Opioid Induced Androgen Deficiency (OPIAD)

[Michael Scally MD]

Varma A, Sapra M, Iranmanesh A. Impact of opioid therapy on gonadal hormones: focus on buprenorphine. Hormone molecular biology and clinical investigation 2018. https://www.degruyter.com/view/j/hmbci.ahead-of-print/hmbci-2017-0080/hmbci-2017-0080.xml?format=INT

Objective The USA is in the midst of an opioid crisis. Understanding the impact of opioids and commonly used treatments for opioid dependence is essential for clinicians and researchers in order to educate and treat the nation's growing population with opioid use disorders. As a relatively new treatment for opioid dependence, buprenorphine is gaining popularity to the extent of becoming not only a preferred approach to the maintenance of opiate addiction, but also an option for chronic pain management. The purpose of this report is to review the available evidence on the endocrine effects of buprenorphine, particularly as it relates to the hypothalamic-pituitary-gonadal (HPG) axis, which is controversial and not fully defined.

Method We conducted a Pubmed search (2000-2017) for human studies in the English language for articles that were available as full length regarding buprenorphine, endocrinopathy, hypogonadism, bone density, opioids. Case reports were also reviewed, although prospective studies and randomized controlled trials received more weight.

Results Opioid induced hypogonadism is well established. Most studies report that buprenorphine being a partial agonist/antagonist may not be impacting the pituitary trophic hormones as much. There are reports of sexual dysfunction in subjects maintained on buprenorphine, some without hormonal correlation. Thus with the understanding that pertinent clinical studies are limited in number, varied in methodology, mostly cross sectional, predominantly in men and small number of participants, more research in this area is warranted.

Conclusion Based on a comprehensive review of the available literature, we conclude that despite its increasing popularity, buprenorphine has not been adequately studied in respect to its long-term effects on the hypothalamic-pituitary-gonadal (HPG) axis. There is a great need for longitudinal systematic trials to define the potential buprenorphine-induced endocrine consequences.

 

[Michael Scally MD]

An Internet Based Survey to Assess Clinicians' Knowledge and Attitudes Towards Opioid Induced Hypogonadism

BACKGROUND: Long term opioid therapy for chronic pain management requires regularly assessing and documenting benefits and side effects. Opioid-induced sex hormone disturbances are a complication that needs to be assessed routinely and perhaps not only when suspected.

There is abundant literature about its prevalence, clinical consequences and treatment yet, routine hormone screening and appropriate treatment are seldom performed in pain clinics. Ignorance, scepticism and/or indifference are possible reasons explaining why opioid induced hypogonadism (OIH) remains underdiagnosed among chronic pain patients.

METHODS: Internet based survey reaching out to pain clinicians to assess their knowledge and attitudes regarding OIH.

RESULTS: A total of 135 responses were received, representing a 23.7% response rate. Analysis of responses showed that 47% of responders were somewhat familiar with this complication but their knowledge about the prevalence and the time to develop was very dispersed. The screening for OIH is decided upon suspicion of its presence (50%) but not routinely (38%).

Lack of knowledge was the most frequent reason adduced for not screening for OIH.

Sex-related symptoms and signs are the most relevant leading to suspicion and screening of OIH. Upon lab confirmation, most responders refer their patients to endocrinology (82%) for further management since most (60%) believe that testosterone replacement would improve their patients' health.

CONCLUSIONS: knowledge and attitudes towards OIH was disperse among this population of pain clinicians invited to participate in the research. Lack of knowledge and incertitude seems to impact the attitudes towards screening and treating OIH. B

Better medical training at undergraduate and postgraduate levels as well as continuous medical education may contribute to raising awareness about this complication and providing early treatment.

Hochberg U, Ojeda A, Brill S, Perez J. An internet based survey to assess clinicians' knowledge and attitudes towards opioid induced hypogonadism. Pain practice : the official journal of World Institute of Pain 2018. https://onlinelibrary.wiley.com/doi/abs/10.1111/papr.12731

 

[Michael Scally MD]

Opioid-Induced Androgen Deficiency (OPIAD): Prevalence, Consequence, and Efficacy of Testosterone Replacement

Opioid analgesics are increasingly prescribed for both cancer-related and non-cancer pain. Chronic opioid use suppresses the hypothalamic pituitary gonadal axis resulting in secondary testosterone deficiency, known as Opioid Induced Androgen Deficiency (OPIAD).

