Introduction and epidemiology
Opioid dependence is a chronic relapsing disorder that impacts the lives of those afflicted. An estimated 11.8 million people age 12 or over in the US have misused opioids in the past year with 11.5 million of these with misuse of prescription pain medications and 948,000 being heroin users . Ninety-one Americans die every day from an opioid overdose (Opioid Overdose-Understanding the epidemic CDC.gov 2017) . The number of overdose deaths involving opioids (including prescription opioids and heroin) quadrupled since 1999 . At the heart of the problem lies the excessive prescription of opioid analgesics of medications such as oxycodone, hydrocodone and methadone to treat chronic non-cancer related pain, despite the high addiction potential related to these drugs .
According to the 2015 Nation Survey on Drug Use ad Health (NSDUH) data, among people aged 12 or older who misused prescription pain relievers in the past year, the most commonly reported reason for their last misuse of a pain reliever was to relieve physical pain (62.6%) and other commonly reported reasons being to feel good (12.1%), to relax or relieve tension (10.8%) reasons being to help with sleep, emotions, to overcome withdrawals and to experiment. Interestingly, with regards to the source of the prescription pain reliever, 53.7% of people who misused a pain reliever in the past year reported that they had obtained the pain reliever from a friend or a relative, while 34% indicated that they obtained it by prescription from one doctor and only 4.9% had bought the misused pain reliever from a drug dealer (Substance Abuse and Mental Health Services Administration -SAMHSA 2016). As evidence of increasing prescription opioid misuse rises there is a growing concern regarding the lack of sufficient knowledge and data regarding long-term health effects of opioids and also the medications that are being used to manage this opioid crisis. In view of the declared opioid crisis which has recently been declared as a national emergency, substance use treatment services in the form of maintenance treatments in the form of methadone and buprenorphine, a partial agonist antagonist, are being vigorously enhanced among other measures.
In this mini review, we focus on the available evidence related to the long-term use of opioids on the endocrine system, with a primary focus on buprenorphine, due to its novelty and increasing popularity, specifically its impact on the hypothalamic-pituitary-gonadal (HPA) axis when used as a maintenance treatment of opioid dependence as well as a long-term treatment of chronic pain.
Buprenorphine – a unique opioid
Opium is extracted from the sap of the poppy plant. Opioid is an all-encompassing term and regardless of the source includes all opioids. The term “opiate” includes all alkaloids of opium including synthetic and semi synthetic alkaloids such as morphine, codeine and heroin. Endorphins, enkephalins and dynorphins are the three major classes of endogenous opioid peptides with endomorphin-1 and endomorphin-2 the two newer classes that have been discovered more recently. Three major classes of opioid receptors have been identified which are μ, δ and κ. These receptors are found in the brain and also throughout the body including endocrine organs such as gonads, thyroid and adrenal cortex. Both endogenous and exogenous opioids exert their effects by binding to one or more of these receptors . Although opioids are most well known for their analgesic effects mediated by the μ opioid receptor agonism and constipation one of the most commonly noted adverse effects, opioids have a clinical impact on almost all the physiological systems.
Buprenorphine is a partial-agonist at the μ opioid receptor and an antagonist at the κ opioid receptors. This drug has a unique pharmacological profile due to the ceiling phenomena associated with its respiratory depression and possibly analgesic effect. Buprenorphine suppresses withdrawals, targets cravings and has a favorable safety profile as regards overdose with relatively minimal abuse potential. Unlike methadone and other pure agonists, it does not cause prolongation of the QTc and is considered to have minimal impact on sex hormones and the immune system. Although, the latter two are not well established .
Methadone has been the treatment of choice for maintenance treatment for several decades. The Drug Addiction Treatment Act (DATA) 2000 act enabled physicians to provide office based treatment of opioid addiction. Buprenorphine was approved by Food and Drug Administration (FDA) in 2002 for treatment of opioid dependence. Being a partial agonist it also blocks the effects of simultaneously used opioids, preventing relapse . In addiction settings, buprenorphine is typically used in combination with naloxone to prevent abuse and diversion of the medication and used by sublingual route. As compared to methadone which can be given only in licensed clinical settings, sublingual buprenorphine has the advantage of being administered in office based settings, making this a preferred treatment option for facilities and patients . It has been established to be safe during pregnancy and breast feeding with lower incidence of neonatal abstinence syndrome in the babies born to mother maintained on substitution therapy .
