Aug2009 – Pain Product Announcements & Warnings

Featured Items: generic sumatriptan succinate, milnacipran (Savella), unapproved topical ibuprofen warning, tumor necrosis factor (TNF) blocker warning, extended-release morphine and naltrexone HCl (EMBEDA).
— All brand names are trademarks of their respective manufacturers. Compiled by Winnie Dawson, MA, RN, BSN.

Generic Sumatriptan Succinate - Receives FDA Approval
Sun Pharmaceutical Industries Ltd. reported an August 2009 FDA approval of their application for a generic version of Imitrex® for acute treatment of adult migraine attacks with and without aura. These sumatriptan succinate tablets are therapeutically equivalent to Imitrex tablets from GlaxoSmithKline.

Milnacipran HCl (Savella®) for Fibromyalgia – Now Available
Following FDA approval in January 2009, the makers of Savella — Forest Laboratories and Cypress Bioscience — have received consent to a minor post-approval cosmetic formulation change and the product is now commercially available. Savella, a selective serotonin and norepinephrine dual reuptake inhibitor (SNRI), is the third product to receive approval for the treatment of fibromyalgia. In clinical trials, patients on milnacipran doses of 100 mg/day and 200 mg/day reported a significant improvement in pain, patient global assessment, and physical function. See prescribing information and the Savella medication guide.

Ibuprofen Topical Products – 8 Makers Receive FDA Warning for Unapproved Analgesics
Progressive Emu, Inc. and 7 other manufacturers of topical ibuprofen pain relievers received FDA warning letters during August 2009 asking them to discontinue the marketing of their products. While these over-the-counter (OTC) products are frequently marketed as “safer alternatives” to oral ibuprofen, the FDA states that “there are no approved applications for topical ibuprofen products.” See the FDA press release for a full list of products and manufacturers.

TNF Blockers Increase Risk of Childhood Cancers – FDA Requires Safety Warning
As follow-up to a June 2008 Early Communication and a year-long review, the FDA has reported their conclusion that the use of tumor necrosis factor (TNF) blockers carries an increased risk of lymphoma and other cancers for children and adolescents. These agents — marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi — are prescribed to treat juvenile idiopathic arthritis, rheumatoid arthritis, Crohn’s disease, and other immune system diseases. Patients who use the drugs for more than 2½ years appear to have an increased risk of cancer. Additionally, the FDA is requiring a safety warning regarding the increased risk of leukemia and new-onset psoriasis in all patients treated with TNF blockers. See the FDA press release and further information.

Extended-Release Morphine Sulfate and Naltrexone HCl (EMBEDA™) – FDA Approved
In August 2009, the FDA and King Pharmaceuticals, Inc. announced the approval of EMBEDA (combination extended-release morphine sulfate and naltrexone hydrochloride), a novel oral capsule for the management of moderate to severe pain. The product is intended for patients who require around-the-clock analgesia for an extended period and it is the first FDA-approved long-acting opioid that has been designed to discourage tampering by reducing drug “liking” and euphoria when crushed or chewed. EMBEDA is is scheduled to be available in September 2009 in 6 fixed-dose combinations. See prescribing information, the interim Risk Evaluation and Mitigation Strategy (REMS), and the medication guide for complete clinical and safety information. Also, see our previous blogpost on EMBEDA.

UDT Study Misinterprets Opioid Analgesic Misuse

Urine Drug Testing (UDT) for monitoring opioid therapy compliance can be a useful clinical tool when judiciously applied in select patients and properly interpreted. However, a large study of UDT results claiming that three-fourths of patients prescribed opioids for chronic pain are noncompliant with the therapy appears to raise more questions than it answers. Inadvertently, the study also reveals significant limitations of relying on UDT as a guide for patient care.

The study, reported in a front-page feature article in the August 2009 edition of Pain Medicine News [Pizzi 2009], was originally presented in poster format at a recent meeting of the International Society of Pharmacoeconomics and Outcomes Research in Orlando, Florida. Researchers retrospectively examined UDT results from 700,000 patients (about 940,000 test samples) with chronic pain who were prescribed opioid analgesics during more than a 33-month period and they found alarming rates of purported medication noncompliance, abuse, or diversion. The outcomes appear to support advantages of universal UDT monitoring in all patients prescribed opioids; however, a closer look suggests potential misinterpretations of the data.

Read more »

Migraine Headache a Risk Factor for CRPS/RSD

Researchers conducted a cross-sectional survey study to evaluate the association of migraine headache with complex regional pain syndrome (CRPS). Findings suggest that migraines may be a significant risk factor in some patients for developing more severe forms of CRPS and at a younger age, which recommends the early diagnosis and aggressive management of these chronic headaches.

CRPS, also known as Reflex Sympathetic Dystrophy (RSD), and migraine headache are chronic, often disabling pain syndromes. CRPS, characterized by severe and relentless pain, affects up to 1.2 million Americans and occurs 2 to 3 times more frequently in women than men [more info here]. About 30 million Americans are afflicted with migraines, occurring 3 times more often in women. Migraine is often misdiagnosed as sinus headache or tension-type headache, with fewer than half of all sufferers receiving an accurate diagnosis of migraine and appropriate treatment [more info].

