Depression Often Behind Medically Unexplained Pain

Pain symptoms that cannot be attributed to organic disease are more frequently and severely experienced by patients with depression, according to psychologists Dirk Frieser and Stephanie Körber at the Institute of Psychology, Johannes Gutenberg University in Mainz, Germany. They questioned 308 patients with pain attending two practices of family physicians about their pain symptoms, anxieties, social support, level of psychological stress, and other concerns. Subsequently, the pain symptoms reported by the patients were medically evaluated by their physicians.

Results indicated that there is a significantly higher occurrence of so-called “somatoform pain” in patients with depression, or who have suffered depression in the prior 12 months, than in patients without depression. Somatoform symptoms — ie, pain that cannot be accounted for medically [see additional definition] — are an astonishingly widespread phenomenon, Frieser believes, accounting for "up to 80% of the pain symptoms reported in general medical practices.” Indeed, results of the physician evaluations verified that pain was somatoform in 73% of the study subjects, and could be explained medically in only 27% of cases.

This does not mean patients are simply imagining that they have these symptoms or are hypochondriacs. Frieser emphasizes, “somatoform symptoms are very real; they impair quality of life, and can also cause clinically relevant disorders that may require psychological treatment.” Where the pain is attributable to an organic cause, it is irrelevant whether the patient has depression or not: The frequency, duration, and the debilitating effect of the pain are roughly equivalent in both patient groups, he says.

Women are more frequently affected by depression and also by somatoform pain disorders than men, Frieser claims. Besides pain, symptoms may include dizziness, sensations of hypersensitivity in various regions of the body, and even fatigue or exhaustion. What is important, according to Frieser, is that not everyone who has somatoform symptoms is properly diagnosed as having a somatoform pain disorder. The extent to which a patient's quality of life is impaired and the severity of their psychological problems are critical factors, and proper treatment requires attending to the patient’s mental health issues.

Caveats: This research was only briefly reported and, while the concepts presented are important considerations for healthcare providers, the stated prevalence of somatoform pain disorders seems quite large. There also is the danger of falsely attributing the varied symptoms of certain disorders, such as fibromyalgia, solely to somatoform origins when, in fact, there also are underlying organic processes requiring medical attention. — SBL

Source: Family physician survey in Mainz: Patients with depression frequently suffer from medically unexplained pain. Johannes Gutenberg University; Mainz, Germany. July 9, 2009. [Click here for document.]

Analgesic Med Guides – A Public Health Failure

Medication (Med) Guides, along with package inserts and “black box” warnings, are among the strongest policy enforcement tools available to the FDA, short of pulling drugs off the market. Unfortunately, Med Guides are unlikely to be effective unless changes are made in their development and use. [Boxed warnings were discussed in our blog post 7/20/09.]

A Medication Guide is a paper handout or brochure provided to patients with prescriptions for drugs that are considered to have serious risks of adverse events, such as due to misuse, abuse, or overdose in the case of certain analgesics. The FDA has considered such Guides, which are developed by drugmakers but approved by the agency, as integral components of their REMS (Risk Evaluation and Mitigation Strategies) requirements for opioid analgesics. For example, the FDA is currently permitting propoxyphene-containing analgesics to remain on the market in the U.S. [see our posting 7/12/09] but requiring Medication Guides for patients. A Medication Guide is an essential educational ingredient of the new FOCUS REMS program for Onsolis [see prior posting 7/17/09].

Med Guides Largely Ineffective

Are such Guides appropriate and effective educational tools for increasing safe use of the respective products? In a comprehensive investigation, Wolf et al. [2006] analyzed literacy qualities of all 40 Medication Guides existing at the time, and also assessed their acceptance among a group of primary care patients (n=251). They found that the average reading level of the Guides was 11th-to-12th grade; none of them met federal recommendations of 6th-to-8th grade level. Most of the Guides also were deemed unsuitable because they failed to provide summary information or limit the scope of content. Accordingly, less than a quarter (23%) of patients in the study reported having used the Guides as a source of information (less than 1 of 6 patients with low literacy levels).

Another study examined critical safety information provided to patients on isotretinoin (Accutane®) and estrogen prescriptions [LaPointe et al 2006]. Investigators found that despite patients (n=500) having received required information handouts and expressing confidence in their knowledge of major risks, their responses on a test of their actual understanding were no better than if they had just guessed.

