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Testosterone deficiency, the unrecognized consequence of the opioid epidemic in men (2022)
Janine David, GP and Associate Specialist in Andrology; Mike Kirby, Editor
Testosterone deficiency resulting from chronic opioid use can have a profound effect on health and quality of life, but it often goes unrecognized and untreated. Here the authors review the problem and discuss strategies for management.
The headline that opioid deaths in the USA, mainly occurring in young people, reached over 100000 in the past 12 months prompted this review.1
This death toll apparently equals more than the total caused by car accidents and gun deaths. Importantly, it is much more common in men than women. Data from the Centres for Disease Control and Prevention (CDC) show that overdose deaths rose 28.5% in the 12 months ending April 2021. This partly explains the increase in available organ body parts to transplant clinics.2
The fatalities will have had lasting repercussions on families and, perhaps even more poignantly on friends, because most of them have occurred among people aged 25–55 years. The rise in deaths was mainly caused by synthetic opioids and aggravated by the widespread use of fentanyl, which may be added surreptitiously to other illegally manufactured drugs to enhance their potency.
In the UK the situation is also very worrying. According to 2020 registrations in England and Wales, there were 4561 deaths related to drug poisoning (equivalent to a rate of 79.5 deaths per million people); this is 3.8% higher than the number of deaths registered in 2019 (4393 deaths; 76.7 deaths per million).3 More than twice as many deaths occurred in men compared with women: among males, there were 109.7 drug poisoning deaths registered per million in 2020 (3108 registered deaths), compared with 49.8 deaths per million among females (1453 deaths).3 Statistics are based on the year of death registration. However, because of death registration delays, around half of these deaths will have occurred in the previous year (2019) and the majority will have occurred before the coronavirus (COVID-19) pandemic in the UK.
*Managing pain in primary care
*Impact of illicit use of prescription opioids around the world
*Impact of opioids on the male endocrine system
The endocrine system can be severely affected by chronic opioid treatment, leading to a decrease in total testosterone levels and opioid-induced hypogonadism (Figure 2). Opioids depress the secretion of hormones at different levels of the hypothalamic-pituitary-gonadal axis and generally increase levels of growth hormone, thyroid-stimulating hormone, and prolactin, but there are conflicting reports on the effects of opioids on arginine, vasopressin, and adrenocorticotropic hormone. In addition, opioids can lead to the development of hypogonadism by directly inhibiting gonadotropin-releasing hormone (GnRH) through the μ-opioid receptor, reducing libido and causing erectile dysfunction (ED), bone loss, and/or infertility.14
The impact occurs rapidly, often within one week, and the highest risk appears to be among patients receiving significant dosages for longer than one month. The use of the more potent opioids is more likely to cause a greater risk of hypogonadism, but the effects seem to be reversible after a few days of withdrawal. As one might expect, long-acting opioids have a greater risk compared with short-acting drugs. There is a significant correlation between increased dosage and the development of opioid-induced androgen deficiency (OPIAD).14
The prevalence of OPIAD ranges from 19% to 86%, with most studies reporting an overall prevalence higher than 50%, confirming the significant impact of opioids in reducing testosterone levels.14,17,18 Figure 3 shows the prevalence of low testosterone among chronic opioid users and men with other conditions.19
A systematic review and metaanalysis of testosterone suppression in opioid users concluded that testosterone level was suppressed in men with regular opioid use regardless of the opioid type and found a mean testosterone difference of 5.7nmol/L between opioid users and controls. Opioids were found to affect testosterone levels differently in men than women, and testosterone was not found to be suppressed in studies examining opioid-using women.20
Opioids can induce several hypogonadism-related signs and symptoms, including sexual dysfunction, mood impairment, fatigue, obesity and cardiovascular disease, osteoporosis, and sexual dysfunction.
*Why more deaths in men than women?
Could suppression of normal testosterone levels be a contributing cause, via increases in anxiety, depression, metabolic syndrome, cardiovascular disease, fall risk, and difficulties with sexual activity?
-Depression
-Sexual dysfunction
-Weight gain and metabolic syndrome
-Cardiovascular side-effects
-Bone health
*Impact of treatment with testosterone
So, would identifying and treating these men with testosterone make a difference to mortality, other adverse health outcomes, and pain?
-Mortality and other adverse health outcomes
-Pain
-Identifying men in the community
Summary
OPIAD is common and can impair satisfactory pain relief. OPIAD also impairs sexual activity, mood, and bone metabolism and is a risk factor for cardiovascular disease and obesity.
Guidelines support screening for testosterone deficiency in this situation. Consideration should be given to screening for testosterone deficiency prior to an opioid prescription, to provide a baseline. From a clinical point of view, the effect is reversible and if the opioid is removed, the deficiency is reversed, usually within a month.
Wherever possible consider alternative pain management strategies, as per NICE guidance, but if treatment is necessary consider using an opioid with a lower MOP affinity such as buprenorphine or tramadol, and enquire about relevant low testosterone symptoms, with testosterone measurements at subsequent follow-up
Current evidence suggests testosterone replacement might be beneficial and synergistic with analgesics to improve pain control in hypogonadal men.
OPIAD can have a profound effect on health and quality of life, and it can hinder a clinician’s ability to effectively treat chronic pain and manage complex comorbidities, but it often goes unrecognized and untreated.
