator) associated with methadone prescriptions (the denominator) were actually declining: the mortality-probability rate decreased from 0.15% to 0.11%. Or, put another way, in the most recent year (2005) methadone prescriptions were used safely without overdose death at least 99.89% of the time. At that, the government report concedes that methadone might be noted in forensic investigations as being present at death but that does not mean it was the cause; thus, the numerators may be skewed larger than they should be by assuming methadone was the culprit when it was only an “innocent bystander,” and incidence rates would be even smaller than noted above. Still, methadone is among the long-acting and extended-release opioid analgesics that the FDA believes need much tighter regulations under REMS for controlling safety risks.

What Are Acceptable Risks?
Similar to the above calculations, severe adverse event risk probabilities would most likely be extremely low for all other analgesics, and it is important to note that the majority of poisonings and fatalities with analgesics have resulted from improper prescribing and/or misuse of the products. In fact, the relatively minuscule incidences of severe adverse events with analgesic products is actually a testament to the effectiveness of the FDA in evaluating, approving, and monitoring medications that are essentially safe when properly prescribed and taken as directed on the product labeling.

Still, the relatively uncommon overdoses and deaths associated with analgesics make for sensational news headlines, especially when celebrities are involved, and the public or safety-advocacy groups clamor for action without knowledge of the already low risks or the ultimate costs of such action. The outcry often is, “It’s worth whatever it takes even if only one life is saved,” and policy makers and regulators listen. Risk-averse public officials take safety very seriously, as Sunstein notes [2007, p 24], “Even when ordinary people can reasonably treat tiny risks as if they were zero, the analysis is altogether different for those whose business is to reduce risks.” However, when it comes to analgesics, the risk-probability threshold at which the FDA decides that remedial regulatory actions are absolutely necessary is unknown, and costs in terms of unnecessary human suffering can be extremely high if such actions serve to deny access to those medications for patients who might benefit from them. FDA representatives have stated that they want to preserve such access, but the recently-mandated REMS program for a newly approved fentanyl product, Onsolis®, demonstrates that the FDA is willing to invoke extremely robust restrictions on analgesic distribution and availability [see blogpost 7/17/09].

Education Not Regulation Needed
How close to zero risk (100% safe use) must an analgesic medication be to satisfy policy makers and the FDA? This question is especially vexing, considering that a large share, possibly most, of the severe adverse events result from misbehaviors (eg, misuse or abuse) related to the drugs. It is interesting to consider that, without much thought (a form of probability blindness) the American public is rather risk-tolerant when it comes to another potent drug — alcohol — which is ubiquitous (61% of all adults imbibe and 12% do so excessively) and hazardous when misused. According to our calculations, using data from the Centers for Disease Control and Prevention for 2006, the risk of death directly related to alcohol use in the U.S. was 0.18% that year, excluding alcohol-involved homicides and non-driving accidents [driving data here, other death data here]. In this perspective, alcohol incurs a higher mortality risk than acetaminophen, propoxyphene, methadone, and probably any other analgesic. And, as was learned years ago, restrictive-distribution regulations (eg, prohibition) do not eliminate alcohol-risk behaviors. Similarly, it seems logical that responsible medication-use behaviors that might serve to lower the risk probabilities for analgesics cannot be achieved by increasingly restrictive regulations.

In sum, it appears that fallacies of REMS result from two misconceptions:

1. erroneously considering that risks of severe adverse events associated with analgesic medications are at such dangerously high levels that an immediate and rigorous response is necessary, and
   
   
2. wrongly assuming that regulations potentially restricting access to the medications will ameliorate either unintentional or volitional misbehaviors contributing to severe adverse events.
   