Healthcare System Fails to Educate

In a best-case scenario, patients should receive vital information about their medications from their healthcare providers; at the least to clarify whatever written materials are provided [Howland 2009]. Yet, an observational study found that busy healthcare providers often fail to adequately instruct patients and communicate even the most critical information regarding prescribed medications [Tarn et al. 2006]. Possible adverse effects were addressed merely one-third of the time; timing and quantity of dose were discussed only 55% of the time. This might expectedly contribute to misunderstandings by patients leading to noncompliance and/or medication misuse, which could be harmful or even fatal in the case of opioids.

Communication by pharmacists at the point of distribution also might be an important source of information for patients. Yet, a recent survey among 1,025 practicing pharmacists in 20 states across the U.S. found that 29% were not familiar with Medication Guides; 60% stated that risk-minimization programs have a negative impact on the daily practice of pharmacy, although many acknowledged it was a necessary duty [Lee et al. 2008].

FDA Needs to Rethink Its Role

From the limited evidence to date, it seems apparent that the FDA’s Medication Guides program is inadequate. Handing patients pieces of paper, even if the patients can read and understand them, is not the same thing as education. Healthcare providers and pharmacists apparently are not fulfilling educator roles (nor are they compensated for such activities). Clearly, the FDA needs to rethink its approach to patient (and caregiver) education, or any mandated REMS programs will be doomed to failure. This also raises the question of whether the FDA should be responsible for such education in the first place, or would that role be better assigned to another government agency or outside enterprise specializing in such education? What do YOU think?

ADDENDUM: FDA Hosts Workshop on Better Communication
Apparently, the FDA recognizes the troubled state of its communication programs for consumers and will be hosting a special workshop titled, “Providing Effective Information to Consumers About Prescription Drug Risks and Benefits.” This will be held September 24-25, 2009 in the Washington, DC, area and is open to the public. However, registration must be received by August 17th and seats are limited — an agenda will not be available until September 21st (just 3 days before the workshop). For complete information, see the Federal Register notice [or, see Docket No. FDA–2009–N–0295].

References: [noted but not linked above]
> Howland RH. What should patients be told about their medications? J Psychosoc Nurs Ment Health Serv. 2009;47(2):17-20.
> LaPointe NMA, Pappas P, Deverka P, Anstrom KJ. Patient receipt and understanding of written information provided with isotretinoin and estrogen prescriptions. J Gen Int Med. 2007;22:98-101.
> Lee LY, Kortepeter CM, Willy ME, Nouriah P. Drug-risk communication to pharmacists: assessing the impact of risk-minimization strategies on the practice of pharmacy. J Am Pharm Assoc. 2008;48(4):494-500.
> Tarn DM, Heritage J, Paterniti DA, et al. Physician communication when prescribing new medications. Arch Intern Med. 2006;166(17):1855-1862.
> Wolf MS, Davis TC, Shrank WH, Neuberger M, Parker RM. A critical review of FDA-approved Medication Guides. Patient Educ Couns. 2006;62(3):316-322.

Pain Management Product Announcements & Warnings

Featured Items: acetaminophen drops, almotriptan malate (Axert), Bryan Cervical Disc device, diclofenac potassium (Zipsor), diclofenac + potassium bicarbonate (Cambia), fentanyl buccal (Onsolis), golimumab (Simponi), ibuprofen injectable (Caldolor), sumatriptan injection (Sumavel DosePro), tapentadol (Nycynta).
— All brand names are trademarks of their respective manufacturers. Compiled by Winnie Dawson, MA, RN, BSN.

Concentrated Acetaminophen Drops – Manufacturer Recall
The U.S. FDA and Brookstone Pharmaceuticals notified healthcare professionals and consumers of a July 2009 recall of all 16 oz. bulk containers of concentrated acetaminophen drops (NDC#42192-504-16). There is concern that the packaging, which was very similar to that used for regular strength liquid acetaminophen, could result in possible dosing errors. See FDA announcement.

