For the purpose of this study, complicated MOH was defined by the presence of at least one of the following conditions [29]: a) comorbidity with other clinically relevant painful condition (e.g. chronic painful disorders such as fibromyalgia or low back pain, neuropathic pain, etc.); b) ongoing or recent comorbidity with psychiatric disorders (i.e. mood disorder, anxiety disorder, substance addiction disorder or eating disorder), as assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Clinician Version [30]; c) moderate/severe psychosocial and environmental problems as defined by DSM-IV Axis IV, assessed at the end of the initial visit by means of a structured interview; d) daily, or almost daily, use of multiple doses of symptomatic medication/s (more than 3 doses/day of analgesics or more than 2 doses/day of triptans, ergots, combinations of acute medications, or analgesics in combination) or anticipatory use of symptomatic medication/s; e) relapse into overuse following previous detoxification treatment.
This set of criteria for defining complicated MOH was deemed to represent the best combination of existing criteria (already proposed in the literature) and the authors’ personal experience in managing MOH patients attending headache centres in Italy, and it has already proved to be highly sensitive in identifying MOH patients in whom effective drug withdrawal may be obtained through the imparting of advice alone [29].
It has been established that abrupt discontinuation of an overused medication may lead to serious withdrawal symptoms such as hypotension, tachycardia, vomiting, intense nervousness, sleep disturbances and even hallucinations and seizures, particularly in patients overusing opioids, barbiturates and tranquillisers, and that these symptoms are best treated under medical supervision in patients with significant complicating medical conditions [1, 14, 19, 20]. Therefore, for ethical reasons, in this study we excluded patients with severe major depression and/or severe psychiatric illnesses and those likely to encounter problems as withdrawal treatment outpatients. Thus, the final set of exclusion criteria were: a) co-existent severe medical (e.g. uncontrolled arterial hypertension, uncontrolled diabetes mellitus, ischaemic cardiopathy, etc.) or psychiatric illness; b) overuse of opioids and/or barbiturate-containing agents; c) treatment with migraine prophylactic drugs within the past three months; d) pregnancy or breastfeeding.
Consecutive new patients, aged 16–65 years, affected by complicated MOH [29] in whom the primary headache was migraine attending a specialist headache centre (INI Grottaferrata Headache Clinic) were evaluated over an eighteen-month period (July 2009 to December 2010).
The patients were evaluated prospectively and the study lasted 14 weeks for each subject (Figure 1). After the first visit, eligible subjects were asked to keep a diagnostic headache diary for four weeks, simply recording their headache pattern and drug use (baseline period). This period was purely observational and at this time no diagnosis or therapeutic indications were given. At the second visit, at the end of this baseline period, the patients still fulfilling the inclusion criteria were randomly assigned (using a computer-generated random number sequence), in equal numbers, to three different treatment groups [24]. Group A received only advice to withdraw the overused medication/s; Group B underwent a standard outpatient detoxification programme consisting of: 1) advice to abruptly withdraw the overused medication/s, 2) prednisone p.o. during the first 10 days (60 mg/day, 2 days; 40 mg/day, 2 days; 20 mg/day, 6 days) [24], 3) individualised preventive treatment begun on day 1 (the preventive agent was chosen on the basis of side-effect profile, comorbid conditions, the patient’s needs and preferences, and the patient’s previous therapeutic experiences). Group C underwent a standard inpatient detoxification programme. After receiving advice about the need to withdraw symptomatic medications, patients in this group were admitted as inpatients to the INI Grottaferrata Headache Clinic for a 10-day period during which they received: 1) abrupt discontinuation of the overused medication/s, 2) close observation and support for 8–10 days, 3) prednisone p.o. (60 mg/day, 2 days; 40 mg/day, 2 days; 20 mg/day, 6 days), 4) individualised preventive treatment as from day 1, and 5) parenteral fluid replacement and administration of antiemetics (metoclopramide i.v).