Persistently low testosterone levels are associated with adverse musculoskeletal, metabolic and neuropsychiatric consequences. Opioid adverse effects occur soon after administration, is dose-duration dependent, and often durable despite withdrawal of opioids. All forms of opioids are implicated. Long-acting opioids may be more harmful and opioids with reduced μ-receptor agonism may be protective.

Testosterone replacement may modulate pain threshold and improve function. Some hypogonadal symptoms may improve with testosterone replacement. Testosterone replacement is recommended for symptomatic hypogonadal males with unequivocally low testosterone levels.

Ho K. Opioid-Induced Androgen Deficiency (OPIAD): Prevalence, Consequence, and Efficacy of Testosterone Replacement. Current Opinion in Endocrine and Metabolic Research 2019. https://www.sciencedirect.com/science/article/pii/S2451965018300462

 

[Anthony Minerva]

Hello,
I have been just told by my GP during my annual check up that my blood shows low testosterone. In the words of the Dr. so low he has never seen before! (displaced-NY'er, me too). So, I've done some research on the web and one possibility is long term use of Morphine, which is me. I have a bad back and am recovering at this time from my second spinal surgury. I hope to be off the meds soon as this fusion I just had should correct the pain producing areas of my back. I have been on Oxycontin for around seven years, with Roxicodone as well, and a liquid form of oxycontin called Oxydose for quick pain releif. I am exhibiting some of the symptoms listed: Quick temper out of nowhere 9I attributed it to the meds, so I was put on Klonipin), poor errection, a disapearing Penis, as I sit up the littley guy goes down into me and I barely see the head, and who knows what else I cannot see. I am 53 yrs of age. I am wondering if anyone else here has been down this particular road as well? My GP wants me to see an endocrinologist when I am back on my feet, spinal surgery was just 16 days ago, and I am somewhat bedridden at this time. Any help will be appreciated!

Don't blame opiates for you being a natural beta

 

[Michael Scally MD]

Opioid-Induced Hypogonadism

Objective: To examine the incidence of screening, diagnosis, and treatment of hypogonadism among men treated with opioids in the United States.

Patients and Methods: Using one of the nation's largest commercial insurance databases, we identified 53,888 men aged 20 years or older who had 90 or more days of opioid prescriptions in a single 12-month period between January 1, 2010, and December 31, 2017, with no history of hypogonadism or testosterone therapy in the preceding 12 months. We matched this cohort to 53,888 men with 14 or fewer days of opioid prescriptions based on age, opioid initiation date, opioid indication, and comparable exclusion criteria.

We assessed whether men, 14 or fewer days after initiation of opioid treatment, received a serum testosterone test, a diagnosis of hypogonadism, or a prescription for testosterone therapy. All men were followed up until they lost coverage from the commercial insurance plan, experienced one of the study outcomes, or the end of study (December 31, 2017).

Results: In the multivariable analyses-adjusting for age, year of opioid initiation, region, comorbid disease, glucocorticoid use, and health care utilization-the 53,888 prolonged opioid users, in comparison with 53,888 short-term users, had an increased incidence of serum testosterone screening (5991 [17.15%; 95% CI, 16.70%-17.61%] vs 3514 [11.55%; 95% CI, 11.11%-12.01%] at 5 years; hazard ratio

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, 1.46; 95% CI, 1.38-1.55), hypogonadism diagnosis (3125 [9.44%; 95% CI, 9.09%-9.80%] vs 1421 [4.85%; 95% CI, 4.55%-5.16%; HR, 1.74; 95% CI, 1.60-1.90]), and receipt of testosterone therapy (1919 [5.76%; 95% CI, 5.49%-6.05%] vs 631 [2.21%; 95% CI, 2.04%-2.43%; HR, 2.41; 95% CI, 2.13-2.74]). Each of these findings persisted across multiple sensitivity analyses.

Conclusion: Prolonged opioid exposure was associated with increased rates of screening, diagnosis, and treatment for opioid-induced hypogonadism, but these rates were much lower than expected based on previous serum-based studies.

Baillargeon J, Raji MA, Urban RJ, et al. Opioid-Induced Hypogonadism in the United States. Mayo Clinic proceedings Innovations, quality & outcomes 2019;3:276-84. https://mcpiqojournal.org/article/S2542-4548(19)30080-3/fulltext

 

[Michael Scally MD]

Sexual Dysfunction in Tramadol Hydrochloride Use Disorder

Evidence suggests that opioids can modulate gonadal function, with consequent decreased release of sex hormones. We attempted to investigate the sexual function of males using tramadol hydrochloride (HCL) and its relationship to levels of free testosterone, luteinizing hormone, and follicle stimulating hormone, and to compare them with heroin use disorder patients and healthy controls.

