Methadone Analgesia Cardiac Concerns Unfounded

Some past reports have suggested that methadone may negatively affect cardiac function, potentially leading to the serious arrhythmia known as torsades de pointes. A recently-reported study in patients with cancer finds that methadone analgesia has little detrimental effect on the QTc interval and can be safely used even in very ill patients.

Researchers at the M.D. Anderson Cancer Center, Houston, Texas, enrolled 100 patients with cancer in a prospective observational study [Reddy et al. 2010]. Subjects were followed clinically and via serial ECGs for QTc changes at baseline prior to initiating methadone analgesia and at 2, 4, and 8 weeks thereafter. QTc prolongation was defined on ECG tracings as >430 milliseconds (ms) in males and >450 ms in females, and clinically significant effects were defined as a QTc interval >25% from baseline or ≥500 ms. All patients had a cancer diagnosis, with most having a limited prognosis of less than 3 months. ECG assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-weeks follow-up, respectively. Reasons for discontinuation were primarily due to hospice transfers or return to the local community and 11 patients discontinued methadone due to typical opioid-related side effects; no dropouts were cardiac related.

At baseline prior to methadone induction, 28 patients (28%) had QTc prolongation and by weeks 2, 4, and 8 after beginning methadone 5 (8%), 3 (8%), and 3 (11%) patients, respectively, still exhibited QTc prolongation. None of the patients had a >25% increase in QTc and only 1 patient had a QTc >500 ms; this person had a QTc of 498 ms at baseline and after increasing to 509 ms without adverse effect at week 2 the QTc resolved by week 4. There was no clinical evidence in any patients of torsades de pointes, ventricular fibrillation, or sudden cardiac death. The researchers conclude that their study supports the safety of methadone analgesia and that it can be“… prescribed without reservation in the palliative care population.”

Commentary: Most publications discussing methadone these days — as well as the ‘black box’ caution on labeling in the U.S. [PI here] — prominently note concerns about its alleged cardiotoxicity, specifically prolongation of the QTc interval that might incur serious arrhythmia including torsade de pointes. However, we have previously discussed controversies surrounding these allegations and limitations of the evidence behind them [see prior blogpost 8/8/09]. This present study by Reddy et al. is of some importance in this ongoing debate about methadone’s cardiac safety for several reasons…

1. These were quite ill patients who might be considered at high risk for cardiac stress and, indeed, more than a quarter of them had prolonged QTc intervals prior to methadone treatment.


2. Of the 28 patients with baseline QTc prolongation, almost all (79%) had one or more risk factors that might have been viewed as a further contraindication for methadone therapy, including: medications known to prolong QTc or invoke torsade de pointes, structural cardiac disease, electrolyte abnormalities, and/or female sex.


3. Despite these many risks, there was only 1 instance of clinically significant QTc prolongation (>500 ms), which was asymptomatic and occurred in a patient with excessive prolongation at baseline; this prolongation became apparent at week 2 and resolved by the week 4 ECG tracing. Remarkably, there was a slight trend toward decreasing median QTc measures in all patients at 4 and 8 weeks, which is worthy of further investigation.


4. QTc prolongation during methadone therapy was more frequent among patients with QTc interval prolongation at baseline; however, there was no significant association between QTc interval and methadone dose (p=0.45).

A limitation of this study was its observational format with lack of a control group and the relatively small numbers of patients by week 8, making it more of a large case series report. However, reports in the past that originally raised concerns about methadone-related arrhythmia were much smaller case series, and included patients on methadone maintenance for addiction. Also, compared with the very much larger dosages reported in studies involving methadone as addiction therapy, the doses of methadone in this study of palliative-care patients with cancer were relatively low but typical of doses used for pain management — median at 2 weeks 23 mg/day, maximum 90 mg/day. Therefore, it would probably be prudent in the future to consider supposed cardiotoxic effects of methadone separately regarding its use for analgesia versus as maintenance therapy for addiction. Reddy and colleagues assert, “To date, all the studies on methadone for pain control have consistently shown that the risk of methadone-induced QTc prolongation and arrhythmia is minimal.” However, they do recommend that, “For patients with significant risk factors for QTc prolongation or on high doses of methadone (>100 mg/day), monitoring with ECGs at baseline and at subsequent intervals may be reasonable.”