Tapentadol (Nucynta™) Immediate Release Tablets – Now Available
Following approval last November, 2008, Nucynta has been given a controlled-substance Schedule II classification and is now available in 50 mg, 75 mg, and 100 mg strengths for patients aged 18 years and older. Tapentadol hydrochloride — a new analgesic option for the treatment of moderate to severe acute pain — combines two mechanisms of action, mu-opioid receptor agonism and inhibition of norepinephrine reuptake. See prescribing information.

Fentanyl Buccal Film (Onsolis®) – FDA Approval For Break-thru Cancer Pain
In July 2009 the FDA approved Onsolis, a new fentanyl formulation delivered through a dissolvable film that adheres to the inside of the user's cheek. It was developed for adult patients with cancer who are already on a regimen of opioid medication for persistent pain but also need a strong agent for severe breakthrough pain that is unresponsive to other analgesics. The product carries a “black box” warning and an associated REMS (Risk Evaluation and Mitigation Strategy) program. See our prior Update post for REMS details and access prescribing information.

Ibuprofen Injectable Formulation (Caldolor™) Approved
Cumberland Pharmaceuticals announced a June 2009 FDA approval of its injectable ibuprofen product for the treatment of pain and fever. This is the first ibuprofen injectable and is approved for hospital use in patients who are unable to take oral analgesic medications. To date, the manufacturer has not published full prescribing information but expects the product to be available before the end of 2009. See press release.

Diclofenac Potassium (Zipsor™) – Liquid NSAID Gets FDA Approval
In July 2009 the FDA approved Zipsor — diclofenac potassium liquid-filled soft gelatin capsules — for the relief of mild to moderate acute pain in adults. The manufacturer, Xanodyne, expects to have the product ready for market within a few months. See prescribing info.

Bryan Cervical Disc – FDA Approved for Disc Replacement
Medtronic received approval in May 2009 from the FDA for the Bryan Cervical Disc. This medical device is approved as a replacement disc for a diseased or bulging C3- to C7-level cervical disc that is causing radicular, intractable neck or arm pain. Adult patients with good bone quality who have not had pain relief after a minimum of 6 weeks of conservative therapy may be disc replacement candidates. More info is available at Medscape and in the draft package insert.

Subcutaneous Sumatriptan Injection (Sumavel™ DosePro™) Approved
Zogenix, Inc. received a July 2009 FDA approval of Sumavel DosePro — a needle-free delivery system for subcutaneous administration of sumatriptan for the treatment of cluster headaches and migraine headache, with or without aura. The product is designed for patient self-administration in 3 easy steps using a proprietary combination of sumatriptan and a prefilled drug-delivery system. See press release.

Diclofenac-Based NSAID + Potassium Bicarbonate (Cambia™) For Migraine
In June 2009 the FDA approved Cambia, a combination drug from Kowa Pharmaceuticals America for the treatment of acute adult migraine, with or without aura. In addition, Cambia was effective in providing relief from photophobia (sensitivity to light), phonophobia (sensitivity to sound), and nausea associated with migraine. Studies demonstrated a more favorable safety profile than triptans currently on the market. Kowa is preparing to launch the product before year’s end — see package insert.

Almotriptan Malate (Axert®) – Approved for Migraine Relief in Adolescents
Axert, originally approved in 2001 for adult migraine pain relief, received a June 2009 FDA approval for acute treatment of migraine headache in adolescent patients aged 12 to 17 years, making it the first triptan to be approved for migraine therapy in adolescents. See prescribing information.

Golimumab (Simponi™) – First FDA-Approved Monthly RA Treatment
Centocor Ortho Biotech, Inc. announced an April 2009 FDA approval of Simponi for the treatment in adults of moderate to severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis. This anti-TNF-alpha agent is the first once-monthly therapy of its kind, administered as a 50 mg subcutaneous injection alone or in combination with methotrexate. Caution should be observed regarding the potential risk of serious infections [see info] associated with TNF-alpha blockers. See prescribing information.

Dosing Ratios: Morphine-to-Methadone Rotation

Effective dosing ratios when switching opioid analgesic therapy from morphine to methadone in cancer patients (as well as for chronic pain) vary widely. Researchers in Spain assessed 54 patients with cancer undergoing opioid rotation to clarify factors that influenced the morphine-to-methadone equianalgesic dose ratio (MMEDR) at Day 10 after the switch. Reasons for switching opioids were uncontrolled pain (10 patients) or side effects (with or without pain, 44 patients).