It has been previously observed that there is an unusually high prevalence of cooccurring migraine headaches in patients with CRPS. To further examine this relationship, B. Lee Peterlin, DO, and colleagues conducted an extensive survey in 124 outpatients with diagnosed CRPS at a pain clinic in the Philadelphia, Pennsylvania area. Most of the subjects were female (80%) and white (91%), averaging about 45 years of age. Of the total participants, 89% reported headaches within the past year and 63% fulfilled criteria for migraine headache. Compared with the prevalence in the general population, these patients with CRPS were 3.6 times more likely to have migraine headaches. Additionally, the presence of aura was reported in a higher percentage of CRPS sufferers with migraine, 60%, than is typically reported in the general population of migraineurs.

Investigators also found that the presence of migraine appeared to be associated with more severe CRPS (eg, pain symptoms present in more extremities). Most of the migraineurs in this study reported having experienced any headaches (81%) or severe headaches (61%) in advance of developing CRPS, and the onset of CRPS was reported at a significantly earlier age in those patients with migraine (mean 35 years of age) than in CRPS-afflicted patients without headaches (mean age 47).

Clinical Perspectives: Based on their data, the investigators conclude that migraine headaches may be a risk factor for developing severe forms of CRPS and at an earlier age than is typical. However, the possible mechanisms influencing this relationship are not clear, and this sort of study cannot confirm that migraine headaches actually cause the development of CRPS. Still, the authors recommend that, in view of the implied risk, aggressive early management of patients suffering from migraine may be warranted. Whether or not such treatment would prevent or forestall development of CRPS is unknown and needs further research, and the study authors do not discuss any particular migraine therapy. Finally, since the presence of aura was reported in a high percentage of migraineurs with CRPS, and since migraine with aura has been associated with increased risk of vascular disease — ischemic stroke, myocardial infarction, angina — assessments of cardiovascular risk profiles could be appropriate in dually-afflicted patients having migraine with aura and CRPS. To confirm the findings of this study, further research on the relationships of migraine and CRPS/RSD should be conducted in larger, more diverse populations of patients.

Reference: Peterlin BL, Rosso AL, Nair S, Young WB, Schwartzman RJ. Migraine may be a risk factor for the development of complex regional pain syndrome. Cephalalgia. 2009(August). Online ahead of print [see full article PDF]. Sources of funding for this study or conflicts of interest were not reported in the journal.

10+ Years on Opioid Analgesics! What Happens?

Little is known about outcomes in patients receiving very long-term opioid therapy for chronic noncancer pain conditions. In a first-of-its-kind study, Forest Tennant, MD, reports on a group of patients administered strong opioids for from 10 to 35 years. All indications are that significant pain relief and ongoing quality of life and physical functioning enhancements outweigh complications of the therapy, which are easily managed.

Tennant’s study included 24 patients aged 30 to 79 years, two-thirds females, and primarily suffering from post trauma neuropathies and arthropathies (29%), spinal degeneration (25%), abdominal adhesions or neuropathies (20%), or fibromyalgia (12.5%). They had been receiving continuous opioid therapy for from 10 to 35 years, taking a long-acting formulation of either morphine, oxycodone, or fentanyl, or methadone. One or more short-acting opioids also were prescribed for pain flares or breakthrough pain. Patients also were prescribed muscle relaxants, sleep aids, hormone replacement medications, and/or dietary supplements as appropriate.

Nearly all patients (92%) reported that their pain was permanently decreased, and the great majority (83%) believed that the opioid regimen continued to relieve their pain as well as it did when treatment first began. All patients reported they could perform a variety of activities and physical functions that they could not do prior to opioid therapy. Hormonal abnormalities were a significant complication in males, which were managed with hormone replacement therapy. Some patients developed other conditions during long-term opioid therapy, including tachycardia, hypertension, hyperlipidemia, diabetes, tooth decay, and weight gain. All of these could be medically managed and whether they were pain related, opioid produced, or simply inherent in the patients and/or a result of aging is unclear at this time. No neurologic complications such as hyperalgesia, dementia, tremor, or seizures were noted; nor were hepatic, renal, or gastrointestinal complications, except for minor constipation.

Tennant concludes: “Even though the number of patients evaluated here is relatively small, the great improvement in their quality of life and physical functioning is so positive and the complications of the therapy so easily managed that long-term opioid therapy should continue to be provided and evaluated.”

Commentary: Overall, the reported outcomes in this study offer hope for patients who might benefit from long-term opioid therapy for chronic or intractable noncancer pain conditions, and Tennant is to be commended for his independent research, which was not supported by outside funding. His study helps to confirm the legitimization of pain as a chronic illness in certain patients and opioids as a justifiable long-term therapy. So much of the literature these days speaks rather negatively of prolonged opioid-analgesic therapy and portrays patients who thrive on those medications as potential drug seekers or abusers needing intense surveillance. Such a perspective would be unheard of if considering insulin or antihypertensives for chronic diseases like diabetes or hypertension, respectively.

It is noteworthy in Tennant’s study that opioid tolerance, hyperalgesia, and constipation were not observed as therapy-limiting complications. The significance of certain other medical complications needs better assessment, taking into account that these were quite ill patients at the outset and the possibility of natural aging or disease-progression effects during many years of treatment. As Tennant acknowledges, his investigation depicts a relatively small case series, and much additional study is needed to determine any cause-effect relationships of medical complications in opioid-maintained patients. This sort of longitudinal study should be replicated in a much larger group of patients, and Tennant is searching for additional practitioners with patients who have been opioid-treated for 10 to 20 years. Ideally, however, these patients might at the least be compared with a matched cohort of patients with chronic pain conditions receiving other than opioid-centered pain-management regimens.