Reference: Reddy S, Hui D, El Osta B, et al.. The effect of oral methadone on the QTc interval in advanced cancer patients: A prospective pilot study. J Palliative Med. 2010,13(1):33-38 [abstract here].
Our thanks also to Andrew Byrne, MD, Redfern, Australia for bringing this article to our attention.

ADDENDUM: Also from M.D Anderson Cancer Center recently, an article on methadone analgesia initiation and rotation in outpatient settings for patients with cancer. The authors note that methadone was safe, with high success rates (ie, relatively few discontinuations) and low side effect profiles. See: Parsons HA, de la Cruz M, El Osta B. Methadone initiation and rotation in the outpatient setting for patients with cancer pain. Cancer. 2010;116(2):520-526. Full article PDF [here]. Insightful discussion by palliative care specialists at the Pallimed weblog [here].

Wrist Pain? Maybe Too Much Sex is to Blame.

Chronic wrist pain due to repetitive strain has plagued computer keyboard users and those working awkwardly with heavy equipment; now, a new report suggests a spicier explanation in some patients — too much sex. So, maybe healthcare providers need to question patients about their sex lives to help reveal the root causes of their wrist complaints.

The condition might be somewhat facetiously charted as “RSI – Repetitive Sex Injury”; however, writing seriously in the journal Medical Hypotheses, researcher John Zenian, says: "Sexual intercourse can explain the increase in the overall incidence of carpal tunnel syndrome seen in recent years, since it is the most widely practiced activity that uses both hands at the same time" [Zenian 2010]. Carpal tunnel syndrome (CTS) is a prevalent form of repetitive strain injury in the United States, affecting anywhere from 1 of 20 persons in the general population to half of all persons in select high-risk groups [data here]. Sexual activity is generally not considered in the workup for a differential diagnosis of CTS; nor as a major contributor to “overuse injury” or cumulative trauma disorder.

Zenian proposes that carpal tunnel syndrome (CTS) can develop during sexual intercourse in the missionary position when the hands of the top person are repeatedly extended while under pressure from the weight of the upper body. Of the well-known risk factors associated with non-occupational carpal tunnel syndrome, age, marital status, and use of hormonal agents may also relate to the frequency of sexual intercourse. Along with those factors, obesity, macromastia (excessive breast size), and large chest circumference incur increased pressure on the wrists due to a heavier upper body. According to Zenian, the bilaterality of CTS in afflicted persons can be explained by the fact that both hands are needed to support the upper body during sexual intercourse. The overall decrease in the frequency of sexual intercourse and a declining incidence of CTS between the 6th and 7th decades of life suggests a possible cause and effect relationship between sexual intercourse and CTS, he notes. However, the popularity of erectile dysfunction medications (eg, sildenafil, tadalafil, others) appears to be eliminating age differences in recent years.

If sexual activity seems a plausible explanation for chronic wrist pain in patients young or old, short of abstinence, what can be recommended?

• Patients can be instructed to limber up their wrists before sex by doing some gentle exercises.


• They should try different positions that are less straining on the wrists.


• Avoid prolonged sexual activity in the same positions, especially those that put pressure on wrists.


• Fitness outside the bedroom counts, too, including exercise and weight control.

REFERENCE: Zenian J. The role of sexual intercourse in the etiology of carpal tunnel syndrome. Med Hypoth. 2010 (Jan 8 – ePub prior to print) [abstract here].

Long-Term Opioid Use for Back Pain – Who, Why?

Researchers from multiple centers in the United States assessed predictors of opioid analgesic use among patients with back pain due to lumbar disc herniation or spinal stenosis. Smoking and nonsurgical treatments were the most significant reasons for continued opioid use; although, fewer than 1 in 10 patients used opioids for 2 years and the importance of smoking as a factor is debatable.