Our sample consisted of 60 opiate use disorder patients (assessed by Structured Clinical Interview for DSM-IV Axis I) (30 heroin and 30 tramadol) and 30 healthy controls. Sexual dysfunction was assessed using the International Index of Erectile Function. Free testosterone, follicle stimulating hormone, and luteinizing hormone levels were measured in morning blood samples using enzyme-linked immunosorbent assay (ELISA).

Results showed that there was a decrease of luteinizing hormone and free testosterone levels in opiate use disorder patients compared with healthy controls, with heroin-dependent patients having significantly lower levels than those using tramadol. Opiates' effect on follicle stimulating hormone had mixed results. Opioid-dependent patients (both tramadol HCL and heroin using patients) developed sexual dysfunction more than healthy controls, which was generalized, with erectile dysfunction being the most affected domain.

These findings are of ultimate importance, considering the fact that people use opioids to enhance their sexual performance in many countries.

Hashim MA, El Rasheed AH, Ismail GAW, et al. Sexual dysfunction in tramadol Hydrochloride use disorder male patients: a case-control study. International clinical psychopharmacology 2019. Sexual dysfunction in tramadol Hydrochloride use disorder... : International Clinical Psychopharmacology

 

[FLTestlab]

My friend that has been using subutex for many years now has low T. He had a history of opiod use due to a bad car accident. After sevreal years using diludid he switched to subutex to try to get off and noticed a big decline in T levels. His doctor that prescribes subutex now also prescribes patients testosterone. Thanks for the article. Ill nees to show him this.

 

[balco]

My friend that has been using subutex for many years now has low T. He had a history of opiod use due to a bad car accident. After sevreal years using diludid he switched to subutex to try to get off and noticed a big decline in T levels. His doctor that prescribes subutex now also prescribes patients testosterone. Thanks for the article. Ill nees to show him this.

I agree testosterone needs to be prescribed when being on long term opiates, but it's just another racket for "addiction" doctors.

 

[Michael Scally MD]

[OA] Health Outcomes Among Long-term Opioid Users With Testosterone Prescription

Key Points

Question What are the health outcomes among long-term opioid users who receive testosterone treatment compared with opioid users who do not?

Findings In this cohort study of 21 272 male long-term opioid users with testosterone deficiency, those who received opioids plus testosterone therapy had significantly lower all-cause mortality and lower incidence of major adverse cardiovascular events, anemia, and femoral or hip fractures than their counterparts who received opioids only in covariate-adjusted and propensity score–matched models.

Meaning This study’s findings suggest that receiving opioids plus testosterone treatment is associated with lower all-cause mortality and a lower incidence of other adverse health outcomes among men with opioid-induced androgen deficiency.

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;2(12):e1917141. Health Outcomes Among Opioid Users With Testosterone Prescription in the VHA

Importance Androgen deficiency is common among male opioid users, and opioid use has emerged as a common antecedent of testosterone treatment. The long-term health outcomes associated with testosterone therapy remain unknown, however.

Objective To compare health outcomes between long-term opioid users with testosterone deficiency who filled testosterone prescriptions and those with the same condition but who did not receive testosterone treatment.

Design, Setting, and Participants This cohort study focused on men in the care of the Veterans Health Administration (VHA) facilities throughout the United States from October 1, 2008, to September 30, 2014. It included male veterans who were long-term opioid users, had low testosterone levels (<300 ng/dL), and received either a testosterone prescription or any other prescription. It excluded male patients with HIV infection, gender dysphoria, or prostate cancer and those who received testosterone in fiscal year 2008. Data were analyzed from April 1, 2017, to April 30, 2019.

Exposure Prescription for testosterone.

Main Outcomes and Measures All-cause mortality and incidence of major adverse cardiovascular events (MACE), vertebral or femoral fractures, and anemia during the 6-year follow-up through September 30, 2015.

Results After exclusions, 21 272 long-term opioid users (mean [SD] age, 53 [10] years; n = 16 689 [78.5%] white) with low total or free testosterone levels were included for analysis, of whom 14 121 (66.4%) received testosterone and 7151 (33.6%) did not.

At baseline, compared with opioid users who did not receive testosterone, long-term opioid users who received testosterone treatment were more likely to have obesity (43.7% vs 49.0%; P < .001), hyperlipidemia (43.0% vs 48.8%; P < .001), and hypertension (53.9% vs 55.2%; P = .07) but had lower prevalence of coronary artery disease (15.9% vs 12.9%; P < .001) and stroke (2.4% vs 1.3%; P < .001).

