{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:00:42Z","timestamp":1788235242706,"version":"build-2803163510"},"reference-count":95,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,26]],"date-time":"2023-02-26T00:00:00Z","timestamp":1677369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Among several opioid-associated endocrinopathies, opioid-associated adrenal insufficiency (OIAI) is both common and not well understood by most clinicians, particularly those outside of endocrine specialization. OIAI is secondary to long-term opioid use and differs from primary adrenal insufficiency. Beyond chronic opioid use, risk factors for OIAI are not well known. OIAI can be diagnosed by a variety of tests, such as the morning cortisol test, but cutoff values are not well established and it is estimated that only about 10% of patients with OIAI will ever be properly diagnosed. This may be dangerous, as OIAI can lead to a potentially life-threatening adrenal crisis. OIAI can be treated and for patients who must continue opioid therapy, it can be clinically managed. OIAI resolves with opioid cessation. Better guidance for diagnosis and treatment is urgently needed, particularly in light of the fact that 5% of the United States population has a prescription for chronic opioid therapy.<\/jats:p>","DOI":"10.3390\/ijms24054575","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T03:29:48Z","timestamp":1677468588000},"page":"4575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["A Closer Look at Opioid-Induced Adrenal Insufficiency: A Narrative Review"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7184-5519","authenticated-orcid":false,"given":"Flaminia","family":"Coluzzi","sequence":"first","affiliation":[{"name":"Department Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, 04100 Latina, Italy"},{"name":"Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant\u2019Andrea University Hospital, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo Ann K.","family":"LeQuang","sequence":"additional","affiliation":[{"name":"NEMA Research, Inc., Naples, FL 34108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1492-5365","authenticated-orcid":false,"given":"Salvatore","family":"Sciacchitano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy"},{"name":"Laboratory of Biomedical Research, Niccol\u00f2 Cusano University Foundation, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Sole","family":"Scerpa","sequence":"additional","affiliation":[{"name":"Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant\u2019Andrea University Hospital, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8380-3607","authenticated-orcid":false,"given":"Monica","family":"Rocco","sequence":"additional","affiliation":[{"name":"Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant\u2019Andrea University Hospital, 00189 Rome, Italy"},{"name":"Department of Surgical and Medical Science and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5658-1471","authenticated-orcid":false,"given":"Joseph","family":"Pergolizzi","sequence":"additional","affiliation":[{"name":"NEMA Research, Inc., Naples, FL 34108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1002\/pds.1833","article-title":"Trends in long-term opioid therapy for chronic non-cancer pain","volume":"18","author":"Boudreau","year":"2009","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.mayocp.2018.04.010","article-title":"Opioid-Induced Adrenal Insufficiency","volume":"93","author":"Donegan","year":"2018","journal-title":"Mayo Clin. Proc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e3766","DOI":"10.1210\/clinem\/dgaa499","article-title":"Prevalence of Opioid-Induced Adrenal Insufficiency in Patients Taking Chronic Opioids","volume":"105","author":"Li","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"601939","DOI":"10.3389\/fnbeh.2020.601939","article-title":"The Hypothalamic-Pituitary-Adrenal Axis: Development, Programming Actions of Hormones, and Maternal-Fetal Interactions","volume":"14","author":"Sheng","year":"2021","journal-title":"Front. Behav. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1097\/AJP.0b013e3181d1059d","article-title":"Opioid Endocrinopathy: A Clinical Problem in Patients with Chronic Pain and Long-term Oral Opioid Treatment","volume":"26","author":"Rhodin","year":"2010","journal-title":"Clin. J. Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/S2213-8587(19)30254-2","article-title":"Opioid-induced endocrinopathies","volume":"8","author":"Fountas","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.psyneuen.2015.03.015","article-title":"Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial","volume":"56","author":"Nenke","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(21)00136-7","article-title":"Adrenal insufficiency","volume":"397","author":"Husebye","year":"2021","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41572-021-00252-7","article-title":"Adrenal insufficiency","volume":"7","author":"Hahner","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1056\/NEJMra1807486","article-title":"Adrenal Crisis","volume":"381","author":"Rushworth","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"802","DOI":"10.3122\/jabfm.2021.04.200610","article-title":"Opioid Education and Prescribing Practices","volume":"34","author":"Price","year":"2021","journal-title":"J. Am. Board Fam. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/pds.4278","article-title":"National trends in long-term use of prescription opioids","volume":"27","author":"Mojtabai","year":"2018","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/MED.0000000000000474","article-title":"Opioid induced adrenal insufficiency: What is new?","volume":"26","author":"Donegan","year":"2019","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"SAT-383","DOI":"10.1210\/js.2019-SAT-383","article-title":"SAT-383 Prevalence of Opioid Induced Adrenal Insuf-ficiency in Patients Taking Chronic Opioids","volume":"3","author":"Li","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1007\/s40618-018-0964-3","article-title":"Testosterone deficiency in non-cancer opioid-treated patients","volume":"41","author":"Coluzzi","year":"2018","journal-title":"J. Endocrinol. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1530\/EJE-18-0530","article-title":"Secondary adrenal insufficiency and pituitary dysfunction in oral\/transdermal opioid users with non-cancer pain","volume":"179","author":"Lamprecht","year":"2018","journal-title":"Eur. J. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/cen.13125","article-title":"Adrenal insufficiency in patients on long-term opioid analgesia","volume":"85","author":"Gibb","year":"2016","journal-title":"Clin. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1136\/postgradmedj-2020-137829","article-title":"Secondary adrenal insufficiency: An insidious consequence of the opioid epidemic?","volume":"97","author":"Fox","year":"2021","journal-title":"Post-Grad. Med. J."},{"key":"ref_19","first-page":"607","article-title":"Recognizing Adrenal Insufficiency in Substance Use Disorder: A Case Study of Opioid-Related Suppression of Hypothalamo-Pituitary-Adrenal Axis","volume":"20","author":"Gordin","year":"2019","journal-title":"Pain Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.4158\/EP-2020-0297","article-title":"Clinical Presentation and Outcomes of Opioid-Induced Adrenal Insufficiency","volume":"26","author":"Li","year":"2020","journal-title":"Endocr. Pract."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.eprac.2021.09.011","article-title":"Secondary Adrenal Insufficiency: Recent Updates and New Directions for Diagnosis and Management","volume":"28","author":"Gruber","year":"2022","journal-title":"Endocr. Pract."},{"key":"ref_22","first-page":"541","article-title":"Central adrenal insufficiency: Who, when, and how? From the evidence to the controversies\u2014An exploratory review","volume":"66","author":"Bitencourt","year":"2022","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1097\/MAJ.0b013e3181db6b7a","article-title":"Delayed Diagnosis of Adrenal Insufficiency Is Common: A Cross-Sectional Study in 216 Patients","volume":"339","author":"Bleicken","year":"2010","journal-title":"Am. J. Med Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4855","DOI":"10.1210\/jc.2010-0982","article-title":"Clinical Review#: The diagnosis and management of central hypoadrenalism","volume":"95","author":"Grossman","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/cen.14587","article-title":"The biochemical diagnosis of adrenal insufficiency with modern cortisol assays: Reappraisal in the setting of opioid exposure and hospitalization","volume":"96","author":"Colling","year":"2022","journal-title":"Clin. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S258","DOI":"10.1038\/sj.bjp.0706456","article-title":"Glucocorticoids: Exemplars of multi-tasking","volume":"147","author":"Buckingham","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0376-8716(85)90014-6","article-title":"Hypothalamus-pituitary-adrenal axis of heroin addicts","volume":"15","author":"Facchinetti","year":"1985","journal-title":"Drug Alcohol Depend."},{"key":"ref_28","first-page":"149","article-title":"Impaired circadian rhythmicity of beta-lipotropin be-ta-endorphin and ACTH in heroin addicts","volume":"105","author":"Facchinetti","year":"1984","journal-title":"Acta Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1210\/jcem-32-2-266","article-title":"Characterization of the Normal Temporal Pattern of Plasma Corticosteroid Levels","volume":"32","author":"Krieger","year":"1971","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1210\/jc.2016-2118","article-title":"Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline","volume":"101","author":"Fleseriu","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1210\/jc.2015-1700","article-title":"ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis","volume":"101","author":"Ospina","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1530\/EJE-09-0746","article-title":"Technical details influence the diagnostic accuracy of the 1 microg ACTH stimulation test","volume":"162","author":"Wade","year":"2010","journal-title":"Eur. J. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.4158\/EP-2019-0177","article-title":"Current knowledge and practices of heath care professionals on opioid-induced adrenal insufficiency","volume":"25","author":"Saeed","year":"2019","journal-title":"Endocr. Pract."