Data for this present study reported in the Journal of Pain were derived from 2,110 patients recruited from 13 spine specialty centers in 11 states as part of a larger study, called “SPORT” (Spine Patient Outcomes Research Trial) [Krebs et al. 2010]. At the outset, roughly 4 of 10 patients (42%) reported taking opioid analgesics and most (78%) said they took opioids daily. Of these patients, 25% reported continued use at 1 year and 21% were still taking opioids at 2 years (only about 9% of all patients in the study). Who were these persons taking opioids?

The researchers examined demographic factors, medical history, and lifestyle information for each subject. At baseline, compared with patients who were not taking opioids, the opioid-analgesic-using patients were more numerous in the lumbar disc herniation group, younger, less educated, less likely to be employed, more likely to have applied for disability, more likely to report a history of mental disorders, and more likely to smoke tobacco. At both the 1-year and 2-year followup points, smoking and the use of nonsurgical treatments were the only significant factors that predicted the continued use of opioid analgesics. Among patients who reported no opioid use at the beginning of the study, 8% reported starting opioid therapy at 12 months and 7% at 24 months; however, there were no significant predictive factors in these patients. Data on specific opioid analgesics taken, and their dosages, were not collected.

COMMENTARY: It should be noted that available nonsurgical treatment options included physical therapy, education/counseling with home exercise instructions, and NSAID agents if appropriate. For patients who did not respond, there were additional physical, psychological, and pharmacologic therapies (including opioids) available based on individual patient needs. Non-surgical treatments were helpful to many and opioid use declined nearly 5-fold from 42% to 9% of patients in the study. Yet, the tone of this report, whether intentional or not, seems to depict a negative outlook toward opioid therapy for these specific back conditions — disc herniation or spinal stenosis — which alternatively can be surgically treated. An underlying message appears to be that the risks of surgery (not discussed in the article) may be preferable to the risks of long-term opioid therapy (discussed in some detail). In this article, the researchers did not report on acceptable pain relief and related outcomes achieved by surgical compared with nonsurgical approaches, and it also would seem that the choice of surgery versus other treatments would (or should?) depend on factors other than the prospect of long-term opioid therapy. (In fairness, it should be noted that earlier reports on the SPORT study did indicate relatively favorable outcomes for surgical approaches [abstracts here and here].)

As baseline, 22% of opioid users and 14% of non-opioid users were tobacco smokers, which are statistically significantly differences but the prevalence of smoking in opioid users was comparable to national averages [data here] at the time of study data collection. The authors note that baseline cigarette smoking independently predicted continued long-term opioid analgesic use, and further state that “smoking may be a marker of substance use disorders in these populations.” However, data collection did not include formal assessments of substance-use disorders and fewer than 2% of participants indicated a history of alcoholism or drug addiction in questionnaires. Therefore, using smoking as a surrogate predictor of past or present substance use problems, which consequently influenced opioid-taking is highly questionable. In contrast to what the authors seem to have intended, this article appears to support the possibility that appropriate non-surgical therapies and the judicious use of opioid pain relievers may be useful for averting or delaying invasive surgery in select patients with painful disk herniation or spinal stenosis.

REFERENCE: Krebs EE, Lurie JD, Fanciullo G, et al. Predictors of long-term opioid use among patients with painful lumbar spine conditions. J Pain. 2010;11(1):44-52 [abstract here].

Pitfalls of Urine Drug Monitoring in Pain Care

Editorial Notes on Pain Topics of Interest & Importance.

Medical practitioners today often focus on objective assessments via diagnostic procedures for guiding patient care. However, relying on urine drug screening and testing for managing opioid-analgesic therapy in patients with pain is fraught with some important but unrecognized problems and challenges.

Numerous articles propose the need for drug monitoring in all patients prescribed opioid analgesics for chronic pain conditions [eg, Gourlay et al. 2006; Hammett-Stabler and Webster 2008; Moeller et al. 2008]. While the authors of such articles may be expert in applying the principles of urine screening and testing described, there have been many cases of patients being mistreated by healthcare providers less skilled in the interpretation of monitoring results. At least two small studies have found that practitioners ordering urine drug assays to monitor patients on long-term opioid therapy typically are not proficient in interpreting the results [Reisfield et al. 2007a, 2007c]. Certainly, improved healthcare provider education might be helpful but, considering the cost and limitations of urine monitoring for guiding treatment and achieving better outcomes, it could be time for a reassessment of such assessments.