We believe a better approach would focus not on more regulation but on better education for healthcare providers, patients, and the public regarding safe analgesic use. Such education may not be the mission of the FDA, in which case they might step aside and turn the task over to other public and private agencies. Of further interest, the above mentioned Cass Sunstein has just been appointed America’s new “regulatory czar,” with broad-ranging responsibilities for reviewing and guiding federal regulations; perhaps, he will bring an enlightened vision for overcoming the probability blindness surrounding opioid REMS initiatives. Any opinions? Add a comment.

References:
> Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical significance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction. 2009;104(6):993-999 [see abstract].
> GAO (U.S. Government Accountability Office). Methadone-Associated Overdose Deaths. March 2009. GAO-09-341 [see document PDF].
> Gardner D. The Science of Fear. Why We Fear the Things We Shouldn’t and Put Ourselves in Greater Danger. New York, NY: Dutton; 2008.
> Sunstein CR. Worst Case Scenarios. Boston, MA: Harvard University Press; 2007.

Dismal Portrait of Chronic Pain Relief; Survey

Despite a year of treatment for chronic pain, 95% of patients were still in moderate to severe pain, according to results of a newly reported survey. In more than half of patients the pain failed to improve at all and nearly 1 in 5 reported that their pain worsened during the year — overall, 46% remained in severe pain at the end of the 12-month study.

The survey, entitled PainSTORY (Pain Study Tracking Ongoing Responses for a Year), is the first of its kind to follow the impact of chronic pain on patients’ lives during the course of 12 months (ending May 2009). Participants included 294 patients in 13 European countries (United Kingdom, France, Germany, Switzerland, Italy, Spain, Ireland, Belgium, Sweden, Denmark, Finland, Netherlands, and Norway). They were suffering from nonmalignant moderate to severe chronic pain associated with osteoarthritis, back pain, osteoporosis, neuropathic pain, mixed pain, or other long-term pain. Participants recorded information about their types of pain, who they had consulted for help, and what treatments they received.

Although nearly all participants continued to suffer pain, the number of them visiting a doctor declined during the year from 83% at the beginning of the survey to 70% at the end. By the end of the year, only 58% had been given a physical examination, 22% were rated on a pain scale, 19% were sent for further tests, and merely 2% had consistently visited a pain specialist. Most patients (83%) were prescribed pain medication but nearly a third also resorted to over-the-counter (OTC) remedies either alone or in combination with other therapies. Only about 1 in 8 patients (12%) were prescribed strong opioid therapy, 25% a weak opioid, and 43% were prescribed nonopioid agents. The research also reveals that less than a quarter (23%) had their prescription changed to a stronger type of pain medication during the year.

Even though their pain persisted unabated in most cases, 64% of patients believed they were taking the most appropriate level of medication and 58% thought that everything possible was being done to help them. However, chronic pain took a high personal toll: 44% of participants reported feeling alone in tackling their pain and two thirds felt anxious or depressed as a result of their pain. They reported feeling trapped by a pain that varied in intensity but continuously affected every aspect of their lives. More than a quarter of patients (28%) said their pain was so bad at times that they wanted to die.

Commentary: The obvious message here seems to be that healthcare practices in Europe are inadequate for persons with chronic pain. However, this was a relatively small study, considering the amount of geography covered, and the researchers do not report how patients were selected for the survey. There could be biases in subject selection and the types and quality of treatments that were available to them. It would be important to know if certain subgroups of patients, receiving select treatments, did better than others; however, with only 294 participants in total such subgroup analyses probably would not have statistical power. Hopefully, this sort of long-term research will be continued and expanded in Europe, and initiated in the United States and other countries. Prior surveys have revealed that chronic pain is a *disease* of epidemic proportions, and increasing worldwide.

Source: The PainSTORY survey was conducted by an independent research company, Ipsos MORI, in collaboration with the European Federation of IASP Chapters, World Institute of Pain, and OPEN Minds. It was sponsored by a restricted educational grant from, and prepared in association with, Mundipharma International Limited, a manufacturer of opioid analgesics. For much more information, visit http://www.painstory.org/.