ADDENDUM: See the latest update on this research (now including 100 cases) at the blogpost “Followup: Safety of Long-Term Opioid Therapy.”

Reference: Tennant F. A 10-year evaluation of chronic pain patients treated with opioids. Heroin Addict Relat Clin Probl [Europad Journal]. 2009;11(1):31-34. [Article PDF available, see p. 31]

“Pain Awareness Month 2009” Sadly Overlooked

Talk about suffering in silence! Next month, September, is “National Pain Awareness Month” and hardly anybody seems to know. Or, care?

This annual observance starts very soon; yet, according to our extensive search there is practically no recognition of it for 2009 — no press releases, special events, not even a commemorative logo. One exception is the PAINWeek09 Conference (September 9-12, 2009 in Las Vegas), and this is an independently organized educational program for healthcare professionals. Other than that, we could find nothing drawing attention to Pain Awareness Month 2009, which is supposed to focus attention on the plights of Americans with pain, especially chronic pain.

Ironically, September also is “National Alcohol & Drug Addiction Recovery Month,” and if patients with pain develop addiction to alcohol or other drugs, including to their pain-relieving medications, there are plenty of folks interested. Three different U.S. government agencies (with combined multibillion-dollar budgets) are dedicated to helping such patients: the Substance Abuse & Mental Health Services Administration, Center for Substance Abuse Treatment (SAMHSA/CSAT); the National Institute on Drug Abuse (NIDA); and, the National Institute on Alcohol Abuse & Alcoholism (NIAAA).

There is an impressive government-supported website for Alcohol & Drug Addiction Recovery Month from SAMHSA/CSAT, featuring announcements and extensive resources, a Facebook presence, and they have enlisted nearly 125 partnering organizations from the public and private sectors to help promote observances throughout the month. Check it out at RecoveryMonth.gov. Certainly, this is worthwhile; there are an estimated 15-million Americans struggling with alcohol abuse or alcoholism, and another 4-million or so affected by other drug abuse and addiction.

Meanwhile, there are many times more people suffering with pain; 50- to 76-million Americans, depending on which survey data one accepts. What do these persons have by way of support? There are no government agencies with “Pain” in their titles. Rather than being acknowledged as a distinct disease or disorder, chronic pain is at best incorporated as one symptom of diseases/disorders served by agencies such as the National Cancer Institute (NCI), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), or the National Institute on Neurological Disorders and Stroke (NINDS). While pain management may be considered important by these agencies, their missions are much broader. There also is an NIH Pain Consortium; however, its purpose is “to enhance pain research and promote collaboration among researchers across the many NIH Institutes and Centers.”

Pain Awareness Month was added to the U.S. National Health Observances Calendar by the American Pain Foundation (APF). Running late this year, APF is still planning to launch its “Conquering Pain Together” campaign [go to this website], including an online petition, toolkit, and other promotional materials to help individuals take action in their local communities. This campaign is expected to culminate in the first ever National Day of Action on Saturday, September, 26th 2009.

Meanwhile, where are the many other professional organizations and advocacy groups serving patients within the U.S. pain community? They seem to have overlooked Pain Awareness Month this year — or, maybe we’re wrong. Let us know.

Real or Fake Vertebroplasty Both Help – Now What?

Two newly reported clinical trials suggest that both real and sham, or fake, vertebroplasty — a widely used surgery to help heal painful spinal compression fractures — work equally well for relieving pain and improving daily function. This raises a number of questions about the effectiveness of this procedure and its future; however, results at first glance may be deceiving and need closer examination.

For vertebral compression fractures, largely in the elderly due to osteoporosis, several treatments (eg, bed rest, bracing, and pain medications) have traditionally fostered modest pain relief and increased activity. Relatively recently, percutaneous vertebroplasty — the injection of cement (polymethylmethacrylate) directly into vertebral fractures to provide immediate stability and pain relief has emerged as a popular treatment option. Despite several studies suggesting positive effects for vertebroplasty as compared with control treatments, there have been no blinded and/or placebo-controlled, randomized trials. Two trials recently reported in the New England Journal of Medicine sought to fill the research gap.

In the first trial — called INVEST (Investigational Vertebroplasty Safety and Efficacy Trial) — researchers in the U.S., UK, and Australia randomly assigned 131 patients with osteoporotic vertebral compression fractures to receive either actual vertebroplasty or a placebo "sham" surgery [Kallmes et al. 2009]. Those in the placebo arm went through the motions of surgery, including being brought into the procedure room and having novocaine injected under the skin and over the bone, but no cement was injected within vertebrae. A second trial, done in Australia, used essentially the same methodology with 78 participants [Buchbinder et al. 2009]. All patients were “blinded”; not told which group they were assigned to.

At one month, the real and sham surgery groups in both trials reported clinically meaningful improvements in pain and disability compared with baseline measures prior to the procedures; however, the extent of improvements in the two groups were statistically equivalent, casting doubt on the effectiveness of actual vertebroplasty. The Australian trial found similar results, and also reported equivalent outcomes at 6 months when 46% of patients receiving surgery and 42% in the sham group perceived their pain as better than prior to the procedures; although, 20% of surgical patients and 14% of sham-group patients said their pain was worse.