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Vitamin D for Pain: Update of Research Evidence

In summer 2008 Pain Treatment Topics published ground-breaking research reviews focusing extensively on the potential benefits of vitamin D for patients with chronic pain conditions, particularly musculoskeletal and back pain [see reports here]. What has happened since that time? This blogpost summarizes relevant research on the subject published during the past year.

In a review last fall, practitioners from the University of Miami School of Medicine reiterated how research evidence has expanded our perspectives on the importance of adequate vitamin D for overall health [Stechschulte et al. 2009]. They note that, in addition to traditionally reducing the risk for bone disease, vitamin D has demonstrated benefits in reducing falls and decreasing musculoskeletal pain, as well as stemming autoimmune diseases, cancers, heart disease, cognitive declines, and overall mortality. On this basis, improving the vitamin D status in all patients has become an essential aspect of healthcare, especially since deficiency or insufficiency can be safely prevented or corrected via inexpensive supplementation.

During the past year research of varying quality has reported on the relationship of vitamin D and pain; although, none of the newer evidence refutes the findings in our earlier reports. Overall, the conclusion still appears to be that vitamin D inadequacies are prevalent in persons with various chronic pain syndromes and, with sufficient vitamin D supplementation, the pain-relieving effects are sometimes quite dramatic. In those cases where pain is unrelieved or only partially resolved there seems to be no harm done, and most likely some healthful effects are achieved in other ways by more adequate vitamin D levels. Following are brief summaries of the research reports organized by topic areas (references with links are at the end of this blogpost).

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Is TENS Really Ineffective for Low-Back Pain?

Understanding Evidence-Based Pain Management (EBPM)

According to a recent evidence review and guidelines in the journal Neurology, the popular pain therapy using a method called TENS — transcutaneous electric nerve stimulation — is largely ineffective for treating chronic low-back pain. However, a closer look suggests that this conclusion may be premature and the research is insufficient to completely dismiss TENS' importance as a pain treatment option.

The TENS unit is a small, portable device delivering mild electrical current to nerves through electrodes connected to the skin at the sites of pain. The approach has been used for various types of pain, although exact mechanisms of its analgesic effects are still under examination. Basic science studies show that TENS activates endogenous pain-control chemicals (eg, endorphins, enkephalins, dynorphins, GABA, serotonin) and their receptors. Along with that, the high and low electrical frequencies produced by the TENS unit inhibit pain signals along affected nerves, blocking the impulses from reaching pain-perception areas in the brain.

Clinical trials on the efficacy of TENS have produced some mixed results; therefore, practice guidelines developers representing the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology analyzed data in TENS studies to reassess its efficacy [Dubinsky and Miyasaki 2009]. Their systematic search of the literature encompassed Medline and the Cochrane Library from inception to April 2009, focusing on TENS for low back pain and in painful diabetic neuropathy(PDN).

The search produced only 7 eligible TENS trials, 5 for low back pain and 2 for PDN. For back pain, 2 moderate quality trials showed pain-relieving benefits of TENS, while 1 moderate quality and 2 high quality trials (randomized, placebo/sham-therapy-controlled) failed to show significant benefits. For PDN, both trials were of moderate quality but demonstrated significant TENS benefits in relieving pain. Based on these findings, particularly the quality of the evidence, the guidelines authors make a strong recommendation against TENS for the treatment of chronic low back pain (Level A – established as ineffective). They note that TENS could be considered in the treatment of PDN, but the recommendation is modest (Level B – probably useful). Furthermore, they note that research into the mechanism of action of TENS is needed, as well as more rigorous efficacy studies.