In order to standardise the educational part of the treatment programme, all advice was issued by the same physician (PR). The advice to discontinue the overused medication/s was given verbally [24] and its imparting, which took about 15 minutes during the second consultation, was structured as follows: a) the role of medication overuse in making headache chronic and in reducing the effectiveness of preventive and behavioural treatments was explained; b) the phenomenon and symptoms of withdrawal headache were explained in detail; c) the beneficial long-term effects, on migraine natural history, of reducing symptomatic medication intake (which include reduction of the migraine-reinforcing properties of short-term pain relief) were emphasised; d) anticipatory use of medication was discouraged; and e) the superiority of the detoxification programme over other therapeutic options was emphasised. In patients assigned to Group A the physician emphasised the importance, for patients, of playing an active role in the management of their headache, without relying solely on medication.
For the treatment of withdrawal headache and associated symptoms, patients could be prescribed the following acute drugs, according to their personal medical history (the rationale was that patients should not use the drug that she or he had previously been abusing) and headache characteristics:
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a)
Antiemetics (metoclopramide 10 mg i.m. or p.o.1 to 3 times per day; chlorpromazine, 25–50 mg i.m. or p.o., domperidone 30 mg rectally or 10 mg p.o.), and (with intake limited to no more than two days per week)
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b)
Acetaminophen (1000 mg p.o. or rectally or i.v on demand, maximum dosage 3 g × day) or naproxen (500 mg p.o. or p.r., maximum dosage 1000 mg × day) or indomethacin (100 mg p.o. or p.r., or 50 mg i.m., maximum dosage 200 mg × day)
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c)
Eletriptan 40 mg p.o., frovatriptan 2.5 mg p.o., almotriptan 12.5 mg p.o., or rizatriptan 10 mg p.o.
Furthermore, the patients were asked to fill in a detailed diagnostic headache diary. The patients assigned to outpatient treatment groups were also told that they could contact the headache centre for medical help and support, should this be needed.
Follow-up visits were scheduled during the 5th and the 10th week after the start of the detoxification programme. All patients failing to attend the follow-up visits were called by telephone within three months from the start of the detoxification programme in order to ascertain their reasons for not adhering to the treatment programme. As in our previous studies [24, 29], the patients were not informed that they were included in a study assessing the effectiveness of simple advice as a withdrawal strategy for MOH. This approach was authorised by the ethics committee of our institute. Therefore, no signed, informed consent was obtained. The research was in compliance with the Helsinki Declaration.
Outcome measures
The primary outcome measures were: a) responders (number of), defined as those subjects who, two months after the start of withdrawal of the overused drug/s, had reverted to an intake of NSAIDs lower than 15 days/month or to an intake of other symptomatic medication/s lower than 10 days/month; b) adherence to the treatment, expressed as the number of patients who completed the follow-up visits; c) responders with headache improvement (number of), defined as those patients who, two months after the start of the drug withdrawal, experienced more than 50% reduction in headache frequency from baseline.
As secondary outcome measures we considered the percentage reduction, two months after the start of the withdrawal, in the number of headache days/month, the number of days with use of symptomatic medication/month, and the number of symptomatic medications/month.
Power calculation and statistical analysis
The main target parameter was the number of responders. On the basis of the results of previous studies, we assumed a responder rate of 55% in the no-intervention group and of 90% in the structured intervention groups, i.e. the study had to have the power to detect a difference of 35%. In applying the above-mentioned percentages, using a power of 0.8% and a significance level of 5%, a minimum of 35 patients per treatment group was required (Fisher’s exact test, two-tailed). We thus needed a total of 105 patients to complete the study. Given the impossibility of performing a satisfactory a priori analysis of the other outcome measures, the adherence to treatment criterion and the other target criteria were subjected to exploratory statistical analysis.
Multi-group comparisons were performed using the one-way analysis of variance for continuous variables and the non-parametric Kruskal-Wallis test for non-normally distributed data. The chi-square test and Fisher’s exact test with Freeman-Halton extension (when applicable) were used for multi-group comparisons of categorical variables. Given that we were performing multiple testing, the level of significance was set at p < 0.025. The analysis was carried out using SPSS 11 for Windows (SPSS Inc., Chicago, IL).