The Impact of Opioids on the Endocrine System

Transcription

1 2005 Volume 1, Issue 9 FROM GRAND ROUNDS AND OTHER CLINICAL CONFERENCES OF THE MGH PAIN CENTER, MASSACHUSETTS GENERAL HOSPITAL The Impact of Opioids on the Endocrine System MGH 1811 MASSACHUSETTS GENERAL HOSPITAL By NATHANIEL K ATZ, MD, MS [Opium] has kept, and does now keep down the population: the women have fewer children than those of other countries the feeble opium-smokers of Assam are more effeminate than women. Charles Alexander Bruce, Report on the Manufacture of Tea and on the extent and produce of the tea plantations in Assam, Calcutta, Opioids have been used for medicinal and analgesic purposes for millennia and today remain a critical part of the medical armamentarium against pain, diarrhea, cough, and other symptoms. Unfortunately, while barely discussed in the modern medical lexicon, opioids have negative effects on the endocrine system that have been observed for at least a century. These effects (Table 1) include decreased testosterone, with loss of libido and other expected effects, in men, and menstrual irregularities and infertility in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to recognize and manage their endocrine complications. PHYSIOLOGY OF OPIOID-ENDOCRINE INTERACTIONS The hypothalamic-pituitary-gonadal process of controlling the secretion of gonadal hormones, testosterone, and estrogen, begins with secretion by the hypothalamus of gonadotropin-releasing hormone (GNRH) (Figure 1). GNRH stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). These two hormones are released into the systemic circulation and interact with the gonads, the testes and ovaries, to secrete testosterone or estrogen, respectively. These sex hormones then feed back to the hypothalamus and pituitary to form a complete feedback loop. Testosterone and estrogen support normal sexual and reproductive growth and behavior. This system is modulated by a complex series of outside influences as well. Opioids are one of a number of such influences and evidence suggests that opioids both endogenous and exogenous can bind to opioid receptors primarily in the hypothalamus, but potentially also in the pituitary and the testes, to modulate gonadal function. 1-6 Decreased release, or interference with the normal pulsatility of release of GNRH at the level of the hypothalamus, has been documented, with consequent decreased release of LH and FSH from the pituitary. Direct effects of opioids on the testes, including decreased secretion of testosterone and testicular interstitial fluid, have been documented. 7 Finally, opioids have been shown to increase pituitary release of prolactin in preclinical studies, 8 with secondary effects of decreasing testosterone secretion (although, as indicated below, prolactin secretion is generally not affected in clinical studies). ENDOCRINE CONSEQUENCES OF OPIOID USE Investigations in animals have demonstrated the acute and chronic effects of opioids on the endocrine system, 9 including decreasing testosterone levels by central reductions of LH release (decreased hypothalamic release of luteinizing-hormone releasing hormone (LHRH), leading to reduced pituitary release of LH), and peripheral effects on the testicle as well Studies in heroin MGH PAIN CENTER Jane C. Ballantyne, M.D. Chief, Division of Pain Medicine Editor, Pain Management Rounds Salahadin Abdi, M.D., Ph.D. Director, MGH Pain Center Martin Acquadro, M.D., D.M.D. Director of Cancer Pain Service Steve Barna, M.D. Medical Director, MGH Pain Clinic Gary Brenner, M.D., Ph.D. Director, Pain Medicine Fellowship Lucy Chen, M.D. Katharine Fleischmann, M.D. Director, Acute Pain Service Jatinder Gill, M.D. Karla Hayes, M.D. Eugenia-Daniela Hord, M.D. Ronald Kulich, Ph.D. Jianren Mao, M.D., Ph.D. Director, Pain Research Group Seyed Ali Mostoufi, M.D. Anne Louise Oaklander, M.D., Ph.D. Director, Nerve Injury Unit Director, Center for Shingles and Postherpetic Neuralgia Gary Polykoff, M.D. Milan Stojanovic, M.D. Director, Interventional Pain Management MGH PAIN CENTER 15 Parkman Street, Suite 324 Boston, MA Fax : The editorial content of Pain Management Rounds is determined solely by the MGH Pain Center, Massachusetts General Hospital. Pain Management Rounds is approved by the Harvard Medical School Department of Continuing Education to offer continuing education credit