Commentary: Popular news media widely reported on the conclusions, with headlines touting TENS as being worthless for back pain. CNN Health (12/31/09) quoted lead author of the guidelines article — Richard M. Dubinsky, MD, MPH — as saying, "Physicians are advised against ordering TENS for patients with chronic low back pain since it is proven not to work." Actually, the evidence does not “prove” anything, the conclusions seem rather tenuous at best, and this may qualify as an example of what we have previously called “Misguided Guidelines” [see article here].

First, a literature search of only Medline and Cochrane Reviews may not be considered comprehensive.

Second, it seems somewhat presumptuous to arrive at a strong clinical recommendation against TENS for low-back pain based on a total of 178 patients treated with TENS in only 5 trials, 3 of which were inadequately powered to produce valid results.

Third, in an editorial accompanying the guidelines article, Andreas Binder, MD, and Ralf Baron, MD [2009], write that the conclusions "may heat up the discussion on the usability of TENS and may be viewed as supporting the critics who questioned the value of TENS in pain therapy”; however, they stress, "absence of evidence is not evidence of absence. The clinical impact of meta-analyses is always limited by the quantity and quality of conducted trials." If anything is ineffective or deficient at this time it would appear to be the quality and quantity of research on TENS for developing definitive practice guidelines.

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Pain Management Fails Due to Rx-Drug Abuse Fears

Millions of Americans with significant acute or chronic pain are being undertreated as physicians fail to provide comprehensive pain treatment, according to recent reviews. The failure is due to inadequate training of physicians, personal biases and, increasingly, fears of prescription analgesic drug abuse.

Writing in The Rx Consultant [December 2009] and the Journal of Pain & Palliative Care Pharmacotherapy [2009], Kathryn Hahn, PharmD, CPE, DAAPM, says the issues are reaching crisis proportions: “We’re in the middle of a storm here and have to figure out some way to navigate through it.” Hahn is associated with the College of Pharmacy at Oregon State University, Chair of the Oregon Pain Management Commission, a State Action Leader for the American Pain Foundation, and a practicing pharmacist specializing in pain management.

“We have more sophisticated pain management techniques available now than ever before,” she says in a news release [2010], “but many doctors are not fully informed about all the options available, and also turn patients away because they’re very concerned about the problems with prescription drug abuse. Because of this, many people suffer needlessly with pain that could be treated, and almost 80% of visits to community pharmacies involve pain issues.” Adequate pain treatment has always been a concern, she continues, in part because it’s not a major part of most physician’s medical training.

Concerns about analgesic abuse are so great that many physicians prefer not to even work with patients who have ongoing pain issues. “I see patients every week who have lost their doctors and don’t know what to do, and these people are scared. It’s particularly bad with elderly and Medicare patients,” Hahn notes. “Prescription drug abuse is a very real problem, we do have to take necessary steps to address it, but right now the pendulum has swung too far and legitimate pain problems are not being managed.”

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NSAID Pain Reliever Risks & Precautions Reviewed

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available without prescription and used by millions of persons to treat fever, inflammation, and acute or chronic pain. Clearly, however, there can be serious risks associated with their use according to a review published in American Family Physician, which also offers precautions and recommendations for safe prescribing.

Amanda Risser, MD, MPH, and coauthors from Oregon Health and Science University in Portland write that the risks of NSAIDS include significant upper gastrointestinal (GI) tract bleeding (particularly in older persons), risks in those receiving anticoagulant therapy, and risks in patients with a history of upper GI tract bleeding associated with NSAID use [Risser et al. 2009]. They further note that there is little evidence to support differences in pain relief afforded by the many available NSAIDs, which can range broadly in monthly cost from less than $5 USD (generic aspirin 325 mg/day or naproxen 440 mg/day) to $165 USD (generic indomethacin extended release 150 mg/day) to $248 USD (Celebrex® 400 mg/day).

The authors offer 5 key clinical recommendations for practice…

1. In persons who have had NSAID-associated ulcers, practitioners should consider prescribing protein pump inhibitors (PPIs), double-dose histamine H2 blockers, or misoprostol along with NSAIDs. Celecoxib may be used alone in these patients [but it should be avoided in patients at increased risk for myocardial infarction]. Women who might become pregnant should not take misoprostol.


