Review
New opioid side effects and implications for long-term therapy

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Summary

Opioids are the foundation for the treatment of acute pain and cancer pain. Their popularity in the chronic pain setting has waxed and waned over the years but there has been a recent resurgence in their use. Opioid induced side effects such as nausea, constipation, tolerance and addiction are well known, but studies have shown that a range of subtle yet significant complications have emerged which have the potential to increase the morbidity of patients who are on long-term opioid therapy. They include hypogonadism, osteoporosis, immune suppression, cognitive impairment and hyperalgesia. Therefore it is important for clinicians to be aware of these side effects and remain vigilant for them. Patients receiving chronic opioid therapy may benefit from a strategy to minimise the occurrence of these side effects.

Introduction

A recent increase in the popularity of the prescription of opioids for chronic pain syndromes has benefited a great many people. Opioid induced side effects such as nausea, constipation, tolerance and addiction are widely known, but new detrimental effects are emerging in the clinical setting as well as in literature. They include hypogonadism, osteoporosis, immune suppression, cognitive impairment and hyperalgesia. The majority of people with chronic pain will have tried opioids and a significant number will be on these drugs indefinitely. In this review, we discuss the impact of some of these side effects and their implications for chronic opioid therapy.

Section snippets

Hypogonadism

A reduction in the level of sex hormones has been observed in survivors of cancer who have consumed opioids for long periods. This has been associated with significantly higher levels of depression, fatigue, and sexual dysfunction.1 Opioid induced androgen deficiency (OPIAD) has recently been identified in men taking long-term opioids through the oral,2 intrathecal3 and transdermal routes.4 OPIAD is a clinical condition characterized by a low serum testosterone and dehydroepiandrosterone

Osteoporosis and increased fracture risk

A North American prospective cohort study of more than 8000 elderly women found that those taking opioids had an increased risk of fracture.11 A large cross-sectional survey of medication usage, combined with measurements of bone mineral density found that opioids and anti-convulsants were associated with a significant reduction in bone mineral density.12

A large Danish case control study demonstrated an increased risk of fractures in patients using opioids. Most of the commonly used opioids

Immune suppression

Optimal immunological function is paramount in facilitating recovery from physiological insults such as infection, trauma and surgery. Its importance in the development and response to cancer has also become apparent during the scientific analysis of the malignancy process. Recent studies have revealed that pain may impair immune function by its effect on the hypothalamic-pituitary-adrenal system18 as well as suppressing Natural Killer (NK) cells, which may be involved in the mounting of

Cognitive impairment

It is intuitive to clinicians that the use of strong opioids will impair cognitive function however there is little published data to support this in the community setting. It should also be acknowledged that pain itself is associated with significant cognitive impairment.25, 26 There is a complex interplay of multiple contributory factors in the maintenance of normal cognition and it is difficult to determine the extent to which these confounding variables contribute to cognitive impairment in

Opioid induced hyperalgesia

Opioid induced hyperalgesia (OIH) may be defined as a decrease in the nociceptive (or pain) threshold caused by exposure to opioids. It has been known for more than a century that opioids can induce a paradoxical exacerbation of painful sensations in spite of their analgesic properties.35 The mechanism for OIH has not been determined conclusively but numerous cellular receptor systems have been implicated. Both peripheral and central mechanisms are thought to be responsible for the phenomenon.

Discussion

Clinicians should be aware of the significant morbidity that may be associated with the long-term use of opioids. It would seem pragmatic to make use of advances at the pre-clinical level in order to optimise the management of patients with chronic pain. Indeed, the American Pain Society has recently published guidelines for chronic opioid therapy despite an apparent lack of robust high-level clinical evidence.40

A strict well-defined trial of opioid therapy should be initiated with the explicit

Conclusion

Opioids have served mankind well and it would be hard to imagine a world without these compounds due to their integral place within modern health care. However, if all things should be consumed in moderation then opioids are certainly no exception. The emerging side effects of opioids such as hypogonadism, osteoporosis, immune suppression, cognitive impairment and hyperalgesia should be considered carefully when these drugs are used for chronic conditions.

Funding source

None of the authors received specific funding from their respective organisations in relation to this article.

Conflict of interest statement

The authors have no conflict of interest to report.

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