The superior efficacy and tolerability of buprenorphine patch [transdermal delivery system (TDS)] in chronic severe pain patients has been established in double blind and open label studies , . Advantages of the buprenorphine TDS over other opioids include non-invasive delivery, bypasses first pass metabolism and sustained stable analgesia over several days.
Opioids and the HPG axis
The hypothalamic-pituitary-gonadal (HPG) axis controls the production of testosterone and estrogen, the two primary sex hormones via the secretion of gonadotropin releasing hormone (GnRH) which in turn stimulates the pituitary to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). These two hormones in turn stimulate the testes to produce testosterone and ovaries to produce estrogen. The sex hormones exert a negative feedback on the hypothalamus and pituitary and thus controlling the secretion of GnRH, LH and FSH.
Chronic opioid use is known to be impact the HPG axis, particularly in men. The effects of long-term opioids including methadone on gonadal hormones are unanimously accepted ,  in both sexes. Males with opioid dependence disorder are known to have testosterone deficiency and sexual dysfunction . A potential mechanism is the inhibition of the hypothalamic GnRH pulsatility by binding to the opioid receptors in the hypothalamus . A direct peripheral effect on the testes with decreased secretion of testosterone and testicular interstitial fluid along with decreased sperm mobility has been suggested as an additional mechanism . Sexual dysfunction may manifest as hypoactive sexual desire, erectile and orgasmic dysfunction associated with long-term use of opioids/opiates. Some evidence suggests that this opioid induced hypogonadism is dose and treatment duration dependent . This study also suggested that the drug induced testosterone suppression is reversible after a month of abstinence. Similarly, there are several studies published on the long-term effect of both intrathecal ,  and oral opioids  for the management of non-cancer related pain. Later in 2008, Daniell  showed that testosterone patch therapy was efficacious in reversing opioid induced androgen deficiency. The results of these studies were like the ones in methadone maintenance, indicating a pattern of opioid induced hypogonadotrophic hypogonadism with symptoms of decreased libido and fatigue in both sexes, erectile dysfunction (ED) in men, amenorrhea, irregular menses and galactorrhea in women leading to infertility and osteoporosis. Prolactin levels were not found to be elevated in any of the above studies indicating a minimal role, if any, of prolactin in opioid induced hypogonadism. Most of these effects have been observed in studies done in patients maintained on methadone or heroine addicted males and those with chronic pain taking systemic opioid on long-term basis.
Studies in females
Daniell  described amenorrhea accompanied by 48–57% lower levels of testosterone, estradiol and dehydroepiandrosterone sulfate in women associated with long-term opioid intake. LH and FSH levels were also lower, thus indicating suppression of ovarian sex hormones and adrenal androgen production among women on long-term opioid therapy. Direct binding of opioids to receptors in the pituitary causing decreased production of LH in females is proposed as the mechanism of action.
Impact of buprenorphine on HPG axis and sexual function
There are only a few studies that have evaluated the impact of buprenorphine on the sexual functioning and testosterone levels in men on buprenorphine.
In one of the first studies, Bliesener et al.  used a two question self-rating scale along with hormonal assays (testosterone, SHBG, free testosterone, estradiol, LH, FSH and prolactin) and found that, in contrast to methadone, buprenorphine at a dose of 8–20 mg/day did not suppress plasma testosterone in heroin addicted men when compared to normal healthy controls. Al-Gommer et al.  in a British study compared sexual dysfunction across three groups (heroin, methadone and buprenorphine) using a self-rated questionnaire and found that sexual dysfunction in various areas associated with buprenorphine was significantly less than methadone or heroin (all p < 0.05). As this study was cross sectional, it did not have a control group and plasma levels of gonadal hormones were not drawn, its generalizability is limited. Hallinan et al. , in a thorough study on 103 men, measured sexual function in methadone and buprenorphine maintained patients in comparison to a community reference group and evaluated the role of several other possible confounds (age, depression, obesity, chronic hepatitis, use of prescribed and non-prescribed substances, opioid medication, dose and duration of treatment and or hormonal status) in association with sexual function measures. They found that buprenorphine maintenance treatment was associated with lower prevalence of erectile dysfunction (ED) in comparison to MMT. On multiple regression, depression, older age and lower total testosterone were associated with lower International Index of Erectile Function (IIEF) which is one of the most standard tests for evaluation of sexual function and erectile function (EF) domain. On multivariate analysis, there was no significant association between IIEF or EF and free testosterone, opioid dose (in methadone and buprenorphine groups), cannabis or other substance use, viral hepatitis or BMI. Thus, suggesting that hormonal suppression may not be the only mechanism through which opioid agonists exert their effects on sexual functioning.
