to the editor: I enjoyed the excellent review on the management of chronic nonmalignant pain, and would like to add that a limit on the maximal opioid dose should be set before initiation of opioid therapy. Opioid doses above 180 mg per day of morphine equivalent have not been assessed for long-term effectiveness or safety. Efficacy studies have included only a rare patient in this dose range. Safety studies have never been published for high-dose opioids.¹ There is good evidence from animal and human studies that high-dose opioids change pain perception, induce numerous hormonal changes, and are possibly immunosuppressive. Pain perception changes include increasing hyperalgesia and allodynia.² Hormonal changes appear to be mediated through the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitarygonadal axis. Specific changes that have been identified include increased prolactin, decreased luteinizing hormone, decreased cortisol, decreased follicle-stimulating hormone, decreased testosterone, and decreased estrogen levels.³ There is also evidence that high-dose opioids are immunosuppressive in patients with human immunodeficiency virus.⁴ Several recent studies of high-dose narcotics revealed an increasing risk of respiratory depression, central sleep apnea, and sleep disordered breathing.⁵ If pain control is not achieved before 180 mg of morphine equivalent per day, then increasing the dose has a number of risks and no known benefit. The physician can now safely say that opioids are not working and are no longer safe. Tapering and stopping the opioid and/or switching to methadone or buprenorphine/naloxone (Suboxone) should be considered.

in reply: We appreciate Dr. Johnston pointing out some important and key factors when the dosage of prescribed opioids start to hit high levels or if the dosage escalates. All of the previously mentioned side effects could occur when dosages greater than 180 to 200 mg per day of morphine equivalent are prescribed. Repeated dose escalations can be a sign of substance abuse or diversion. We would like to reiterate that, in theory, opioids have no maximum ceiling dose and that there are no studies dictating what is a maximum “safe” and “standard” dose. The determined maximum dose of morphine was by consensus statement based on maximum opioid doses used in some randomized trials and the average doses used in some observational studies.^1–4 Physicians should reassess all patients receiving chronic opioid treatment with dose escalation via more intensive monitoring and consider addressing the reason that higher doses are needed for pain control. Interventions may include rotating or switching opioids, or, if appropriate, weaning or discontinuing opioid therapy.