After adjusting for covariates, opioid users who received testosterone had significantly lower all-cause mortality (hazard ratio

---

 = 0.51; 95% CI, 0.42-0.61) and lower incidence of MACE (HR = 0.58; 95% CI, 0.51-0.67), femoral or hip fractures (HR = 0.68; 95% CI, 0.48-0.96), and anemia (HR = 0.73; 95% CI, 0.68-0.79) during the follow-up period of up to 6 years, compared with their counterparts without a testosterone prescription.

In covariate-adjusted models, men who received opioids plus testosterone were more likely to have resolved anemia compared with those who received opioids only during the 6-year follow-up (HR = 1.16; 95% CI, 1.02-1.31). Similar results were obtained in propensity score–matched models and when analyses were restricted to opioid users with noncancer pain or those who did not receive glucocorticoids.

Conclusions and Relevance This study found that, in the VHA system, male long-term opioid users with testosterone deficiency who were treated with opioid and testosterone medications had significantly lower all-cause mortality and significantly lower incidence of MACE, femoral or hip fractures, and anemia after a multiyear follow-up. These results warrant confirmation through a randomized clinical trial to ascertain the efficacy of testosterone in improving health outcomes for opioid users with androgen deficiency.

 

[Michael Scally MD]

[OA] Origins of the Opioid Crisis and Its Enduring Impacts

Overdose deaths involving opioids have increased dramatically since the mid-1990s, leading to the worst drug overdose epidemic in U.S. history, but there is limited empirical evidence on the initial causes.

In this paper, we examine the role of the 1996 introduction and marketing of OxyContin as a potential leading cause of the opioid crisis. We leverage cross-state variation in exposure to OxyContin’s introduction due to a state policy that substantially limited OxyContin’s early entry and marketing in select states.

Recently-unsealed court documents involving Purdue Pharma show that state-based triplicate prescription programs posed a major obstacle to sales of OxyContin and suggest that less marketing was targeted to states with these programs. We find that OxyContin distribution was about 50% lower in “triplicate states” in the years after the launch.

While triplicate states had higher rates of overdose deaths prior to 1996, this relationship flipped shortly after the launch and triplicate states saw substantially slower growth in overdose deaths, continuing even twenty years after OxyContin's introduction.

Our results show that the introduction and marketing of OxyContin explain a substantial share of overdose deaths over the last two decades.

Alpert AE, Evans WN, Lieber EMJ, Powell D. Origins of the Opioid Crisis and Its Enduring Impacts. National Bureau of Economic Research Working Paper Series 2019;No. 26500. Origins of the Opioid Crisis and Its Enduring Impacts

 

[Michael Scally MD]

Opioids and the Hypothalamic-Pituitary-Gonadal (HPG) Axis

Context: Hypogonadism is a well-established consequence of opioid use. It has been reported in both men and women, although more widely studied in men.

Evidence acquisition: PubMed was searched for articles in English until December 2019 for opioids and hypogonadism. Bibliography of retrieved articles was searched for relevant articles.

Evidence synthesis: The prevalence of opioid-induced hypogonadism (OIH) varies between studies but was reported to be 69% in a recent systematic review. There is large heterogeneity in the studies, with different factors shown to have stronger association with hypogonadism such as specific types of opioids, higher doses, and longer durations of use.

The consequences of OIH include sexual dysfunction, depression, decreased quality of life, and low bone density. There is paucity of randomized controlled trials assessing the efficacy of testosterone replacement therapy (TRT) for OIH in men, and even less studies on treating OIH in women. TRT studies in men reported varying outcomes with some studies favoring and others showing no clear benefit of TRT on different measures.

Conclusions: Despite the high prevalence of OIH, it remains underrecognized and undertreated with multiple endocrine and metabolic consequences. A reasonable approach in patients using opioids includes informing them of this complication and its potential consequences, screening for signs and symptoms of hypogonadism then sex hormone levels if prolonged opioid use > 3 months, and treating patients diagnosed with hypogonadism, if and when clinically indicated, with sex hormones if chronic opioids are planned to be continued for ≥ 6 months.