},{"key":"ref_34","first-page":"150035","article-title":"Opioid-induced secondary adrenal insufficiency presenting as hypercalcaemia","volume":"2015","author":"Lee","year":"2015","journal-title":"Endocrinol. Diabetes Metab. Case Rep."},{"key":"ref_35","unstructured":"Centers for Disease Control and Prevention (2019, April 15). Pocket Guide: Tapering Opioids for Chronic Pain. CDC, Available online: https:\/\/www.cdc.gov\/drugoverdose\/pdf\/clinical_pocket_guide_tapering-a.pdf."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s11102-021-01202-y","article-title":"Opioids and pituitary function: Expert opinion","volume":"25","author":"Gadelha","year":"2022","journal-title":"Pituitary"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1507\/endocrj.EJ21-0359","article-title":"Opioid-induced adrenal insufficiency in transdermal fentanyl treatment: A revisited di-agnosis in clinical setting","volume":"69","author":"Kondo","year":"2022","journal-title":"Endocr. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"G25","DOI":"10.1530\/EJE-20-0361","article-title":"Endocrinology in the time of COVID-19: Management of adrenal insufficiency","volume":"183","author":"Arlt","year":"2020","journal-title":"Eur. J. Endocrinol."},{"key":"ref_39","first-page":"e23021","article-title":"Secondary Adrenal Insufficiency After COVID-19 Diagnosed by Insulin Tolerance Test and Corticotropin-Releasing Hormone Test","volume":"14","author":"Hamazaki","year":"2022","journal-title":"Cureus"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.4103\/jfmpc.jfmpc_1405_21","article-title":"Adrenal crisis in a patient with APS2 due to COVID-19: A case report","volume":"11","author":"Naik","year":"2022","journal-title":"J. Fam. Med. Prim. Care"},{"key":"ref_41","unstructured":"(2022, December 15). Society for Endocrinology. Adrenal Crisis during COVID-19 Pandemic. Society for Endocrinology. Available online: https:\/\/www.endocrinology.org\/clinical-practice\/clinical-guidance\/adrenal-crisis\/covid-19-adrenal-crisis-information\/."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"A74","DOI":"10.1210\/jendso\/bvac150.153","article-title":"ODP580 A Case of New Onset Primary Adrenal Insufficiency in COVID Infection","volume":"6","author":"Beshay","year":"2022","journal-title":"J. Endocr. Soc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41574-022-00700-8","article-title":"Is there a role for the adrenal glands in long COVID?","volume":"18","author":"Kanczkowski","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1056\/NEJMra0804635","article-title":"Predisposing Factors for Adrenal Insufficiency","volume":"360","author":"Bornstein","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1038\/s41467-022-29145-3","article-title":"Adrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19","volume":"13","author":"Paul","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.jpain.2006.04.011","article-title":"DHEAS deficiency during consumption of sustained-action prescribed opioids: Evidence for opioid-induced in-hibition of adrenal androgen production","volume":"7","author":"Daniell","year":"2006","journal-title":"J. Pain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1210\/jc.2015-1710","article-title":"Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline","volume":"101","author":"Bornstein","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s40122-021-00272-x","article-title":"Factors Influencing Pain Expression in Patients with Cancer: An Expert Opinion","volume":"10","author":"Mercadante","year":"2021","journal-title":"Pain Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.2147\/JPR.S243435","article-title":"Naldemedine: A New Option for OIBD","volume":"13","author":"Coluzzi","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3093","DOI":"10.2174\/092986711796391660","article-title":"Bone metastatic disease: Taking aim at new therapeutic targets","volume":"18","author":"Coluzzi","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"515","DOI":"10.2147\/TCRM.S79409","article-title":"The unsolved case of \u201cbone-impairing analgesics\u201d: The endocrine effects of opioids on bone metabolism","volume":"11","author":"Coluzzi","year":"2015","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s00228-011-0992-9","article-title":"Tramadol-induced adrenal insufficiency","volume":"67","author":"Debono","year":"2011","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/papr.12646","article-title":"Oral Prolonged-Release Oxycodone\/Naloxone for Managing Pain and Opi-oid-Induced Constipation: A Review of the Evidence","volume":"18","author":"Morlion","year":"2018","journal-title":"Pain Pract."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.2147\/TCRM.S141332","article-title":"The challenge of perioperative pain management in opioid-tolerant patients","volume":"13","author":"Coluzzi","year":"2017","journal-title":"Ther Clin Risk Manag."