Long term harms of opioids

Recognised long term harms of opioids include:

  • fractures and falls
  • endocrine dysfunction
  • immune system
  • opioid induced hyperalgesia
  • cardiovascular events
  • gastrointestinal complications and bleeding

 

Controlled studies on long-term (≥1 year) opioid therapy are very limited, but evidence suggest that the increased risk of serious harms appears to be dose dependent.1,2

The risk of these adverse events is not unique to substance misuse, with one study finding the risk of adverse events being 23.7 fold more common from opioid use than misuse.2  Compared to days without opioid exposure, the authors found current opioid exposure (not substance misuse) was associated with a 2.5 fold higher risk of a serious adverse drug event.

 

Fractures and Falls

  •  Opioid use increases the risk and incidence of falls;3 30% of people over 65 and 50% of people older than 80 will have at least one fall per year.4
  • A meta-analysis of 30 studies found an increase in risk of falls, fractures and fall injuries among older people who use opioids.5  One study based in the USA, regarding elderly patients with a diagnosis of osteoarthritis, found that the incidence of falls was greater for patients prescribed opioids, than for those prescribed COX2 inhibitors or NSAIDs (OR 3.3 and 4.1).6
  • Not only is the risk of falling increased, but also the risk of fracture.  In a study looking at patients treated for falls, matched against controls, adults aged over 65 years with hip fractures were more than four times more likely to be treated with opioids prior to the fall (OR 4.497, 95% CI 2.724 o 7.424) than patients without fracture7. Falls occur mostly at initiation or following a dose escalation8.

 

Endocrine System

  • Long-term administration of opioids is associated with endocrine abnormalities, including:
    • Sex hormone dysfunction
    • Adrenal dysfunction

 

Sex hormone dysfunction

The most commonly observed endocrine disorder with long term use of opioids is secondary hypogonadism, or opioid-induced androgen deficiency (OPIAD)9 due to suppression of the hypothalamic-pituitary gonadal (HPG) axis, altering the sex hormone-hypothalamic feedback loop. The dosage or duration of opioid treatment required to cause these may be as short as one week10, and occurs with both intrathecal, oral and transdermal use.9,11,12 One systematic review and meta-analysis found that hypogonadism is present among approximately 63% of male patients on long-term opioids.13

Sex hormone deficiency can lead to14:

  • anaemia
  • decreased libido
  • decreased muscle mass
  • depression
  • erectile dysfunction
  • fatigue
  • menstrual irregularities
  • osteoporosis
  • vasomotor instability
  • weight gain

 

Adrenal dysfunction

Suppression of the hypothalamic-pituitary-adrenal (HPA) axis results in adrenal insufficiency, leading to lower blood cortisol and adrenocorticotropic hormone (ACTH) levels due to opioid use can present with symptoms including13,15, 16

  • fatigue
  • malaise
  • abdominal discomfort, anorexia
  • orthostatic hypotension

Hypocorticism has been seen to present in about 15%17 of patients.

NICE advises reducing the dose in persons with adrenocortical insufficiency.18

 Screening and diagnosis:

  • Inform patients about side effects of endocrine dysfunction before starting treatment.
  • Routinely ask about symptoms suggestive of sex hormone deficiency at regular follow-up visits.
  • If symptomatic, test serum testosterone, sex-binding globulin, LH/FSH, DHEAS in both men and women, oestradiol levels in women and early morning cortisol levels.
  • Monitor blood pressure.
  • If endocrine impairment is demonstrated, refer the patient to an endocrinologist for advice regarding the benefits of hormonal replacement therapy.

 

For further information on adrenal insufficiency: Recommendations | Adrenal insufficiency: identification and management | Guidance | NICE

 

Immune system

Both animal and human studies have demonstrated that opioids have an immunomodulating effect, though results from in vitro, in vivo and patient studies are inconsistent.19-21 The relevance of these findings to the clinical use of opioids is not known due to the differences in immune system measures, the range of opioid doses and the relative scarcity of participants in the available studies.22

Opioids modulate the immune system directly by binding to µ-opioid receptor on immune cells, or indirectly by binding to receptors within the central nervous system.23  By activating the descending pathways of the HPA axis and the sympathetic nervous system, glucocorticoids are released, along with noradrenaline, both acting on leucocytes resulting in reduction of immune response.23

Opioids may differ in their propensity to cause immunosuppression; morphine decreases the effectiveness of both natural and acquired immunity24; tramadol,25 tapentadol and buprenorphine have a weaker immunosuppressive action.22

Individual risk factors in those with an immunosuppressed status, due to frailty, disease such as cancer or HIV, or those who have undergone invasive surgery should be considered when treating with opioids. 

 

Opioid Induced Hyperalgesia

  • Prolonged use of opioids can lead to a state of abnormal pain sensitivity, called opioid induced hyperalgesia (OIH), where patients receiving opioid therapy become more sensitive to pain26, pre-existing pain may be aggravated27, or the pain may be different from the original pain being treated.26
  • The exact mechanisms for developing OIH are not fully understood, but OIH may be diagnosed if the patient on long-term opioid therapy presents with increased pain. OIH should not be confused with breakthrough pain resulting from development of opioid tolerance. Opioid tolerance responds to increase in dose, whereas with OIH pain increases with increasing dosage.28     
  • Pain related to disease progression must be ruled out before a diagnosis of OIH is made.
  • Management of opioid induced hyperalgesia is challenging and requires time and patience, and understanding from the patient and their family.26  It requires opioid dose reduction or weaning28.  In cancer pain, changing to an alternative opioid preparation may be considered (switching).29