In an Italian study, Quaglio et al.  studied 201 males with a mean age of 31, maintained on buprenorphine (116) and methadone (85) using the IIEF. Of these, 58% reported no ED, 24% reported mild to moderate ED and 18% severe ED. Men on buprenorphine reporting less ED as compared to methadone maintained patients on univariate analysis but this was not confirmed on multivariate analysis. These authors did not find a significant association between either methadone or buprenorphine dose and ED, or with reported duration of either methadone or buprenorphine treatment and ED. Additionally, they highlighted the importance of psychological and social factors associated with ED such as comorbid depression, sexual preference and partner characteristics which are an important factor for patients in methadone or buprenorphine treatment. In another European study, Giacomuzzi et al.  examined the pattern of sexual behavior and dysfunction prevalence within buprenorphine and methadone maintenance treatment in the absence of hormonal assays and found a much higher sexual excitation disturbance (p = 0.006) in the methadone group.
In contrast, buprenorphine induced symptomatic hypogonadism has been reported in 10 cases in patients recruited from a pain clinic who had a history of prescription opioid abuse or dependence . In an Indian study that used the brief male sexual functioning inventory (BMSFI), 83% of the men maintained on buprenorphine reported at least one sexual dysfunction symptom. Similar results were also found in patients maintained on naltrexone therapy . No hormonal assays were done in either of these studies , . Cioe et al.  suggest that there is a high prevalence of ED (34%) among opioid-dependent males prior to initiating maintenance treatment with buprenorphine. However, they did not find a correlation between total testosterone and ED but instead found older age to be significantly associated. Thus, highlighting the need to explore the role of other contributing factors such as smoking, hepatitis C status, comorbid psychiatric disorders such as depression and medications for its treatment in causing ED. Table 1 below summarizes the existing studies in males and females on buprenorphine and impact on sexual functioning/ sex hormones.
Studies in females
Literature regarding sexual dysfunction in females on opioid maintenance treatment is even more scant. The mechanism of impact of long-term opioids on female sex hormones is rather complex varying not only within the menstrual cycle but also with puberty and menopause. Opioids may impact cyclic production of LH and FSH and hyperprolactinemia. This in turn interferes with estrogen and progesterone levels thus causing oligomenorrhea/amenorrhea and decrease in libido. Due to the phases of the menstrual cycles, performing hormonal assay studies which require precision and accuracy may be more tedious to perform in women. These authors did not find any studies evaluating the effect of long-term use of buprenorphine for opioid maintenance in women in comparison to men on methadone or relative to healthy controls.
Effect of long-term administration of transdermal buprenorphine (35 μg/h every 72 h) has been studied in men and women observing the impact on the HPA and HPG axes in a 6-month follow-up study by Aloisi et al. . In females, no significant changes were noted other than an increase in total testosterone levels at 3 months, while a decrease in free testosterone levels was noted in men at 3 months They did not find HPA axis inhibition and found no androgen deficiency. In a similar longitudinal study, hormonal effects of transdermal buprenorphine (35 μg/h every 72 h) in women suffering from persistent non-malignant pain was examined in 18 subjects by Aurilio et al. . These authors also did not report any evidence of hypogonadism.
Osteoporosis and risk of fractures
Long-term use of opioids has been linked to osteoporosis and increased risk of fractures secondary to the lowering of testosterone levels , . In addition, increased risk of fractures could also be attributed to the direct central nervous effect of sedation with opioids and direct effect on osteoblasts . The authors of this review did not find any studies examining at the impact of buprenorphine on bone density or osteoporosis, neither when used for opioid maintenance nor for chronic pain management. It has been assumed that as the impact of buprenorphine on testosterone levels is less as compared to pure agonist opioids, risk of osteoporosis would also be lower. However, long-term effects of buprenorphine on bone density are yet to be examined.