These two studies are interesting and important for a number of reasons. First, having two separate research teams conduct essentially the same trials in different, multinational populations adds significant rigor and reliability to the results. Second, the researchers acknowledge longstanding controversies surrounding the use of sham surgeries in unsuspecting (blinded) patients [Buchbinder et al. 2009; also, Macklin 1999]; however, these trials exemplify that without such an approach the extent to which the surgical procedure itself influences outcomes would be unknown. We have recently noted similar situations involving surgeries for migraine headaches [click for blogpost] and real versus sham acupuncture procedures [click for PDF]. Furthermore, several questions and concerns are raised by these studies that impact clinical decisions regarding whether or not to recommend vertebroplasty for patients:

• What might account for both real and sham groups experiencing improvements? As one possibility, the researchers suggest a strong placebo effect in the sham-procedure group; although, one of the trials reported that within 2 weeks 63% of patients in the sham group correctly guessed they had not received actual vertebroplasty [Kallmes et al. 2009]. Another possibility is lasting effects of local anesthesia, which both groups received, or the natural history of vertebral compression factures, which can improve with time, rest, and medications.
  


• There were no adjustments taking into account other medical treatments that patients in either study group may have received concurrently, which could have been confounding factors. Along those lines, it would have been better if a third group — receiving usual medical treatment — had been included for comparison with real and sham vertebroplasty. Also, the researchers did not evaluate a procedure similar to vertebroplasty, called kyphoplasty, whereby small balloons are first inflated within collapsed vertebra to create caverns for cement infusions. Granted, adding a 3rd and 4th group might have made these trials impractical from a subject-recruitment standpoint.
  


• The followup time of 6 months, in only one of the trials, may have been insufficient to detect long-term benefits of real vertebroplasty. The Australian research team planned to do a 2-year followup, but this will not be completed until 2010 and there may be insufficient patients by that time to have adequate statistical power for valid assessments.
  


• Another concern is that, based on these studies in about 200 patients total, the 750,000 Americans with painful vertebral compression fractures each year might be denied insurance coverage for vertebroplasty, which can cost more than $2,000. And, this also may raise questions about other interventional procedures, such as kyphoplasty or nerve blocks, for which evidence from randomized, well-controlled trials may be lacking.

The important message from these trials may be that, although the exact mechanisms need better definition, vertebroplasty did significantly relieve back pain and improve functionality in many patients after other therapies had failed. This seems most salient for patients and their families. Therefore, it may be premature to shut the door on vertebroplasty as an option until further evidence can be gathered. "I think we should take the middle road," lead author of the INVEST trial, David Kallmes, MD, said in Healthday News [August 5, 2009]. "We should discuss with the patient in a completely informed manner what the options are, and I think we have options. I still counsel patients that they should try ongoing medical therapy but I don't think it's unethical to do the [vertebroplasty] procedure at this point."

References:
> Buchbinder R, Osborne RH, Ebeling PR, Wark JD, et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. N Engl J Med. 2009;361(6):557-568.
> Kallmes DF, Comstock BA, Heagerty PJ, Turner JA, et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med. 2009;361(6):569-579.

EMBEDA, New Opioid Approved with “Interim REMS”

The U.S. Food and Drug Administration (FDA) and King Pharmaceuticals, Inc. announced yesterday, August 13, 2009, that EMBEDA™ (extended-release morphine sulfate and naltrexone hydrochloride) has been approved. The product is for oral use in the management of moderate to severe pain requiring around-the-clock opioid analgesia. EMBEDA is the first FDA-approved long-acting opioid that is designed to reduce drug liking and euphoria when tampered with by crushing or chewing. King anticipates a September 2009 launch for EMBEDA.

Using King’s proprietary technology, EMBEDA capsules contain extended-release morphine pellets, each with an inner core of naltrexone, an opioid-receptor antagonist. If taken as directed, the morphine relieves pain while sequestered naltrexone passes through the body with no intended clinical effect. If pellets are crushed or chewed, the naltrexone is released and absorbed with the morphine, blocking morphine's subjective and analgesic effects. However, according to the manufacturer, the clinical significance of this effect has not been established, and there is no evidence that the naltrexone component reduces EMBEDA’s abuse liability.

However, it is still hoped that this new type of product will experience less misuse and abuse than other long-acting prescription opioids, which have become of great concern to the FDA. This latest product approval was a positive sign that the FDA is not holding up release of new opioid analgesics while pursuing development of their Risk Evaluation and Mitigation Strategy (REMS) initiatives for opioids. During an FDA teleconference, Bob Rappaport, MD, Director, FDA Division of Analgesics, Anesthetics, and Rheumatology Products, noted that EMBEDA will have an “interim REMS” consisting of a medication guide and special communications sent to prescribers explaining this new drug. [Click for prescribing information and medication guide.]

Rappaport further commented that the opioid REMS initiative is probably the largest project that the FDA has ever pursued, but he did not give a date for finalization. He reiterated that the FDA wants to preserve accessibility of opioids for patients with pain but is determined to put an end to the “epidemic of abuse and addiction” surrounding opioid analgesics. He further said that either the FDA will accomplish this goal or “somebody else will step in and do it.” The implication seemed to be that the “somebody else” (he didn’t say who) would be more uncompromising and restrictive than the FDA.

