Evaluation and treatment of opioid-induced hyperalgesia
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Date
2007
Authors
Hay, Justin Luke
Editors
Advisors
White, Jason
Somogyi, Andrew
Bochner, Felix
Somogyi, Andrew
Bochner, Felix
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Abstract
Methadone is effective as an opioid substitution therapy, yet its use results in adverse effects such as tolerance and increased pain sensitivity to certain modalities of pain. Recent research has indicated that opioids have the potential to increase pain sensitivity following both acute and chronic dosing. While the pain sensitivity profile of methadone maintained patients is well established, no studies have compared the similarities and differences of chronic opioid users with different aetiologies, namely, chronic pain patients with moderate to severe pain and patients with a substance use disorder on a methadone maintenance treatment program.
Furthermore, limited guidelines exist for the treatment of acute pain in opioid-tolerant patients. Recent animal research and human studies in opioid-naïve patients have shown that the addition of ultra-low doses of an opioid antagonist can enhance the antinociceptive effectiveness and reduce adverse effects of opioid agonists. Moreover, recently developed, high potency opioid agonists such as remifentanil have shown to be antinociceptive in both experimental pain models and for acute pain following surgery. The antinociceptive effectiveness and safety of these novel and emerging pharmacotherapies have not been previously determined in methadone maintained patients. Additionally, animal models exist for the increased pain sensitivity observed following continuous opioid dosing of morphine. However, no comparable model exists for methadone.
The central aims of the studies contained herein were to investigate the effect of chronic methadone administration on pain sensitivity in both humans and rats, and investigate novel,
acute pharmacological strategies for modifying nociception in opioid tolerant populations. The first two studies primarily evaluated the pain sensitivity of methadone maintained patients, chronic pain patients managed with methadone or morphine, former opioid users and opioid-naïve healthy subjects. The subsequent two studies investigated two unique approaches in providing antinociception in methadone maintained patients. While the administration of ultra-low doses of naloxone to these patients indicated limited success in providing antinociception, relatively high doses of remifentanil demonstrated that these
patients are cross-tolerant to the physiological effects of other opioids. The subsequent study investigated the effect of a range of subcutaneous, continuously administered doses of
methadone on pain sensitivity in the Sprague-Dawley rat and established a dose of methadone that can induce hyperalgesia. The current findings indicate that further investigations of this drug are justified especially with regard to its impact on nociception.
School/Discipline
School of Medical Sciences
Dissertation Note
Thesis (Ph.D.) -- School of Medical Sciences, 2007
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