Friday, November 12, 2010

Naloxone ‘Reboots’ Opioid Pain-Relief System

NaloxoneIn a prior research report we described potential benefits of using low-doses of the opioid antagonist naloxone to “reboot” the body’s natural opioid-receptor system in patients who are not achieving adequate pain relief with opioid medications [Leavitt 2009]. While anecdotes are not conclusive scientific evidence, a new case report describes a protocol and provides further support for this novel application of naloxone.

Colleagues from the Liaoning University of Traditional Chinese Medicine, Liaoning Province, China, recently informed us of an important case study of naloxone for reversing resistance to high-dose morphine in a 56-year-old male patient with terminal bladder cancer [Dongfeng et al. 2010]. Despite surgery, chemotherapy, and radiotherapy the carcinoma metastasized and the disease was progressing. The patient experienced severe, refractory abdominal and low back pain that could not be controlled with high-dose oral morphine and transdermal fentanyl analgesia equivalent to 1,200 mg morphine per day in total, plus the patient received adjuvant therapy (eg, acetaminophen, carbamazepine) as well as morphine (30 mg oral or 10 mg IV three times daily) for breakthrough pain flares. Adverse effects of opioid analgesia — delirium, nausea, vomiting, and constipation — were significant and intolerable.

The clinicians report that, after discontinuing fentanyl for 12 hours and morphine for 4 hours, they administered 0.4 mg of naloxone IV and 10 mg diazepam IV. As expected, within 10 minutes the patient experienced severe opioid withdrawal — including increased pain, dysphoria, accelerated heart rate, and pallor — whereupon he was immediately given 10 mg morphine IV. At 15 minutes the patient was administered 5 mg morphine IM, and by 20 minutes after naloxone-induced opioid withdrawal symptoms were relieved. The patient claimed he had not felt so clear-headed in a very long time and was able to achieve a better quality of life and excellent pain control (VAS score 0 to 2), without breakthrough pain, on 60 mg oral morphine every 4 hours until he eventually died from the cancer.

In this patient, apparent tolerance to high-dose opioid pharmacotherapy resulted in ineffective pain control while producing intolerable side effects. Although controversial, some of the literature would suggest that the patient possibly suffered from opioid-induced hyperalgesia, which might be resolved by discontinuing opioids entirely or temporarily (eg, “drug holiday”); however, this would unlikely benefit intractable chronic pain in a patient with terminal cancer. Rotation to a different opioid analgesic might be another strategy, but this was not reported in the case study above and may not benefit endogenous antinociceptive systems that have become dysfunctional and resistant to opioids as a class.

As we noted in our previous report [Leavitt 2010], Jane Loitman [2006] at the Washington University School of Medicine, St. Louis, Missouri, described 3 cases of refractory pain similar to the above, in which she administered 0.6 to 1.2 mg naloxone IV that precipitated severe withdrawal. This was relieved within 20 minutes by readministration of opioid analgesics and, in all cases, the patients achieved greater pain relief than before the brief detoxification procedure and at lower opioid doses.

Although the mechanisms behind this need further elaboration, research by Loitman and others suggests that appropriately low doses of opioid antagonists (naloxone, and also naltrexone) appear to reset the endogenous opioid-receptor system, somewhat analogous to how “rebooting” a malfunctioning computer clears memory, refreshes the software, and often restores normal function. This may be an important concept for patients experiencing intractable chronic pain without relief from opioids, and research also has demonstrated benefits of low-dose naloxone (0.08 to 0.4 mg) administered in the post-operative setting to enhance opioid analgesic effects at lower doses. Anecdotally we recently heard of naloxone being routinely administered postop prior to opioid analgesia at a major East Coast medical center in the U.S.; however, details regarding the protocol were unavailable.

Although rare, adverse reactions to naloxone have been reported and, due to the stresses of the detoxification procedure, the Chinese authors caution that there may be risks of the brief detoxification procedure in patients who are elderly, or those with heart disease or other organ dysfunction. More research is needed to define optimal patient selection and naloxone doses for achieving maximum benefit, with the least risk, and for the longest duration of time.

Technical Side Note: Naloxone is actually a stereoisomer with two enantiomers that are mirror images of each other — levo-(-)-naloxone and dextro-(+)-naloxone. For unknown reasons, all commercially available naloxone is exclusively the levo enantiomer, which is a pure opioid-receptor antagonist. The dextro enantiomer of naloxone has interesting qualities of suppressing glial cell (eg, microglia, astrocyte) activation, and such activation is believed to play an important role in inflammation and neuropathic pain. Certain opioids — eg, morphine, methadone, perhaps others — may activate glia, which might contribute to tolerance and/or hyperalgesia. Additionally, dextro-naloxone stems opioid-induced release of dopamine, so this enantiomer could theoretically play a role in developing more effective and abuse/addiction-resistant opioid analgesics. Some of this is under investigation at present and there could be an interesting and vital future for a racemic mixture containing both levo- and dextro-naloxone in pain management practice. However, this is one of those potentially important areas of medical science that offers much promise but appears to garner minimal funding for ongoing exploration.

> YinDongfeng, XingYuqing, TangGuangyi, ZhuYing. A successful case of naloxone reversing morphine resistance. 2010(Nov); unpublished manuscript. Liaoning University of Traditional Chinese Medicine and The Department of Oncology of the affiliated hospital of Liaoning.
> Leavitt SB. Opioid Antagonists, Naloxone & Naltrexone — Aids for Pain Management: An Overview of Clinical Evidence. Pain Treatment Topics. 2009(Mar) [
PDF here]. Abridged version published as: Leavitt SB. Opioid Antagonists in Pain Management. Practical Pain Management. 2009(Apr);9(3):10-21 [PDF here].
> Loitman JE. Enhanced analgesia with opioid antagonist administration. J Pall Med. 2006;9(6):1250-1253 [
abstract here].