Mayo Clinic Proceedings Home

Opioid-Induced Adrenal Insufficiency

      Abstract

      One in 10 Americans experience chronic pain. Although opioids do play a role in the management of pain, long-term opioid use may lead to adverse effects. Endocrine-related adverse effects have been described but remain poorly recognized. Opioid-induced adrenal insufficiency occurs because of suppression of hypothalamic-pituitary-adrenal communication and may be challenging to diagnose but has been reported in 9% to 29% of patients receiving long-term opiate therapy. Little data exist to guide case detection and patient management. Treatment includes cessation of opiates (the inciting factor) if possible and glucocorticoid replacement.

      Abbreviations and Acronyms:

      CRH (corticotropin-releasing hormone), CST (cosyntropin stimulation test), DHEA-S (dehydroepiandrosterone sulfate), HPA (hypothalamic-pituitary-adrenal), MEDD (morphine equivalent daily dose), OIAI (opioid-induced adrenal insufficiency)
      CME Activity
      Target Audience: The target audience for Mayo Clinic Proceedings is primarily internal medicine physicians and other clinicians who wish to advance their current knowledge of clinical medicine and who wish to stay abreast of advances in medical research.
      Statement of Need: General internists and primary care physicians must maintain an extensive knowledge base on a wide variety of topics covering all body systems as well as common and uncommon disorders. Mayo Clinic Proceedings aims to leverage the expertise of its authors to help physicians understand best practices in diagnosis and management of conditions encountered in the clinical setting.
      Accreditation Statement: In support of improving patient care, Mayo Clinic College of Medicine and Science is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.
      Credit Statements:
      AMA: Mayo Clinic College of Medicine and Science designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.
      MOC: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 MOC point in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
      Learning Objectives: On completion of this article, you should be able to (1) review the pathophysiology of opioid-induced adrenal insufficiency, (2) evaluate a patient with suspected opioid-induced adrenal insufficiency, and (3) implement optimal treatment for opioid-induced adrenal insufficiency.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine and Science (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation.
      In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Bancos reports consulting fees from Diurnal Group PLC for work not related to this article. Dr Donegan reports no competing interests.
      Method of Participation: In order to claim credit, participants must complete the following:
      • 1.
        Read the activity.
      • 2.
        Complete the online CME Test and Evaluation. Participants must achieve a score of 80% on the CME Test. One retake is allowed.
      Visit www.mayoclinicproceedings.org, select CME, and then select CME articles to locate this article online to access the online process. On successful completion of the online test and evaluation, you can instantly download and print your certificate of credit.
      Estimated Time: The estimated time to complete each article is approximately 1 hour.
      Hardware/Software: PC or MAC with Internet access.
      Date of Release: 7/1/2018
      Expiration Date: 6/30/2020 (Credit can no longer be offered after it has passed the expiration date.)
      Questions? Contact [email protected] .
      Currently, the United States is experiencing an opioid epidemic. According to the National Center for Health Statistics, prescriptions for opioids increased 4-fold between 1999 and 2010 and are now one of the most commonly prescribed medications, with 3% to 4% of US adults receiving long-term opioid treatment.
      • Boudreau D.
      • Von Korff M.
      • Rutter C.M.
      • et al.
      Trends in long-term opioid therapy for chronic non-cancer pain.
      Although an estimated 25.3 million adult Americans (11.2%) experience chronic pain,
      • Nahin R.L.
      Estimates of pain prevalence and severity in adults: United States, 2012.
      opioids play a limited role in chronic pain management. They are often associated with adverse effects, some of which are well recognized (constipation, sedation, and nausea), whereas others remain underappreciated, such as endocrine-related adverse effects, in particular opioid-induced adrenal insufficiency (OIAI).
      Symptoms of adrenal insufficiency include fatigue, nausea, vomiting, weight loss, dizziness, and muscular aches, many of which overlap with or may compound symptoms related to chronic pain syndrome. This issue in turn may interfere with an opioid taper and the ultimate goal of opioid cessation. Given that most physicians will encounter patients receiving long-term opioid treatment, it is important to recognize OIAI because adrenal insufficiency is associated with increased morbidity and possibly mortality and as such patients need to be counseled appropriately before opioid initiation.