2 TABLE 1: Endocrine effects of opioids Central hypogonadism Decreased hypothalamic GNRH Decreased pituitary LH, possibly FSH Decreased testicular testosterone; ovarian estradiol Decreased testicular interstitial fluid Cortisol deficiency Growth Hormone deficiency Loss of libido, impotence Infertility (males and females) Depression, anxiety, fatigue Loss of muscle mass and strength Amenorrhea, irregular menses, galactorrhea Osteoporosis and fractures Uncertain,?Addisonian crisis Uncertain addicts, compared to healthy controls, have demonstrated decreased testosterone levels in males, with an associated decrease in LH and/or FSH consistent with central hypogonadism. 7,16-21 In one study measuring hormonal status one month after cessation of heroin use, testosterone levels returned to normal. 21 In methadone-maintained male patients, several studies have demonstrated decreased testosterone levels consistent with central hypogonadism. One of these studies 20 demonstrated a dose-response effect, in that patients on low dose methadone (10-60 mg/day) had no evidence of suppression compared with those on high dose ( mg/day). The second study 7 demonstrated a peripheral effect on the testicle, with decreased secretion of testosterone and testicular interstitial fluid, and decreased sperm motility. One case series described amenorrhea and galactorrhea in female heroin addicts. 22 Several studies have compared patients undergoing intrathecal opioid treatment for nonmalignant pain with patients with a comparable pain syndrome, but not on opioid therapy. These studies have documented hypogonadism associated with low LH values and normal or low FSH levels in both males and females When compared to the chronic pain control group, these laboratory findings were associated with decreased libido or impotence in males and irregular or absent menses in females. Interestingly, in one study, 15% of patients developed hypocorticism and 15% growth hormone deficiency. 23 Although one patient with hypocorticism developed an Addisonian crisis, the clinical consequences of low cortisol observed in several studies of opioid therapy have not been confirmed in controlled studies. Symptoms were reported to have improved in most patients with hormone supplementation. None of these studies reported elevation of prolactin levels, suggesting that prolactin is not significantly related to the mechanism by which opioids produce hypogonadism. Three studies have been published on the effects of long-term oral opioid therapy in males with chronic pain. FIGURE 1: Interactions between opioids and the endocrine system The Hypothalamic-Pituitary-Gonadal Axis OPIOIDS + LHRH (GnRH) + LH FSH Testosterone Estrogen Hypothalamus Testes Ovaries Pituitary In the first, 29 endocrine function was measured in 54 patients on sustained-release opioids and compared to 27 healthy controls. Hormone levels were much lower in opioid users than in control subjects in a dose-related pattern (P<0001 for all comparisons) and total testosterone levels were subnormal in 74% of the opioid group, with an apparent dose-response effect. Eighty-seven percent (39 of 45) of the opioid-ingesting men who reported normal erectile function before opioid use, reported severe erectile dysfunction or diminished libido after beginning opioid therapy. The second study 30 was a case series in cancer survivors with chronic pain taking opioids who had abnormally low testosterone levels. This was confirmed with a follow-up case-control study 31 comparing 20 cancer survivors on opioids to 20 matched controls. Among the opioid group, 18/20 (90%) exhibited hypogonadism, compared to 8/20 controls (40%) (median testosterone levels were statistically significantly lower in the opioid group). LH, but not FSH levels, were statistically significantly lower in the cases. Importantly, clinically significant consequences of these laboratory abnormalities were also demonstrated. Sexual desire (measured by the Sexual Desire Inventory); anxiety and depression (measured by the Hospital Anxiety and Depression Scale); and overall quality of life (measured by the Functional Assessment of Chronic Illness Therapy with general and fatigue subscales [FACT-G/FACIT-F]) were all significantly lower in the opioid group than in the controls. An unpublished study 32 also compared endocrine status in male patients on opioid therapy to healthy controls and found that of 25 patients, 68% had either free or total testosterone values below the normal range. Among men over age 50, 87.5% had low free testosterone levels. Mean free and total testosterone and LH values were significantly lower than in normal controls. FSH and prolactin levels were normal. LHRH = luteinizing-hormone releasing hormone GNRH = gonadotropinhormone releasing hormone LH = luteinizing hormone FSH = follicle-stimulating hormone