2. Whenever possible, NSAIDs should be avoided in patients with preexisting kidney disease, congestive heart failure, or cirrhosis to prevent acute renal failure.


3. For patients at risk for renal failure, and in those taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, practitioners should consider monitoring serum creatinine levels after starting NSAID therapy.


4. NSAIDs and aspirin should be avoided if possible in patients taking anticoagulants. If it is necessary to combine NSAID and anticoagulant use, an increase in international normalized ratio (INR) should be expected and patients should have appropriate INR monitoring, warfarin dose adjustments, and GI prophylaxis.


5. In breast-feeding women, ibuprofen, indomethacin, and naproxen are considered safe to use.

It should be noted that all of the recommendations are based on evidence rated at level “C”; that is, coming from consensus statements, expert opinion, case series, or commonly accepted practice. The highest level of evidence (“A”) would have come from consistent, good-quality, patient-oriented evidence such as randomized, controlled clinical trials — but this was unavailable.

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Low-Level Laser Therapy Reduces Neck Pain

An extensive review of the literature found that low-level laser therapy can effectively reduce nonspecific acute neck pain immediately after treatment and for several months in patients with chronic neck pain. In some cases there may be advantages of this approach over traditional pharmacotherapies, if laser therapy is properly applied.

Low-level laser therapy (LLLT) is a relatively uncommon, noninvasive treatment for neck pain, in which nonthermal, or “cold,” laser irradiation is applied to sites of pain. An international group of researchers conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy of LLLT in neck pain [Chow et al. 2009]. Their search included all studies prior to August 2008 comparing efficacy of LLLT with placebo (eg, sham laser) or with active control (eg, exercise) in acute and chronic, nonspecific neck pain; studies involving diagnosed pathological conditions (eg, rheumatoid arthritis, neurological disease) were excluded.

There were 16 RCTs identified for evaluation (14 of good quality), encompassing a total of 820 patients. In acute neck pain, evidence was limited to two trials with mixed results, showing that patients were around 70% more likely to experience reduced pain following LLLT as compared with placebo (relative risk [RR] 1.69 [95% CI 1.22-2.33]). Five trials of LLLT for chronic neck pain showed a 4-fold improvement with this therapy (RR 4.05 [2.74-5.98]). In 11 trials reporting changes in VAS scores (100 mm visual analogue scale) the average baseline pain was roughly 60 mm and LLLT reduced pain intensity by a third, or about 20 mm. Seven trials provided longer-term followup data after completion of treatment for chronic pain, and initial pain relief persisted during 3 months with a mean VAS reduction of 22 mm. LLLT appeared effective regardless of the level of baseline pain, symptom duration, age, or sex, and 5 studies also demonstrated a reduction in disability following LLLT. Only half of the trials reported data regarding adverse events associated with LLLT, but those noted were mild and not different from placebo.

Clinical Concepts: Part of what makes LLT so attractive is its ease of use and painless application, since it does not promote heat like a surgical laser. The exact mechanism of how LLLT reduces pain is unclear, but the authors speculate that it could involve reducing inflammation, stemming nerve conduction of painful stimuli, and/or ameliorating muscle fatigue. In the past, LLLT has demonstrated mixed clinical efficacy for low back pain and rheumatoid arthritis; however, the current analysis of LLLT for neck pain demonstrated a clinically significant 33% reduction in pain [see our prior blogpost discussing clinical significance in pain trials].

The wide range of data in this current review suggests that the effectiveness of LLLT may depend on the experience and skill of the practitioner in selecting an effective LLLT protocol in terms of wavelength, energy, time variables, and irradiation points (see below). Despite this, the authors assert that the long-term results of LLLT contrast favorably with those for nonsteroidal antiinflammatory drugs or other analgesic agents, for which side effects are common and pain relief ends rapidly when drug use is discontinued. Furthermore, added benefits may be gained when LLLT is used in the context of a regular exercise and stretching program.

