FINAL REPORT: Central Mechanisms of Opioids in the Transformation of Migraine

Published in PAIN, Volume 155, Issue 2, February 2014

Published in the British Journal of Pharmacology, Volume 171, Issue 9, May 2014

Published in Current Opinion on Neurology, Volume 29, Issue 3, June 2016

Summary

This project investigated the effects of opioids (narcotic pain relievers) on basic mechanisms of migraine, with the goal of understanding how certain types of opioids may in fact worsen migraine. We found that morphine had complex effects on the brain excitability underlying migraine. Initial studies indicated that morphine reduced the threshold for activation of cortical spreading depression (CSD), the spreading wave of activity that is believed to be the basis for the migraine aura.

These results suggested that medications like morphine could have effects that predispose patients to more frequent migraine. However, subsequent studies indicated that morphine had complex effects on repetitive CSD evoked by continuous stimulation. These effects included a reduced frequency of spreading depression events, but an increase in their amplitude and a slower recovery from CSD. We are currently doing further experiments to try to better understand these effects.

Hypothesis vs. Findings

The hypotheses of the original proposal were partially validated. We learned that morphine has complex effects on the brain excitability underlying migraine.

We diverged from our original hypothesis to investigate the effects of different types of opioids that target different opioid receptors. These drugs have been studied in clinical trials for other types of pain, but have not been studied for migraine. We found two medications that inhibited CSD.

These findings are exciting, because these drugs do not have many of the same side effects of morphine. Based on their tolerability and mechanisms of action, we believe that they may be candidates for new migraine therapies. We are now planning further basic as well as clinical studies to investigate the possibility that these medications may be a novel treatment for migraine.

Unanswered Questions

The most interesting question generated by our research is whether medications that target the delta opioid receptor represent a novel treatment for migraine.  Answering this question with further basic and clinical studies will have substantial implications for the field of migraine and for migraine patients.

What This Research Means to You

We studied two opioids that target the delta opioid receptor, a different opioid receptor than morphine. These drugs do not have many of the side effects associated with morphine and were well tolerated. While more studies must be conducted to confirm and develop these findings, we believe they may be candidates for new migraine therapies.

Read Dr. Charles’s excellent review of migraine, published in The New England Journal of Medicine, 377;6 August 10, 2017.