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.aprim.2018.09.021","article-title":"Adrenal insufficiency in a patient treated with tramadol","volume":"51","year":"2019","journal-title":"Aten Primaria"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"211","DOI":"10.5055\/jom.2015.0270","article-title":"Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency","volume":"11","author":"Eichenbaum","year":"2015","journal-title":"J. Opioid Manag."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.drugalcdep.2012.01.013","article-title":"Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR","volume":"124","author":"Peng","year":"2012","journal-title":"Drug Alcohol Depend."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1213\/00000539-199301000-00031","article-title":"Peripheral mechanisms of opioid analgesia","volume":"76","author":"Stein","year":"1993","journal-title":"Anesth. Analg."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.coph.2008.12.009","article-title":"Peripheral mechanisms of opioid analgesia","volume":"9","author":"Stein","year":"2009","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1093\/brain\/awg115","article-title":"Peripheral opioid analgesia in experimental human pain models","volume":"126","author":"Tegeder","year":"2003","journal-title":"Brain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/978-1-0716-0884-5_7","article-title":"Immunohistochemical Analysis of Opioid Receptors in Peripheral Tissues","volume":"2201","author":"Schmidt","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Estomba, H., Hoyos, I.M., Gianzo, M., Arenaza, I.U., Casis, L., Irazusta, J., and Subir\u00e1n, N. (2016). Expression and Localization of Opioid Receptors in Male Germ Cells and the Implication for Mouse Spermatogenesis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152162"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bja.2017.11.110","article-title":"Cardiac \u03bc-opioid receptor contributes to opioid-induced cardioprotection in chronic heart failure","volume":"121","author":"He","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3109\/00365528709090997","article-title":"Opioids and Opioid Receptors in Peripheral Tissues","volume":"22","author":"Hedner","year":"1987","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/0165-6147(85)90098-7","article-title":"Enteric neuropeptides: Role in neuromuscular activity of the gut","volume":"6","author":"Makhlouf","year":"1985","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00726-011-1163-0","article-title":"Role of the mu-opioid receptor in opioid modulation of immune function","volume":"45","author":"Roy","year":"2013","journal-title":"Amino Acids"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Brejchova, J., Holan, V., and Svoboda, P. (2020). Expression of Opioid Receptors in Cells of the Immune System. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010315"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1136\/ard.2006.067066","article-title":"Beta-endorphin, Met-enkephalin and corresponding opioid receptors within syn-ovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis","volume":"66","author":"Mousa","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s00210-005-0013-6","article-title":"Effects of the local administration of selective mu-, del-ta-and kappa-opioid receptor agonists on osteosarcoma-induced hyperalgesia","volume":"372","author":"Baamonde","year":"2005","journal-title":"Naunyn Schmiedeberg Arch. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1016\/j.peptides.2006.07.004","article-title":"Endogenous beta-endorphin induces thermal analgesia at the initial stages of a murine osteosarcoma","volume":"27","author":"Baamonde","year":"2006","journal-title":"Peptides"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1124\/mol.120.119388","article-title":"Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions","volume":"98","author":"Fricker","year":"2020","journal-title":"Mol. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1006\/bbrc.1996.0156","article-title":"Tissue Distribution of Opioid Receptor Gene Expression in the Rat","volume":"218","author":"Wittert","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3409\/fb63_3.187","article-title":"The Effect of CRH, Dexame-thasone and Naltrexone on the Mu, Delta and Kappa Opioid Receptor Agonist Binding in Lamb Hypothalamic-Pituitary-Adrenal Axis","volume":"63","author":"Oeltgen","year":"2015","journal-title":"Folia Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nature15721","article-title":"Oxygen regulation of breathing through an olfactory receptor activated by lactate","volume":"527","author":"Chang","year":"2015","journal-title":"Nature"},{"key":"ref_76","first-page":"461","article-title":"The expression of genes encoding opioid precursors and the influence of opioid receptor agonists on steroidogenesis in porcine adrenocortical cells in vitro","volume":"62","author":"Krazinski","year":"2011","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0006-8993(02)02648-3","article-title":"Inhibitory effects of opioids on voltage-dependent Ca2+ channels and catecholamine secretion in cultured porcine adrenal chromaffin cells","volume":"942","author":"Kitamura","year":"2002","journal-title":"Brain Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"7473","DOI":"10.1073\/pnas.77.12.7473","article-title":"Release of enkephalins and enkephalin-containing polypeptides from perfused beef adrenal glands","volume":"77","author":"Kilpatrick","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","first-page":"63","article-title":"Catecholamine and ATP metabolites released from perfused adrenal glands of guinea-pig","volume":"48","author":"Sasahara","year":"2000","journal-title":"Jpn. J. Vetinary Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/0024-3205(80)90461-0","article-title":"Opioid peptides in adrenal gland","volume":"27","author":"Yang","year":"1980","journal-title":"Life Sci."