Hypogonadism Risk Higher With Long vs Short-Acting Opioids

Kate Johnson

February 27, 2012

February 27, 2012 (Palm Springs, California) — Men treated with long-acting opioids may have a higher risk of developing hypogonadism compared with those receiving short-acting formulations, a new study suggests.

"Over half of all men on daily opioids are hypogonadal," Andrea Rubinstein, MD, from Kaiser Permanente in Santa Rosa, California, told Medscape Medical News. "The odds of being hypogonadal on a long-acting opiate are 4.7 times higher than the odds on a short-acting equipotent dose."

The findings go against 20 years of assumptions and provide the first evidence for a safety advantage of short-acting formulations, she said.

"For the last 20 years, the movement has been towards long-acting opiates...because we believed it was the safer way to go," she noted. "But there's never been any evidence in the literature that says there's a safety or efficacy difference between the long- and short-acting opiates."

The findings were presented here at the American Academy of Pain Medicine (AAPM) 28th Annual Meeting.

Common Problem

This retrospective study, ranked 1 of the top 6 studies offered here, included 81 men aged between 18 and 80 years who had no previous diagnosis of hypogonadism and who were taking a stable, daily dose of opioids for chronic pain.

The opioids they were taking included hydrocodone (25), oxycodone (8 continuous-release, 10 immediate-release), morphine controlled-release (12), fentanyl patch (4), methadone (14), and buprenorphine (8).

Morning testosterone levels taken for all men revealed that 57% were hypogonadal, defined as a testosterone level lower than 250 ng/dL.

"This is a common problem," said Dr. Rubinstein. "If you take testosterone levels on all your patients on daily opioids, you will find more than half are low."

She said that although the phenomenon has been reported since the 1970s, many physicians are not aware of how common and how profound it can be.

"It occurs quickly, usually within days to weeks. Patients do not need to be on the drug for years for this to occur," she said. "It seems to be reversible: Take the drug away, and testosterone levels usually rise. And, not in all cases, but in some cases, when this happens it is profound, and men can become hypogonadal to near-castrate levels."

When testosterone levels were compared taking type of opioid into account, the analysis showed that a significantly higher number of men receiving long-acting formulations were hypogonadal compared with men receiving short-acting formulations (74% vs 34%; P < .001).

After controlling for dose (converted to morphine standardized equivalents) and body mass index (BMI), patients receiving long-acting opioids had 4.78 times greater odds of becoming hypogonadal than patients receiving short-acting opioids (P = .008).

Although BMI and age were also significantly related to hypogonadism, the effects were small (P-value, 0.65 and 0.64, respectively).

The morbidity associated with hypogonadism is significant and includes osteoporosis, decreased function, decreased libido, depression, pain, obesity, and insulin resistance, said Dr. Rubinstein.

"All these other conditions are being managed, often with other drugs and their side effects, so this is a significant problem."

She said a hypothesis for why short-acting opioids might be less harmful is that their serum levels fluctuate, rather than remaining stable, as is the case with long-acting formulations

"Men make [luteinizing hormone (LH)] about every 90 minutes, and every time they make LH they produce testosterone," she explained. "Imagine that there's some threshold of serum drug level...and imagine that in order for LH to be released and cause a surge in testosterone, the serum level has to be below that level."

With short-acting opioids, she said, "at certain times of day when the drug level is low and coincides with this cyclical LH burst, testosterone is produced. Why we think this might be true is that when we check these men, LH is often very low too."

Important to Practice

Asked to comment on the findings, moderator of the session James Watson, MD, from the Mayo Clinic, Rochester, Minnesota, said, "This might be the first evidence that we actually have that there might be a safety difference between the long-acting and the short-acting agents, and that's very important to how we practice."

He said that in general, opioid-related hypogonadism "is an underreported phenomenon. Not that we don't think it occurs, but we often don't ask the right questions to bring it out," he told Medscape Medical News. "The first step is to get people to be aware of how frequent this is."

Once it is recognized, he said, physicians can consider how to intervene. "It does suggest that maybe one of the ways that you can intervene would be to transition [patients] from a long- to short-acting opioid. But we still don't know, once [hypogonadism] has set, whether you can reverse it by simply changing the duration of agent."

In addition, identifying risk factors for hypogonadism might be important going forward, he said.

"When you're looking at a patient to treat with long-term opioids, can you look at certain parameters in that patient that might suggest they're at higher risk of developing hypogonadism if you put them on a long-acting agent? Is this an elderly person who already has osteopenia, or someone who already has low libido or fatigue issues?" he said. "Are there certain characteristics that would help us identify those patients who are at higher risk for this to define who are better candidates for short- vs long-acting opioids?"

Funding for the study was provided by the Kaiser Permanente Northern California Community Benefits Program. Dr. Rubinstein and Dr. Watson have disclosed no relevant financial relationships.

American Academy of Pain Medicine (AAPM) 28th Annual Meeting: Abstract 229. Presented February 24, 2012.

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