Janine David, GP and Associate Specialist in Andrology; Mike Kirby, Editor
Testosterone deficiency resulting from chronic opioid use can have a profound effect on health and quality of life, but it often goes unrecognized and untreated. Here the authors review the problem and discuss strategies for management.
The headline that opioid deaths in the USA, mainly occurring in young people, reached over 100000 in the past 12 months prompted this review.1
This death toll apparently equals more than the total caused by car accidents and gun deaths. Importantly, it is much more common in men than women. Data from the Centres for Disease Control and Prevention (CDC) show that overdose deaths rose 28.5% in the 12 months ending April 2021. This partly explains the increase in available organ body parts to transplant clinics.2
The fatalities will have had lasting repercussions on families and, perhaps even more poignantly on friends, because most of them have occurred among people aged 25–55 years. The rise in deaths was mainly caused by synthetic opioids and aggravated by the widespread use of fentanyl, which may be added surreptitiously to other illegally manufactured drugs to enhance their potency.
In the UK the situation is also very worrying. According to 2020 registrations in England and Wales, there were 4561 deaths related to drug poisoning (equivalent to a rate of 79.5 deaths per million people); this is 3.8% higher than the number of deaths registered in 2019 (4393 deaths; 76.7 deaths per million).3 More than twice as many deaths occurred in men compared with women: among males, there were 109.7 drug poisoning deaths registered per million in 2020 (3108 registered deaths), compared with 49.8 deaths per million among females (1453 deaths).3 Statistics are based on the year of death registration. However, because of death registration delays, around half of these deaths will have occurred in the previous year (2019) and the majority will have occurred before the coronavirus (COVID-19) pandemic in the UK.
*Managing pain in primary care
*Impact of illicit use of prescription opioids around the world
*Impact of opioids on the male endocrine system
The endocrine system can be severely affected by chronic opioid treatment, leading to a decrease in total testosterone levels and opioid-induced hypogonadism (Figure 2). Opioids depress the secretion of hormones at different levels of the hypothalamic-pituitary-gonadal axis and generally increase levels of growth hormone, thyroid-stimulating hormone, and prolactin, but there are conflicting reports on the effects of opioids on arginine, vasopressin, and adrenocorticotropic hormone. In addition, opioids can lead to the development of hypogonadism by directly inhibiting gonadotropin-releasing hormone (GnRH) through the μ-opioid receptor, reducing libido and causing erectile dysfunction (ED), bone loss, and/or infertility.14
The impact occurs rapidly, often within one week, and the highest risk appears to be among patients receiving significant dosages for longer than one month. The use of the more potent opioids is more likely to cause a greater risk of hypogonadism, but the effects seem to be reversible after a few days of withdrawal. As one might expect, long-acting opioids have a greater risk compared with short-acting drugs. There is a significant correlation between increased dosage and the development of opioid-induced androgen deficiency (OPIAD).14
The prevalence of OPIAD ranges from 19% to 86%, with most studies reporting an overall prevalence higher than 50%, confirming the significant impact of opioids in reducing testosterone levels.14,17,18 Figure 3 shows the prevalence of low testosterone among chronic opioid users and men with other conditions.19
A systematic review and metaanalysis of testosterone suppression in opioid users concluded that testosterone level was suppressed in men with regular opioid use regardless of the opioid type and found a mean testosterone difference of 5.7nmol/L between opioid users and controls. Opioids were found to affect testosterone levels differently in men than women, and testosterone was not found to be suppressed in studies examining opioid-using women.20
Opioids can induce several hypogonadism-related signs and symptoms, including sexual dysfunction, mood impairment, fatigue, obesity and cardiovascular disease, osteoporosis, and sexual dysfunction.
*Why more deaths in men than women?
Could suppression of normal testosterone levels be a contributing cause, via increases in anxiety, depression, metabolic syndrome, cardiovascular disease, fall risk, and difficulties with sexual activity?
-Depression
-Sexual dysfunction
-Weight gain and metabolic syndrome
-Cardiovascular side-effects
-Bone health
*Impact of treatment with testosterone
So, would identifying and treating these men with testosterone make a difference to mortality, other adverse health outcomes, and pain?
-Mortality and other adverse health outcomes
-Pain
-Identifying men in the community
Summary
OPIAD is common and can impair satisfactory pain relief. OPIAD also impairs sexual activity, mood, and bone metabolism and is a risk factor for cardiovascular disease and obesity.
Guidelines support screening for testosterone deficiency in this situation. Consideration should be given to screening for testosterone deficiency prior to an opioid prescription, to provide a baseline. From a clinical point of view, the effect is reversible and if the opioid is removed, the deficiency is reversed, usually within a month.
Wherever possible consider alternative pain management strategies, as per NICE guidance, but if treatment is necessary consider using an opioid with a lower MOP affinity such as buprenorphine or tramadol, and enquire about relevant low testosterone symptoms, with testosterone measurements at subsequent follow-up
Current evidence suggests testosterone replacement might be beneficial and synergistic with analgesics to improve pain control in hypogonadal men.
OPIAD can have a profound effect on health and quality of life, and it can hinder a clinician’s ability to effectively treat chronic pain and manage complex comorbidities, but it often goes unrecognized and untreated.
