Predicting treatment response using pharmacy register in migraine

The success of precision medicine depends on the ability to identify patient groups with a specific response to a drug. The predictive power to classify patients depends on the quality and size of the initial cohort used to build the models [1]. Retrieving treatment response data for a large cohort is resource intensive and can take a long time. Identification of treatment response markers, e.g. in existing pharmacological databases that are easily accessible, is an alternative and simple strategy for assessing large cohorts. Although several countries maintain registry databases with information on individual medication use [2], this approach has never been tested. Migraine is an ideal condition to test the accuracy of prediction of treatment response from pharmacological databases. Migraine affects 15–20% of the population [3] and both acute and prophylactic treatments are available [4]. Triptans are migraine-specific acute drugs with no effect on peripheral pain [5] and are reported to be effective in 60–70% of treated migraine patients [6]. There are several (non-specific) prophylactic drugs for migraine available and the current choice of prophylactic treatment is made by trial and error [4, 7].

In Denmark, the national pharmacy database holds individual-level data on all prescriptions and subsequent purchases of drugs [8]. In a large clinical sample of migraine patients, we have collected information regarding migraine treatment response for both acute and prophylactic drugs [9]. We hypothesized that drug purchases can predict treatment response. To test this hypothesis, we combined the Danish pharmacy database with our clinical migraine sample and provide an estimate of the sensitivity and specificity to predict treatment response.

Patients were recruited as part of the migraine genetic cohort at the Danish Headache Centre (tertiary headache referral centre) from 2010 to 2016. All patients were interviewed by medical doctors or senior medical students specifically trained in using a semi-structured interview to diagnose headache according to the International Classification of Headache Disorders (ICHD) [10]. A total of 1913 migraine patients with or without typical aura answered questions regarding medication use and treatment response to relevant headache pharmacological treatments including acute treatment (following categories: triptans (general, non-specific), ergotamine, non-migraine specific analgesics) and prophylactic treatment (following categories: Beta-blockers, Angiotensin II antagonists, Antiepileptics, ACE-inhibitors, and Anti-depressives). Acute treatment effect was considered positive if the patient reported at least 50% pain reduction within two hours of taking the drug. Prophylactic treatment was considered effective if the patient reported a reduction of at least 50% in the number of migraine attacks with three months of drug use. Patients who did not remember or had not tried the medication in question were registered as missing data.

Using a large clinical migraine cohort (n = 1913) including information on treatment response, we found a highly significant association between the number of purchases of triptans and positive treatment response, defined as having at least 50% reduction in symptoms within two hours of treatment start. We showed that the sensitivity was high (> 80%) for prediction of positive response to triptans and that the sensitivity was above 70% if the patients had more than ten purchases. We did not find evidence for an association between treatment response and purchases of non-migraine specific analgesics or ergotamines. We did not expect to observe an association, as non-migraine specific analgesics can be bought over-the-counter and are used for many other indications putatively introducing substantial statistical noise.

It is expected that migraine patients who purchase triptans more than once only do so if they experience a positive response. However, we observed an expected increase in sensitivity with number of purchases, although ten purchases of triptans were needed to reach 70% sensitivity. Since this is a retrospective study, this may be a consequence of recall bias. In addition, the positive response criterion of having 50% reduction of symptoms within two hours might exclude patients with marginally less or slower effect of triptans. An interesting future study would be to assess the individual migraine drugs. We demonstrated that analysing single drugs necessitates fewer purchases of the drug to gain the 80% specificity. However, a larger sample size is needed and, although more labour intensive, prospective studies may be needed. However, a key future goal is to compare treatment outcome with genetics, which requires that all participants must be genotyped. Here, thousands of patients are usually required to gain enough statistical power to assess common variants. Thus, a prospective migraine diary-based study seems less feasible.

We found a highly significant association between purchases of prophylactic drugs and a positive treatment response, defined as a more than a 50% reduction of their migraine attacks, from using angiotensin II antagonists, beta-blockers, or antiepileptics. We found a high sensitivity (> 80%) predicting positive treatment response from the number of purchases, and a specificity above 70% after at least three or four purchases depending on the drug. Whereas triptans are specific migraine drugs, the prophylactic drugs are not. As a result, the prediction model for prophylactic drugs necessitates knowledge of the prescription indication. Some drugs may be used to treat a multitude of conditions (e.g. epilepsy, arterial hypertension). Hence, we repeated the analysis excluding patients with comorbid disease. The association remained significant, although we observed a significant drop in the average number of purchases of antiepileptics.

Our study design included general triptan use and response, thus we were unable to test for an association between number of different triptans purchased and patients reporting no treatment effect. Future studies including more complex analysis of the types of triptans, patterns of medication exposures, etc., may aid in the characterization of migraine patient groups.

Precision medicine may offer new strategies to treat migraine, and access to existing large cohorts and pharmacy databases may help reach the required larger sample sizes. Based on the current results we recommend using ten purchases for triptans and three or four purchases for prophylactics. We anticipate that using fewer purchases, e.g. three triptans, may be sufficient; however, this should be evaluated in future studies. Notably, more than 75% of the triptan users have purchased triptans at least ten times, and 55–63% of the prophylactic users have at least three or four purchases. Additional factors may also influence treatment response, such as the use of other drugs [13–15], i.e. polypharmacy, as well as presence of co-morbid disorders. Here, it is possible that temporal aspect when additional drugs are prescribed, as a prescription could reflect treatment of adverse-effects. Further, it is easy to imagine that migraine patients with co-morbid depression may experience a better response to anti-depressants [16]. Most likely, genetic factors may also condition the treatment response, as seen for lithium and anti-psychotics [17–19], although studies on migraine drugs so far have been inconclusive or lack replication [13, 15].

We conclude that a national pharmacy database is a valuable resource to identify a positive treatment response for migraineurs. As a general recommendation, we suggest using ten purchases for triptans and three or four purchases for prophylactic drugs, to predict positive treatment response. In future studies, more detailed information about treatment response and failure would improve the correlation with the number of purchases and perhaps enable us to predict treatment failure. We expect that a lower number of purchases than the ten suggested here may be sufficient.