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      Opioids and Their Endocrine Effects: A Systematic Review and Meta-analysis

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          Abstract

          Context

          The increased use of opioids has resulted in an unprecedented opioid epidemic. Chronic opioid use causes hypogonadism, but its frequency, as well as the effects of opioids on other hypothalamo–pituitary–end organ hormone axes, remains unclear.

          Objective

          The aim of this systematic review and meta-analysis was to assess the effects of opioid use on pituitary function.

          Methods

          Eight electronic databases were searched for articles published up to May 8, 2018. Fixed or random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals (CI). This study is reported following the PRISMA and MOOSE guidelines.

          Data synthesis

          52 studies (22 low risk of bias) were included describing 18 428 subjects, consisting of patients with chronic pain ( n = 21 studies) or on maintenance treatment for opioid addiction ( n = 9) and healthy volunteers ( n = 4). The most frequently used opioid was methadone ( n = 13 studies), followed by morphine ( n = 12). Prevalence of hypogonadism was 63% (95% CI: 55%–70%, 15 studies, 3250 patients, 99.5% males). Prevalence of hypocortisolism relying on dynamic and nondynamic testing was 15% (95% CI: 6%–28%, 5 studies, 205 patients, 57.5% males) and including only studies using the insulin tolerance tests 24% (95% CI 16%–33%, 2 studies, n = 97 patients). In 5 out of 7 studies, hyperprolactinemia was present. No clear effects on the somatotropic and hypothalamo–pituitary–thyroid axes were described.

          Conclusions

          Hypogonadism occurs in more than half of male opioid users, and hypocortisolism in approximately one-fifth of all patients. Periodical evaluation of at least the gonadal and adrenal axes is therefore advisable.

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          Most cited references47

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          Long-term opioid management for chronic noncancer pain.

          Meredith Noble, Jonathan R Treadwell, Stephen J. Tregear … (2010)
          Opioid therapy for chronic noncancer pain (CNCP) is controversial due to concerns regarding long-term effectiveness and safety, particularly the risk of tolerance, dependence, or abuse. To assess safety, efficacy, and effectiveness of opioids taken long-term for CNCP. We searched 10 bibliographic databases up to May 2009. We searched for studies that: collected efficacy data on participants after at least 6 months of treatment; were full-text articles; did not include redundant data; were prospective; enrolled at least 10 participants; reported data of participants who had CNCP. Randomized controlled trials (RCTs) and pre-post case-series studies were included. Two review authors independently extracted safety and effectiveness data and settled discrepancies by consensus. We used random-effects meta-analysis' to summarize data where appropriate, used the I(2) statistic to quantify heterogeneity, and, where appropriate, explored heterogeneity using meta-regression. Several sensitivity analyses were performed to test the robustness of the results. We reviewed 26 studies with 27 treatment groups that enrolled a total of 4893 participants. Twenty five of the studies were case series or uncontrolled long-term trial continuations, the other was an RCT comparing two opioids. Opioids were administered orally (number of study treatments groups [abbreviated as "k"] = 12, n = 3040), transdermally (k = 5, n = 1628), or intrathecally (k = 10, n = 231). Many participants discontinued due to adverse effects (oral: 22.9% [95% confidence interval (CI): 15.3% to 32.8%]; transdermal: 12.1% [95% CI: 4.9% to 27.0%]; intrathecal: 8.9% [95% CI: 4.0% to 26.1%]); or insufficient pain relief (oral: 10.3% [95% CI: 7.6% to 13.9%]; intrathecal: 7.6% [95% CI: 3.7% to 14.8%]; transdermal: 5.8% [95% CI: 4.2% to 7.9%]). Signs of opioid addiction were reported in 0.27% of participants in the studies that reported that outcome. All three modes of administration were associated with clinically significant reductions in pain, but the amount of pain relief varied among studies. Findings regarding quality of life and functional status were inconclusive due to an insufficient quantity of evidence for oral administration studies and inconclusive statistical findings for transdermal and intrathecal administration studies. Many patients discontinue long-term opioid therapy (especially oral opioids) due to adverse events or insufficient pain relief; however, weak evidence suggests that patients who are able to continue opioids long-term experience clinically significant pain relief. Whether quality of life or functioning improves is inconclusive. Many minor adverse events (like nausea and headache) occurred, but serious adverse events, including iatrogenic opioid addiction, were rare.
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            Hypogonadism in men consuming sustained-action oral opioids.

