PALM SPRINGS, CALIF. – Low testosterone levels were nearly five times more likely in men on long-acting or sustained-release opioids, compared with equipotent short-acting or immediate-release formulations, judging from the findings of a study of 81 men on daily opioids for chronic pain.
Neither the age of the patient nor the total daily dose of opioid significantly affected the risk of hypogonadism, Dr. Andrea Rubenstein reported in her award-winning poster and a plenary presentation at the annual meeting of the American Academy of Pain Medicine.
With her associates, Dr. Rubenstein reviewed records on the morning measurements of total testosterone levels in men who were on a stable dose of an opioid for at least 3 months and who had no history of hypogonadism. In all, 46 of the 81 men had total testosterone levels below 25 ng/dl (57%), consistent with published reports of a high rate of hypogonadism in men on chronic opioid therapy ranging from 54% to 86%.
Previous studies, however, evaluated only men on sustained-release or intrathecal formulations and could not identify what aspect of opioid use may be contributing to hypogonadism.
Dr. Andrea Rubenstein
The current study found that 34 of 46 men on long-acting or sustained-release opioids had low total testosterone levels (74%), compared with 12 of 35 men on short-acting or immediate-release opioids (34%), a significant difference, said Dr. Rubenstein, an anesthesiologist and pain specialist at Kaiser Permanente Medical Group, Santa Rosa, Calif.
After adjusting for the effects of dosage and body mass index (BMI), men on long-acting or sustained-release opioids were 4.8 times more likely to have low testosterone levels, compared with men on short-acting or immediate-release formulations.
Higher BMI had a small but significant association, increasing the risk for hypogonadism by 13%.
Opioid-related androgen deficiency has been documented in one fashion or another since the 1970s, and appears to come on quickly, within days or weeks of starting chronic opioid therapy, she said.
"This phenomenon is not new, even though it’s kind of a hot topic this year," Dr. Rubenstein said.
For the past 20 years, the trend has been to put more and more patients on long-acting opioids because these were believed to be safer than short-acting formulations. If the association between hypogonadism and long-acting opioids holds up in further studies, "it will be the first evidence of a difference in safety, though not in the direction we had thought," she said.
Dr. Steven Linder
Dr. Steven Linder of the Veterans Affairs Healthcare System Hospital, Palo Alto, Calif., commented on the study in an interview at the poster presentation. The V.A. is seeing a large number of young veterans with spinal and other injuries who are on long-term opioids, and often these patients are not screened for hypogonadism. Dr. Rubenstein’s study is an important reminder to check testosterone levels in men on long-acting or sustained-release opioids, he said.
If unrecognized and untreated, hypogonadism can lead to osteoporosis, low libido, lower function and mood, insulin resistance, increased pain, and obesity. Often, these are managed with other medications that contribute side effects, Dr. Rubenstein said.
"The last thing we need in a guy on 40 mg of methadone for back pain is to get osteoporosis of the spine," she said.
Patients in the study included 25 on hydrocodone, 8 on continuous-release oxycodone, 10 on immediate-release oxycodone, 12 on continuous-release morphine, 4 on the fentanyl patch, 14 on methadone, and 8 on off-label sublingual buprenorphine. (Only the patch form of buprenorphine is approved to treat pain.)
The study was limited by its small size, "but in the opioid literature, 81 is a nice number," she said. The study also is limited by its retrospective design, potential bias if the symptoms of hypogonadism played a role in the initial referral, and questionable generalizability if the men at this tertiary-care pain clinic are not representative of men with chronic pain in the general population.
The investigators next will repeat the study on a much larger sample of patients, and if the association is replicated, will design a prospective study to see if changing opioid therapy modifies the risk for hypogonadism. The findings of the current study are too preliminary to generate recommendations, she said.
The current study excluded patients with a history of cancer, HIV, or endocrine disease other than hypothyroidism.
Dr. Rubenstein and her associates reported having no financial disclosures.