      Pathophysiology

      Opioids, endogenous and exogenous, exert their effects through opioid receptors, primarily μ, δ, and κ receptors. These G protein–coupled receptors are located throughout the body including the hypothalamus and the pituitary gland. In studies in healthy volunteers, administration of high doses of intravenous naloxone (>10 mg), an opioid receptor antagonist with a higher affinity for the μ receptor, led to increased cortisol levels and an augmented corticotropin response to corticotropin-releasing hormone (CRH) stimulation.
      • Delitala G.
      • Devilla L.
      • Arata L.
      Opiate receptors and anterior pituitary hormone secretion in man: effect of naloxone infusion.
      • Allolio B.
      • Schulte H.M.
      • Deuss U.
      • Kallabis D.
      • Hamel E.
      • Winkelman W.
      Effect of oral morphine and naloxone on pituitary-adrenal response in man induced by human corticotropin-releasing hormone.
      Given that naloxone is an opioid antagonist, this finding suggests that endogenous opioids exert tonic inhibition on the hypothalamic-pituitary-adrenal (HPA) axis. In addition, in the acute setting, different opioids with varying receptor affinity—eg, morphine (μ receptor agonist), met-enkephalin (δ receptor agonist), and nalorphine or pentazocine (μ antagonist and κ receptor agonist)—can lead to HPA axis suppression. This result indicates that the modulating effect may not be mediated or solely mediated by the μ receptor, but perhaps δ or κ receptors may also be involved.
      • Delitala G.
      • Grossman A.
      • Besser M.
      Differential effects of opiate peptides and alkaloids on anterior pituitary hormone secretion.

      Short-term Opioid Administration

      The HPA response to the short-term administration of opioids appears to differ between animals and humans, making extrapolation of findings challenging. A single intraperitoneal injection of morphine in rodents is associated with increased corticotropin and glucocorticoid levels.
      • Jezová D.
      • Vigas M.
      • Jurcovicová J.
      ACTH and corticosterone response to naloxone and morphine in normal, hypophysectomized and dexamethasone-treated rats.
      • Buckingham J.C.
      • Cooper T.A.
      Differences in hypothalamo-pituitary-adrenocortical activity in the rat after acute and prolonged treatment with morphine.
      Furthermore, the primary site of opioid action on the HPA axis is thought to be the hypothalamus. However, a positive dose-dependent effect of endogenous and exogenous opioid exposure on adrenal steroid synthesis was seen in Wistar rats,
      • Kapas S.
      • Purbrick A.
      • Hinson J.P.
      Action of opioid peptides on the rat adrenal cortex: stimulation of steroid secretion through a specific μ opioid receptor.
      suggesting that opioid effects may in fact occur on multiple levels. In contrast, a single dose of oral
      • Allolio B.
      • Schulte H.M.
      • Deuss U.
      • Kallabis D.
      • Hamel E.
      • Winkelman W.
      Effect of oral morphine and naloxone on pituitary-adrenal response in man induced by human corticotropin-releasing hormone.
      or intravenous
      • Delitala G.
      • Grossman A.
      • Besser M.
      Differential effects of opiate peptides and alkaloids on anterior pituitary hormone secretion.
      • Gold P.W.
      • Extein I.
      • Pickar D.
      • Rebar R.
      • Ross R.
      • Goodwin F.K.
      Supression of plasma cortisol in depressed patients by acute intravenous methadone infusion.
      opioid in humans resulted in suppression of the HPA axis. The effect of opioids on adrenal steroidogenesis in humans has not been examined.