            Harry W. Daniell (2002)
            Naturally occurring opiates (endorphins) diminish testosterone levels by inhibiting both hypothalamic gonadotrophin releasing hormone production and testicular testosterone synthesis. Heroin addicts treated with a single daily dose of methadone and nonaddicts receiving continuous intrathecal opioids quickly develop low luteinizing hormone and total testosterone levels. A similar pattern was sought in men consuming commonly prescribed oral opioids. Free testosterone (FT), total testosterone (TT), estradiol (E(2)), dihydrotestosterone (DHT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured in 54 community-dwelling outpatient men consuming oral sustained-action dosage forms of opioids several times daily for control of nonmalignant pain. Hormone levels were related to the opioid consumed, dosage and dosage form, nonopioid medication use, and several personal characteristics and were compared with the hormone analyses of 27 similar men consuming no opioids. Hormone levels averaged much lower in opioid users than in control subjects in a dose-related pattern (P < .0001 for all comparisons). FT, TT, and E(2) levels were subnormal in 56%, 74%, and 74%, respectively, of opioid consumers. Forty-eight men (89%) exhibited subnormal levels of either FT or E(2). Either TT or E(2) level was subnormal in all 28 men consuming the equivalent of 100 mg of methadone daily and in 19 of 26 (73%) consuming smaller opioid doses. Eighty-seven percent (39 of 45) of opioid-ingesting men who reported normal erectile function before opioid use reported severe erectile dysfunction or diminished libido after beginning their opioid therapy. Commonly prescribed opioids in sustained-action dosage forms usually produce subnormal sex hormone levels, which may contribute to a diminished quality of life for many patients with painful chronic illness.
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              The impact of opioids on the endocrine system.

              James A. Mazer, Nathaniel Katz (2009)
              Opioids have been used for medicinal and analgesic purposes for centuries. However, their negative effects on the endocrine system, which have been known for some times, are barely discussed in modern medicine. Therefore, we conducted a systematic review of the impact of opioids on the endocrine system. A review of the English language literature on preclinical and clinical studies of any type on the influence of opioids on the endocrine system was conducted. Preliminary recommendations for monitoring and managing these problems were provided. Long-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symptoms of opioid-induced hypogonadism include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, osteoporosis, and compression fractures in both men and women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to monitor patients taking opioids and manage endocrine complications. Therefore, patients on opioid therapy should be routinely screened for such symptoms and for laboratory abnormalities in sex hormones. Opioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use. Patients on long-term opioid therapy should be prospectively monitored, and in cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, or sex hormone supplementation after careful consideration of the risks and benefits.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Endocrinol Metab
                Journal ID (iso-abbrev): J. Clin. Endocrinol. Metab
                Journal ID (publisher-id): jcem
                Title: The Journal of Clinical Endocrinology and Metabolism
                Publisher: Oxford University Press (US )
                ISSN (Print): 0021-972X
                ISSN (Electronic): 1945-7197
                Publication date Collection: April 2020
                Publication date (Electronic): 12 September 2019
                Publication date PMC-release: 12 September 2019
                Volume: 105
                Issue: 4
                Electronic Location Identifier: dgz022
                Affiliations
                [1 ] Department of Medicine, Division of Endocrinology, Leiden University Medical Center , Leiden, The Netherlands
                [2 ] Centre for Endocrine Tumors Leiden (CETL), Leiden University Medical Center , Leiden, The Netherlands
                [3 ] Department of Clinical Epidemiology, Leiden University Medical Center , Leiden, The Netherlands
                [4 ] Walaeus Library, Leiden University Medical Center , Leiden, The Netherlands
                [5 ] Department of Neurosurgery, Leiden University Medical Center , Leiden, The Netherlands
                [6 ] Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham , Birmingham, UK
                [7 ] Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners , Birmingham, UK
                [8 ] Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust , Birmingham, UK
                Author notes
                Correspondence and Reprint Requests: Amir H. Zamanipoor Najafabadi, Department of Neurosurgery, Clinical Epidemiology, Center for Endocrine Tumor Leiden, and Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands. E-mail: amir@ 123456lumc.nl

                These authors contributed equally to this work as first author.

                These authors contributed equally to this work as senior author.

                Author information
                http://orcid.org/0000-0002-3660-6093
                http://orcid.org/0000-0002-2523-8707
                http://orcid.org/0000-0002-1333-7580
                http://orcid.org/0000-0001-5208-921X
                http://orcid.org/0000-0002-1194-9866
                http://orcid.org/0000-0002-4696-0643
                http://orcid.org/0000-0001-5817-3594
                http://orcid.org/0000-0003-2400-2070
                Article
                Publisher ID: dgz022
                DOI: 10.1210/clinem/dgz022
                PMC ID: 7054712
                PubMed ID: 31511863
                SO-VID: 3a5a054d-8dde-4250-8feb-256e8453da25
                Copyright © © Endocrine Society 2019.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 01 July 2019
                Date accepted : 24 October 2019
                Date: 03 March 2020
                Related
                Page count
                Pages: 10
                Categories
                Subject: Meta-Analysis

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: opioids,analgesics,hypogonadism,hypocortisolism,pituitary
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: opioids, analgesics, hypogonadism, hypocortisolism, pituitary

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