Tension Myositis Syndrome & Chronic Pain Myths

Chronic pain, especially nonspecific pain that is unexplained by structural or organic pathology, is a frustrating challenge for healthcare providers and patients alike. Tension Myositis Syndrome (TMS) — focusing on mind-body, psychosomatic pain related to unresolved emotional distress — has been proposed as a primary cause. However, whether TMS is more myth than reality and its clinical validity need careful consideration.

A New Paradigm of Chronic Pain Needed?
This subject came to our attention in a recent article titled “Treating Chronic Pain – There is a Better Way!” by Colleen Perry at the popular Huffington Post website [see article]. Perry, a marriage and family therapist in California, claims a new paradigm is needed when it comes to chronic pain and its treatment. She contends that many conditions are often mistakenly treated with drugs and/or surgery, including back pain, neck and shoulder pain, migraine headaches, fibromyalgia, carpal tunnel syndrome, repetitive strain injury, pelvic pain, irritable bowel syndrome, and others. For a better solution, she recommends a concept called Tension Myositis Syndrome, or TMS, which was originally proposed by John Sarno, MD, in the 1970s to describe disorders that appear to be purely physical but actually originate from distressful emotions. Perry asserts that “we cannot talk about reforming our healthcare system without taking into account the billions of dollars that are wasted by the American Medical Association's widespread refusal to recognize chronic pain as a mind-body disorder [which is the essence of TMS].”

Indeed, it does appear that TMS has not received serious recognition or study from mainstream medicine, even though Sarno — professor of Clinical Rehabilitation Medicine, New York University School of Medicine, and attending physician at the Rusk Institute of Rehabilitation Medicine — claims to have successfully treated thousands of patients merely by educating them on his beliefs of an emotional basis for their pain symptoms. His approach hinges on mind-body connections whereby pain arises from unresolved emotional issues; in effect, the brain causes the pain as a diversion or distraction from emotions that are threatening to the patient.

The phrase “Tension Myositis Syndrome” refers to the emotional disturbances behind the condition (tension), the involvement of skeletal muscles (myositis), and the multitude of symptoms (syndrome). Most recently, Sarno says the condition should be called “Tension Myoneural Syndrome” to include nervous system involvement, and others have suggested “The Mindbody Syndrome” as easier for the lay public to remember. TMS most clearly seems applicable to chronic pain without evidence of structural or organic pathology — nonspecific in nature; however, Sarno believes TMS should be considered even in cases where there is evident pathology, at least as a contributing factor.

Where is the evidence to support TMS?
Advocates claim there are inherent difficulties in performing clinical trials to validate psychosomatic characteristics of TMS, consequently there is very little supportive research literature. However, there is extensive popular literature on the subject (eg, see document here, or website here), and Sarno’s most recent book, The Divided Mind: The Epidemic of Mind Body Disorders (2006), and earlier works have sold very well. The “cure” for TMS requires identifying and managing underlying psychological stressors; in some persons, merely acknowledging the existence of threatening unconscious emotions allegedly has relieved all pain. Specific treatment modalities have included, reading books on the subject, cognitive behavioral therapy, hypnotic suggestion, and guided imagery. In one case-series report of 51 patients with chronic back pain diagnosed as TMS, treatment consisted of office visits, written and audio educational materials, guided journaling, and psychotherapy for select patients [Schecter et al. 2007]. During 3 to 12 months of followup there were significant decreases in pain scores and medication use, while physical health and activity scores increased significantly; however, reports such as these must be considered anecdotal.

In an interesting controlled clinical trial published several months ago in JAMA [Kroenke et al. 2009], researchers randomly assigned patients diagnosed with depression and chronic pain (back, hip, or knee) to either usual care (n=127; standard antidepressants and analgesics) or an experimental intervention (n=123; including the usual analgesics plus optimized antidepressant medication regimens and a multi-session pain self-management program consisting of an examination of negative emotions, relaxation techniques, behavioral modification, and other approaches for increasing self-efficacy). Compared with usual care, the intervention group experienced significantly greater reductions in both depression and pain. Unfortunately, there was no third group receiving usual care plus the self-management program; that is, to separate out effects of enhanced antidepressant therapies that could have, themselves, manifested pain relief. Still, in a sense, the intervention might be considered a form of “medication-assisted TMS-management therapy,” and it seems to support the value of attending to possible psychosomatic influences as a component of chronic pain management.