      Long-term Opioid Administration

      The effect of long-term administration of opioids in rodents is variable, with adrenal suppression seen with higher doses (2 mg/kg per day vs 0.5 mg/d intraperitoneally), whereas rats given morphine at increasing doses (10-100 mg/kg) subcutaneously twice a day for 16 days were found to have elevated basal corticosterone levels.
      • Houshyar H.
      • Cooper Z.D.
      • Woods J.H.
      Paradoxical effects of chronic morphine treatment on the temperature and pituitary-adrenal responses to acute restraint stress: a chronic stress paradigm.
      The results of most human studies (Table 1) suggest that long-term administration of opioids (oral, intravenous, or intrathecal) leads to suppression of the HPA axis.
      • Palm S.
      • Moenig H.
      • Maier C.
      Effects of oral treatment with sustained release morphine tablets on hypothalamic-pituitary-adrenal axis.
      • Abs R.
      • Verhelst J.
      • Maeyaert J.
      • et al.
      Endocrine consequences of long-term intrathecal administration of opioids.
      • Facchinetti F.
      • Grasso A.
      • Petraglia F.
      • Parrini D.
      • Volpe A.
      • Genazzani A.R.
      Impaired circadian rhythmicity of β-lipotrophin, β-endorphin and ACTH in heroin addicts.
      One study, however, reported a significant increased corticotropin response to CRH stimulation in patients treated with long-term opioid therapy compared with controls, with no difference seen in basal cortisol or peak cortisol levels following CRH administration between the groups.
      • Rhodin A.
      • Stridsberg M.
      • Gordh T.
      Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment.
      Proposed mechanisms of reported interindividual differences in results include opioid receptor polymorphisms that may alter opioid receptor affinity
      • Wand G.S.
      • McCaul M.
      • Yang X.
      • et al.
      The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade.
      or genetic variations in interleukin 1β (a stimulator of corticotropin and CRH).
      • Kershaw S.G.
      • Della Vedova C.B.
      • Majumder I.
      • et al.
      Acute opioid administration induces hypothalamic-pituitary-adrenal activation and is mediated by genetic variation in interleukin (Il)1B.
      Conversely, differences in study outcomes may be a consequence of methodology or differences in study population.
      Table 1Summary of the Literature Regarding Opioid-Induced Adrenal Insufficiency, Stratified by Opiate
      ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; HPA = hypothalamic-pituitary-adrenal axis; ITT = insulin tolerance test; MEDD = morphine equivalent daily dose; MOA = mode of administration.
      OpioidReference, yearNo. of participantsMOADurationDose (MEDD)
      Oral MEDD obtained from the study or converted using Agency Medical Directors' Group calculator at www.agencymeddirectors.wa.gov/files/dosingcalc.xl.
      Effect on HPA
      MorphineAllolio et al,
      • Allolio B.
      • Schulte H.M.
      • Deuss U.
      • Kallabis D.
      • Hamel E.
      • Winkelman W.
      Effect of oral morphine and naloxone on pituitary-adrenal response in man induced by human corticotropin-releasing hormone.
      1987
      6 Males and 1 female (placebo-controlled)OralSingle dose30-mg slow releaseReduction in cortisol (124 vs 275 nmol/L), corticotropin (1.2 vs 2.9 pmol/L), and β-endorphin (28 vs 47 pmol/L) with decreased peak response to CRH
      Palm et al,
      • Palm S.
      • Moenig H.
      • Maier C.
      Effects of oral treatment with sustained release morphine tablets on hypothalamic-pituitary-adrenal axis.
      1997
      5 (Double-blind, randomized, placebo-controlled, crossover)Oral1 wkDay 1, 60 mg; day 2, 120 mg; day 3-7, 180 mgSignificant reduction in cortisol and corticotropin (24 vs 10 pg/mL) with reduced response in CRH stimulation (in 2 patients tested)
      Abs et al,
      • Abs R.
      • Verhelst J.
      • Maeyaert J.
      • et al.
      Endocrine consequences of long-term intrathecal administration of opioids.
      2000
      73 Received opioids and 20 chronic non-cancer pain–matched controlsIntrathecalLong-term (mean, 26.6±16.3 mo)Mean daily 4.8±3.2 mg (morphine, n=68; hydromor-phone, n=5)Decreased urinary free cortisol (36 vs 50.7 μg/L) and a reduced peak cortisol after ITT (245.4 vs 300.8 μg/L)
      FentanylOltmanns et al,
      • Oltmanns K.M.
      • Fehm H.L.
      • Peters A.
      Chronic fentanyl application induces adrenocortical insufficiency.
      2005
      1 (Case report)Patch2 y480 mgAdrenal crisis with reduced response to CRH
      Schimke et al,
      • Schimke K.E.
      • Greminger P.
      • Brändle M.
      Secondary adrenal insufficiency due to opiate therapy - another differential diagnosis worth consideration.
      2009
      1 (Case report)Patch7 mo180 mgSecondary adrenal insufficiency with failure of cortisol to increase following corticotropin stimulation
      TramadolDebono et al,
      • Debono M.
      • Chan S.
      • Rolfe C.
      • Jones T.H.
      Tramadol-induced adrenal insufficiency.
      2011
      1 (Case report)Oral3 y15 mgLow basal cortisol (54 nmol/L) with failure to reach peak with corticotropin stimulation test (537 nmol/L; peak >550 nmol/L)
      • Alkatib A.A.
      • Cosma M.
      • Elamin M.B.
      • et al.
      A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency.
      MethadoneGold et al,
      • Gold P.W.
      • Extein I.
      • Pickar D.
      • Rebar R.
      • Ross R.
      • Goodwin F.K.
      Supression of plasma cortisol in depressed patients by acute intravenous methadone infusion.
      1980
      4 (Placebo-controlled crossover)IntravenousSingle dose20 mgSuppression of cortisol, mean decrease of 76.9 ng/mL (73.4%±2.8% change)
      HeroinRasheed & Tareen,
      • Rasheed A.
      • Tareen I.A.
      Effects of heroin on thyroid function, cortisol and testosterone level in addicts.
      1995
      50 Heroin-addicted males and 25 male control patientsInhaled vapors1-y history of addictionNot statedSignificantly reduced cortisol levels in heroin addicts compared with controls, although in the normal reference range (12 vs 16.96 μg/dL; reference range, 8-22 μg/dL)
      Mixed opioidsGibb et al,
      • Gibb F.W.
      • Stewart A.
      • Walker B.R.
      • Strachan M.W.
      Adrenal insufficiency in patients on long-term opioid analgesia.
      2016
      48 Patients with chronic noncancer pain (25 female and 23 male)Oral: tramadol, oxycodone, morphine, or dihydroco-deine

