STOWE, VT—Tolerance to migraine prophylactic drugs may be influenced by the order of drug administration, use of other medications, the endogenous opioid systems, and environmental cues, according to research presented at the Headache Cooperative of New England’s 22nd Annual Headache Symposium.
“Pursuing mechanisms of tolerance to migraine management could unlock common mechanisms of migraine prevention and improve management strategies,” said Paul B. Rizzoli, MD, Assistant Professor at Harvard Medical School, Boston. The research “ended up leading in some very interesting directions,” he added.
The Four Types of Tolerance
Dr. Rizzoli and Elizabeth Loder, MD, MPH, Associate Professor of Neurology at Brigham and Women’s Hospital, Boston, searched PubMed articles from 1960 to January 2011 and selected 140 articles for review based on their relevance to treatment of migraine with preventive agents.
According to the literature, approximately 1% to 8% of patients develop tolerance to a previously effective prophylactic regimen, and this treatment barrier can be understood with four broad explanations—pharmacokinetic tolerance, pharmacodynamic tolerance, cross tolerance, and behavioral tolerance.
Pharmacokinetic Tolerance
Pharmacokinetic tolerance to prophylactic agents occurs when metabolic adaptations change drug levels, and it can be easily resolved by increasing the medication dose, noted Dr. Rizzoli.
Pharmacodynamic Tolerance
In contrast, pharmacodynamic tolerance describes changes in the effect of a drug over time, not the level, and it is not entirely understood. “In the long run, learning the details of pharmacodynamic tolerance could lead to fundamental changes in the way medications are developed and administered,” Dr. Rizzoli told Neurology Reviews.
Oppositional models for pharmacodynamic tolerance suggest that “the body creates some sort of response to the drug that somehow neutralizes the beneficial effect,” said Dr. Rizzoli. For example, a mechanism in the oppositional pathway may cause patients with migraine to develop tolerance to prophylactic treatment with the antiepileptic drug (AED) gabapentin.
The exact mechanisms of tolerance in AEDs and migraine drugs are not clear but are likely pharmacodynamic, said Dr. Rizzoli. He speculated that identifying the tolerance mechanism in relation to seizure would allow researchers to understand the mechanism in migraine as well.
Cross Tolerance
Identifying prophylactic drugs with similar mechanisms of action may also reveal cross tolerance. In an animal model, “if you make [animals] tolerant to a benzodiazepine and then give them valproate, valproate won’t work. The tolerance transfers to valproate,” said Dr. Rizzoli. However, this particular tolerance operates in one direction, so tolerance to valproate might not transfer to a benzodiazepine.
Clinicians may benefit from having a chart of possible interrelationships between migraine preventives. “The relationship in which these drugs are used could be important,” said Dr. Rizzoli. “It might make us pay more attention to recording the order in which drugs were used.”
A Common Mechanism
Dr. Rizzoli noted an unusual pattern in the use of other migraine prophylactic drugs, such as beta-blockers, calcium channel blockers, and tricyclic antidepressants. In these agents, unlike in AEDs, “no tolerance is found to the nonmigraine uses, but tolerance is noted when used for migraine,” he said. A common mechanism of action may be responsible for tolerance development in these agents—the endogenous opioid systems.
Just as long-term use of opioids for pain may result in hyperalgesia, long-term use of prophylactic migraine medication could make headaches worse. “Opioid mechanisms are probably intimately related to medication overuse headache,” said Dr. Rizzoli. However, “because studies of migraine prophylaxis occur over relatively short periods of time, this possibility has not been carefully evaluated,” Dr. Rizzoli and his colleagues noted in the September 2011 issue of Headache.
If the theory about opioid mechanisms is correct and researchers learn more about how preventive agents influence the opioid receptor complex, Dr. Rizzoli anticipates the development of novel agents or synergistic combinations of agents.
Homeostatic Theory of Tolerance
According to the homeostatic theory, which is a type of behavioral model, repeated drug exposure alone is not enough to cause tolerance to prophylactic drugs. The drug must be present at the time of the headache, and tolerance develops when the body works to restore homeostasis in response to the combined disturbance of the headache and drug, said Dr. Rizzoli. Thus, patients may benefit from avoiding taking prophylactics at the onset of a migraine, and they could be encouraged to use environmental keystones such as calendars and diaries to track headache-free days.
Dr. Rizzoli also suggested that chronic migraine could be viewed as a failure of homeostasis. “Perhaps after a period of chronic pain, the organism accepts [migraine] as the new normal,” he said. “The organism, in trying to establish this new homeostatic balance, actually fights attempts to treat the headache.” However, he added, this theory is “all speculative.”