Inherent Dangers & Caveats
Other research seems to contradict TMS interpretations of chronic pain. An extensive systematic review examining the influence of psychological factors on the onset and continuation of complex regional pain syndrome (CRPS, also known as reflex sympathetic dystrophy, or RSD) found that, while many patients with CRPS are stigmatized as being psychologically different, there was no evidence of psychosomatic effects [Beerthuizen et al. 2009]. European investigators have recently expressed concerns about inappropriately attributing somatic pain complaints having no evident clinical pathology to purely psychological origins, or “psychologization,” which could serve as a barrier to effective pain management [Crombez et al. 2009].

Some researchers, such as Norton M. Hadler, MD, have for many years described psychosomatic aspects of chronic pain disorders in pejorative terms [eg, Hadler 1978; Hadler et al. 2007]. For example, Hadler and colleagues consider work-related cumulative strain disorders and backache as mere “surrogate complaints” reflecting psychological distress over poor working conditions and unrewarding work rather than as bona fide maladies. They write: “No physician, employer, human resource professional, claims adjuster, or worker is likely to realize that the backache is intolerable and disabling because the job is intolerable, unsatisfying, or insecure” [Hadler et al. 2007]. The implication in Hadler’s publications through the years is that many persons with pain complaints are psychologically unfit malingerers hoping to take advantage of workers’ compensation or other assistance for bogus conditions having no basis in structural or organic pathology. And, while he does not specifically name tension myositis syndrome, concepts of TMS used inappropriately would appear to bolster Hadler’s arguments opposing physical origins of the complaints.

Therefore, a final concern is whether treatment of TMS would be covered by health insurance and/or other compensation systems. Especially, since it appears that the psychological basis of the disorder opens the door for a variety of alternative therapies, often delivered by nonmedical practitioners. So, there may be dangers in broadly accepting TMS unless its scientific validity can be confirmed. Even if TMS is more myth than reality, as with all myths there still may be some innate truth behind it since pain is a subjective experience and emotional discord may exacerbate pain perception. However, whether or not mind-body connections play a central or peripheral role in chronic pain, and the extent to which discovering and managing emotional underpinnings can have remedial effects, requires more investigation. Any opinions? Post your comments below.

References:
> Beerthuizen A, van’t Spijker A, Huygen F, Klein J, de Wit R. Is there an association between psychological factors and the complex regional pain syndrome type 1 (CRPS1) in adults? A systematic review. Pain. 2009;145(1-2):52-59.
> Crombez G, Beirens K, Van Damme S, et al. The unbearable lightness of somatization: a systematic review of the concept of somatization in empirical studies of pain. Pain. 2009;145(1-2):31-35.
> Hadler NM. Legal ramifications of the medical definition of back disease. Ann Intern Med. 1978;89(6):992-999.
> Hadler, NM, Tait RC, Chibnall JT. Back pain in the workplace. JAMA. 2007;297(14):1594-1596.
> Kroenke K, Bair MJ, Damush TM, et al. Optimized antidepressant therapy and pain self-management in primary care patients with depression and musculoskeletal pain: a randomized controlled trial. JAMA. 2009;301(20):2099-2110.
> Schechter D, Smith AP, Beck J, et al. Outcomes of a mind-body treatment program for chronic back pain with no distinct structural pathology – a case series of patients diagnosed and treated as tension myositis syndrome. Altern Ther Health Med. 2007;13(5):26-35.