      Patch: fentanyl or buprenor-phine
      Long-term (at least 6 mo use)Median, 68 mg (40-153 mg)4 (8.3%) patients had a basal cortisol level of <100 nmol/L, 3 of whom had inadequate response to corticotropin stimulation test
      Merdin et al,
      • Merdin A.
      • Merdin F.A.
      • Gündüz Ş.
      • Bozcuk H.
      • Coşkun H.Ş.
      Opioid endocrinopathy: a clinical problem in patients with cancer pain.
      2016
      20 Patients with chronic cancer-associated painNot specifiedLong-term (≥1 mo use)Median, 180 mg/d (10-420 mg/d)Serum cortisol level was lower than the normal reference range in 3 patients (15%) and higher than normal range in 8 (40%) (reference range, 4.3-22.4 μg/dL). Corticotropin level was normal in 17 of 18 patients (94.5%) (reference range, 0-65 pg/mL)
      Rhodin et al,
      • Rhodin A.
      • Stridsberg M.
      • Gordh T.
      Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment.
      2010
      39 Patients with chronic noncancer pain, 20 chronic non-cancer controlsMethadone and slow-release morphine or oxycodoneLong-term (>1 y)Mean in males treated with methadone, 1596 mg; and in females. 1322 mgPeak corticotropin level following CRH was higher in the opioid-treated group than in controls (73.7 IE/L vs 39.2 IE/l) with no difference in basal or peak cortisol level
      a ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; HPA = hypothalamic-pituitary-adrenal axis; ITT = insulin tolerance test; MEDD = morphine equivalent daily dose; MOA = mode of administration.
      b Oral MEDD obtained from the study or converted using Agency Medical Directors' Group calculator at www.agencymeddirectors.wa.gov/files/dosingcalc.xl.

      Epidemiology

      The true prevalence, pathophysiology, optimal investigation, and treatment outcome in OIAI remain elusive. Available data are primarily limited to small placebo-controlled trials, retrospective studies, or case reports with varying opioid formulations, frequency, and modes of administration. In addition, investigations for adrenal insufficiency have not been consistent, making interpretation or comparison of the available results difficult.
      In a study examining the effects of long-term intrathecal morphine or hydromorphone therapy in 73 individuals, the prevalence of OIAI was 9.2% based on a basal cortisol level of less than 5 μg/dL (to convert to nmol/L, multiply by 27.588), 15% based on an insulin tolerance test, and 20% based on 24-hour urinary free cortisol level below the reference range (20-90 μg/24 h; to convert to nmol/24 h, multiply by 2.76).
      • Abs R.
      • Verhelst J.
      • Maeyaert J.
      • et al.
      Endocrine consequences of long-term intrathecal administration of opioids.
      In another study of 17 patients receiving long-term treatment with opioids (≥20 mg of morphine equivalent daily doses [MEDDs] for >4 weeks), 29% (5 of 17) had a basal cortisol level of less than 5 μg/dL (the timing of cortisol measurement was not clear), and 10% (1 of 10) did not reach the threshold cutoff (20 μg/dL) following a 1-μg corticotropin stimulation test.
      • Nenke M.A.
      • Haylock C.L.
      • Rankin W.
      • et al.
      Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses: a pilot randomized, placebo-controlled trial.
      More recently, 12% of patients (3 of 25) receiving different opioids with a median daily opioid dose of 68 mg had negative findings on a corticotropin stimulation test.
      • Gibb F.W.
      • Stewart A.
      • Walker B.R.
      • Strachan M.W.
      Adrenal insufficiency in patients on long-term opioid analgesia.
      Therefore, the estimated prevalence of OIAI varies from 9% to 29%.
      Several factors, such as increasing opioid dose and longer duration of action, have been identified as risk factors for the development of opioid-induced androgen deficiency; however, risk factors for the development of OIAI have not been identified or systematically studied. Among those with chronic cancer pain receiving 20 mg or more of MEDDs for 1 month or longer, no association was found with MEDD or patient sex and corticotropin or cortisol concentration.
      • Merdin A.
      • Merdin F.A.
      • Gündüz Ş.
      • Bozcuk H.
      • Coşkun H.Ş.
      Opioid endocrinopathy: a clinical problem in patients with cancer pain.
      In opposition, a study involving 48 individuals with noncancer-associated pain receiving long-term opioid therapy (median MEDD, 68 mg) in whom morning cortisol concentrations were grouped into tertiles, lower basal cortisol levels were associated with female sex, increased body mass index, and younger age.
      • Gibb F.W.
      • Stewart A.
      • Walker B.R.
      • Strachan M.W.
      Adrenal insufficiency in patients on long-term opioid analgesia.