Median prior morphine dose for the entire sample was 220 mg/day (range: 30–1000 mg/d). Initial MMEDR was 5:1 or 10:1 in 82% and 18% of patients, respectively. The stable median MMEDR at Day 10 was 5:1 (range: 2:1–15:1). Multiple linear regression analysis showed that the reason for switching (pain vs. side effects) and prior morphine dose (less than 300 mg/d vs. 300 or more mg/d) were significantly (p < .001) associated with the stable MMEDR. Therefore, these are predictive factors for more accurately selecting an appropriate conversion ratio (as shown in the Table below).

Caution: These ratios apply only to opioid-tolerant patients and are somewhat lower than those reported elsewhere in the literature. The same conversion factors should NOT be used in reverse, as when converting from methadone to morphine.

Reference: Benítez-Rosario MA, Salinas-Martín A, Aguirre-Jaime A, Pérez-Méndez L, Feria M. Morphine-methadone opioid rotation in cancer patients: analysis of dose ratio predicting factors. J Pain Symptom Manage. 2009(Jun);37(6):1061-1068.
Also see…
> Rotation From Other Opioids to Methadone Reviewed. Pain-Topics Updates, 2008;16.
> Toombs JD. Oral Methadone Dosing for Chronic Pain: A Practitioner's Guide. Pain Treatment Topics, 2008(Mar).

“Chilling Effects” of FDA “Black Box” Warnings

As noted in our prior posting [7/12/09], the FDA is currently permitting propoxyphene-containing analgesics to remain on the market in the U.S., but is requiring “black box” warnings regarding overdose risks. Earlier, the FDA had ruled to require stronger warnings of internal bleeding and liver damage with OTC pain relievers (NSAIDs and acetaminophen). However, according to some evidence, boxed warnings can have negative effects on prescribing going beyond what might have been anticipated.

Unexpected Consequences

Clearly, the FDA has a medicolegal duty to warn healthcare providers and the public of special or newfound risks associated with products under its purview. “Black box” warnings, the strongest notice of caution, appear in product labeling and are, of necessity, brief and concise. Conscientious drug prescribers heed such warnings, at the least for liability reasons.

Unfortunately, the FDA does not provide easy access to full disclosure of reasons behind their warnings; explaining, for example, which patients under what circumstance might be at greatest risk for the stated adverse effects. Consequently, there can be a pervasive “chilling effect,” producing changes in prescribing behavior that may have unexpected negative consequences.

Harmful Fallout of Antidepressant Warnings

For example, in 2003 the FDA issued an advisory about risks of suicidal thinking and behavior (suicidality) in pediatric patients taking antidepressants, although a boxed warning was not implemented until 2005. The warning was extended in 2007 to include young adults and all antidepressant drugs [see FDA Announcement]. The warning was issued despite the absence of a single suicide death in clinical trials examining antidepressants. (Antidepressants also are often prescribed for persons of all ages to treat certain pain conditions as well as concurrent depression, which is common as noted in earlier post [7/19/09].)

A recently reported extensive investigation by Libby and colleagues [2009] at the University of Colorado, Denver, found that, starting in 2003, there were sudden decreases in newly diagnosed cases of depression and reductions in prescribing of antidepressant drugs in all age groups in the U.S. The researchers assert that unintended negative effects of the warnings were substantial, persistent, and widespread. Economic costs to society of untreated depression increased considerably. Most likely due to untreated depression, there was a “significant increase in pediatric suicide deaths for the first time in more than a decade.” Among youths, aged 10 to 19, there was an upward trend in suicide rates. (For another, very extensive review, see McCain JA, P&T, 2009[Jul];34[7]:355-367.)

Apparently, the FDA has said it would revisit this policy if there was evidence of unintended consequences [Libby et al. 2009]. There is the question, however, of when the FDA will examine the issues and why they did not consider the possibility of such chilling effects and consequences in advance of their warning.