Wehbeh L, Dobs AS. Opioids and the Hypothalamic-Pituitary-Gonadal (HPG) Axis. J Clin Endocrinol Metab. 2020;105(9):dgaa417. doi:10.1210/clinem/dgaa417 Opioids and the Hypothalamic-Pituitary-Gonadal (HPG) Axis

 

[Michael Scally MD]

[OA] Long-term Opioids Linked to Hypogonadism and the Role of Testosterone Supplementation Therapy

Opioids play a pivotal role in managing chronic pain with increasing prescription rates over the last few years. Hence, it is crucial to focus on the adverse effects of narcotics, and one of the lesser-known side effects is hypogonadism.

Opioids act on the hypothalamus, pituitary, and directly on the gonads affecting serum testosterone levels. Narcotic-induced androgen insufficiency contributes to sexual dysfunction, infertility, hyperalgesia, and involving various body functions overall, affecting the quality of life.

Opioid-induced hypogonadism is very challenging to diagnose for the clinicians, as the patients often under-report the symptoms. There are no established guidelines to analyze androgen insufficiency and dealing with their manifestations successfully. We did a substantial search in PubMed and Google Scholar, using various combinations of keywords to collect data to evaluate the impacts of opioids on serum testosterone levels.

This study aims to highlight the clinical significance of opioid-induced androgen deficiency and the diagnostic techniques to recognize and credible treatment alternatives, including testosterone replacement therapy. Health care providers should screen the patients routinely for the signs and symptoms and monitor them often for the hormonal changes to select the patients cautiously for testosterone replacement therapy.

Marudhai S, Patel M, Valaiyaduppu Subas S, Ghani MR, Busa V, Dardeir A, Cancarevic I. Long-term Opioids Linked to Hypogonadism and the Role of Testosterone Supplementation Therapy. Cureus. 2020 Oct 5;12(10):e10813. doi: 10.7759/cureus.10813. PMID: 33173622; PMCID: PMC7645309. Long-term Opioids Linked to Hypogonadism and the Role of Testosterone Supplementation Therapy

 

[Michael Scally MD]

Opioids, Testosterone and Suicide

In this commentary, I propose that inhibition of testosterone production by opioids may contribute to the pathophysiology of suicidal behaviour among male opioid users. The inhibitory impacts of opioid substances on the hypothalamic–pituitary– gonadal axis have been recognized for several decades. All opioids reduce testosterone production because they hamper secretion of hypothalamic gonadotropin- releasing hormone and disrupt its normal pulsatility. Opioid use decreases levels of testosterone in men regardless of the route of administration.

…

Research studies are needed to find out whether testosterone supplementation may reduce suicidal behaviour among male opioid users. Testosterone supplementation may be an effective treatment intervention in men who use opioids and who are also at high risk of suicide. On a more general note, it is necessary to evaluate which are the best interventions to prevent suicide in opioid users. A connection between opioid use disorder and suicidality indicates that there may be advantages of coordination between opioid abuse prevention and suicide prevention efforts.

Public health resources aimed to tackle both suicide and opioid use disorder need to be created and put into practice. A high-quality assessment of acute and chronic suicide risk along with prompt access to mental health treatment is of vital significance to reduce opioid-related deaths by suicide. Individuals with opioid use disorders need to be screened for suicide ideation, intent and plan regularly and continuously during treatment.

Sher L. Opioids, testosterone and suicide. Aust N Z J Psychiatry. 2020 Sep;54(9):939-940. doi: 10.1177/0004867420937807. Epub 2020 Jul 1. PMID: 32611240. SAGE Journals: Your gateway to world-class research journals

 

[Michael Scally MD]

When Purdue Pharma agreed last month to plead guilty to criminal charges involving OxyContin, the Justice Department noted the role an unidentified consulting company had played in driving sales of the addictive painkiller even as public outrage grew over widespread overdoses.

Documents released last week in a federal bankruptcy court in New York show that the adviser was McKinsey & Company, the world’s most prestigious consulting firm. The 160 pages include emails and slides revealing new details about McKinsey’s advice to the Sackler family, Purdue’s billionaire owners, and the firm’s now notorious plan to “turbocharge” OxyContin sales at a time when opioid abuse had already killed hundreds of thousands of Americans.

In a 2017 presentation, according to the records, which were filed in court on behalf of multiple state attorneys general, McKinsey laid out several options to shore up sales. One was to give Purdue’s distributors a rebate for every OxyContin overdose attributable to pills they sold.

The presentation estimated how many customers of companies including CVS and Anthem might overdose. It projected that in 2019, for example, 2,484 CVS customers would either have an overdose or develop an opioid use disorder. A rebate of $14,810 per “event” meant that Purdue would pay CVS $36.8 million that year.