      Diagnosis

      In a patient taking opiates who presents with symptoms of adrenal insufficiency, baseline cortisol and corticotropin measurement in addition to synthetic corticotropin (cosyntropin) stimulation testing (CST) is recommended.
      • Bancos I.
      • Hahner S.
      • Tomlinson J.
      • Arlt W.
      Diagnosis and management of adrenal insufficiency.
      In OIAI, we expect to find a low cortisol level along with a low or inappropriately normal corticotropin concentration and a failure to mount an appropriate cortisol response after synthetic corticotropin administration. Alternative causes of secondary adrenal insufficiency, such as exogenous glucocorticoid use or pituitary abnormalities, should be considered before diagnosing OIAI because management may be different. Opioid-induced adrenal insufficiency occurs primarily due to suppression of the HPA axis, rather than suppression/destruction of the adrenal cortex, and as such, mineralocorticoid deficiency does not occur. Dehydroepiandrosterone sulfate (DHEA-S), a weak adrenal androgen hormone produced by the zona reticularis in response to corticotropin stimulation, levels will be low and can be used as an indirect marker of low corticotropin level.
      Importantly, current tests to assess adrenal insufficiency have limitations and must be interpreted in the appropriate clinical context. Not all patients with OIAI may have an abnormal CST result. As illustrated by Ospina et al,
      • Ospina N.S.
      • Al Nofal A.
      • Bancos I.
      • et al.
      ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis.
      sensitivity of the 250-μg CST in secondary adrenal insufficiency is suboptimal (64%; 95% CI, 52%-73%), with a likelihood ratio for a negative result being only 0.39 (0.3-0.52). The CST is reliant on adrenal cortex atrophy, which occurs in primary adrenal insufficiency or prolonged absence of corticotropin. However, the onset of OIAI is unknown, and some background corticotropin may be present (partial secondary adrenal insufficiency) depending on the dose, duration, and individual susceptibility to opiates. This factor may explain the suboptimal performance of the test. In this situation, the administration of supraphysiologic synthetic corticotropin may stimulate the adrenal cortex enough to mount a cortisol response above the cutoff considered diagnostic (18-20 μg/dL). Although basal cortisol cutoffs utilized to assess adrenal insufficiency vary institutionally and given the limitations in diagnostic accuracy, the following diagnostic approach using morning basal cortisol, corticotropin, and DHEA-S levels initially, as outlined in the Figure, can be considered. Among patients referred for HPA axis assessment, a morning (8-9 AM) basal cortisol level of greater than 10 μg/dL or less than 5 μg/dL predicted a sufficient or insufficient response to the 250-μg CST.
      • Yip C.E.
      • Stewart S.A.
      • Imran F.
      • et al.
      The role of morning basal serum cortisol in assessment of hypothalamic pituitary-adrenal axis.
      Although the low-dose (1-μg) CST could be considered, it is unclear if it would provide any additional value over the 250-μg CST, it contributes to technical difficulties related to accurate dilution, and it is not universally available. A 24-hour urinary free cortisol measurement does not perform well in the assessment of adrenal insufficiency and is not indicated. It is important, however, to consider the overall hormonal assessment when diagnosing OIAI because partial adrenal deficiency may present with equivocal results that should prompt further investigations. Alternatively, when clinical suspicion for OIAI is high and investigation results remain equivocal, a therapeutic trial of physiologic glucocorticoid hormone replacement for a few months can be considered and continued if symptom improvement is sustained.
      Figure thumbnail gr1
      FigureSuggested diagnostic flowchart for opioid-induced adrenal insufficiency (OIAI). CST = cosyntropin stimulation test; DHEA-S = dehydroepiandrosterone sulfate; ITT = insulin tolerance test.