Methadone Misdirections

As another example, in late 2006 the FDA issued an advisory and revised boxed warning on methadone, including notice of cardiac toxicities (QT prolongation and Torsade de Pointes) with the drug [see FDA Advisory]. However, the warnings did not fully disclose evidence in support of this contention and, in fact, the everyday clinical significance of methadone’s alleged cardiotoxic effects is still quite uncertain [for example, see Cruciani 2008]. There have been no deaths reported in the literature directly and solely attributable to methadone-induced arrhythmia.

Curiously, the FDA failed to include in its 2006 revisions any special alert about the need for reduced dosing when starting opioid-naïve patients on oral methadone analgesia (2.5 to 10 mg every 8-12 hours, 30 mg/day maximum). Prior prescribing instructions allowed methadone induction doses of up to 80 mg/day, which could incur hazardous overdose in some patients. [Also see, blog entry from RW Newman, MD.]

At present, it is unknown how many severe adverse events may have occurred due to unintentional methadone overdose when prescribers were unaware of the dosing changes buried within the revised product instructions. Nor is it known how many patients were denied methadone analgesia entirely due to vague concerns about cardiac arrhythmia expressed in the black box warning.

Warnings Are Not Education

In sum, while the FDA relies on “black box” warnings as a policy-enforcement tool, the nature and extent of evidence driving such decisions is often not revealed. In any event, warnings are not the same as providing healthcare providers and the public with the education they need for fully informed and rational clinical decision making. Hopefully, the FDA will have an appreciation of this as they contemplate warnings for propoxyphene drugs and other opioid analgesics coming under their proposed REMS (Risk Evaluation and Mitigation Strategy) initiatives.

Your comments are welcomed.

Reference [noted but not linked above]: Libby AM, Orton HD, Valuck RJ. Persisting decline in depression treatment after FDA warnings. Arch Gen Psychiatry. 2009;66(6):633-639.

Who is Most Likely to Have Depression with Pain?

Researchers at Wayne State University, Detroit, MI, examined the prevalence of chronic pain, its coexistence with depression, and demographic factors that might explain a link between pain and depression. They used computer-assisted telephone interviews to obtain a representative community sample (n=1,179) in the state of Michigan.

The sample prevalence of chronic pain due to any cause was about 22%, and more than a third (35%) of those participants with chronic pain also had depression. Overall, participants with either chronic pain or pain-plus-depression were more likely to be female, employed less than full-time, and have less education than persons without either condition. Having depression along with chronic pain was not associated with a particular pain condition or site.

Middle-aged women in the sample were most likely to have both pain and depression, as were African Americans. The authors suggested that in middle-aged women chronic pain might not be the cause of depression, rather preexisting mood problems could be associated with a vulnerability to developing chronic pain in some cases. Concurrent depression appears to decrease with age, although pain tends to be worse among older persons.

Based on their findings, the authors recommend that healthcare providers should screen patients complaining of chronic pain for depression, paying close attention to middle-aged women and African Americans in whom risks of comorbid depression appear to be greatest. While this seems like prudent guidance, it also should be noted that this was a somewhat modest-sized survey, covering a small portion of the United States, and relied upon participant self-reports of their pain and mood disorders rather than verified clinical records.

Reference: Miller LR, Cano A. Comorbid Chronic Pain and Depression: Who Is at Risk? J Pain. 2009;10(6):619-627. [See abstract.]

New Fentanyl REMS – FDA Adds Pain to Pain Relief

The U.S. FDA announced approval yesterday (7/16/09) of a new buccal-soluble fentanyl product (Onsolis®) to treat breakthrough cancer pain in opioid-tolerant adults. The strong opioid medication, fentanyl, is embedded in a dime-sized film that adheres to the user’s cheek and is absorbed through the mouth’s mucus membranes. Having an added treatment option for severe pain would be good news were it not for very extensive restrictions surrounding the product’s prescribing and distribution.

Since Onsolis, as with all opioids, may be misused or abused, it is subject to the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program, requiring the drugmaker to have a plan for managing risks. The FDA claims there are special risks with transmucosal fentanyl products, although they have not provided data to fully explain this. Nevertheless, this new product will only be available through a restricted-distribution program called FOCUS (Full Ongoing Commitment to User Safety). Complying with the FOCUS Program includes: [also see Onsolis Q&A]

• Each prescriber and patient must complete an enrollment process for the FOCUS Program. Prescribers must become trained and pass a qualifying test of competency. Patients must study provided educational materials. Qualified prescribers and patients are entered into a database at a FOCUS program support center.
  
