Risks from long term opioid therapy

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.

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.

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
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.