      Treatment

      Cortisol release, stimulated by corticotropin, is regulated by the suprachiasmatic nucleus in the hypothalamus and follows a circadian rhythm. Therefore, in states of cortisol deficiency, replacement is aimed at replicating the physiologic cortisol profile to eliminate symptoms associated with adrenal insufficiency while avoiding the complications of excess replacement. This process remains a challenge with currently available oral glucocorticoid preparations (Table 2). Hydrocortisone is the most commonly used glucocorticoid. Endogenous glucocorticoid production is estimated to be between 5 and 10 mg/m.
      • Nahin R.L.
      Estimates of pain prevalence and severity in adults: United States, 2012.
      • Esteban N.V.
      • Loughlin T.
      • Yergey A.L.
      • et al.
      Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry.
      Hydrocortisone doses ranging from 15 to 25 mg/d, given in divided doses 2 to 3 times a day with the majority given on waking (50%-66%) are typically recommended. Alternative glucocorticoid preparations with a longer half-life are available (prednisone, prednisolone, and dexamethasone) and may improve compliance but are more likely to be associated with excess glucocorticoid effects and greater suppression of endogenous cortisol release.
      • Filipsson H.
      • Monson J.P.
      • Koltowska-Häggström M.
      • Mattsson A.
      • Johannsson G.
      The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients.
      Adequacy of replacement is based on symptomatic control because there is no single reliable variable to assess optimal dosing. Among those with secondary adrenal insufficiency such as OIAI, mineralocorticoid replacement is not required.
      Table 2Management of Opioid-Induced Adrenal Insufficiency
      ManagementInstructionConsiderationAlternative
      MedicationHydrocortisone 15-25 mg/d in divided doses, eg, 10 mg on waking, 5 mg 6-8 h laterDHEA supplementation in women (25 mg/d)Dose-equivalent prednisone/prednisolone
      EducationSick day rule 1: Double your daily glucocorticoid replacement therapy in times of sickness

      Sick day rule 2: Administer IM corticosteroid in times of sickness and inability to take orally (if family or patient can administer IM corticosteroids)

      Corticosteroid card or written adrenal insufficiency action plan stating sick day rules

      Medic alert bracelet or necklace indicating the presence of adrenal insufficiency
      Annual check of IM corticosteroid expiration dateDexamethasone 4 mg, methylprednisolone 40 mg
      Emergency/adrenal crisisAdminister 100 mg hydrocortisone IV/IM, IV hydrationOptimize education regarding sick day rules to prevent adrenal crisisDexamethasone 4 mg, methylprednisolone 40 mg
      Procedure/operationAdminister 100 mg hydrocortisone IV/IM before procedure followed by 200 mg/d IV until able to eat and drinkNoneDexamethasone 4 mg, methylprednisolone 40 mg
      DHEA = dehydroepiandrosterone; IM = intramuscular; IV = intravenous.
      Adrenal androgens contribute minimally to male androgen concentrations; however, they contribute considerably to the female androgen pool. Among long-term opioid users, DHEA-S levels are reported to be lower than in those who do not use opioids.
      • Daniell H.W.
      DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production.
      Dehydroepiandrosterone sulfate supplementation in both primary and secondary adrenal insufficiency has been examined with overall statistically significant although clinically minimal effect.
      • Alkatib A.A.
      • Cosma M.
      • Elamin M.B.
      • et al.
      A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency.
      None of the studies specifically examined DHEA-S supplementation in OIAI. Although routine supplementation is not recommended, a trial may be of use, especially in younger women with low libido, depressive symptoms, and decreased energy who are receiving optimal glucocorticoid replacement.
      • Bornstein S.R.
      • Allolio B.
      • Arlt W.
      • et al.
      Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline.
      More recently, in an attempt to optimize cortisol replacement, several methods of cortisol delivery have been developed. Continuous subcutaneous infusion of glucocorticoids allows for finer dose alteration and replication of the circadian rhythm. Alternatively, new oral formulations using delayed and sustained-release multiparticulate tablets (Chronocort, Diurnal Group PLC) or immediate release with a sustained-release core (Plenadren, Shire) to better resemble a physiologic profile have been developed but are currently under study.
      • Bornstein S.R.
      • Allolio B.
      • Arlt W.
      • et al.
      Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline.
      It is worth noting that the use of these novel agents has not been investigated in the setting of OIAI.
      In the event of adrenal crisis, characterized by nausea, vomiting, myalgias, postural hypotension, and eventually cardiovascular collapse, prompt treatment with adequate hydration (1 L of 0.9% saline over 1 hour followed by an infusion based on patient needs) and parenteral glucocorticoids (100 mg of intravenous hydrocortisone followed by 200 mg of hydrocortisone per day) are essential.
      • Bornstein S.R.
      • Allolio B.
      • Arlt W.
      • et al.
      Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline.
      The best treatment for adrenal crisis is prevention and requires education of both physicians and patients. Patients should be instructed to increase corticosteroids in the event of stress (trauma, surgery, or major psychological stress) and illness (typically double or triple dose for 2-3 days) and if unable to tolerate oral intake or if symptoms are severe, intramuscular corticosteroids are required. In addition, utility of a medic alert bracelet/necklace or a corticosteroid card is helpful to inform responders of the patient’s unique needs.
      Limited data, based on case reports, suggest that complete cessation of opioids leads to reversal of OIAI (Table 1). The time to recovery or the lowest opioid dose at which the HPA axis recovers is unknown. Therefore, periodic assessment of adrenal function once opioids have been discontinued is recommended.

