Long term harms of opioids

Data regarding long-term harms from randomised controlled trials are limited as most trials are of relatively short duration, although observational studies can provide more information.

In a well-designed retrospective large cohort study Solomon et al studied the safety of opioids compared with non-selective non-steroidal anti-inflammatory drugs (NSAIDs), and selective cyclooxygenase-2 inhibitors (coxibs). Opioid use increased the relative risk of many of the outcomes studied. Unexpectedly, gastrointestinal tract bleeding was similar for non-selective NSAID users and opioid users, although it was lower for coxib users. Compared with non-selective NSAIDs, the relative risk for cardiovascular events (including myocardial infarction, heart failure) was higher for opioids than coxibs. Use of opioids was associated with an increased risk for side effects requiring hospitalisation compared with use of non-selective NSAIDs and all-cause mortality was higher for patients prescribed opioids.

Fractures and Falls

• Opioids increase the risk and incidence of falls. This is of particular importance in elderly patients.
• In a systematic review of observational studies the relative risk of any fracture in patients on opioids compared to non-use was 1.38 (six studies, 95% CI 1.15 to 1.66).
• Risks of falls associated with opioids were similar to risks associated with benzodiazepines (RR=1.34, 95% CI 1.24 to 1.45), and antidepressants (RR=1.60, 95% CI 1.38 to 1.86).

Endocrine System

• Long-term administration of opioids is associated with endocrine abnormalities.
• Influences on both the hypothalamic-pituitary-adrenal axis
and the hypothalamic-pituitary-gonadal axis have been demonstrated in patients taking oral opioids with consequent hypogonadism and adrenal insufficiency in both sexes.
• Hypogonadism and decreased levels of dehydroepiandrosterone sulfate have been reported in men and women.
• Endocrine effects are probably dose related and can lead to:
  • Amenorrhoea in women
  • Reduced libido in both sexes
  • Erectile dysfunction in men
  • Infertility
  • Depression and fatigue

• Patients (particularly women of childbearing age) should be told about these effects before starting opioids.
• Endocrine function should be monitored regularly if a patient reports symptoms consistent with potential dysfunction, such as decreased libido, sexual dysfunction or fatigue. (NB these symptoms can also occur as part of the presentation of chronic pain)
• Recommended tests include:
  • blood pressure
  • electrolytes (especially if tramadol is used)
  • fasting glucose levels
  • thyroid function tests
  • serum testosterone, sex-binding globulin, LH/FSH and oestradiol levels
  • bone density (in an ‘at-risk’ group).

• If endocrine impairment is demonstrated, patients should be referred to an endocrinologist for advice regarding the benefits of hormonal replacement therapy.
• There is insufficient evidence to recommend routine monitoring of asymptomatic patients taking opioids in the long-term for hormonal deficiencies.

Immune System

• Both animal and human studies have demonstrated that opioids have an immunomodulating effect. These effects are mediated via opioid receptors both on immune effector cells and in the central nervous system.
• In animals, opioids have been demonstrated to have effects on antimicrobial response and anti-tumour surveillance.
• Opioids may differ in their propensity to cause immunosuppression. In animal studies, buprenorphine has been demonstrated to have no impact on immune function. The relevance of these findings to the clinical use of opioids is not known.

Opioid Induced Hyperalgesia

• Both animal and human studies have demonstrated that prolonged use of opioids can lead to a state of abnormal pain sensitivity, sometimes called opioid induced hyperalgesia (OIH).
• The prevalence of OIH in clinical practice is unknown. The published literature examines the phenomena in three groups: 1) patients undergoing surgery who receive high doses of opioids perioperatively 2) patients receiving methadone maintenance for opioid addiction and 3) experimental pain testing on healthy volunteers exposed to acute opioid administration.
• There are neurobiological similarities between the symptoms of hyperalgesia and allodynia that typify neuropathic pain, opioid induced hyperalgesia and opioid tolerance. Mechanisms for these phenomena relate to neuroplastic changes in the peripheral and central nervous system that lead to sensitisation of pronociceptive pathways.
• Opioid induced hyperalgesia is not usually seen in the absence of observed tolerance to opioid analgesia.
• While there are many proposed mechanisms for OIH, five mechanisms are probably the most the important involving:
• the central glutaminergic system particularly the excitatory amino acid N-methyl-D-aspartate
• increase in spinal dynorphins leading to release of excitatory neuropeptides from primary afferents
• activation of neurons in the rostroventral medulla that facilitate spinal nociceptive processing
• genetic mechanisms which influence pain sensitivity, response to analgesia and
• decreased reuptake of neurotransmitters from primary afferent neurons and enhanced nociceptive response in spinal neurons
• Clinically, hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality.
• Management of opioid induced hyperalgesia requires opioid dose reduction or changing to an alternative opioid preparation.

Further reading

Fractures and Falls

• Solomon, DH, Rassen JA, Glynn RJ, et al. The Comparative Safety of Analgesics in Older Adults With Arthritis. Archives of Internal Medicine 2010;170:1968-1978.

Endocrine System

• Daniell HW: DHEAS deficiency during consumption of sustained-action prescribed opioids: Evidence for opioid-induced inhibition of adrenal androgen production. Journal of Pain 2006;7:901-907.
• Daniell HW: Hypogonadism in men consuming sustained-action oral opioids. Journal of Pain 2002; 3: 377-384.
• Daniell HW: Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of non-malignant pain. Journal of Pain 2008; 9: 28-36.
• Seyfried O, Hester J. Opioids and the Immune system. British Journal of Pain. 2012; 6:17-24.

Immune System

• Boland JW , McWilliams K , Ahmedzai SH, et al. Effects of opioids on immunologic parameters that are relevant to anti-tumour immune potential in patients with cancer: a systematic literature review. British Journal of Cancer 2014; 111: 866-873
• Sacerdote P. Opioids and the immune system. Palliative Medicine 2006; 20 Suppl 1: s9-15.

Opioid Induced Hyperalgesia

• Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006; 104:570–587.
• Cohen SP, Christo PJ, Wang S, et al. The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus. Regional Anesthesia and Pain Medicine 2008; 33: 199-206.
• Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: Effect of long-acting maintenance agent. Drug and Alcohol Dependence 2001; 63: 139-146.
• Lee M, Silverman S, Hans H, et al A comprehensive review of opioid induced hyperalgesia. Pain Physician 2011; 14: 145-161.
• Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002; 100: 213–217.
• Tompkins DA, Campbell CM. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Current Pain and Headache Reports 2011; 15: 129-36.