Clinically low testosterone levels can lead to the development of hypogonadism in men. Signs indicative of hypogonadism – defined as failure of the testis to produce physiological levels of testosterone and the normal number of spermatozoa caused by disruption of one or more levels of the hypothalamus-pituitary-gonadal (HPG) axis include:²

• Testicular atrophy
• Anaemia
• Diminished facial hair growth
• Infertility in both genders
• Irregular menstrual cycles
• Muscle wasting
• Decreased bone density (osteopenia or osteoporosis)
• Alterations in body composition such as increased fat mass and decreased lean body mass.

Opioid prescribing is a balancing act

Apart from the effect on the endocrine system, long-term opioid use has also been linked to the onset of metabolic syndrome, which is a major risk factor for cardiovascular (CV) disease, as well as mood disturbances, stress reactivity and aggression in men.⁴

Furthermore, long-term opioid use has been shown to affect the gastrointestinal tract and the respiratory control centres in the brain causing a reduction in respiratory function, emphasising the need for vigilant opioid therapy management.^1,2,4

Before prescribing opioids, pain relief benefits should be weighed against potential risks. Extended-release opioids have been linked to a higher risk of androgen suppression compared to equivalent doses of immediate-release opioids. Fentanyl is associated with the highest risk, followed by methadone and oxycodone.^1,3

Coluzzi et al stress that testosterone levels should be measured in all men before opioid treatment is prescribed, and opioids with a low affinity for the μ-opioid receptor should be prioritised.¹

How do opioids impact testosterone levels?

As mentioned, opioids exert their effects on the HPG axis primarily by interacting with μ-opioid receptors in the hypothalamus. This interaction inhibits the pulsatile release of GnRH from the hypothalamus, subsequently reducing the secretion of luteinizing hormone and, to a lesser extent, follicle-stimulating hormone from the pituitary gland.⁵

Consequently, testosterone release from the gonads declines. Furthermore, opioids may elevate prolactin levels, leading to galactorrhoea (a milky nipple discharge) and gynaecomastia (overdevelopment or enlargement of the breast tissue).⁵

In a systematic review and meta-analysis by Bawor et al, investigated the relationship between opioid use and testosterone levels, providing a comprehensive estimate of testosterone suppression.⁴

The review included 17 studies, comprising seven cohort studies and 10 cross-sectional studies. Their analysis revealed a significant reduction in testosterone levels among men using opioids compared to controls, with a mean difference of 5.7nmol/l.⁴

How effective is TTh in relieving pain?

The good news is that OPIAD is potentially reversible, with testosterone levels often normalising within a month after opioid withdrawal. Continuing opioids with a low impact on the HPG axis can be considered for symptomatic men with reduced testosterone levels.¹

If opioid cessation is necessary, alternative non-opioid therapies should be explored for managing chronic pain. Current guidelines suggest considering testosterone therapy (TTh) if pain relief with non-opioids is inadequate or if patients cannot discontinue opioid treatment.¹

Basaria et al (2015) conducted a randomised, double-blind, parallel placebo-controlled trial to assess the efficacy of TTh on pain perception and other androgen-dependent outcomes in men living with OPIAD who experience chronic non-cancer pain and have total testosterone levels <12.2mmol/l. Participants were randomly assigned to receive either daily transdermal TTh or a placebo for 14 weeks.⁶

The study observed a significant improvement in pain sensitivity among participants receiving TTh, indicated by increased pressure pain threshold at the thumb and reduced punctate mechanical pain ratings. TTh also led to lower temporal summation scores for mechanical pain and showed trends towards improvements in cold pain after-sensations.⁶

Furthermore, men in the TTh group experienced an increase in sexual desire and improvements in certain domains of quality of life, including role limitations secondary to emotional problems. There was also a significant reduction in fat mass and an increase in lean body mass observed in the TTh group compared to the placebo group. Importantly, the frequency of adverse events did not differ between the TTh and placebo groups, suggesting that TTh was well-tolerated.⁶

The authors concluded that their findings indicate that TTh may offer benefits in alleviating pain sensitivity and improving other androgen-dependent outcomes in men living with OPIAD.⁶

Raheem et al (2017) investigated the treatment of OPIAD and its impact on opioid requirements and quality of life in patients with chronic pain. Data from men undergoing TTh were compared with a non-treatment group.⁷