 

References:

  1. Chou R, Deyo R, Devine B, et al. The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evid Rep Technol Assess (Full Rep). 2014(218):1-219.
  2. Winn AN, Check DK, Farkas A, Fergestrom NM, Neuner JM, Roberts AW. Association of current opioid use with serious adverse events among older adult survivors of breast cancer. JAMA Network Open. 2020;3(9):e2016858-e2016858.
  3. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with the use of morphine and opiates. Journal of internal medicine. 2006;260(1):76-87.
  4. NICE. Falls in older people: assessing risk and prevention. CG161. https://www.nice.org.uk/guidance/cg161/resources/falls-in-older-people-assessing-risk-and-prevention-pdf-35109686728645. Published 2013. Accessed 09/10/2024.
  5. Yoshikawa A, Ramirez G, Smith ML, et al. Opioid use and the risk of falls, fall injuries and fractures among older adults: a systematic review and meta-analysis. The Journals of Gerontology: Series A. 2020;75(10):1989-1995.
  6. Rolita L, Spegman A, Tang X, Cronstein BN. Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. Journal of the American Geriatrics Society. 2013;61(3):335-340.
  7. Machado-Duque ME, Castaño-Montoya JP, Medina-Morales DA, Castro-Rodríguez A, González-Montoya A, Machado-Alba JE. Association between the use of benzodiazepines and opioids with the risk of falls and hip fractures in older adults. International psychogeriatrics. 2018;30(7):941-946.
  8. Peach EJ, Pearce FA, Gibson J, Cooper AJ, Chen LC, Knaggs RD. Opioids and the Risk of Fracture: A Self-Controlled Case Series Study in the Clinical Practice Research Datalink. Am J Epidemiol. 2021 Jul 1;190(7):1324-1331. doi: 10.1093/aje/kwab042. PMID: 33604606; PMCID: PMC8245882 9. 
  9. Elliott J, Opper S, Agarwal S, E Fibuch E. Non-analgesic effects of opioids: opioids and the endocrine system. Current pharmaceutical design. 2012;18(37):6070-6078.
  10. Roberts LJ, Finch PM, Pullan PT, Bhagat CI, Price LM. Sex hormone suppression by intrathecal opioids: a prospective study. The Clinical journal of pain. 2002;18(3):144-148.
  11. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. The Journal of Pain. 2002;3(5):377-384.
  12. Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. The Journal of Pain. 2008;9(1):28-36.
  13. De Vries F, Bruin M, Lobatto DJ, et al. Opioids and Their Endocrine Effects: A Systematic Review and Meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 2019;105(4):1020-1029.
  14. Colameco S, Coren JS. Opioid-induced endocrinopathy. Journal of Osteopathic Medicine. 2009;109(1):20-25.
  15. Scherrer JF, Salas J, Lustman PJ, Burge S, Schneider FD, Investigators RRNoT. Change in opioid dose and change in depression in a longitudinal primary care patient cohort. Pain. 2015;156(2):348.
  16. The National Institute for Health and Care Excellence (NICE). Adrenal insufficiency: identification and management NICE guideline [NG243] Web site. https://www.nice.org.uk/guidance/ng243. Published 2024. Accessed Published: 28 August 2024.
  17. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. The Journal of Clinical Endocrinology & Metabolism. 2000;85(6):2215-2222.
  18. NICE. Clinical Knowledge Summaries (CKS): Analgesia – mild-to-moderate pain: Scenario: Weak opioids. https://cks.nice.org.uk/topics/analgesia-mild-to-moderate-pain/management/weak-opioids/#recommended-doses. Published 2021. Updated November 2021. Accessed 25/09/2023, 2023.
  19. Plein LM, Rittner HL. Opioids and the immune system–friend or foe. British journal of pharmacology. 2018;175(14):2717-2725.
  20. Taniguchi Y, Tamiya A, Matsuda Y, et al. Opioids impair Nivolumab outcomes: a retrospective propensity score analysis in non-small-cell lung cancer. BMJ Supportive & Palliative Care. 2020.
  21. Cronin-Fenton DP, Heide-Jørgensen U, Ahern TP, et al. Opioids and breast cancer recurrence: A Danish population-based cohort study. Cancer. 2015;121(19):3507-3514.
  22. Franchi S, Moschetti G, Amodeo G, Sacerdote P. Do all opioid drugs share the same immunomodulatory properties? A review from animal and human studies. Frontiers in Immunology. 2019;10:2914.
  23. Sacerdote P. Opioids and the immune system. Palliative medicine. 2006;20(8_suppl):9-15.
  24. Sacerdote P, Franchi S, E Panerai A. Non-analgesic effects of opioids: mechanisms and potential clinical relevance of opioid-induced immunodepression. Current pharmaceutical design. 2012;18(37):6034-6042.
  25. Liu Z, Gao F, Tian Y. Effects of morphine, fentanyl and tramadol on human immune response. Journal of Huazhong University of Science and Technology. 2006;26:478-481.
  26. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain physician. 2011;14(2):145.
  27. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. The Journal of the American Society of Anesthesiologists. 2006;104(3):570-587.
  28. Yi P, Pryzbylkowski P. Opioid induced hyperalgesia. Pain Medicine. 2015;16(suppl_1):S32-S36.
  29. Mercadante S, Arcuri E. Hyperalgesia and opioid switching. American Journal of Hospice and Palliative Medicine. 2005;22(4):291-294.

 

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