3 A final study 33 compared endocrine function in 17 men treated with buprenorphine for addiction, 37 men on high-dose methadone and 51 healthy blood donors served as controls. Patients treated with buprenorphine had significantly higher testosterone levels and a significantly lower frequency of sexual dysfunction compared with patients treated with methadone. The testosterone level of buprenorphinetreated patients did not differ from that of the healthy controls. This is the first study to demonstrate the possibility that not all opioids may be alike in terms of endocrine effects, although it is not clear in this study that equivalent doses of methadone and buprenorphine were compared. Interestingly, one preclinical study 34 in rats demonstrated that reducing testosterone levels by castration significantly increased sensitivity to pain (as measured by two standard assays: tail flick and hot plate). This increase in pain sensitivity was reversed by testosterone supplementation. This raises the provocative possibility that in chronic pain patients on opioid therapy, opioid-induced hypogonadism which occurs in a majority of male patients on opioids could potentially have the undesirable effect of increasing pain sensitivity. The only evidence addressing this hypothesis in humans is quite indirect. A randomized, placebo-controlled study 35 of 53 female patients with AIDS wasting syndrome was conducted that compared transdermal testosterone to placebo. This syndrome is known to be associated with markedly decreased serum androgen levels. Pain scores were captured incidentally with the pain item on the SF-36 quality of life survey. A trend towards improved pain score (p=0.059) was observed in 1 of the 2 testosterone treatment groups compared to placebo. Several studies have examined the possibility of opioidinduced alterations of other endocrine functions. In general, it does not appear that opioids alter thyroid function in any meaningful way. 36,37 Opioids have been found in several studies to decrease cortisol levels, as well as cortisol responses to adrenocorticotropin (ACTH) challenges. 23,38,39 The clinical significance of this is unclear. One study also documented decreased growth hormone secretion in the setting of opioid therapy, also of unclear significance. Hypogonadism from any cause may also affect serum lipid profiles, although the consistency and clinical importance of these effects is uncertain. 40 In summary, a number of lines of evidence including preclinical studies, heroin addiction, methadone maintenance indicate that intrathecal and oral opioids in both cancer and non-cancer pain suppress testosterone secretion, primarily via central mechanisms (although a peripheral component may be important as well). This suppression appears to have important clinical consequences, including decreased sexual desire and performance, potentially increased anxiety and depression, and reduced quality of life. Some studies have found a dose-response effect, with increas- TABLE 2: Symptoms of hypogonadism Loss of libido Impotence Infertility (males and females) Depression and anxiety Loss of muscle mass and strength Loss of gender role Fatigue Amenorrhea, irregular menses, galactorrhea Osteoporosis and fractures Pain? Loss of opioid effect? ing testosterone suppression with increasing opioid doses. One study suggests that all opioids may not be alike in this regard. Two provocative studies, one in rats and one in women with AIDS wasting syndrome, suggest the possibility that decreased testosterone levels may be associated with increased pain. Opioids also appear to affect the endocrine system in other ways, including decreasing cortisol and growth hormone levels (Table 2). DIAGNOSIS OF OPIOID-INDUCED ENDOCRINOPATHY The signs and symptoms of hypogonadism are well known (Table 2), and include loss of sexual desire and performance, alterations in gender role, fatigue, mood alterations, loss of muscle mass and strength, abnormal menses, infertility, and finally, osteoporosis and fractures. 31,41-43 Many of these symptoms are also widespread in patients with chronic pain Therefore, it is unclear to what extent on an epidemiologic basis such symptoms in patients on opioids for chronic pain are due to opioid-induced hypogonadism or to chronic pain and its associated conditions. All patients with chronic pain on opioid therapy should be assessed prospectively for symptoms that could be potentially related to opioid-induced hypogonadism (Table 2). While there are no available standards for laboratory monitoring of patients on opioids for chronic pain, the available data suggest that endocrine monitoring should be routine (Table 3). The usual laboratory studies include total testosterone, free testosterone (and/or sex hormone-binding globulin), estradiol, LH, and FSH. Monitoring of bone density should also be considered in at-risk patients, since patients with fractures associated with hypogonadism often have no other symptoms of hypogonadism. 41 The diagnosis of hypogonadism is made by low levels of testosterone, with a customary cutoff of total (bound and free) testosterone <300 ng/dl. Whether hypogonadism in a patient on opioid therapy is due to opioids or some other cause becomes a pragmatic issue of whether any other causes of hypogonadism are present. If not; the presumptive diagnosis and