  
• Registered prescribers fax prescriptions for Onsolis to the FOCUS support center to start the verification process and also send via courier an original, hardcopy prescription for Onsolis to a FOCUS-authorized pharmacy. There will be a limited number of participating pharmacies in each part of the country (not community pharmacies).
  
  
• Meanwhile, the patient receives a followup counseling call from the FOCUS support center to be certain the patient is properly qualified and all educational materials and instructions were understood.
  
  
• The FOCUS pharmacy must confirm that the patient and prescriber are active in the FOCUS program database and the patient-counseling call has been successfully completed. If everything is in order, and the original, hardcopy prescription has been received, the FOCUS pharmacy dispenses Onsolis and ships the medication directly to the patient’s home via a secure courier. The whole process is expected to take no more than 5-days. (Inpatient facilities — hospitals, nursing homes, hospices — cannot participate.)

During a hastily-called conference call, not announced to the general public, FDA representatives conceded that the FOCUS program was not field tested in advance. So, it is completely unknown if the program will work and how many prescribers, patients, or pharmacies might be willing to overcome the obstacles of time and inconvenience to qualify — or whether it will actually minimize drug misuse and abuse. The sponsor of Onsolis has been charged with the burden of gathering necessary data to assess and justify the program’s effectiveness.

An added barrier may be cost. The FDA does not seem to concern itself with costs; however, there surely will be much added expense to the drug’s sponsor and the entire healthcare system for the FOCUS program, which no doubt will be passed along to consumers. Will insurance plans pay the price? Or, will Onsolis be a product for elite patients who can qualify and afford it?

And, according to the FDA, similar REMS programs will be extended to the two other approved transmucosal fentanyl formulations — Actiq® and Fentora®. The agency hopes, but cannot demand, that the individual manufacturers will cooperate in a unified approach to avoid 3 separate (and incompatible?) REMS programs.

Is this a harbinger of what lies ahead for a REMS under consideration by the FDA that will cover extended-release opioids? The FDA claims that, since Onsolis is much different than extended-release opioids, they do not foresee the FOCUS program setting a precedent for other types of opioids. They also have stated in the past that their objective with REMS is to reduce opioid medication misuse, abuse, overdose, and addiction while maintaining access to opioid analgesics for all patients with pain who need them. However, the FOCUS program may be indicative of the lengths to which the FDA is willing to go, a mindset of sorts, to achieve their REMS mission. And, to some, this may be viewed as tantamount to limiting access, as well as adding much pain to pain relief in America.

What do you think? (Add a comment.)

Swearing — An Under-Appreciated “Analgesic”?

Ever wonder if shouting expletives upon stubbing a toe or smashing a finger actually eases the pain? Researchers believe that’s true, and think they know why.

Investigators at Keele University in the UK had 64 volunteers hold their hands in a tub of ice water [cold-pressor pain test] for as long as possible while repeating a swear word of their choice; each then repeated the experiment but using a commonplace word they would use to describe a table. While swearing, subjects’ heart rates increased and they were able to tolerate the ice water for longer periods of time.

The researchers suggest that the accelerated heart rates in cussing volunteers may denote increased aggression in a classic fight-or-flight response, thus downplaying feebleness in favor of a more pain-tolerant stoicism. Apparently, swearing triggers both emotional and physical responses — it may nullify the link between fear of pain and pain perception, the researchers note in the journal NeuroReport.

Caveats: In the overall scheme of things, this was rather marginal research that garnered major media headlines. It was a small trial in 64 subjects who were all undergraduate students. It may tell us more about responses in a select group of college students than human nature overall. Also, there was no randomization or control group; each subject served as his/her own control in performing both sides of the experiment, which can bias outcomes.

Our conclusion… don’t try this at home!

Reference: Stephens R, Atkins J, Kingston A. Swearing as a response to pain. NeuroReport. 2009(Aug);20(12):1056-1060.

FDA Right in Not Banning Propoxyphene Analgesics

Last week (July 7), the FDA decided to allow continued marketing in the United States of medications containing the pain reliever propoxyphene. However, they are requiring stronger label warnings regarding overdose, a Medication Guide for patients, and further study of possible harmful cardiac effects [see FDA info].