Participants with total testosterone levels of <10.4mmol/l were identified. Follow-up total testosterone levels were significantly higher in the TTh group compared to the non-TTh group (17.2mmol/l versus 8.4mmol/l).⁷

Median follow-up numeric rating scale scores were significantly lower in the TTh group compared to the non-TTh group (0 versus 2). Additionally, the mean morphine equivalent dose (MED) decreased by 21mg in the TTh group, whereas it increased by 2.5mg in the non-TTh group.⁷

The study highlights that TTh treatment can lead to reduced opioid requirements in men living with chronic pain and the effectiveness of TTh in correcting opioid-induced endocrine abnormalities.⁷

Jasuja et al (2020) conducted a cohort study comparing health outcomes among long-term opioid users (n=21 272) with testosterone deficiency who were either prescribed TTh therapy (n=14 121 [66.4%]) or received other prescriptions (n=7151 [33.6%]). Primary endpoints included all-cause mortality, major adverse CV events (MACE), vertebral or femoral fractures, and anaemia during the six-year follow-up.⁸

Participants who received TTh were more likely to have obesity, hyperlipidaemia, and hypertension but had a lower prevalence of coronary artery disease and stroke at baseline.⁸

After adjusting for covariates, opioid users receiving TTh exhibited significantly lower all-cause mortality and incidence of MACE, femoral or hip fractures, and anaemia compared to those without TTh prescriptions.⁸

In covariate-adjusted models, opioid users receiving both opioids and TTh were more likely to resolve anaemia compared to those receiving opioids only. Similar findings were observed in propensity score–matched models and among opioid users living with non-cancer pain or those not receiving glucocorticoids.⁸

The study suggests that long-term opioid users with testosterone deficiency who were treated with both opioid and TTh experienced significantly improved health outcomes over a multi-year follow-up.⁸

Conclusion

Opioid use in individuals living with chronic non-cancer pain can lead to OPIAD, which contributes to poor pain control and hyperalgesia, posing significant challenges to effective pain management.

Beyond its endocrine effects, androgen deficiency is linked to metabolic syndrome, mood disturbances, and CV risk factors, further complicating the clinical picture.

Given the diverse manifestations of OPIAD, the management of chronic pain with opioids necessitates a careful balancing act, weighing the benefits of pain relief against the risks of androgen suppression.

TTh has emerged as a promising intervention for alleviating pain sensitivity and improving androgen-dependent outcomes in men with OPIAD. Clinical trials have demonstrated the efficacy of TTh in enhancing pain control, improving quality of life, and reducing opioid requirements.

Observational studies have shown that long-term opioid users with testosterone deficiency who receive TTh experience significantly overall improved health outcomes.

Overall, recognising and addressing OPIAD as a consequence of the opioid epidemic is crucial for optimising pain management strategies and improving the well-being of affected individuals.

For more information on the subject, please watch this free webinar available at: https://live.arealive.org/webinars/public/index.html#webinar&id=webinar4

References

1. Coluzzi F, Billeci D, Maggi M, Corona G. Testosterone deficiency in non-cancer opioid-treated patients. J Endocrinol Invest, 2018.
2. Smith HS, Elliott JA. Opioid-induced androgen deficiency (OPIAD). Pain Physician, 2012.
3. Rubinstein AL, Carpenter DM. Association Between Commonly Prescribed Opioids and Androgen Deficiency in Men: A Retrospective Cohort Analysis. Pain Med, 2017.
4. Bawor M, Bami H, Dennis BB, et al. Testosterone suppression in opioid users: a systematic review and meta-analysis. Drug Alcohol Depend, 2015.
5. Kotlińska-Lemieszek A, Żylicz Z. Less well-known consequences of the long-term use of opioid analgesics: a comprehensive literature review. Drug Des Devel Ther, 2022.
6. Basaria S, Travison TG, Alford D, et al. Effects of testosterone replacement in men with opioid-induced androgen deficiency: A randomized controlled trial. Pain, 2015.
7. Raheem OA, Patel SH, Sisul D, et al. The Role of Testosterone Supplemental Therapy in Opioid-Induced Hypogonadism: A Retrospective Pilot Analysis. Am J Mens Health, 2017.
8. Jasuja GK, Ameli O, Reisman JI, et al. Health Outcomes Among Long-term Opioid Users With Testosterone Prescription in the Veterans Health Administration. JAMA Netw Open, 2019.