Secrets of Acupuncture for Pain Revealed – a Bit

Researchers at the University of Michigan Chronic Pain and Fatigue Research Center provide the first evidence of how acupuncture may relieve pain by enhancing the action of opioid receptors in the brain. However, this may not completely explain why sham (fake) acupuncture also seems to relieve pain.

Acupuncture has been used to treat pain for centuries, possibly by activating the body’s intrinsic painkillers (eg, endorphins), but how it works at the cellular level has been a mystery. In a recently-reported study, participants included 20 women who had been diagnosed with fibromyalgia and experienced pain at least 50% of the time. During the study they agreed not to take any new medications for their fibromyalgia pain [Harris et al. 2009]. The women were randomly assigned to receive either traditional Chinese acupuncture or sham acupuncture treatments during the course of 4 weeks. Brain imaging (positron emission tomography, or PET) was performed during the first treatment session and repeated a month later following the 8th treatment. Results showed that true acupuncture produced both short- and long-term increases in the binding availability of mu-opioid receptors (MOR) in multiple limbic regions of the brain that process and dampen pain signals (eg, cingulate, caudate, and amygdala); whereas, these effects were largely absent in the sham acupuncture group. “Interestingly, both acupuncture and sham acupuncture groups had reductions in clinical pain,” according to lead author, Richard E. Harris, PhD [in a press release], “but the mechanisms leading to pain relief are distinctly different.” Since opioid analgesics, such as morphine, work by binding to MORs, and those receptors bind opioids more effectively following acupuncture, an implication of this research is that patients with chronic pain treated with acupuncture might be more responsive to opioid medications, Harris suggests.

Commentary: This was a small study and the benefits of opioid analgesics for augmenting pain relief in patients treated with acupuncture were not tested. Furthermore, the study does not shed much light on controversies about sham acupuncture being as effective as real acupuncture in reducing chronic pain [eg, see here]. Meanwhile, an interesting and just-reported study examined brain function associated with “placebo analgesia” induced by sham therapy [Watson et al. 2009]. For this study, participants were administered pain-inducing laser stimulation on their forearms and, then, prior to a second round of painful laser stimuli they were told an anesthetic cream was being applied — in fact, however, they all received an inactive “sham” cream. Brain imaging (via functional magnetic resonance imaging, or fMRI) was performed during the experiment. The sham-cream treatment resulted in significant reductions in pain, and corresponding changes in brain activity were largely centered in prefrontal cortical areas (that is, “thinking areas” of the brain, as opposed to pain-modulating limbic structures noted in the acupuncture study above). The researchers suggest that the main placebo-analgesic effect came from a reduced anticipation of pain due to the (sham) therapy; in other words, participants thought and believed the cream would help so it did.

Relating back to the acupuncture studies, and this may be rather speculative, it seems plausible that acupuncture therapy (real or sham) may affect multiple brain regions. Whether treatment is applied with needles or dull sticks there are neurological processes at work, and a belief in the effectiveness of the treatment may be as potent in relieving pain as the influence on opioid receptors. This needs further study since it could have clinical relevance for various pain therapies.

References:
> Harris RE, Zubieta JK, Scott DJ, Napadow V, Gracely RH, Clauw DJ. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs). NeuroImage. 2009;47(3),1077-1085 PMID: 19501658
> Watson A, El-Deredy W, Iannetti GD, et al. Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception. Pain. 2009;145:24-30.

ADDENDUM — [1/23/2010] an interesting trial on this subject was reported last May 2009, finding that acupuncture was effective for low back pain; however, it was unclear whether real acupuncture versus simulated acupuncture was superior, or if both actually represented placebo effects. At one year posttreatment, patients receiving acupuncture (real or sham) were more likely than those receiving usual care (non-acupuncture) to have clinically meaningful improvements in dysfunction but not in symptom relief.
> Cherkin DC, Sherman KJ, Avins AL. A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic low back pain. Arch Intern Med. 2009;169(9):858-866 [abstract here].