4 TABLE 3: Diagnosis of opioid-induced endocrinopathy Clinical evaluation Symptoms (Table 2) Laboratory evaluation Free and total testosterone, LH, FSH, estradiol Consider growth hormone, morning cortisol Consider bone densitometry Rule-out other causes of central hypogonadism Idiopathic gonadotropin or gonadotropin-releasing hormone (luteinizing hormone releasing hormone) deficiency Pituitary-hypothalamic injury Tumors Trauma Radiation Corticosteroid therapy management options point to opioids as the focus of attention. MANAGEMENT OF OPIOID-INDUCED ENDOCRINOPATHY There are no accepted standards for the management of presumptive opioid-induced hypogonadism. Therefore, clinical judgment must be relied upon. In patients who appear to have opioid-induced hypogonadism, several considerations will influence treatment decisions (Table 4). The first issue is to determine to what extent the laboratory abnormalities are clinically important by assessing sexual function, mood, and the other symptoms noted above. For patients with symptoms, or even laboratory abnormalities and unclear clinical status, the first question is whether to switch opioids. It is presently unknown if all opioids at equi-analgesic doses cause an equal degree of endocrine dysfunction. In some patients, opioid rotation is fairly straightforward and a reasonable first step. In others, such as those on high doses or who have failed multiple opioids, opioid rotation is difficult and testosterone supplementation will be more appropriate. Serum total (bound and free) testosterone concentrations <300 ng/dl are generally considered indicative of hypogonadism in men and the biochemical goal of hormone replacement therapy with testosterone is to increase serum total testosterone concentrations to within the normal physiologic range of ng/dl Several formulations of testosterone are available, including intramuscular injections, transdermal patches, and transdermal gel. Most of the clinical trial data and experience that have accumulated is with TABLE 4: Management of opioid-induced hypogonadism Consider opioid rotation Consider strategies that allow opioid dose reduction Concomitant non-opioid analgesics Non-pharmacologic modalities Testosterone supplementation Consider consultation with an endocrinologist Choose formulation and dose Intramuscular injection Transdermal patch Transdermal gel Monitor prostate specific antigen (PSA) in males Monitor clinical and laboratory results intramuscular injections, but transdermal formulations are more acceptable to most patients. Therefore, a reasonable approach is to begin with a transdermal formulation and then switch to injections in patients who are unable to normalize testosterone levels with the transdermal formulations. It must be remembered that testosterone supplementation is not free of side effects, including local site reactions, sleep apnea, abuse and misuse, and various hematologic abnormalities, particularly polycythemia. Oligospermia, priapism, male pattern baldness, and gynecomastia may occur in men, while menstrual irregularities and virilization may occur in women. Perhaps the most worrisome side effect is the potential for stimulation of growth, benign or otherwise, of the prostate gland. While exogeneous testosterone has not been firmly linked to the development of prostate cancer, patients must be monitored (rectal examinations and prostate specific antigen [PSA]) for such effects (Table 5). Similarly, the possibility of abnormalities in serum lipids should be monitored, although there are no definite links between testosterone supplementation and clinically significant lipid abnormalities. CONCLUSIONS Opioid-induced hypogonadism due to central suppression of hypothalamic secretion of GNRH is TABLE 5: Monitoring of patients on testosterone supplementation Symptoms of hypogonadism Free and total testosterone, sex hormone binding globulin Rectal examinations and prostate specific antigen (PSA) Complete blood count Lipid profile

