Published: 4 June 2026

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Beyond pain relief: Undesirable effects of opioids

Published: 4 June 2026
Prescriber Update 47(2): 26–27
June 2026

Opioids, such as morphine, tramadol, oxycodone and fentanyl, are a class of medicines indicated for management of short-term moderate or severe acute pain or for chronic pain related to malignancy.

Undesirable opioid effects now include endocrine, hepatobiliary and gastrointestinal side effects, and data sheets are being updated to include them. This article provides an overview of these undesirable effects.

Endocrine effects: Suppression of the hypothalamic-pituitary axes

Long term opioid use (more than 1 month) has the potential to disrupt the secretion of certain hormones from the pituitary gland due to stimulation of opioid receptors in the hypothalamus.^1,2

Hypothalamic-pituitary-gonadal (HPG) axis

Opioids can inhibit the release of hypothalamic gonadotrophin releasing hormone (GnRH), reducing secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH) and suppressing gonadal sex steroid production (hypogonadism).²

These effects on the HPG axis may lead to low testosterone and oestrogen levels. Clinical symptoms such as reduced libido (both sexes), erectile dysfunction and menstrual irregularities can then occur.^2,3

Hypothalamic-pituitary-adrenal (HPA) axis

Opioids regulate the hypothalamus-pituitary-adrenal axis via opioid receptors in the hypothalamus, pituitary and adrenal glands. They mainly act centrally to inhibit adrenocorticotropic hormone (ACTH) secretion. Reduced ACTH release has a downstream effect on cortisol production in the adrenal glands.²

Reversible adrenal insufficiency may occasionally occur, requiring monitoring and glucocorticoid replacement therapy. Symptoms include fatigue, dizziness, nausea, vomiting and low blood pressure.³

Hyperprolactinemia

Opioids can cause hyperprolactinemia in males and females, likely by inhibition of the tuberoinfundibular dopaminergic system.²

Prescribing considerations^1,2,4

In general, higher opioid exposure leads to a greater potential for suppression of the above endocrine pathways. Higher doses, longer durations of treatment and use of long-acting formulations can increase the risk.

Partial agonists, such as buprenorphine, may cause less suppression of the HPG and HPA axes compared to full agonist opioids, such as morphine and oxycodone.

Symptoms of opioid-induced endocrinopathies may by subtle and have a gradual onset. They can overlap with other opioid side effects or medical conditions (including chronic pain) making recognition challenging.

Encourage patients who may be at risk of opioid-induced endocrinopathies to report potential associated signs and symptoms and investigate accordingly.

Hepatobiliary effects: Sphincter of Oddi spasm^3,5,6

Opioids, particularly morphine, cause contraction and spasms of the Sphincter of Oddi, a muscular valve controlling bile and pancreatic juice flow into the intestine.

Sphincter of Oddi spasm can cause increased biliary pressure, increasing the risk of biliary tract symptoms and pancreatitis.

Administer opioids with caution and with appropriate monitoring in patients with pancreatitis and diseases of the biliary tract.

GI effects: Oesophageal dysfunction^3,7

Opioid-induced oesophageal dysfunction is defined by oesophageal symptoms along with abnormal oesophageal motility following long-term opioid use.

Dysphagia is the most frequently reported symptom. Other symptoms include heartburn, regurgitation and non-cardiac chest pain.

Consider discontinuation or weaning of opioids in patients presenting with symptoms suggestive of opioid-induced oesophageal dysfunction.

More information

• See the opioid data sheets and consumer medicine information (CMI): Search for a data sheet or CMI.

References

1. Incze M and Bogler O. 2024. Endocrine adverse effects of long-term opioid use. JAMA Internal Medicine 184(7): 831–2. DOI: https://doi.org/10.1001/jamainternmed.2024.0863 (accessed 29 April 2026).
2. Gadelha MR, Karavitaki N, Fudin J, et al. 2022. Opioids and pituitary function: Expert opinion. Pituitary 25(1):52–63. DOI: 10.1007/s11102-021-01202-y (accessed 23 April 2026).
3. Seqirus (NZ) Ltd. 2026. Tramal New Zealand Data Sheet 26 February 2026. URL: www.medsafe.govt.nz/profs/Datasheet/t/TramalcapSRtabinjoraldrops.pdf (accessed 23 April 2026).
4. Medina II WA and Conermann T. 2022. Opioid-induced endocrinopathy (updated 15 Nov 2022). In: StatPearls [Internet]. URL: https://www.ncbi.nlm.nih.gov/books/NBK559211/ (accessed 29 April 2026).
5. Afghani E, Lo SK, Covington PS, et al. 2017. Sphincter of Oddi function and risk factors for dysfunction. Frontiers in Nutrition 4(1):1–9. DOI: 10.3389/fnut.2017.00001 (accessed 23 April 2026).
6. Medsurge Pharma Limited. 2026. Morphine Sulfate New Zealand Data Sheet 17 February 2026. URL: www.medsafe.govt.nz/profs/Datasheet/m/morphinesulfatemedsurgeinj.pdf (accessed 5 May 2026).
7. Snyder DL and Vela MF. 2023. Diagnosis and management of opioid-induced esophageal dysfunction. Current Treatment Options in Gastroenterology 21: 138-45. DOI 10.1007/s11938-023-00418-0 (accessed 23 April 2026).