      Conclusion

      Available data from small heterogeneous studies suggest that 9% to 29% of patients receiving long-term treatment with opiates have development of adrenal insufficiency. However, predictors and the timing of the OIAI onset are unclear. Given the widespread use of narcotics in every field of medicine, physicians should be aware of the potential for endocrine-related adverse effects, in particular OIAI. We suggest careful consideration of OIAI in any patient receiving long-term opiate therapy who manifests symptoms and signs suggestive of adrenal insufficiency. Prospective large studies need to be designed with the goals of elucidating factors associated with OIAI, developing the best approach to case detection of OIAI, and establishing an appropriate management and monitoring plan.

      References

        • Boudreau D.
        • Von Korff M.
        • Rutter C.M.
        • et al.
        Trends in long-term opioid therapy for chronic non-cancer pain.
        Pharmacoepidemiol Drug Saf. 2009; 18: 1166-1175
        • Nahin R.L.
        Estimates of pain prevalence and severity in adults: United States, 2012.
        J Pain. 2015; 16: 769-780
        • Delitala G.
        • Devilla L.
        • Arata L.
        Opiate receptors and anterior pituitary hormone secretion in man: effect of naloxone infusion.
        Acta Endocrinol (Copenh). 1981; 97: 150-156
        • Allolio B.
        • Schulte H.M.
        • Deuss U.
        • Kallabis D.
        • Hamel E.
        • Winkelman W.
        Effect of oral morphine and naloxone on pituitary-adrenal response in man induced by human corticotropin-releasing hormone.
        Acta Endocrinol (Copenh). 1987; 114: 509-514
        • Delitala G.
        • Grossman A.
        • Besser M.
        Differential effects of opiate peptides and alkaloids on anterior pituitary hormone secretion.
        Neuroendocrinology. 1983; 37: 275-279
        • Jezová D.
        • Vigas M.
        • Jurcovicová J.
        ACTH and corticosterone response to naloxone and morphine in normal, hypophysectomized and dexamethasone-treated rats.
        Life Sci. 1982; 31: 307-314
        • Buckingham J.C.
        • Cooper T.A.
        Differences in hypothalamo-pituitary-adrenocortical activity in the rat after acute and prolonged treatment with morphine.
        Neuroendocrinology. 1984; 38: 411-417
        • Kapas S.
        • Purbrick A.
        • Hinson J.P.
        Action of opioid peptides on the rat adrenal cortex: stimulation of steroid secretion through a specific μ opioid receptor.
        J Endocrinol. 1995; 144: 503-510
        • Gold P.W.
        • Extein I.
        • Pickar D.
        • Rebar R.
        • Ross R.
        • Goodwin F.K.
        Supression of plasma cortisol in depressed patients by acute intravenous methadone infusion.
        Am J Psychiatry. 1980; 137: 862-863
        • Houshyar H.
        • Cooper Z.D.
        • Woods J.H.
        Paradoxical effects of chronic morphine treatment on the temperature and pituitary-adrenal responses to acute restraint stress: a chronic stress paradigm.
        J Neuroendocrinol. 2001; 13: 862-874
        • Palm S.
        • Moenig H.
        • Maier C.
        Effects of oral treatment with sustained release morphine tablets on hypothalamic-pituitary-adrenal axis.
        Methods Find Exp Clin Pharmacol. 1997; 19: 269-273
        • Abs R.
        • Verhelst J.
        • Maeyaert J.
        • et al.
        Endocrine consequences of long-term intrathecal administration of opioids.
        J Clin Endocrinol Metab. 2000; 85: 2215-2222
        • Oltmanns K.M.
        • Fehm H.L.
        • Peters A.
        Chronic fentanyl application induces adrenocortical insufficiency.
        J Intern Med. 2005; 257: 478-480