5 likely common in both male and female patients on long-term opioid therapy because of addiction or chronic pain. Potential symptoms include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, alteration of gender role, osteoporosis, and compression fractures and, in men, impotence, and, in females, menstrual irregularities, galactorrhea, and infertility. Therefore, patients on opioid therapy should have routine screening for such symptoms, which may be difficult to distinguish from symptoms that are common in patients with chronic pain or addiction and for associated laboratory abnormalities. Patients with opioid-induced hypogonadism should probably undergo opioid rotation if this is likely to be straightforward. In patients who cannot easily be rotated or who have failed opioid rotation, testosterone supplementation should be offered after consideration of likely risks and benefits. Patients who undergo testosterone supplementation require appropriate monitoring of both benefits and potential risks. Dr. Nathaniel Katz is a Neurologist and Pain Management Specialist. He is currently Director, Pain and Opioid Research, Inflexxion, Inc. Between 1990 and 2001, Dr. Katz provided patient care at Brigham and Women s Hospital and the Dana Farber Cancer Institute in Boston. He has a longstanding interest in the use of opioids for acute and chronic pain, including their complications. References 1. Cicero T. Effects of exogenous and endogenous opiates on the hypothalamic-pituitary-gonadal axis in the male. Fed Proc 1980;39(8): Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF. Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 2001;25(4): Genazzani AR, Genazzani AD, Volpogni C, et al. Opioid control of gonadotrophin secretion in humans. 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6 37. Rasheed A, Tareen IA. Effects of heroin on thyroid function, cortisol and testosterone level in addicts. Pol J Pharmacol 1995;47(5): Allolio B, Deuss U, Kaulen D, et al. FK , a met-enkephalin analog, blocks corticotropin-releasing hormone-induced adrenocorticotropin secretion in normal subjects but not in patients with Cushing s disease. J Clin Endocrinol Metab 1986;63: Taylor T, Dluhy RG, Williams GH. beta-endorphin suppresses adrenocorticotropin and cortisol levels in normal human subjects. J Clin Endocrinol Metab 1983;57: von Eckardstein A, Kliesch S, Nieschlag E, Chirazi A, Assmann G, Behre HM. Suppression of endogenous testosterone in young men increases serum levels of high density lipoprotein subclass lipoprotein A-I and lipoprotein(a). J Clin Endocrinol Metab 1997;(10): Anderson FH, Francis RM, Selby PL, Cooper C. Sex hormones and osteoporosis in men. Calcif Tissue Int 1998;62(3): Ebeling PR. Osteoporosis in men. 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J Clin Endocrinol Metab 1997;82(8): McClure RD, Oses R, Ernest ML. Hypogonadal impotence treated by transdermal testosterone. Urology 1991;37(3): Abstract of Interest Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids R AJAGOPAL A, VASSILOPOULOU-SELLIN R, PALMER JL, KAUR G, BRUERA E. CANCER 2004;100(4): BACKGROUND: Profound hypogonadism has been noted in patients receiving intrathecal opioids. The purpose of the current study was to determine whether chronic consumption of oral opioids by male survivors of cancer also would lead to central hypogonadism and whether this hypogonadism was associated with symptoms of sexual dysfunction, fatigue, anxiety, and depression. METHODS: A case-control study was conducted at The University of Texas M. D. Anderson Cancer Center (Houston, TX), in which 20 patients who were chronically consuming opioids were compared with 20 matched controls. Patients completed the Sexual Desire Inventory (SDI), the Hospital Anxiety and Depression Scale (HADS), the Functional Assessment of Chronic Illness Therapy with general and fatigue subscales (FACT-G/FACIT-F), and the Edmonton Symptom Assessment System (ESAS) questionnaires. Serum samples were collected for testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). RESULTS: Comparing the opioid group with the control group, 18 of the 20 patients (90%; 95% confidence interval [CI], 65-98%) exhibited hypogonadism, compared with 8 of the 20 control patients (40%; 95% CI, 19-64%). The median testosterone level was 145 ng/dl versus ng/dl (5.0 nmol/l vs nmol/l; P < ), the median FSH level was 2.85 milli-international Units (miu)/ml versus 5.3 miu/ml (P = 0.08), the median LH level was 1.8 miu/ml versus 4.2 miu/ml (P = ), the median SDI-dyadic score was 18.5 versus 40 (P = 0.01), the median SDI-solitary score was 0 versus 5 (P = 0.007), the HADS (anxiety) score was 8.5 versus 5.5 (P = 0.053), the HADS (depression) score was 7.5 versus 1.5 (P = ), the FACT-G score was 64 versus 96.3 (P = ), and the FACIT-F score was 24 versus 46 (P = ). CONCLUSIONS: Survivors of cancer who chronically consumed opioids experienced symptomatic hypogonadism with significantly higher levels of depression, fatigue, and sexual dysfunction. With the increasing use of opioids among patients with cancer, further research in improving quality-of-life outcomes is warranted. Copyright 2004 American Cancer Society. 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