Abstract
The aim of this study was to evaluate the rates and predictors of relapse, after successful drug withdrawal, in migraine patients with medication overuse headache (MOH) and low medical needs. The study population, study design, inclusion criteria and short-term effectiveness of the medication withdrawal strategies have been described elsewhere (Rossi et al., Cephalalgia 2006; 26:1097). Relapsers were defined as those patients fulfilling, at follow-up, the new International Classification of Headache Disorders, 2nd edn, appendix criteria for MOH. Complete datasets were available for 83 patients. At 1 year's follow up, the relapse rate was 20.5±. Univariate analysis showed that patients who relapsed had a longer duration of migraine with more than eight headache days/month, a longer duration of drug overuse, had tried a greater number of preventive treatments in the past, had a lower reduction of headache frequency after withdrawal, and had previously consulted a greater number of specialists. Binary logistic regression analysis was performed, and three variables emerged as significant predictors of relapse: duration of migraine with more than eight headache days/month [odds ratio (OR) 1.57, P = 0.01], a higher frequency of migraine after drug withdrawal (OR 1.48, P = 0.04) and a greater number of previous preventive treatments (OR 1.54, P = 0.01). In patients with migraine plus MOH and low medical needs, relapse seems to depend on a greater severity of baseline migraine.
Introduction
Medication overuse headache (MOH) following successful drug withdrawal has a poor prognosis (1). Prospective studies that included patients with triptan-induced MOH have reported relapse rates after successful drug detoxification therapy of 38% in the first year and around 42% after 4 years (2, 3). Patients with tension-type headache had higher relapse rates than migraine patients, and analgesic overusers had higher relapse rates than ergot and triptan overusers (2). In a recent study including patients not overusing triptans, 39.6% of 240 patients relapsed at 1 year's follow-up (4). The frequency of the primary headache disorder, ergotamine overuse and pretreatment disability as measured by Migraine Disability Assessment were all found to be predictors of relapse [indeed, the reported odds ratio (OR) values and their confidence intervals (CIs) raise some doubts over the statistical interpretation of the results]. These, and older studies investigating rates and predictors of relapse in MOH, were conducted on non-selected populations of headache patients (1, 5, 6).
MOH is a heterogeneous disorder with regard to many factors, such as the primary headache type, the pattern and severity of medication overuse, its underlying reason, the types of drug overused, the psychiatric and physical comorbidities, the socio-environmental pressures on individual patients and individual patients’ past therapeutic experiences. In order to improve the management of this condition, some authors have suggested dividing MOH into simple and complex subtypes (7, 8). In accordance with this suggestion, we have recently demonstrated that in simple MOH patients (defined as having low medical needs) in whom migraine was the primary headache type, effective drug withdrawal may be obtained through the imparting of advice alone (9). The aim of this second study was to evaluate the rates and predictors of relapse after successful drug withdrawal in this same sample of simple MOH patients.
Methods
The study population, study design, inclusion criteria and short-term effectiveness of drug withdrawal strategies have already been described in detail elsewhere (9). Briefly, 118 patients diagnosed with probable MOH plus migraine, in accordance with revised International Classification of Headache Disorders, 2nd edn (ICHD-II) criteria (10) and presenting low medical needs (no previous detoxification treatments, no co-existent, significant and complicating medical illnesses, no current psychiatric comorbidity, no overuse of agents containing opioids, benzodiazepines or barbiturates), were randomly assigned to three different withdrawal strategies. During the research period, new criteria for MOH were published, for inclusion in the appendix to ICHD-II (11). According to these new appendix criteria, all the probable MOH patients included in this study could be diagnosed as MOH.
Group A (n = 40) received only strong advice to withdraw the overused medication. Group B (n = 39) underwent a standard out-patient detoxification programme (advice to withdraw abruptly the overused medication + prednisone p.o. for the first 8 days + personalized preventive treatment starting on day 1). Group C (n = 39) underwent a standard in-patient drug withdrawal programme (abrupt discontinuation of the overuse medication + prednisone p.o. for the first 8 days + personalized preventive treatment starting on day 1 + parenteral fluid replacement and administration of antiemetics + close observation and support for 8 days). No significant difference emerged between the three groups with regard to socio-demographic variables, migraine subtype, migraine duration, MOH duration, number of headache days per month or number of doses and types of overused medication (P > 0.025) (9).
At follow-up after 2 months, 13 patients had dropped out of the study. A total of 89 had successfully completed their withdrawal therapy (i.e. they had reverted to an episodic pattern of headache and to intake of symptomatic medication on < 10 days/month) and were enrolled in this study.
The following data were recorded at baseline: (i) socio-demographic status; (ii) frequency and intensity of headache, duration of migraine and duration of migraine with headache on more than eight headache days/month; (iii) type of medication overused, frequency of drug intake and duration of medication overuse; and (iv) number of specialists previously consulted and number of preventive treatments tried prior to the current consultation. After completing the detoxification programme, two additional items were recorded: the number of days with headache/month after withdrawal and the number of symptomatic medications/month after withdrawal.
