FINAL REPORT: Behavioral Model of Medication Overuse Headache

Published in Cephalalgia, Volume 29, Issue 12, December 2009

Summary

Medication overuse headache (MOH) is a disorder that develops from the frequent use of medications taken for the treatment of migraine headache pain. MOH affects an estimated 3-5% of the general population. The mechanisms underlying the development of MOH remain unknown. Among the medications associated with the development of MOH are opiates and triptans. While the effects of repeated opiate or triptan use for headache are unknown, it is possible that these medications may elicit neural adaptations in peripheral nociceptive fibers that innervate the dura that contribute to the increased frequency and occurrence of such headaches.

Our preclinical studies were designed to explore possible neuroadaptive changes elicited by sustained exposure to morphine in order to give insight into possible causes of MOH. We found that morphine treatments elicited acute cutaneous allodynia of the facial regions that resolves after discontinuation. Additionally, morphine increased the expression of calcitonin gene related peptide (CGRP) and nNOS in trigeminal primary afferent neurons identified with Flurogold to innervate the dura. Critically, these neuroadaptive changes persist for long periods of time and can result in different effects that occur even long after the discontinuation of the medication. Stimuli known to elicit migraine headache, such as NO donor or stress, produce facial allodynia in morphine pre-treated rats while having no effects in vehicle treated animals. Such persistent neuroadaptive changes may be relevant to the processes that promote MOH. Acute and chronic blockade of nNOS did not prevent morphine-induced cutanoeus allodynia. More importantly, the blockade of CGRP fully reversed morphine-induced facial allodynia both during morphine infusion or after exposure to a stimulus known to elicit migraine headache, i.e. stress.

Hypothesis vs. Findings

We began by investigating the peripheral sensory fibers within the trigeminal ganglia following sustained exposure to morphine, and we found a remarkable and persistent upregulation of CGRP and nNOS. This discovery was relevant to the known efficacy of CGRP antagonists in migraine pain. Additionally, we found that assay of NGF in the skin was negative suggesting that our research would benefit from focus on of the role of CGRP and nNOS as potential mediators of medication overuse headache. For this reason, we believe that our hypothesis of NGF-dependency was not supported, and we modified the experiments to fit the data observed.

Unanswered Questions

Additional studies will be necessary to better understand the mechanisms of medication overuse headache specifically related to opiates and to other medications such as triptans. In particular, we are now poised to understand if initiating factors of headache (i.e. stress, NO donors or induction of CSD) are capable of producing activation of dural afferents in animals pre-exposed to morphine (but with normal sensory thresholds) and whether activation of afferents is dependent upon nNOS and results in release of CGRP.

Learn More

A few chance encounters led Frank Porreca, PhD into headache research, where he has joined a dedicated group of scientists who are making unprecedented advances in understanding headache pain. Dr. Porreca studies the mechanisms of headache and other types of pain with the goal of developing new and improved medications. MRF recognized Dr. Porreca’s work by awarding him a grant for his project Behavioral Model of Medication Overuse Headache.

Dr. Porreca began his career as a biomedical engineer and developed an interest in pharmacology, the study of the effects of medications on the body, after assisting a colleague with a study of the cardiovascular system. His new interest eventually motivated Dr. Porreca to complete a PhD in pharmacology and begin a new career in pain research, studying neuropathic and cancer pain. An opportunity to present a paper at an American Headache Society conference, where he met prominent headache researchers, showed Dr. Porreca that his research could apply to headache medicine.

Dr. Porreca’s study Behavioral Model of Medication Overuse Headache examines how certain drugs affect the nervous system and change the body’s pain thresholds. The goal of this research is to provide a better overall understanding of how these changes trigger episodes of headache pain in migraine sufferers. He also hopes this research will provide greater insight into Medication Overuse Headache, a chronic headache which can occur when a migraine sufferer uses acute medications on a near daily basis for a prolonged period of time.

In addition to running an active pain-research laboratory at the University of Arizona Medical School, Dr. Porreca also teaches neuroscience and pharmacology to medical and graduate students and post-doctoral fellows. He finds migraine an interesting topic for research because headache pain, unlike most other pain, is not caused by an injury to the body. In his spare time, Dr. Porreca enjoys playing golf and spending time with his family.

Dr. Porreca says that enormous progress is being made in pain research and that the “science has never been better.” He hopes that advances in understanding the mechanisms of pain will soon be used to develop improved treatments for migraine and other pain disorders. Dr. Porreca personally finds it “extraordinarily rewarding” to make a new discovery, no matter how small, and is thrilled to be part of the committed group of scientists making a difference for pain sufferers. Though much progress is being made in the field, Dr. Porreca thinks migraine research remains severely underfunded. He encourages suffers to let their lawmakers know how widespread migraine is and how more funding can make a difference in the lives of millions of people.