},{"key":"ref_81","first-page":"1101","article-title":"Opiate-like materials in the adrenal medulla: Evidence for storage and secretion with catecholamines","volume":"16","author":"Viveros","year":"1979","journal-title":"Mol. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/0024-3205(86)90262-6","article-title":"Modulation of bovine adrenal gland secretion by etorphine and diprenorphine","volume":"38","author":"Barron","year":"1986","journal-title":"Life Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/oxfordjournals.bmb.a071794","article-title":"Actions and distributions of opioid peptides in peripheral tissues","volume":"39","author":"North","year":"1983","journal-title":"Br. Med. Bull."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1677\/joe.0.1040387","article-title":"Control of zona glomerulosa function in the isolated perfused rat adrenal gland in situ","volume":"104","author":"Hinson","year":"1985","journal-title":"J. Endocrinol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1677\/joe.0.1400091","article-title":"The role of neuropeptides in the regulation of adrenal zona glomerulosa function: Effects of substance P, neuropeptide Y, neurotensin, Met-enkephalin, Leu-enkephalin and corticotrophin-releasing hormone on aldosterone secretion in the intact perfused rat adrenal","volume":"140","author":"Hinson","year":"1994","journal-title":"J. Endocrinol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0167-0115(94)90135-X","article-title":"The role of neuropeptides in the regulation of adrenal vascular tone: Effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, neurotensin, Met-enkephalin, and Leu-enkephalin on perfusion medium flow rate in the intact perfused rat adrenal","volume":"51","author":"Hinson","year":"1994","journal-title":"Regul. Pept."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1677\/joe.0.1440503","article-title":"Action of opioid peptides on the rat adrenal cortex: Stimulation of steroid secretion through a specific mu opioid receptor","volume":"144","author":"Kapas","year":"1995","journal-title":"J. Endocrinol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1042\/bj3050577","article-title":"Mu-opioids activate phospholipase C in SH-SY5Y human neuroblastoma cells via calcium-channel opening","volume":"305","author":"Smart","year":"1995","journal-title":"Biochem. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.regpep.2010.08.008","article-title":"Stimulatory effect of naloxone on plasma cortisol in human: Possible direct stimulatory action at the adrenal cortex","volume":"166","author":"Coiro","year":"2011","journal-title":"Regul. Pept."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1677\/joe.0.1510301","article-title":"The steroidogenic effects of beta-endorphin and joining peptide: A potential role in the modulation of adrenal androgen production","volume":"151","author":"Clarke","year":"1996","journal-title":"J. Endocrinol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jsat.2018.03.001","article-title":"Effects of medication assisted treatment (MAT) for opioid use disorder on functional outcomes: A systematic review","volume":"89","author":"Maglione","year":"2018","journal-title":"J. Subst. Abus. Treat."},{"key":"ref_92","first-page":"e12345","article-title":"Opioid-Induced Hyperalgesia in a Cancer Patient on High-Dose Methadone Maintenance Therapy: A Case for Subspecialty Opioid Use Disorder Primary Care","volume":"12","author":"Ezeh","year":"2020","journal-title":"Cureus"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1111\/pme.12926","article-title":"Opioid Related Endocrinopathy: Table 1","volume":"16","author":"Gudin","year":"2015","journal-title":"Pain Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s11914-020-00585-4","article-title":"The Effect of Opiates on Bone Formation and Bone Healing","volume":"18","author":"Coluzzi","year":"2020","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1001\/archinte.166.19.2087","article-title":"Association Between Mental Health Disorders, Problem Drug Use, and Regular Prescription Opioid Use","volume":"166","author":"Sullivan","year":"2006","journal-title":"Arch. Intern. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4575\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:43:06Z","timestamp":1760121786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4575"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,26]]},"references-count":95,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24054575"],"URL":"https:\/\/doi.org\/10.3390\/ijms24054575","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,26]]}}}