The Effect of Opioid Therapy on Endocrine Function

https://doi.org/10.1016/j.amjmed.2012.12.001Get rights and content

Abstract

Opioids are an established option in the analgesic armamentarium for managing moderate-to-severe chronic pain. Long-term opioid use, however, is associated with several potential adverse effects and toxicities, such as peripheral edema, immune suppression, hyperalgesia, sleep apnea, and changes in endocrine function, many of which are not fully appreciated. Opioid endocrinopathy can greatly affect patients, causing reduced sexual function, decreased libido, infertility, mood disorders, osteoporosis, and osteopenia. Furthermore, although opioid endocrinopathy appears to be common, many patients do not report their symptoms, thus causing this adverse effect to go unnoticed and without clinical monitoring, particularly in patients chronically taking the equivalent of ≥100 mg of morphine daily. Indeed, diagnosing hypogonadism as opioid-related can be challenged by other influences on endocrine function, such as pain pathophysiology, comorbidities, other drug therapies, and patient age. Management options for opioid endocrinopathy include discontinuing opioid therapy, reducing the opioid dose, switching to a different opioid, and hormone supplementation.

Section snippets

Comorbidities Associated With Hypogonadism

Pain typically does not occur absent underlying illness, injury, or other comorbidities. Indeed, pain pathophysiology, pain comorbidities, opioid dosage, and patient age, and several other factors can be direct causes of or contributors to hypogonadism. The Hypogonadism in Males (HIM) study demonstrated a relation between hypogonadism and several comorbid conditions.12 Ninety-five primary care practices assessed hypogonadism within a population of 2162 men aged ≥45 years regardless of the

Opioid Effects on the Hypothalamic-Pituitary-Gonadal Axis

Opioids have a well-documented effect on 2 endocrine systems.2, 18, 19 The first is the hypothalamic-pituitary-gonadal axis. In the normally functioning system, gonadotropin-releasing hormone (GnRH) is released by the hypothalamus and targets the pituitary gland, which is then stimulated to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH).2 These hormones enter the systemic circulation and stimulate the end organs of the axis—the testes or ovaries—to respectively produce

Effect of Opioids on the Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal axis is another endocrine system that can be affected by opioids.18 The cascade for this system is initiated with the release of corticotropin-releasing hormone (CRH) from the hypothalamus, targeting the pituitary. The pituitary is then stimulated to release adrenocorticotropic hormone (ACTH), which enters the systemic circulation and induces the adrenal glands to produce 2 hormones, cortisol and dehydroepiandrosterone (DHEA). Cortisol is important for

Monitoring and Treatment

Standards have not been established for monitoring and treating opioid-induced hypogonadism or hypoadrenalism. Based on the literature and clinical experience, however, patients taking opioid therapy equivalent to ≥100 mg of morphine daily should be monitored for the development of hypogonadism.18 Patients may not necessarily report symptoms of hypogonadism, such as sexual dysfunction, menstrual irregularities, or fatigue. Therefore, monitoring should include specific questioning regarding

Summary

Managing opioid-induced endocrine dysfunction in clinical practice begins with monitoring for symptoms, coupled with appropriate diagnostic tests, in all patients taking long-term opioids. Nonopioid analgesic approaches and/or opioid rotation should be considered in the management of opioid-induced endocrine dysfunction. Furthermore, when supported by a risk-benefit analysis and with appropriate consultation, hormone supplementation may be an option for certain individuals.

Author Disclosures

The author of this article has disclosed the following industry relationships:

  • Michael J. Brennan, MD, consultant: Covidien, Endo Pharmaceuticals Inc, Purdue Pharma; speakers bureau: Covidien, Endo Pharmaceuticals Inc, inSYS Therapeutics Inc, Johnson & Johnson, Purdue Pharma, Teva/Cephalon; stockholder: Apricus Biosciences, Inc., Pfizer Inc, Teva Pharmaceuticals, Zalicus.

Acknowledgments

Research and editorial support was provided by Miller Medical Communications, LLC, and by Rebecca A Bachmann, PhD, of BookishProse.

References (68)

  • M. Kinjo et al.

    Bone mineral density in subjects using central nervous system-active medications

    Am J Med

    (2005)
  • L.J. Forman et al.

    The response to analgesia testing is affected by gonadal steroids in the rat

    Life Sci

    (1989)
  • E.C. Stoffel et al.

    Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats

    Pain

    (2003)
  • H.W. Daniell et al.

    Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency

    J Pain

    (2006)
  • H.W. Daniell

    DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production

    J Pain

    (2006)
  • J.E. Morley et al.

    Comparison of screening questionnaires for the diagnosis of hypogonadism

    Maturitas

    (2006)
  • J.M. Kaufman et al.

    Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men

    J Urol

    (2004)
  • P.K. Agarwal et al.

    Testosterone replacement therapy after primary treatment for prostate cancer

    J Urol

    (2005)
  • M. Khera et al.

    Testosterone replacement therapy following radical prostatectomy

    J Sex Med

    (2009)
  • P.G. Fine et al.

    Establishing “best practices” for opioid rotation: conclusions of an expert panel

    J Pain Symptom Manage

    (2009)
  • J.D. Harris

    Management of expected and unexpected opioid-related side effects

    Clin J Pain

    (2008)
  • N. Katz et al.

    The impact of opioids on the endocrine system

    Clin J Pain

    (2009)
  • J. Ninković et al.

    Role of the mu-opioid receptor in opioid modulation of immune function

    Amino Acids

    (2011; Dec 15)
  • M.J. Krantz et al.

    QTc interval screening in methadone treatment

    Ann Intern Med

    (2009)
  • B. Lo et al.

    Palliative sedation in dying patients: “we turn to it when everything else hasn't worked.”

    JAMA

    (2005)
  • C. Guilleminault et al.

    Obstructive sleep apnea and chronic opioid use

    Lung

    (2010)
  • K.W. Saunders et al.

    Relationship of opioid use and dosage levels to fractures in older chronic pain patients

    J Gen Intern Med

    (2010)
  • T. Mulligan et al.

    Prevalence of hypogonadism in males aged at least 45 years: the HIM study

    Int J Clin Pract

    (2006)
  • A. Guay et al.

    Hypogonadism in men with erectile dysfunction may be related to a host of chronic illnesses

    Int J Impot Res

    (2010)
  • L.R. Webster et al.

    Sleep-disordered breathing and chronic opioid therapy

    Pain Med

    (2008)
  • S. Colameco et al.

    Opioid-induced endocrinopathy

    J Am Osteopath Assoc

    (2009)
  • J.C. Ballantyne et al.

    Opioid therapy for chronic pain

    N Engl J Med

    (2003)
  • G. Ragni et al.

    Gonadal function in male heroin and methadone addicts

    Int J Androl

    (1988)
  • A. Rasheed et al.

    Effects of heroin on thyroid function, cortisol and testosterone level in addicts

    Pol J Pharmacol

    (1995)
  • Cited by (119)

    • Management of pain

      2023, Palliative Radiation Oncology
    • Laboratory-induced stress and craving predict opioid use during follow-up among individuals with prescription opioid use disorder

      2021, Drug and Alcohol Dependence
      Citation Excerpt :

      There are a several ways to interpret the absence of this finding. Chronic opioid use is associated with complex changes in the stress response system, including cortisol and DHEA (Brennan, 2013; Daniell, 2006; de Vries et al., 2019). Exposure to a short-term stressor typically results in activation of the HPA axis and increased cortisol.

    View all citing articles on Scopus

    Statement of Author Disclosure: Please see the Author Disclosures section at the end of this article.

    View full text