This decision came after the acetaminophen debacle just a week earlier [see our blog post], and after an FDA expert panel last January recommended discontinuing propoxyphene products (including Darvon® and Darvocet® brands). It also was bad news for the watchdog group “Public Citizen,” which had petitioned the FDA more than 3 years ago to ban propoxyphene. In a lengthy, research-filled, albeit highly biased, document, Public Citizen contended that risks associated with propoxyphene far outweighed any benefits [see petition document].

Weak But Popular Opioid Analgesic

Propoxyphene, in clinical use since 1957, is considered a fairly weak synthetic opioid (1/2-1/3 as potent as codeine) for treating mild-to-moderate pain. Despite this, it remains very popular; there are about 25 million prescriptions written for propoxyphene drugs annually in the U.S. Propoxyphene’s primary metabolite, norpropoxyphene, is strong, long acting, and toxic — it can accumulate in harmful amounts if propoxyphene is taken in excess and/or with alcohol or other CNS depressant drugs. Both propoxyphene (sometimes designated as “dextropropoxyphene”) and norpropoxyphene have been shown to alter cardiac electrical conduction and contraction, at least in animal experiments. However, to this day, it is unknown whether the cardiac effects found in nonclinical studies occur in patients exposed to therapeutic concentrations of propoxyphene drugs, according to FDA data. The FDA intends to study this issue further; although, if cardiotoxicity was a prominent, frequent, and fatal adverse effect it should have been apparent long ago.

Overdose, Suicide Deaths a Prime Concern

The FDA’s admirable restraint in not banning propoxyphene was somewhat surprising in that health authorities in the UK had ordered a phased removal of the analgesic in 2005. In the UK, “co-proxamol” (propoxyphene + acetaminophen) had been associated with nearly a fifth of all drug-related suicides, according to a recent report [Hawton et al. 2009]. With the ban there have, indeed, been reductions in co-proxamol-related suicides during the past few years, but with a corresponding shift to increased deaths with other analgesics and drugs overall.

The FDA had reports of 1,400 propoxyphene-related deaths since 1957, although there was no proof that the analgesic had directly caused all deaths. Most fatalities were drug overdoses and suicides, involving multiple agents in up to 93% of cases. On an annualized basis, the per-prescription incidence rate of propoxyphene-related mortality could be as low as 0.0001% ([1,400 deaths / 52 years] divided by 25-million-Rx/year). In other words, 99.99% of the time propoxyphene has been used without deadly effect. (The Public Citizen group’s petition claimed a higher annualized rate of roughly 338 deaths, which still results in a tiny 0.001% mortality incidence per year.)

Keeping Pain Relief Options Available

While propoxyphene drugs have been in clinical use for more than 50 years, and some clinicians consider these analgesics of questionable value today, they apparently still offer important pain relief options for many patients. In fact, after discontinuation in the UK, one study found that nearly half of patients previously taking propoxyphene were unable to find a suitable alternative [Ottewell and Walker 2008]. So the FDA’s decision to keeping this pain-relief option available in the U.S. is commendable.

Furthermore, in contrast to what the Public Citizen group described as “propoxyphene’s deadly nature,” the analgesic has had a remarkable record of safety when used as directed. There is no inherent evil lurking in propoxyphene molecules; on the other hand, case-series studies of propoxyphene-related overdose deaths have found a history of depression in more than half (55%), undetermined mental illness in a further 21%, and chronic alcohol abuse in up to a third of victims [Dywer and Jones 1984].

Quite possibly, with propoxyphene, as well as with other opioids, the incidences of related overdoses and suicides reflect failures of the mental healthcare and addiction treatment systems. Solving such problems would be beyond FDA purview but are, nonetheless, vital issues to take into account if significant increases in analgesic safety are to be achieved. Of potentially lesser value are “black box” warnings and Medication Guides [blog-post coming on this], or, worse yet, banning or restricting access to certain opioids.

What do you think? Click on the “comments” link below to share your opinions.

