Testosterone Cypionate and Opioids (Oxycodone, Hydrocodone, Tramadol): Drug Interaction Guide

Is there a direct interaction between testosterone cypionate and opioids?

The Depo-Testosterone label's drug interactions section says androgens may increase sensitivity to oral anticoagulants, so the anticoagulant dose may need to be reduced, with INR and prothrombin time checked more often. It also says serum oxyphenbutazone levels may rise when it is given with an androgen, and that androgens may lower blood glucose and insulin requirements in men with diabetes [1]. Opioids are not on that list [1].

The opioid labeling points at a different group of drugs. FDA's 2016 action added boxed warnings to nearly 400 opioid, opioid cough and benzodiazepine products about combined use, naming extreme sleepiness, respiratory depression, coma and death [6]. FDA's patient information names benzodiazepines and other central nervous system depressants, including alcohol, and lists misuse and abuse, addiction, overdose and death among opioid risks [6]. Testosterone is not named there [6].

The link between the two drug types is hormonal: opioids can lower testosterone, and testosterone cypionate is replacement therapy for confirmed hypogonadism [1][2][3].

How opioids affect testosterone

Testosterone cypionate is approved for hypogonadism caused by testicular failure or by a pituitary or hypothalamic problem [1]. The author of the oral-opioid study describes opioids as diminishing testosterone by inhibiting hypothalamic gonadotropin-releasing hormone production and testicular testosterone synthesis [3].

The measurements point the same way. In 73 people (29 of them men) receiving intrathecal opioids for nonmalignant pain, testosterone was below 9 nmol/L in 25 of the 29 men and was significantly lower than in a non-opioid control group. Luteinizing hormone was under 2 U/L in 20 of the 29 men. Mean duration of opioid treatment in that group was 26.6 months [2].

The Depo-Testosterone label specifies that hypogonadism be confirmed with morning serum testosterone measured on at least two separate days, both below the normal range [1].

How much do opioids lower testosterone?

The most detailed oral-opioid data come from a 2002 study of 54 community-dwelling men taking sustained-action oral opioids several times a day for nonmalignant pain, compared with 27 similar men taking no opioids [3]. Total testosterone was subnormal in 74%, free testosterone in 56% and estradiol in 74%; 89% had a low free testosterone or estradiol level [3]. Hormone levels averaged lower in a dose-related pattern, and 39 of the 45 men who reported normal erections before starting opioids reported severe erectile dysfunction or reduced libido afterward [3].

Both studies are small and observational, and they cannot predict what will happen to one man's numbers [2][3].

Does tramadol affect testosterone the same way?

Tramadol is a Schedule IV opioid analgesic that carries the full opioid boxed warning, and it is converted by CYP2D6 to a metabolite with stronger mu-opioid activity. The testosterone data above come from sustained-action oral opioids and intrathecal opioids as groups, so they do not establish a tramadol-specific effect on testosterone [2][3].

What about buprenorphine and methadone?

In a 2005 study of men in opioid-dependence treatment, 17 men on buprenorphine had a mean testosterone of 5.1 ng/mL, compared with 2.8 ng/mL in 37 men on high-dose methadone (P<0.0001). The buprenorphine group's level did not differ from 51 healthy blood donors, and sexual dysfunction was less frequent on buprenorphine (P<0.0001) [5]. The authors concluded that buprenorphine, unlike high-dose methadone, seems not to suppress plasma testosterone in this population; this is one small study [5].

Does testosterone worsen breathing during sleep?

Testosterone's own effect on breathing has been measured, though with testosterone esters in general rather than cypionate specifically. In a randomized, double-blind, placebo-controlled crossover study, 17 healthy men over 60 received three intramuscular injections of testosterone esters at weekly intervals (500 mg, then 250 mg, then 250 mg) or matching placebo, with an 8-week washout between periods [4]. Testosterone shortened total sleep time by about an hour, lengthened the time spent with low oxygen by about 5 minutes a night, and raised the total and non-REM respiratory disturbance indices by about 7 events an hour (P<0.05). Upper airway dimensions did not change [4].

That was a short, high-dose regimen in 17 healthy men. The Endocrine Society's 2018 guideline recommends against starting testosterone therapy in men with untreated severe sleep apnea [7]. Opioid labeling carries its own warnings about slowed or difficult breathing [6].

For the product itself, see testosterone cypionate.