Rx-Opioid Misuse by Students – REMS Won’t Help

A recently-reported study found that 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. This raises questions about public health issues that go beyond Rx-opioid misuse — problems that probably would not be resolved by FDA-mandated Risk Evaluation and Mitigation Strategies [REMS] for opioids.

The report, published in the August 2009 issue of the Archives of Pediatrics and Adolescent Medicine, combined U.S. government surveys spanning 2002 to 2006 that questioned 12,441 high-school seniors [McCabe et al. 2009]. About half the sample was female, most were 18 years of age, 62% were white, 10% African American, and 28% were from other racial groups. Students were asked a series of questions relating to how often, if at all, they used prescription opioids on their own without doctors’ orders; most importantly, the questions assessed their motivations for doing so.

The surveys revealed that 12.3% of the students had used opioids for “nonmedical” reasons. The medications involved included hydrocodone, oxycodone, hydromorphone, meperidine, morphine, opium, and codeine (methadone was not listed). The top reasons were what might be expected: to relax or relieve tension (named as a motive by 56%), to feel good or get high (54%), to experiment (52%), or to have a good time with friends (30%) — more than one reason could be named.

Surprisingly, however, a large percentage of students (45%) said that they used the drugs specifically to relieve physical pain. This is not a new problem; past studies, between 1976 and 1984, mentioned by the study authors had similarly found that 50% of high-school seniors were motivated to misuse Rx-opioids for self-medicating physical pain. Another noteworthy finding in the present study was that when pain relief was a primary reason for misusing opioids the students were less likely to use other addictive drugs, alcohol, or marijuana. This appears to confirm that these young persons were specifically seeking analgesic effects afforded by opioids, which raises several concerns:

• First, this and prior survey studies raise a very serious public health question: Why are so many young persons suffering from untreated (or mistreated) physical pain, causing them to illicitly seek remedies on their own? Resolving this vital issue, perhaps by providing better medical care for these youngsters along with education on the perils of misusing medications, might decrease Rx-opioid-use problems by half.
  


• Second, solutions being pursued by the FDA as part of their opioid-REMS initiatives would have little impact in diminishing these problems. In prior blogposts we have noted that remedies such as Medication Guides are ineffective [7/25/09], and that highly restrictive REMS approaches may limit access to opioid medications for everyone [7/17/09]. In fact, as an unintended consequence of REMS, the substance misuse problems in these young persons might shift from opioid analgesics to abuse of alcohol, marijuana, or other drugs, including heroin — anything that will help them to self-medicate their pain.
  


• Third, the term “Nonmedical Use” as used in this and similar studies seems to be a misnomer that biases an understanding of the data. Rather, “Medical Misuse” would more accurately reflect the intended medical purpose (analgesia) but without authorization (eg, prescription) for such use, and this could be important for properly assessing the problems and finding solutions. Other surveys, essentially assessing medical misuse behaviors, have used terms such as “Abuse” or “Diversion” to record this, depending on the government agency, which further impedes an understanding of the problems.

From the data in this study it appears that Rx-opioid misuse problems are not centered on males more than females, or more in minority populations. But the study examined only high-school seniors, and the prevalence of these problems across all age groups could be extensive. There is a need to interpret available data from perspectives of motivations driving Rx-opioid misuse, and to think through all of the potential consequences of actions intended to resolve the problems. REMS, in principle, may seem to offer solutions but also could make matters worse.

Reference: McCabe SE, Boyd CJ, Cranford JA, Teter CJ. Motives for nonmedical use of prescription opioids among high school seniors in the United States. Arch Pediatr Adolesc Med. 2009(Aug);163(8):739-744.

Methadone Arrhythmia – Debate Rages On

In the August 2009 edition of the Annals of Internal Medicine there is a series of letters highly critical of consensus guidelines on “QTc Interval Screening in Methadone Treatment” published in the journal last spring [See: letters and response; original guidelines article]. The major themes of the letters are:

1. ECG monitoring in all patients prescribed methadone as recommended in the Annals guidelines is impractical and overly inclusive;
   


2. overall incidence rates of potentially hazardous QTc prolongation associated with methadone are low;
   


3. fatal arrhythmia (torsade de pointes) due to methadone alone has not been adequately verified;
   


4. evidence regarding ECG monitoring to predict methadone-induced arrhythmia is equivocal at best; and
   


5. the guidelines might end up restricting access to methadone and, for patients benefitting from methadone therapy, there often is no effective alternative to help them.

Therefore, as a risk mitigation strategy, serial ECG monitoring in all patients prescribed methadone would be an ineffective and costly approach to problems that, at most, probably rarely occur. There appears to be such widely-divergent opinion about this issue because relatively scant research data or documented experience from daily practice is available to guide evidence-based conclusions. In one of the letters, however, the medical director for a group of clinics recounts that in their 10 years of experience with 5,000 patients taking methadone daily (50,000 patient-years, 18.25 million doses) they have not encountered any evidence of fatal arrhythmia (torsade de pointes) attributable to methadone therapy. In response, the general position of the guidelines authors appears to be, the fact that there is no verifiable evidence of significant numbers of patients dying from methadone-induced arrhythmia does not disprove its occurrence. They provide a number of reasons why it is difficult if not impossible to unambiguously determine methadone as a cause of fatal cardiac events; however, this still fails to bolster their argument for routine, serial ECG monitoring as a risk mitigation measure.