Six- and 12-month follow-up
The follow-up was prospectively planned and the patients were requested to give their consent to follow-up on entering the study. They were asked to keep a headache diary to record the pattern of their headache and drug use. Follow-up visits were scheduled to take place 6 and 12 months after the start of the detoxification programme. Follow-up assessments were based on a standard questionnaire. The following items were assessed: (i) frequency and clinical characteristics of headache; (ii) types of symptomatic medication currently used and frequency of their use; and (iii) types of preventive medication currently used, and compliance with the prescribed therapy (regularity of intake). All patients failing to attend the follow-up visits were telephoned by a trained physician (P.R.). Relapsers were defined as those patients fulfilling, at follow-up, the new ICHD-II appendix criteria for MOH.
Statistical analysis
Bivariate comparisons of groups were performed using the χ2 test and Fisher's exact test for categorical variables and t-test for continuous variables. The results of the bivariate analysis comparing patients with and without relapse 1 year after withdrawal were used to construct a binary logistic regression analysis to determine the OR of relapse, controlling for predictors. This approach was used because there was not enough power to evaluate every combination. A level of significance of P < 0.05 was taken as significant.
Results
Patient population
Of the 89 patients enrolled, 40 (44.9%) overused analgesics, 22 (24.7%) overused triptans, 18 (20.2%) overused combinations of analgesics, six (6.7%) overused combinations of acute medications and three (3.4%) overused ergots. The mean duration of migraine was 23.4 ± 14.3 years, the mean duration of migraine with headache on more than 8 days/month was 8.6 ± 6.9 years, and the mean duration of MOH was 4.2 ± 3.7 years.
Follow-up data
Twelve months after withdrawal, complete datasets were available for 83 (93.2%) patients (29 from group A, 26 from group B and 28 from group C). The preventive treatments prescribed to the MOH patients are summarized in Table 1.
Preventive treatments prescribed to medication overuse headache patients and optimized∗ at follow-up visits
Only dosage modification, we did not combine preventive treatments.
Ten patients received preventive medication at the follow-up visit 2 months after the start of the detoxification programme, whereas six received preventive medication at the 6-month follow-up visit.
Preventive treatment was prescribed at the start of the detoxification programme.
Preventive treatment was prescribed at the start of the detoxification programme.
Seventeen patients (20.5%) relapsed within 1 year of withdrawal (13.8% of those in group A, 23.1% of those in group B and 25% of those in group C; P > 0.05). Table 2 summarizes the results of the bivariate analysis comparing the relapsers and non-relapsers, which showed that the patients who relapsed had a longer duration of migraine with headache on more than 8 days/month, a longer duration of drug overuse, had previously tried a greater number of preventive treatments, had a higher headache frequency after withdrawal, and had previously consulted a greater number of specialists. These five variables were considered as potential predictors of relapse on binary logistic regression analysis. The model was highly significant (χ2 = 11.64, d.f. = 2, P < 0.001) and explained 72.4% of the variance in the relapse rate 1 year after withdrawal. Three variables emerged as significant predictors of relapse: a greater number of previous preventive treatments (OR 1.54, CI 1.2, 2.1, P = 0.01), a lower improvement after drug withdrawal (OR 1.48, CI 1.2, 2.9, P = 0.04) and a longer duration of migraine with more than eight headache days/month (OR 1.57, CI 1.2, 3.7, P = 0.01).
Predictors of relapse within a year of successful drug withdrawal: results of bivariate analysis
Discussion
This is the first study to investigate the long-term outcome of MOH in migraine patients with low medical needs. The relapse rate (20.5%) was consistent with that reported in the subgoup of patients with MOH plus migraine studied by Katsarava et al. (2). This similarity in outcome rate may be explained by the fact that the German authors excluded patients with major depression. No comparisons can be made with studies conducted in the pre-triptan era.
Our study has confirmed that relapse after withdrawal therapy is a major concern even in patients with simple MOH. Its findings have two practical implications. First, the inclusion criteria we used to define simple MOH can be considered adequate for selecting patients who may achieve drug withdrawal with simple advice alone, but not for predicting a favourable long-term outcome in these patients. Future studies aiming to define MOH subclasses with different medical needs should consider the role of additional factors, such as psychological and social issues (8). Second, our findings strengthen the notion that the most practical strategy in MOH is to prevent medication overuse through education and early and appropriate migraine prophylaxis in patients who present a high headache frequency (12).
Other authors (5) have found that the withdrawal therapy strategy (4, 5), like the socio-demographic variables, use of preventive treatment, duration of migraine and duration of drug overuse, has no impact on the outcome (2–5). In our study, the type of drug overused did not influence the prognosis. This concurs with the findings of Suhr et al. (4), but contradicts those of Katsarava et al., who found use of analgesics to be a risk factor for relapse (2, 3). This discrepancy may be attributable, among other things, to the inclusion of patients with mixed headache (migraine and tension-type headache) in the German study or to the use of different inclusion criteria and outcome measures.
We found three predictors of relapse. Patients who presented a longer duration of migraine with headache on more than 8 days/month, a higher frequency of migraine after drug withdrawal, and who had previously tried a greater number of preventive treatments were found to be at increased risk of relapse. These findings suggest that relapse depends on a greater severity of baseline migraine, at least in patients with migraine plus MOH and low medical needs. A high frequency of headache is known to be a factor in migraine chronification and in the development of MOH (13, 14). In a recent study it was demonstrated that 60% of chronic migraine patients complicated by probable MOH presented a headache frequency of > 10 days/month 3 months after successful drug withdrawal and the administration of preventive treatments (15). Considered in the context of our findings, these data suggest that a large proportion of migraine patients are at risk of relapse after withdrawal and highlight the need for future research into effective relapse prevention strategies.