Special Topics in Pain: Opioids

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Association Between Commonly Prescribed Opioids and Androgen Deficiency in Men: A Retrospective Cohort Analysis.

Author(s): Rubinstein, et al.
Journal: Pain Medicine. 2017; 18:637-644. 28 references.
Reprint: Andrea Rubinstein, MD, Kaiser Permanente Medical Group, 3559 Roundbarn Blvd, Santa Rosa, CA 95405, USA. E-mail: andrea.l.rubinstein@kp.org
Faculty Disclosure: Abstracted by N Walea, who has nothing to disclose.
Objective: Review and evaluate the latest advances and newest information in the area of Opioids; Review and evaluate the latest advances and newest information in the area of Endocrine System

Editor’s Note:  Androgen deficiency caused from suppression of the hypothalamic-pituitary-gonadal axis is a well-known side effect of chronic opioid therapy, though chronic pain itself may contribute to low androgen levels in men.  From this study, it appears that dosing regimens with a more steady-state serum opioid concentration negatively affect testosterone more so than short-acting opioids.  While patients in this study had been using opioids for at least 90 days, one also must consider whether those on these long-acting formulations had been taking opioids for a longer period than those solely on short-acting formulations and whether that was a cofounder in the data.  Nonetheless, androgen monitoring and treatment of androgen deficiency may become more common in the future.

Class: Pharmacology: Opioids; Organ system: endocrine

Androgen deficiency is a common, well-known risk with chronic, daily opioid use and can have serious and expensive health consequences, including loss of libido, erectile dysfunction, depression, osteoporosis, muscle loss, and fatigue.

This was a retrospective cohort analysis conducted using data from a large integrated health care delivery system in California having approximately 3.2 million members. Administrative databases contain records of inpatient and outpatient utilization, pharmacy utilization and lab test orders and results. Men ages 18 to 80 who had a morning total testosterone test in the period from Jan 1, 2007, through December 31, 2011, were eligible for the study if they had purchased a minimum of 90 days' supply of one prescribed opioid in the outpatient setting within the 100 days before the testosterone test date. The independent variables for the analyses were the specific opioid, the dose of the opioid (converted to morphine standardized equivalents [MSE]), age, obesity, diabetes, hypertension hyperlipidemia, hypertension and statin use.

There were 1,159 men using exactly one of the opioids of interest in the 100 days before the total testosterone test. Of subjects on fentanyl, 69.2% were androgen deficient, as were 60.8% of those on methadone, 52.1% of those on morphine (extended release formulation), 50.4% of those on oxycodone, 42.9% of those on hydromorphone, 35.5% of those on codeine, and 34.2% of those on hydrocodone.

Fentanyl, methadone, and oxycodone were all associated with higher odds of androgen deficiency than hydrocodone. Dose and opioid were found to have significant interaction; that is, the effect of dose differed depending on the individual opioid. Higher dose was associated with increased odds of androgen deficiency among subjects taking hydrocodone or oxycodone. Obesity was a significant contributor to androgen deficiency, as was age ≥ 50 plus the presence of two or more of the comorbidities diabetes, hypertension and hyperlipidemia.

Oxycodone is the only opioid in this study that was used both in short-acting (IR) and long-acting (ER) formulations. Androgen deficiency was present in 44.4% of subjects on short-acting oxycodone, 50.0% of subjects on long-acting oxycodone, and in 63.6% of subjects on both long-acting and short-acting oxycodone.

The study found that men age 50 and above having at least 2 comorbidities (diabetes, hypertension or hyperlipidemia) were more likely to have androgen deficiency. Additionally, obesity was independently associated with androgen deficiency. However, analysis was unable to elucidate in the subjects whether any of these relationships were bidirectional.

The findings show that the highest odds of androgen deficiency are associated with opioids that maintain the most stable serum drug levels. Transdermal fentanyl, which is designed to maintain a very steady serum drug level has the highest odds ratio, followed by methadone, with an elimination half-life between 8 and 59 hours. Oxycodone ER and morphine ER, both 12-hour formulations, showed similar results to each other. Subjects on hydrocodone and codeine, two short-acting opioids were least likely to be androgen deficient. The key issue thus many not be the inherent  properties of any one drug, but the way that drug formulation maintains serum drug levels. Because testosterone in men is produced in a pulsatile fashion periodically throughout every 24-hour cycle, it has been hypothesized that the nadirs in drug level that occur more frequently between doses of short-acting opioids may allow some testosterone to be produced during these nadirs, which may be sufficient  to maintain normal testosterone levels. By contrast, drugs that maintain constant serum levels may suppress testosterone production more completely.  

When making opioid prescribing decisions all risks should be weighed against benefits for each patient; understanding these risks can help better inform prescribing decisions.

Important Points:
Transdermal fentanyl, methadone, and oxycodone (long and short-acting formulations combined) were associated with higher odds of androgen deficiency when compared to hydrocodone. Higher dose was associated with increased odds of androgen deficiency only in hydrocodone and oxycodone. Age ≥ 50 years and the presence of two or three of the comorbidities diabetes, hypertension, and hyperlipidemia was associated with androgen deficiency; however this association was not as strong as the association between fentanyl, methadone, or oxycodone and androgen deficiency.

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