FDA investigated several safety issues associated with the class of opioid pain medicines:
- Serotonin syndrome
- Adrenal insufficiency
- Androgen deficiency
Serotonin syndrome
A search of the FDA Adverse Event Reporting System (FAERS) database for the period January 1, 1969, to June 12, 2013, identified 43 cases of serotonin syndrome in which opioids were used concomitantly with other serotonergic drugs. The review excluded meperidine, tramadol, and tapentadol, which were already labeled for the risk of serotonin syndrome at the time of the review. The most commonly reported opioids associated with serotonin syndrome were fentanyl (n=28), oxycodone (n=7), and methadone (n=5). Other reported opioids included hydromorphone, morphine, alfentanil/remifentanil/sufentanil, hydrocodone, naltrexone, and pentazocine. Although there were no reports of serotonin syndrome with an opioid used alone, five cases reported that serotonin syndrome occurred with the use of two or more opioids concurrently. All of these five cases reported use of fentanyl along with at least one other opioid [oxycodone (n=4), morphine (n=1), hydromorphone (n=1), and hydrocodone (n=1)].
Adrenal insufficiency
A search of FAERS for the period January 1, 1969, to February 5, 2014, identified 37 cases of adrenal insufficiency reported with the use of opioids. Twenty-seven cases reported opioid monotherapy, and 10 reported use of more than one opioid at the same time. The most commonly reported opioids associated with adrenal insufficiency were fentanyl (n=10) and oxycodone (n=10), followed by buprenorphine or buprenorphine/naloxone (n=7), hydromorphone (n=6), and tramadol (n=4). When reported, the time to onset of adrenal insufficiency after the start of opioid therapy ranged from within 1 day to more than 1 year; however, many of the cases reported adrenal insufficiency after at least 1 month of use. Many of the patients were hospitalized. Of the 37 cases, 21 described that the patients received corticosteroid treatment. Sixteen cases reported discontinuing or reducing the dose of the opioid. Of the 16, nine of these patients improved, three had ongoing symptoms, and four did not report an outcome. Some patients experienced a relief in symptoms when they were switched from one opioid to another.
Androgen deficiency
We reviewed the medical literature to evaluate the association between opioids and androgen deficiency. 1-21 A range of studies in a variety of settings demonstrated decreased gonadal hormones in men and women taking long-term opioids. However, most of the studies were descriptive prevalence studies that did not include baseline values for the hormone levels, and there was a lack of comparability between the opioid-treated groups and control groups regarding medical, physical, lifestyle, and psychological factors that may influence gonadal hormone levels. Due to limitations of the studies, it is unclear whether the low gonadal hormone levels and associated symptoms and signs in men and women could be attributed to long-term opioid use or to other factors such as the patient’s underlying medical condition warranting opioid treatment; physical, mental, or life stressors; weight changes; or concomitant medication or supplement use.