It has long been known that all opioids may disrupt endocrine system function and, among other effects, ongoing use of these drugs may lower testosterone levels in men. A recently reported study is the first to show significant differences in that risk between short-acting and long-acting opioid analgesics; however, a clear understanding of these effects will depend on future research.
Writing in the Clinical Journal of Pain, researchers from the Kaiser Permanente Northern California (KPNC) healthcare system report a retrospective investigation of 81 men between the ages of 26 and 79 years (mean age ≈52) who had been seen in a chronic-pain clinic between January 2009 and June 2010 [Rubinstein et al. 2013]. None of the subjects had a prior history of low testosterone or other endocrine disorder, and all were on stable doses of daily opioid analgesics for at least 90 days.
The research objective was to examine several variables related to opioid analgesic use, including daily dose and duration of opioid action (eg, long-acting vs short-acting/immediate release), to assess their influences on total serum testosterone levels in men with chronic pain and taking daily opioids. More than half of the male patients, 57% (46/81), were taking long-acting opioid (LAO) analgesics — either, methadone, oxycodone, morphine CR, fentanyl, or buprenorphine — and the remaining 43% (35/81) were taking short-acting opioid (SAO) formulations of oxycodone or hydrocodone.
Total serum testosterone levels were assessed in the morning in all subjects. Low serum total testosterone (TT), or hypogonadism, was defined in this study as ≤250 ng/dL [normal physiologic TT range in adult males is ≈300 to 1,200 ng/dL]. Data also were available on body mass index (BMI) for each subject.
Results indicated that, on average, about half (53%) of all men in this population receiving daily opioids were hypogonadal (TT <250 ng/dL). In men receiving long-acting opioids (LAO), nearly three-quarters (74%, or 34/46) had low testosterone compared with only about a third (34%, 12/35) of men taking short-acting opioids (SAO) exclusively. [This was a statistically significant difference, as calculated from study data: TT mean, 95% CI in LAO group = 169 ng/dL, 130-205 ng/dL versus TT mean, 95% CI in SAO group = 314 ng/dL, 267-363 ng/dL; P<0.001.]
After controlling for daily opioid dosage and BMI, men in the LAO group had nearly 5 times greater odds of becoming hypogonadal than did men in the SAO group [OR=4.78; 95% CI, 1.51-15.07; P=0.008]. Separately, BMI was marginally but significantly associated with low testosterone [OR=1.13; 95% CI, 1.03-1.24; P=0.006], whereas the daily opioid dose was not significantly associated with low testosterone [OR=1.02; 95% CI, 0.99-1.05; P=0.29].
The researchers conclude that, among a contemporary sample of men receiving long-term daily opioids for chronic pain, there appears to be a high prevalence of hypogonadism. This lowered testosterone was associated with the duration of opioid action — with long-acting formulations conferring greater risk than short-acting opioids — but the total daily dose of opioid medication itself may not be a determining factor.
COMMENTARY: We consider this study by Rubinstein et al. as representing relatively low-quality evidence, in that future and larger studies of this nature are likely to elaborate and/or modify the outcome results. In fact, the researchers noted in a press release that a much larger retrospective study along these lines of 1,500 male patients with chronic pain is currently underway.
Therefore, this present study may have been prematurely published. However, it seemed pertinent to write about it in this UPDATE because (a) it is an important topic, and (b) the study was widely featured in mass media reports — largely reiterating press releases — that did not question its quality or external validity.
Several limitations are worth considering, most of which are prudently raised by the researchers themselves in their journal article:
- Group sizes in this study were relatively small; although, the large effect size for TT differences between LAO and SAO groups suggests a low probability of Type I error, or false-positive findings. Still, due to small sample sizes, there was inadequate statistical power to assess associations between specific opioids and low testosterone, which could be clinically important. Along with that, only a limited range of opioid analgesics was evaluated in the study (also note, the long-acting buprenorphine studied was the oral formulation, not the transdermal system approved for pain management).
- Ranges of standardized morphine-equivalent doses (MED) of opioid analgesics across both groups varied widely from 5 mg to 2,400 mg/day, and patients in the SAO group were generally on lower doses, <100 mg/d MED. Even though the daily MED did not appear to be a primary determinant of hypogonadism, statistically, the researchers do note that larger studies are needed to clarify and affirm this relationship.
- The interaction of body mass index and hypogonadism needs further elaboration. Although the effect size for this relationship was small in this study, the researchers calculated that for each unit increase in BMI patients had an additional 13% higher odds of having low testosterone. Also of interest, patient age was not associated with hypogonadism as might be expected; although, again, small samples sizes might not have detected potential effects of age.
- The researchers further concede that future studies, both prospective and epidemiologic in design, are necessary to control for other causes of hypogonadism and better elaborate possible relationships between the type of opioid analgesic and testosterone suppression. The present study could not control for or assess the prevalence of other factors potentially associated with hypogonadism, such as atherosclerosis, metabolic syndrome, dyslipidemia, hypertension, and type 2 diabetes.
- Finally, the researchers also note that the men in their study had been referred to their clinic for unspecified problems associated with inadequate pain management; therefore, the subjects may represent a select population and symptoms of hypogonadism — eg, increased pain, depressed mood, decreased response to opioid therapy — may have contributed to referral to their clinic in the first place.
Potential endocrinopathy and subsequent sexual dysfunction in both men and women are well-documented risks of ongoing opioid analgesic therapy for chronic pain conditions. For example, this has been discussed in a Pain-Topics Current Comments paper titled “Opioid-Induced Sexual Dysfunction: Causes, Diagnosis, & Treatment” [available here].
Endocrine deficiency and hypogonadism influencing sexual dysfunction are caused by suppression of gonadal hormones and adrenal androgens. Symptoms may include weight gain, fatigue, depression, osteoporosis, vasomotor instability, decreased libido, erectile dysfunction, and menstrual cycle irregularities. In many cases, endocrine deficiencies associated with opioid therapy can be medically managed, such as by testosterone supplementation in appropriately selected male patients.
Anecdotally, rotation from one opioid medication to another has been suggested as helping to ameliorate some cases. However, this study by Rubinstein and colleagues raises important questions about how distinct opioid formulations may differentially affect hypogonadism to begin with and which might be the best alternative choices for potentially minimizing low testosterone and its adverse effects. Hopefully, more definitive answers will be forthcoming from their larger study in progress or from other research.
REFERENCE: Rubinstein AL, Carpenter DM, Minkoff JR. Hypogonadism in Men With Chronic Pain Linked to the Use of Long-acting Rather Than Short-acting Opioids. Clin J Pain. 2013; online ahead of print [abstract here].
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