Previously, we have expressed doubts about the Annals guidelines in the “Misguided Guidelines” edition of our Pain-Topics e-Briefing Newsletter [click for PDF]. Furthermore, in 2003 we coauthored a report with Mori Krantz, MD — lead author of the recent Annals guidelines paper — titled “Methadone Cardiac Concerns” [see report]. In that, a commonsense approach based on available evidence was proposed:

Some patients prescribed methadone may have conditions associated with increased risks of arrhythmia, including: cardiovascular disease, electrolyte imbalances, and prescribed medications or abuse of cardiotoxic substances that may foster cardiac repolarization disturbances. Furthermore, in some individuals, methadone — alone or, more commonly, in combination with other drugs and/or cardiac risk factors — can prolong the QT interval, which might contribute to the development of the serious arrhythmia torsade de pointes in susceptible patients. A sound understanding of methadone’s potential for QT-prolongation in the context of other arrhythmia risk factors will allow clinicians to provide individualized patient assessments and treatment plans, including ECG monitoring in appropriately selected patients, that preserve heart health and optimize safety. Current evidence, however, does not support altering approved methadone dosing practices or routine, serial ECG monitoring in all patients. The relatively small potential risk of adverse cardiac events with methadone should be weighed against the significant benefits of this medication for pain relief or addiction therapy.

More recent evidence does not seem compelling enough to override the essential recommendations in our 2003 report. In fact, many of the recommendations were recently incorporated into guidance from the American Association for the Treatment of Opioid Dependence (“QTc Interval Screening – AATOD Policy and Guidance Statement,” March 2009 [see document]). Still unknown, however, is what if any guidance may be forthcoming from the U.S. Center for Substance Abuse Treatment (CSAT); this was the agency that convened a meeting more than a year ago to discuss methadone arrhythmia concerns and possibly develop guidelines in the first place. The guidelines article published in the Annals by Krantz and colleagues (who also were on the CSAT panel) does not represent any official position or endorsement of the government.

Thanks to Drew Rosielle MD, at Pallimed.org, and Andrew Byrne, MD (Australia), for bringing these latest letters in the Annals to our attention.
ADDENDUM: For an excellent 35-minute audiovisual lecture by Gavin Bart, MD, interpreting the Annals Methadone QTc Guidelines article [click here].

Surgery Relieves Migraines But Limitations Noted

For the 30 million Americans seeking relief from migraine headaches, relatively minor surgical procedures reported in the August 2009 edition of the journal Plastic and Reconstructive Surgery could be a solution. Although, a close look at the data suggests limitations that should be considered.

A blinded, controlled clinical trial was designed to demonstrate the efficacy of surgical deactivation of 3 common migraine headache trigger sites. In 75 patients with confirmed moderate-to-severe migraine headache, trigger sites were identified as located in either frontal, temporal, or occipital regions of the head. A trigger site is where migraine begins and settles, and it corresponds in these cases to regional irritation of trigeminal nerve branches. Average age of patients was 45 years (range 26-76), and there was a mix of those experiencing migraines with and without aura; patient sex was unspecified in the report.

Patients were randomly assigned to receive either actual (n=49) or sham (n=26) surgery in their predominant trigger site, but they were not told (were blinded to) which procedure they would receive. The actual surgeries, performed under anesthesia, generally involved incisions in the identified trigger regions with selective removal of affected nerve and muscle tissues. Sham surgeries (control group) involved the same procedures but without removing any muscle or nerve tissues. The procedures were performed in an ambulatory surgery center and required about one hour each; patients were able to resume usual activities within a week.

Approximately 84% of the actual surgery group and 58% of the sham surgery group had at least a 50% reduction in migraine headaches (frequency, intensity, duration) at the 1-year followup (p < 0.05). Most important, 57% of patients in the actual surgery group reported complete elimination of migraine headache, compared with only about 4% in the sham surgery group (p < 0.001). Compared with the sham surgery group, those receiving actual surgery also demonstrated statistically significant improvements in migraine-specific assessments of quality of life, disability, and other measures, and these were not dependent on the trigger site or presence versus absence of aura. The most common surgical complication was slight hollowing of the temple in the group with temporal migraine headache. As a side benefit, the actual surgery for frontal migraine was similar to a traditional cosmetic “forehead lift,” thus alleviating frown lines and creating a more youthful look.

Caveats & Limitations: This study demonstrates that surgical deactivation of peripheral migraine headache trigger sites may be an effective alternative treatment for select patients who suffer from frequent migraine headaches that are difficult to manage with other therapies. However, it also is important to look at the data from this trial in ways that are important to patients.

The use of invasive sham surgeries in human clinical trials has been questioned on ethical grounds; however, this trial is an example of how without such a control group the benefit of a new procedure might be overstated. Prior research, using the same surgical procedures but without a sham-surgery control group, had reported a 92% response rate (50% reduction of migraine symptoms). In this present trial, the surgical-response rate is diminished by the fact that nearly 3 of every 5 patients receiving the sham surgery procedure had a favorable response, which the researchers attributed to possible placebo effects or, perhaps, merely undermining tissues during the sham procedure may have altered neurosensory function in a beneficial way, but this is unknown for certain. To explain treatment failures in the actual surgery group, of which there were 16.3% (8/49), the researchers suggest the possibility of misdiagnosed trigger sites or the presence of multiple trigger sites that were not all treated.