        • Schimke K.E.
        • Greminger P.
        • Brändle M.
        Secondary adrenal insufficiency due to opiate therapy - another differential diagnosis worth consideration.
        Exp Clin Endocrinol Diabetes. 2009; 117: 649-651
        • Debono M.
        • Chan S.
        • Rolfe C.
        • Jones T.H.
        Tramadol-induced adrenal insufficiency.
        Eur J Clin Pharmacol. 2011; 67: 865-867
        • Rasheed A.
        • Tareen I.A.
        Effects of heroin on thyroid function, cortisol and testosterone level in addicts.
        Pol J Pharmacol. 1995; 47: 441-444
        • Gibb F.W.
        • Stewart A.
        • Walker B.R.
        • Strachan M.W.
        Adrenal insufficiency in patients on long-term opioid analgesia.
        Clin Endocrinol (Oxf). 2016; 85: 831-835
        • Merdin A.
        • Merdin F.A.
        • Gündüz Ş.
        • Bozcuk H.
        • Coşkun H.Ş.
        Opioid endocrinopathy: a clinical problem in patients with cancer pain.
        Exp Ther Med. 2016; 11: 1819-1822
        • Rhodin A.
        • Stridsberg M.
        • Gordh T.
        Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment.
        Clin J Pain. 2010; 26: 374-380
        • Facchinetti F.
        • Grasso A.
        • Petraglia F.
        • Parrini D.
        • Volpe A.
        • Genazzani A.R.
        Impaired circadian rhythmicity of β-lipotrophin, β-endorphin and ACTH in heroin addicts.
        Acta Endocrinol (Copenh). 1984; 105: 149-155
        • Wand G.S.
        • McCaul M.
        • Yang X.
        • et al.
        The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade.
        Neuropsychopharmacology. 2002; 26: 106-114
        • Kershaw S.G.
        • Della Vedova C.B.
        • Majumder I.
        • et al.
        Acute opioid administration induces hypothalamic-pituitary-adrenal activation and is mediated by genetic variation in interleukin (Il)1B.
        Pharmacol Biochem Behav. 2015; 138: 9-13
        • Nenke M.A.
        • Haylock C.L.
        • Rankin W.
        • et al.
        Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses: a pilot randomized, placebo-controlled trial.
        Psychoneuroendocrinology. 2015; 56: 157-167
        • Bancos I.
        • Hahner S.
        • Tomlinson J.
        • Arlt W.
        Diagnosis and management of adrenal insufficiency.
        Lancet Diabetes Endocrinol. 2015; 3: 216-226
        • Ospina N.S.
        • Al Nofal A.
        • Bancos I.
        • et al.
        ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis.
        J Clin Endocrinol Metab. 2016; 101: 427-434
        • Yip C.E.
        • Stewart S.A.
        • Imran F.
        • et al.
        The role of morning basal serum cortisol in assessment of hypothalamic pituitary-adrenal axis.
        Clin Invest Med. 2013; 36: E216-E222
        • Esteban N.V.
        • Loughlin T.
        • Yergey A.L.
        • et al.
        Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry.
        J Clin Endocrinol Metab. 1991; 72: 39-45
        • Filipsson H.
        • Monson J.P.
        • Koltowska-Häggström M.
        • Mattsson A.
        • Johannsson G.
        The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients.
        J Clin Endocrinol Metab. 2006; 91: 3954-3961
        • Daniell H.W.
        DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production.
        J Pain. 2006; 7: 901-907
        • Alkatib A.A.
        • Cosma M.
        • Elamin M.B.
        • et al.
        A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency.
        J Clin Endocrinol Metab. 2009; 94: 3676-3681
        • Bornstein S.R.
        • Allolio B.
        • Arlt W.
        • et al.
        Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2016; 101: 364-389