Metformin for the Prevention of Episodic Migraine (MPEM)


About this study

Migraine is the third most prevalent disease in the world. Preventive treatment is indicated in about 40% of individuals with episodic migraine. Although 4 treatments are approved by the US Food and Drug Administration for prevention of episodic migraine, none were designed to prevent migraine, efficacy is modest, and all have significant adverse-event profiles. As a result, less than 1/3 of migraine sufferers with who are candidates for prevention receive drug treatment and of those who are treated, more than 85% have discontinued the preventive drug within one year. Migraine pain is associated with the activation and sensitization of specific receptors involved in pain-promoting pathways. Metformin, which is a widely available, well-tolerated anti-diabetic medication, can downregulate pain-promoting pathways. Metformin has demonstrated positive results in animal models of migraine in the laboratory. Given the longstanding use and established safety record of metformin, the investigators will evaluate the safety and efficacy of metformin for preventive treatment of high-frequency episodic migraine in a randomized, double-blind, placebo-controlled, crossover trial.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  1. age 18-65 years
  2. a diagnosis of migraine with or without aura for >1 year according to the International Classification of Headache Disorders-IIIb
  3. 5-14 migraine days per month on average during the preceding 3 months. Women of reproductive ability must use a reliable form of contraception beginning 3 months before study enrollment, throughout the study, and for at least 1 month after study completion.

Exclusion Criteria:

  1. a diagnosis of diabetes mellitus or polycystic ovarian syndrome
  2. overuse of acute migraine treatments
  3. failure to respond to 3 or more previous preventive drug treatments
  4. change in dose of migraine-preventive medication within 2 months of beginning the baseline diary phase
  5. significant somatic or psychiatric disease
  6. known alcohol or other substance abuse
  7. pregnant or breastfeeding.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Amaal Starling, M.D.

Closed for enrollment

More information


  • Chronic pain is a critical medical problem afflicting hundreds of millions of people worldwide with costly effects on society and health care systems. Novel therapeutic avenues for the treatment of pain are needed that are directly targeted to the molecular mechanisms that promote and maintain chronic pain states. Recent evidence suggests that peripheral pain plasticity is promoted and potentially maintained via changes in translation control that are mediated by mTORC1 and MAPK pathways. While these pathways can be targeted individually, stimulating the AMPK pathway with direct or indirect activators achieves inhibition of these pathways via engagement of a single kinase. Here we review the form, function and pharmacology of AMPK with special attention to its emerging role as a potential target for pain therapeutics. We present the existing evidence supporting a role of AMPK activation in alleviating symptoms of peripheral nerve injury- and incision-induced pain plasticity and the blockade of the development of chronic pain following surgery. We argue that these preclinical findings support a strong rationale for clinical trials of currently available AMPK activators and further development of novel pharmacological strategies for more potent and efficacious manipulation of AMPK in the clinical setting. Finally, we posit that AMPK represents a unique opportunity for drug development in the kinase area for pain because it is pharmacologically manipulated via activation rather than inhibition potentially offering a wider therapeutic window with interesting additional pharmacological opportunities. Altogether, the physiology, pharmacology and therapeutic opportunities surrounding AMPK make it an attractive target for novel intervention for chronic pain and its prevention. Read More on PubMed

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