Some Technical Notes: The application of LLLT is complicated by multiple variables, such as the wavelength of the laser, its energy, and duration of application, which can produce different effects in different human tissues. In the current study, these variables were not consistent across trials; for example, the energy delivered per treatment point on the neck ranged from 0.06 to 54 Joules and the irradiation duration lasted between 1 and 600 seconds. A dose-response effect was associated with LLLT, but the accumulated data could not provide definitive guidance regarding the best practice for LLLT. Still, the authors propose from their analysis that the optimum mean dose per point for wavelengths of 820–830 nm (nanometers) was 5·9 Joules, with an irradiation time of 39.8 seconds, and for 904 nm, 2.2 Joules delivered for 238 seconds. Along with that, when treating neck pain with LLLT, irradiation of known trigger points, acupuncture points, tender points, and symptomatic zygapophyseal joints is advisable, they note.

Reference: Chow RT, Johnson MI, Lopes-Martins RAB, Bjordal JM. Efficacy of low-level laser therapy in the management of neck pain: A systematic review and meta-analysis of randomized placebo or active-treatment controlled trials. Lancet. 2009;374(9705):1897-1908 [abstract here]. (At the time of this posting a courtesy PDF of the full article was available here, but this may be discontinued.)

Acetaminophen-Plus-Ibuprofen Combo for Acute Pain

Newly-reported research suggests that, for acute pain following minor surgery, combining acetaminophen-plus-ibuprofen may be superior to each of the ingredients alone. However, there is a question as to whether this is the best treatment for such pain.

Acetaminophen (APAP) is often used along with a nonsteroidal antiinflammatory drug (NSAID), such as ibuprofen, for acute pain. Currently, these drugs must be given individually and sometimes at different time intervals, which can be a complex and difficult-to-follow regimen. Researchers in New Zealand examined a new APAP-ibuprofen combination product — Maxigesic® (not yet approved in the U.S.) — in a randomized controlled trial to assess its efficacy compared with each ingredient administered as monotherapy [Merry et al. 2010].

Adults (more than 16 years of age) having one or more wisdom teeth removed under general or local anesthesia were randomly assigned to either (a) APAP 500 mg plus ibuprofen 150 mg per tablet (combination product, n=44); (b) APAP 500 mg per tablet alone (n=47); or (c) ibuprofen 150 mg per tablet alone (n=44). Subjects were instructed to take 2 tablets of their assigned medication before the operation, then 2 tablets every 6 hours for up to two days. The report, appearing in the January 2010 edition of the British Journal of Anaesthesia, concludes that the combination product was significantly superior (p < .01) in relieving pain than either APAP or ibuprofen alone (which were equivalent to each other). Adverse reactions were minimal and more evident in the APAP group (vomiting and other GI symptoms, headache, drowsiness), with the ibuprofen group reporting no medication-related side effects at all.

Caveats: On closer inspection, there are several aspects of this research — which was sponsored and overseen by the manufacturer of Maxigesic — that are of concern:

1. The researchers used a somewhat novel primary outcome measure consisting of the area under the curve of visual analogue scale (VAS – 100 mm) pain measurements taken for up to 48 hours after surgery, divided by time, at rest and during activity. In essence, this produces a measure of average pain intensity throughout the study period, but it is unhelpful for gauging if there were times, particularly during the early postsurgical period, when either one of the agents or the combo was better than the other.


2. Average VAS measures (100 mm scale) during activity over two days were APAP 40, ibuprofen 40, combo 28. Since there is no other control group for comparison — either placebo or alternate analgesia — it is difficult to gauge if this is a clinically significant improvement even at the lowest mean pain score.


3. In a global pain-rating measure, more subjects reported “nil” or “mild” pain with the combo (68%), but this was a statistically significant improvement only over APAP (38%) rather than ibuprofen (54%) alone.


4. Importantly, a majority of all patients required “rescue analgesia,” either fentanyl in the hospital or codeine during the first or second day at home (group, % of patients): APAP, 63%; ibuprofen, 58%; combo, 57%. Differences between groups were not statistically significant.


