Treatment Options
Once the diagnosis of OIH has been made, there are a number of treatment options from which to carefully choose. Provided that the initial painful injury or tissue damage has resolved and the pain persists in spite of—and because of—opioid treatment, the most straightforward approach is to discontinue the offending opioid. This should be done gradually to minimize adverse withdrawal effects. It should be noted that hyperalgesia may likely worsen early in the discontinuation process. This presents a challenging ethical situation in which the clinician may have difficulty convincing the patient that the medication prescribed to treat pain may have been causing or worsening the pain and that the pain may get worse still before it ultimately resolves.
If legitimate pain persists and some amount of analgesia with opioids is required, other strategies beyond total opioid discontinuation should be explored. Patients experiencing OIH may obtain relief by reducing the opioid dose. There are reports of patients finding an acceptable balance of analgesia and relief from hyperalgesia upon opioid dose reduction.
Switching from one structural class of opioids to another has been an effective option for mitigating OIH in some studies. Studies to date have demonstrated that OIH is more strongly associated with opioids from the phenanthrene class (Table 2). Titration of the phenanthrene opioid and conversion to another may provide resolution of OIH. Codeine, hydromorphone, morphine, and structurally similar opioids undergo glucuronidation as part of their metabolism. Avoidance of an NMDA receptor–activating glucuronide metabolite is possible by switching to an opioid that is structurally unique, such as fentanyl. At this writing, OIH has not been demonstrated in trials involving oxymorphone.
Supplementing opioid therapy with a cyclo-oxygenase 2 (COX-2) inhibitor is another strategy that has some support. By reducing prostaglandin synthesis, COX-2 inhibitors can decrease the sensitization of pronociceptive neurons. Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors appear to have analgesic effects independent of their ability to suppress prostaglandin synthesis peripherally. COX-2 inhibitors also have demonstrated the ability to antagonize the NMDA receptor. Centrally, NSAIDs are capable of antagonizing the NMDA receptor by blocking glutamate, substance P, and other excitatory amino acids. Independent of this, NMDA receptor activation can upregulate COX-2 expression.
Given the attention the NMDA receptor has received for its role in OIH, antagonizing this receptor would seem to be a reasonable treatment strategy. Ketamine has been much researched, but its adverse effects can be severe. While it antagonizes NMDA and provides an anesthetic effect that would promote analgesia, side effects are common, diverse, and severe. These effects include tachyarrhythmia, hypertension, cognitive impairments, and psychomimetic reactions, including mood changes, vivid dreams, delirium, hallucinations, and sedation. Ketamine is effective in reversing hyperalgesia and augmenting the effects of opioids in patients receiving large doses, but its adverse effects prevent it from being a viable treatment option.
Dextromethorphan is another NMDA receptor antagonist that has been investigated for the treatment of OIH. A combination product containing a 1:1 mixture of morphine and dextromethorphan has been studied. Studies failed to demonstrate that combination therapy could achieve superior analgesia compared with morphine alone. Similar therapy failures occurred in a study that used a 2:1 mixture of the same agents. The studies have been criticized for having an insufficient amount of dextromethorphan to adequately antagonize the NMDA receptor. What remains unknown is the dose of dextromethorphan necessary to either augment an opioid's analgesia or prevent the OIH caused by NMDA receptor activation.
Methadone is an opioid with unique qualities that make it a compelling option for treating pain in the patient with OIH. In addition to its analgesic effects through binding to the mu opioid receptor, methadone is a weak NMDA receptor antagonist. It has been reported that the addition of even a low dose of methadone has been effective for reducing hyperalgesia. In one case, the addition of low-dose methadone (10 mg twice daily) improved reports of pain markedly, with a reduction in total opioid dose of 40% to 50%. Switching from the offending opioid to methadone has been a popular treatment strategy. Tramadol and meperidine also have some NMDA receptor antagonist activity.
Another treatment modality that has some potential for treating OIH is buprenorphine. Buprenorphine is a partial opioid agonist at the mu receptor and also has kappa receptor antagonist activity. Dynorphin, a kappa receptor agonist, is known to increase during treatment with opioids. Activation of the kappa receptor largely antagonizes the mu receptor–mediated effects of opioids. The clinical utility of buprenorphine in treating OIH has yet to be fully explained.