Thursday, May 17, 2012

Do Short-Acting Opioids Affect Sex Hormones Less?

Sex HormonesSex hormone deficiencies, or hypogonadism, can be a common adverse effect of ongoing opioid use in both men and women. A newly reported study found that this problem was less prevalent in a sample of men taking short-acting rather than long-acting opioid analgesics for chronic pain. However, this was a preliminary investigation and study limitations should be taken into account. Furthermore, hypogonadism is an effect that can be medically managed and need not automatically require discontinuation of opioids or a change of formulation.

In a poster presentation at this year’s meeting of the American Academy of Pain Medicine (AAPM), a team of investigators from the Kaiser Permanente Health Care System in Northern California reported on a comparison of hypogonadism in men taking daily long-acting (N=46) versus short-acting (N=35) opioid analgesics for chronic noncancer pain [Rubinstein et al. 2012]. They examined total testosterone levels in the 81 men, aged 18 to 80 years, during 2009-2010. All of them had been on stable daily opioid dosing for at least 3 months and none had a prior diagnosis of hypogonadism.

Results indicated that 74% of men on long-acting opioids were hypogonadal (<250 ng/mL testosterone), compared with only 34% of subjects taking short-acting opioids (P<0.001). When controlling via logistic regression for morphine-equivalent dosage and body mass index (BMI), patients taking long-acting opioids had 4.78 times greater odds of becoming hypogonadal than did the men on short-acting opioids (95% confidence interval, 1.51-15.07, P=0.008). In a multivariate analysis, subject age and opioid dose were not significantly associated with hypogonadism; BMI effects were small, and probably not clinically important, but statistically significant (P=0.006).

Long-acting formulations reported in the study included fentanyl, methadone, morphine CR, oxycodone CR, and buprenorphine. Interestingly, buprenorphine had effects similar to short-acting opioids, producing hypogonadism in only 3 of 8 (37%) of men taking this drug. Of the 2 short-acting formulations studied — oxycodone IR and hydrocodone — hydrocodone exhibited hypogonadal effects in the least percentage of patients (7/25, or 28%). The researchers conclude that this first-of-its-kind study showed that the daily use of long-acting opioids increases the risk of hypogonadism in men when compared with daily use of short acting opioids.

COMMENTARY: The potential for hypogonadal effects of all opioids as a class has been known for a number of decades. This topic was discussed in a well-documented paper developed by Stephen Colameco, MD, for Pain Treatment Topics [see “Opioid-Induced Sexual Dysfunction: Causes, Diagnosis, & Treatment,” PDF here]. These adverse effects can be readily identified if practitioners are alert to the possibility and medically managed; for example, testosterone supplementation is a well-studied therapy for hypogonadism in men.

The present study by Rubinstein and colleagues was an award-winning poster presentation at the annual AAPM conference, so it garnered considerable interest and some notice in the mass media. However, numerous limitations of this research should be taken into account before accepting any firm conclusions.

This was a retrospective cohort study of patient records drawn from the database of an extremely large healthcare system and there could have been selection bias. It is not known how long patients actually had been taking opioids, other than the 90-day minimum for study inclusion, and comorbid physical conditions potentially affecting hormonal levels were not reported.

Samples sizes were small but adequate to produce significant results statistically. However, it is of some concern that the odds ratio confidence interval for hypogonadism, comparing long- vs short-acting opioids, was so wide — 1.51 to 15.07 — suggesting high variability and a lack of precision in the statistically significant point estimate of 4.78. It is possible at the lower end of the confidence range that the results have only minimal if any clinical significance.

In a feature article in Pain Medicine News [here], lead investigator, Andrea Rubinstein, MD, speculates that cyclic periods of low drug serum levels associated with short-acting opioids might stimulate more adequate testosterone production than is seen with longer-acting agents, which have more steady serum levels if properly dosed, without such troughs. However, this is unverified and there can be substantial disadvantages of the peaks and troughs manifest by short-acting opioids occurring throughout the day on a long-term basis.

Rubinstein concedes that their sample size was small and did not allow for comparisons between individual opioids. Furthermore, she adds, the patients may not have been representative of a general population of patients with chronic pain and that larger, prospective trials will be needed to verify differential effects of long- vs short-acting opioids on sex hormones in men and women.

REFERENCE: Rubinstein AL, Carpenter DM, Minkoff J. Hypogonadism in Men Using Daily Opioid Therapy for Chronic Noncancer Pain is Associated with Duration of Action of Opioid. Poster presentation at the 2012 Annual Meeting of the American Academy of Pain Medicine, February 23-26, 2012, Palm Springs, CA; abstract #229 [available here].

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