5. Doses of APAP — 5000 mg on day 1, 4000 mg day 2 — were at or exceeded the recommended safe maximum of 4 grams. Liver function tests were not performed, and many practitioners may justifiably feel uncomfortable routinely prescribing such doses even for a short duration.


6. Subjects were carefully selected, excluding those who weighed less than 50 kg, were taking any blood-thinning medication, or had a history of gastric, hepatic, or renal disease, among other criteria. Therefore, the external validity of this approach for many clinical populations may be questionable.

An earlier report comparing ibuprofen (2400 mg/d) vs APAP (3000 mg/d) vs a combination of the two following minor orthopedic surgery found that ibuprofen reduced pain to a greater extent than APAP, and combining the two agents provided no advantage [Dahl et al. 2004]. Of interest, doses of ibuprofen in this study were considerably greater (2400 vs 1500 mg/day 1) and APAP much lower (well within the safety range) than in the study by Merry et al. above. Taken together, the data from both studies suggest that ibuprofen alone, at reasonably higher doses, may be the most advantageous nonopioid analgesic.

Still, is this treatment optimal for acute pain following minor surgery? Since both studies noted that administration of opioid medication was required on a “rescue” basis, it raises the question of whether simply prescribing oral opioid analgesia at the outset, perhaps followed during day 2 or 3 by ibuprofen and/or APAP if needed, might be a superior approach. Any comments readers?

References:
> Dahl V, Dybvik T, Steen T, et al. Ibuprofen vs. acetaminophen vs ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction. Eur J Anaesth. 2004;21(6):471-475 [abstract].
> Merry AF, Gibbs RD, Edwards J, et al. Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial. Br J Anaesth. 2010 104(1):80-88 [PDF available here].

Jan2010 – Pain Product Announcements & Warnings

Featured Items: Tylenol Arthritis Pain Caplets recall, diclofenac sodium topical gel (Voltaren gel) hepatic toxicity warning, generic hydromorphone HCl approved.
— Brand names are trademarks of the respective manufacturers. Compiled by Winnie Dawson, MA, RN, BSN.

Tylenol® Arthritis Pain Caplets — Product Recall Expanded
Johnson & Johnson has announced a voluntary, precautionary recall of all 100-count bottles of Tylenol Arthritis Pain Caplets with the red E-Z Open Cap. Consumers have reported a mildew-like smell and complaints of nausea, vomiting, stomach pain, and diarrhea. None of the health complaints have been serious and all were temporary. The company believes that the odor was caused by trace amounts of a chemical in the wooden pallets that are used to transport and store the product before shipping. J & J plans to ship new bottles of Tylenol Arthritis Pain Caplets in January. Consumers can receive a product refund by calling the company at 888-222-6036.

Diclofenac Sodium Topical Gel (Voltaren®) — Stronger Hepatic Toxicity Warning
The FDA issued a December 2009 “Dear Healthcare Professional…” letter to alert clinicians of a revision in the prescribing information for diclofenac sodium topical gel. Post-marketing surveillance has identified reports of drug-induced hepatic toxicity — occasionally severe enough to result in death or liver transplantation — including liver necrosis, jaundice, fulminant hepatitis, and liver failure. Because hepatotoxicity cases have been reported within the first month or two of treatment, liver enzyme tests (specifically, aspartate transaminase and alanine transaminase) should be performed within 4 to 8 weeks of treatment initiation. Voltaren gel should be used cautiously when prescribing for patients already taking drugs known to be potentially hepatotoxic (eg, antibiotics, anti-epileptic drugs); the lowest effective dose should be used for the shortest time possible. To learn more, see the full prescribing information and the letter to healthcare professionals.

Generic Hydromorphone Hydrochloride Approved
Lannett Company announced the December 2009 FDA approval of their hydromorphone hydrochloride tablets, the generic equivalent of Purdue Pharmaceuticals’ Dilaudid®. News sources have reported market shortages for hydromorphone and Lannett expects to be able to ship all 3 dosage strengths — 2 mg, 4 mg, and 8 mg tablets — within several weeks. Hydromorphone is a potent schedule II opioid agonist used for the management of moderate to severe pain.