In any case, the available data do indicate a complete migraine-remission rate attributable to the actual surgery of 53% (57% [actual]-4% [sham]), which gives a number-needed-to-treat (NNT) of about 2 (1/.53). In other words, 1 of every 2 properly diagnosed patients undergoing actual surgery might be expected to have a complete remission of their migraines at 1 year. Beyond complete relief it is difficult to predict how many might partially benefit because so many patients having the sham surgery experienced a 50% reduction of symptoms. Also, it is important to acknowledge that any surgical procedure carries some risk; although, adverse events reported in this trial were minor.

Some of the subgroup sizes in this trial, especially for sham surgery, were quite small and may not have had statistical power to fully delineate significant treatment or placebo effects. Further research enrolling larger numbers of patients could be advantageous; meanwhile, insurance plans might consider the procedure experimental and be unwilling to cover costs. There also is a question of long-term benefits beyond the 12 months that were assessed in this trial. In a press release, Bahman Guyuron, MD, developer of the technique and lead researcher, said he has a “large number of patients who have remained symptom-free for more than 5 years.” However, it would be helpful if this number could be better defined and substantiated.

Reference: Guyuron B, Reed D, Kriegler JS, et al. A placebo-controlled surgical trial of the treatment of migraine headaches. Plast. Reconstr. Surg. 2009(Aug);124(2):461-468. [See abstract.]

Misleading Report Says Antidepressant Use Doubled

In a previous blogpost [7/20/09] we noted a “chilling effect” of FDA black box warnings on antidepressants that caused a sharp reduction in their prescribing. The fallout was an increase in suicides and escalating economic costs, as noted in a compelling evidence review [for details, see lengthy report].

Now comes an article in the August 2009 edition of the Archives of General Psychiatry observing how antidepressant use has doubled in the United States, and more than 10% of the population — 27 million Americans — took these medications in 2005 alone [Olfson and Marcus 2009]. Quite an impressive number, which news media quickly featured in dramatic headlines — completely missing the point that the data are outdated!

This just-published research compared household-reported data from 1996 with those from 2005. Only toward the end of their report do the authors acknowledge, “In October 2004, the U.S. Food and Drug Administration issued a ‘black box’ warning that antidepressants pose significant risks of suicide in children and adolescents.” They neglect to mention that the warning also was extended in 2007 to include young adults, and that prior to the warnings antidepressant prescribing had been expanded to include the treatment of certain pain conditions and other disorders, which accounted for increasing usage trends during 1996 to 2005.

In an understatement, the authors do concede that as a result of FDA actions, “[prescribing] trends may change in more recent years.” Indeed, trends have changed dramatically during the past few years (as we reported). So much so, that it makes this 1996-2005 comparison of little value for today, and quite misleading.

Caveats: It is not unusual for data-review studies to rely on information from several years prior, even though today’s situation may be entirely different. Government data are particularly notorious for lagging behind. News media rarely take this into account, and there are serious risks for practitioners and policy makers in not accurately distinguishing between historical data trends and current realities.

Reference: Olfson M, Marcus SC. National patterns of antidepressant medication treatment. Arch Gen Psychiatry. 2009;66(8):848-856.

Cigarette Smoking Can Trigger Painful Migraine

According to a study from Spain, cigarette smoking can act as a precipitating factor for headaches, specifically migraines. Furthermore, this investigation of 361 medical students at the University of Salamanca found that smokers have more frequent migraine attacks and that smoking more than 5 cigarettes a day can trigger this headache.

In the study, 16% of all students fulfilled migraine criteria and 20% of all students were smokers. However, the percentage of migraineurs who smoked was greater (29%) and migraine frequency in those who were both migraine sufferers and smokers was higher than in those who were nonsmoking migraine sufferers. Therefore smoking clearly seems to be a precipitating factor for this type of headache and there also was a direct relationship between the number of cigarettes consumed and the frequency of migraine attacks, with migraines typically provoked by smoking more than 5 daily cigarettes. Although a greater percentage of students with migraines smoked, they actually smoked less than those who did not suffer migraines; apparently, the migraineurs knew they were more likely to have an attack if they exceeded the 5 cigarette limit, so the prospect of pain was a self-limiting factor.

This was an interview study among young adult students, so generalization to a wider population (and outside of Spain) may or may not be valid. Still, a reduction in cigarette smoking, or quitting, would be worthy of discussion as a preventative measure in tobacco-smoking migraineurs.

Reference: López-Mesonero L, Márquez S, Parra P, et al. Smoking as a precipitating factor for migraine: a survey in medical students. J Headache Pain. 2009;10(2):101-103.

Opioid Deaths – the Enemy is Us?

Writing about medication errors in the July 2009 edition of Pharmacy & Therapeutics journal, pharmacist Matthew Grissinger describes the case of a 77-year-old woman found dead two days after being prescribed fentanyl transdermal patches for sciatic pain [see article]. This is a telling tale of what can go wrong with powerful opioid analgesics, for which the drugs themselves are often erroneously held accountable.