The effect of opioids on HPA axis may be variable. Some authors have raised concerns about chronic opioid induced adrenal insufficiency related to the effect of opioids on the circadian rhythm of the HPA axis. Heroin addicts were found to have constant ACTH and cortisol plasma level throughout the day unlike the normal circadian rhythm with high values in the morning and low values in the evening in healthy controls . Similar results were found in opioid treated chronic pain patients where long-term cortisol exposure was found to be elevated . Furthermore, opioid withdrawals are associated with significant hypercortisolism  which has been shown to resolve over time with normalization of the HPA axis with treatment of withdrawal symptoms using methadone or buprenorphine . Although there are some animal studies examining the effect of buprenorphine on the release of anterior pituitary hormones and in the adrenal and thyroid in rat models ,  our current search did not reveal any human studies in this area.
Buprenorphine’s k-opioid receptor antagonism has been proposed as one possible mechanism to explain its favorable impact on gonadal axis. As stimulation of the k-opioid receptor may cause suppression of the gonadal axis buprenorphine antagonism on this receptor may be counteracting the μ opioid receptor mediated depression of this axis. The typical dose of buprenorphine used for opioid maintenance and chronic pain is not beyond 24 mg/day. Some authors suggest  that higher than normally used doses may cause reduction in testosterone levels.
Although the role of psychosocial factors, medical and psychiatric comorbidities cannot be ignored in patients with chronic pain as well as those on maintenance treatment of opioid dependence. However, these factors have not been adequately addressed in the literature in conjunction with hormonal evaluation. Moreover, there is considerable variability in the methodology of the various studies cited. Self-administered scales have been used by some studies while others have used the IIEF which is a more validated measurement instrument for assessment of sexual dysfunction in terms of EF, orgasmic function, sexual desire and intercourse satisfaction. Additionally, non-sexually active subjects or those without partners were either not clearly identified in the studies or confounded the results.
Low testosterone is a correctable cause of sexual dysfunction that may be encountered in both men and women at various ages, although several factors could be contributing to such symptoms. It has been a balancing act to minimize use of narcotics for chronic pain management while looking at non-opioid and non-pharmacological ways to deal with chronic pain. Although increasingly, long-term use of opioids for noncancer-related pain is being discouraged and efforts are being made to minimize and taper patient off long-term opioids, eliminating opioids from the treatment plan may not be an option for all. In patients where use of opioids for pain management is inevitable, physicians may continue weighing the risks of addiction potential, tolerance and the long-term impact of opioids on HPA and HPG axes. It is very likely that transdermal buprenorphine may emerge as the primary preferred treatment for some with chronic pain and also be used for opioid rotation which is a strategy often suggested to avoid development of tolerance.
Buprenorphine/naloxone continues to be increasingly used for both maintenance treatment of opioid dependence and pain management as data regarding its safety and efficacy in both these conditions is promising. Currently there is limited data regarding the endocrine impact of buprenorphine/naloxone and more research is needed in this area especially longitudinal evaluation with monitoring of hormonal assays. With safety in pregnancy and breast feeding being established  further studies evaluating the clinical impact of buprenorphine/naloxone treatment on the reproductive health and bone density of females are desirable in the coming years.
As the impact on gonadal hormones becomes more clear, the role of potential treatment options such as hormone replacement therapy and opioid rotation will also need to be explored. Future research is likely to lead to the development of consensus guidelines regarding baseline and periodic assessment of hormonal panels and bone density in patients being maintained on buprenorphine in the long-term for either of the two indications discussed above. Additionally, if a relationship with dose/duration of treatment is identified, this may reiterate the need to set limits on maximum dosage and duration of treatment with this partial agonist-antagonist that also has a κ antagonist action.
The US is in the middle of an opioid epidemic.
Methadone has been the gold standard for treatment of opioid dependence.
Partial agonist/antagonist buprenorphine has been gaining popularity due to its ease of use in office based setting, safety in overdose and ceiling phenomena.
Transdermal buprenorphine patch is also gaining popularity as a preferred treatment of chronic non-cancer related pain.
Long-term use of opioids is known to impact testosterone levels and sexual functioning.
There is limited and inconsistent evidence around buprenorphine’s effects on the HPG axis. Although, so far evidence suggests a favorable side effect profile in this respect, longitudinal trials with hormonal assays in comparison to healthy controls are absent.
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About the article
Published Online: 2018-02-17
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Ethical approval: The conducted research is not related to either human or animals use.