References [noted but not linked above]:
> Dywer PS, Jones IF. Fatal self-poisoning in the UK and the paracetamol/dextropropoxyphene combination. Hum Toxicol. 1984;3(Suppl.):145–174S.
> Hawton K, Bergen H, Simkin S, et al. Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis. BMJ. 2009;338 (online ahead of print).
> Ottewell L, Walker DJ. Co-proxamol: where have all the patients gone? Rheumatology. 2008;47(3):375.

Acetaminophen Debacle; Much Ado About Very Little

Last week the FDA convened a panel to consider serious adverse events — poisonings, liver damage, and deaths — that have been associated with acetaminophen during many years. The panel recommended placing severe restrictions on the distribution of OTC acetaminophen products and the banning of Rx opioid-acetaminophen combination products. While acknowledging that the risk to individual patients of developing liver injury is very low, the FDA noted that acetaminophen-containing products are used extensively and “the absolute number of liver injury cases is a public health concern.”

How Big is the Public Health Concern?

The FDA had assembled considerable background data for its panel and the several hundred pages of documentation can be accessed at http://tinyurl.com/lxwfgo. The FDA’s data can be viewed from different perspectives, and there are always limitations; however, based on our examination, the validity and necessity of the panel’s recommendations should be questioned.

According to the FDA’s most recent data, in 2005 there were a remarkable 28 billion doses of products containing acetaminophen distributed in the United States. Using further data one can estimate the overall harm potential:

• Assuming an average per-dose amount of 500 mg, there were 14 billion grams of acetaminophen distributed in 2005 (28 billion x .5 g).
  


• FDA data indicate that the average median acetaminophen amount associated with liver injury was 6.25 grams (range 5-7.5 g), which suggests that there was a worst-case potential for 2.24 million severe adverse events in 2005 (14 billion g / 6.25 g/event).
  


• Based on various summaries in the FDA data, during 2005 there were about 2,700 acetaminophen-associated poisoning/liver-failure cases and an estimated 460 deaths or a total 3,160 severe adverse events. This is merely 0.14% of the total potential adverse events (3,160 / 2.24 million).
  


• Put another way, during 2005, taking into account a conservative, worst-case scenario, 99.86% of the time acetaminophen products were used safely. And, presumably, the trends have not changed significantly since 2005, according to the FDA’s documentation.

Even a single case of liver failure or death attributed to a product is cause for alarm and concern. However, does a 0.14% incidence rate, affecting roughly 0.001% of the U.S. population, signal a public health threat of such proportions that it requires an immediate, rigorous, and widespread governmental response that limits access to important analgesics?

These and other data from the FDA can be employed in alternate analyses but, due to the colossal number of acetaminophen doses distributed each year (denominator) and the relatively minuscule incidence of adverse events (numerator), the ultimate dimensions of the problem or risk are always quite small. In fact, this same sort of analytical perspective could (should?) be applied to risks associated with opioid analgesics, which are currently under scrutiny as part of the FDA’s REMS (Risk Evaluation and Mitigation Strategy) initiative directed at those medications.

Addressing the Wrong Questions

Both for acetaminophen and the opioid-REMS initiative, it seems that the wrong questions are being addressed. Rather than asking, “How can the public be better educated on safely using vital pain relievers?” the question pursued by the FDA seems to be, “How should access for all persons to certain analgesics be further controlled so as to prevent a minority of persons from misusing them and doing themselves harm?”

Acetaminophen products have very favorable safety profiles when used as directed. Most adverse events are accidental, relating to taking too much of the drug or in combination with alcohol. Black box warnings, lowering the maximum dose, and other restrictive measures recommended for acetaminophen by the FDA panel will do no good unless consumers attend to and can clearly understand such directives; however, there were no recommendations proffered for how to more effectively communicate safety information and better educate consumers. Instead, the government approach to risk reduction appears to be directly or indirectly limiting or denying access to analgesics of concern.

All medicines are potentially poisonous to some extent; 100% safe use is an unrealistic goal. Yet, nearly 300 years ago it was recognized that, "In the hands of the wise, poison is medicine. In the hands of a fool, medicine is poison." What is most needed when it comes to acetaminophen safety (as well as for opioids) is not more regulation, but better education of patients/consumers and the healthcare providers who serve them. You be the judge, and let your representatives in Congress know what you think.

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This Policy was last reviewed and revised on January 28, 2011.

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The above information was last reviewed/revised on: January 31, 2013.