To begin, the woman was prescribed hydrocodone + acetaminophen (5 mg/500 mg; 4/day); however, after a week of this regimen she still had severe pain. Her physician then prescribed fentanyl 50-mcg/hour patches (one every 48 to 72 hours) but did not provide to the patient directions for their use. It also might be questioned whether the woman had achieved adequate opioid tolerance, as specified in the [drug labeling], after taking the relatively weak hydrocodone combination for only 7 days before being switched to the much more potent fentanyl. A friend of the patient picked up the prescription and was given a box of 5 patches, but the pharmacist did not provide recommended [instructions]. The friend was unfamiliar with fentanyl but still helped apply a patch to the patient’s buttock, the site of her pain, and went home without checking on the patient any further.

After not hearing from the patient for two days, the friend went to the woman’s apartment and found her dead in bed. The patient had a heating pad placed on her lower back and buttock area, as was her usual practice. Only 3 patches remained in the box and, according to Grissinger, it was suspected that the woman had at some point applied a second patch without first removing the original one. Heat over the patches, which increases the rate of fentanyl absorption, plus the excessive fentanyl dose, plus possibly inadequate opioid tolerance to begin with, were a lethal combination.

Was this a rare and unusual case? Probably not, and there is no way of knowing for certain how many fentanyl-related (and other opioid) adverse events or even deaths have come about due to such failures of communication. Remarkably, such communication failures are not uncommon [see prior blogpost Analgesic Med Guides – A Public Health Failure]. Opioids like fentanyl have been demonstrated as safe IF they are properly prescribed and used as directed — necessary instructions and warnings are clearly stated in various formats (eg, labeling, package inserts, etc.). However, such directions must be heeded by healthcare providers and passed along to patients and/or their caregivers in ways that they can understand and will act upon.

The patient’s friend also may have been remiss in leaving the elderly woman alone after administering a powerful opioid drug, but she had not been cautioned otherwise. Only the patient, who suffered the consequences, was completely innocent — although, she might have sought more information about her new medication. Her improper actions probably appeared in data records as opioid “misuse” or “abuse” rather than “unintentional medical misuse,” which would be more accurate but is not classified as such in government statistics.

There is plenty of blame to go around in this case but one thing is clear; there was no inherent evil lurking in the opioid molecules themselves. Unfortunately, while we have previously expressed concern about overly aggressive and restrictive FDA actions to prevent such incidents [see blogpost New Fentanyl REMS – FDA Adds Pain to Pain Relief], tragic cases like this highlight the need for healthcare professionals to assume responsibility on our own for educating patients and ensuring opioid safety; otherwise, the government will find ways of forcing us to do it.

As Pogo, the title character of a long-running daily comic strip, once said: “We have met the enemy and he is us!”

Vitamin D Deficits Engender More Pain in Women?

Previous investigations have shown an association of deficient vitamin D levels and chronic musculoskeletal pain syndromes [see reports]. In a recently published report, researchers in the UK [Atherton et al. 2009] examined the association between vitamin D status (measured as 25(OH)D [25-hydroxyvitamin-D]) and chronic widespread pain (CWP) in a nationwide population sample of 45-year-old white adults (n=6,824). CWP, which was consistent with American College of Rheumatology criteria as being a component of fibromyalgia, was present in 11.1% of the men and 12.5% of women.

Overall, women with CWP had mean 25(OH)D concentrations of roughly 19 ng/mL, compared with 21 ng/mL in women without CWP. In men, comparable concentrations were 21 ng/mL and 21.4 ng/mL, respectively. The prevalence of CWP varied by 25(OH)D concentration in women but not in men, and this was not accounted for by differences in lifestyle, social factors, anxiety, depression, or diet. In women with CWP, 41% had 25(OH)D levels less than 30 ng/mL, and the lowest prevalence of CWP, 18%, was in women with 25(OH)D ranging from 30 to 40 or more ng/mL, which is normally an adequate vitamin D concentration. Despite these trends, the authors conclude that their study does not support vitamin D status as a key determinant of CWP; albeit, there is some evidence for an association in women.

Clinical Commentary: This study actually provides little clarification of the association between vitamin D deficiency and pain. Average vitamin D concentrations in all subjects — men and women, with and without CWP — were similar and fell below the usually accepted optimal range of 30 to 50 ng/mL. It is presently unknown why some persons are more adversely affected by deficient vitamin D levels than others. Of interest in this study, nearly 1 in 5 women with CWP had vitamin D concentrations within the optimal range, which suggests that they may have needed vitamin D levels above what is usually considered an “adequate” threshold.

Another interesting outcome was an association of CWP with a body mass index (BMI) curve that was U-shaped; that is, there was a higher CWP prevalence in both underweight and obese subjects, and these two groups also had the lowest 25(OH)D concentrations. These relationships would be worthy of further investigation.

The researchers did not assess parathyroid hormone (PTH) levels, which, if elevated, would have been a diagnostic marker of painful osteomalacia associated with inadequate vitamin D (no matter what level the actual 25[OH]D concentration was at). Finally, it is disappointing that the researchers apparently did not provide vitamin D supplementation for subjects with CWP, at the least those with suboptimal 25(OH)D levels, to observe any pain relief.

Reference: Atherton K, Berry DJ, Parsons T. Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey. Ann Rheum Dis. 2009;68:817-822.
Also see: Pain Treatment Topics has comprehensive research papers on this topic of vitamin D for chronic pain syndromes [click here].