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1 Authors and Disclosures Marco Trucco, MD, Piero Meineri, MD, Luigi Ruiz, MD, Maurizio Gionco, MD, on behalf of the "Gruppo Neurologico Ospedaliero Interregionale per lo Studio delle Cefalee" (Neurological Hospital Interregional Group for the Study of Headaches) Headache Centre, Department of Neurology, Santa Corona Hospital, Pietra Ligure (SV), Italy (M. Trucco); Headache Centre, Department of Neurology, S. Croce e Carle Hospital, Cuneo, Italy (P. Meineri); Headache Centre, Department of Neurology, SS. Antonio e Biagio e C. Arrigo Hospital, Alessandria, Italy (L. Ruiz); Headache Centre, Department of Neurology, Mauriziano Hospital, Torino, Italy (M. Gionco). Address all correspondence to M. Trucco, Headache Centre, Department of Neurology, Santa Corona Hospital, Via XXV Aprile 38, I Pietra Ligure (SV), Italy. From Headache Medication Overuse Headache: Withdrawal and Prophylactic Therapeutic Regimen Marco Trucco, MD; Piero Meineri, MD; Luigi Ruiz, MD; Maurizio Gionco, MD Posted: 08/05/2010; Headache. 2010;50(6): Blackwell Publishing Abstract and Introduction Abstract Background. Medication overuse headache (MOH) is a secondary headache, whose diagnostic criteria were settled by the Second Edition of the International Classification of Headache Disorders and its subsequent revisions. Its diagnosis and treatment represent a growing problem worldwide and a challenge for headache specialists. Objective. The aim of this study was to evaluate the efficacy of a therapeutic regimen for withdrawal of the overused drug and prophylaxis of headache in a population of patients suffering from MOH in 8 hospitals of Piemonte Liguria Valle d'aosta. Patients and Methods. Seventy patients, 58 females (82.9%) and 12 males (17.1%), mean age at observation ± years, affected by MOH following International Headache Society diagnostic revised criteria were treated as inpatients (n = 40) or in Day Hospital (n = 30). Headache Index (HI) and Daily Drug Intake (DDI) were used for evaluating the severity of headache and medication overuse. The patients were treated by abrupt discontinuation of the overused drug and by a therapeutic protocol including i.v. hydration, dexhamethasone, metoclopramide, and benzodiazepines for 7 15 days. Prophylactic medication was started at the beginning of therapeutic protocol. Patients underwent follow-up controls 1, 3, and 6 months after discharge. The initial diagnosis was MOH in all patients included in the study. The overused medications were simple analgesics in 18 cases (25.7%), combination analgesics in 26 cases (37.1%), triptans alone in 9 cases (12.9%), or in combination with analgesics in 13 cases (18.6%), and ergot derivatives (in combination) in 4 cases (5.7%). We collected data from 59 patients at first follow-up (1 month), 56 after 3 months, and 42 after 6 months. Results. Mean HI was 0.92 at admission, 0.19 at discharge, 0.35 after 30 days, 0.39 after 3 months, and 0.42 after 6 months. Mean DDI was 2.72 at admission, 0.22 at discharge, 0.31 after 1 month, 0.38 after 3 months, and 0.47 after 6 months. These results proved to be highly statistically significant. Conclusions. The protocol was generally effective, safe, and well-tolerated. The results tend to remain stable with time, and seem to be encouraging about long-term use of this therapeutic protocol on a larger number of patients suffering from MOH. Introduction Chronic overuse of all symptomatic headache drugs (ergotamine, analgesics, opioids, and triptans), alone or in combination, in patients with primary headache disorders, [1] is frequently associated with the development of a secondary headache, called medication overuse headache (MOH). This definition was recently settled by the Second Edition of the International Classification of Headache Disorders [2] and its subsequent revisions. [3,4] The current diagnosis of MOH no longer requests improvement after discontinuation of medication overuse, but should be directly given to patients with a primary headache plus ongoing medication 1 of 10 8/11/10 10:42 AM

2 overuse. [4] Revised International Headache Society (IHS) criteria for MOH are shown in Table 1. Table 1. Revised Criteria for Medication Overuse Headache Appendix 8.2. Medication overuse headache Diagnostic criteria A. Headache present on 15 days/month B. Regular overuse for >3 months of 1 or more acute/symptomatic treatment drugs as defined under subforms of Ergotamine, triptans, opioids or combination analgesic medications on 10 days/month on a regular basis for >3 months 2. Simple analgesics or any combination of ergotamine, triptans, analgesics opioids on 15 days/month on a regular basis for >3 months without overuse of any single class alone C. Headache has developed or markedly worsened during medication overuse The prevalence of this condition is increasing worldwide; its prevalence in general population is 1 1.4% with a peak prevalence in women in their 50s (5.0%), [5] and it is therefore considered a major health problem. The pathophysiology of MOH is not known, and is still a matter of debate. [6] The treatment of MOH generally includes discontinuation of the overused medication. [7,8] This can lead to "withdrawal headache," in addition to other symptoms such as nausea, vomiting, anxiety, tachycardia, sleep disturbances, arterial hypotension. [9] Various therapeutic protocols for this entity were proposed, [5 16] but controlled trials dealing with all the aspects of this complex issue and consensus guidelines for the treatment of MOH are currently not available. We studied the efficacy of a therapeutic regimen for the withdrawal of the overused drug and prophylactic treatment, since years in use in our Hospitals, in a population of 70 patients suffering from MOH, diagnosed with new criteria in 8 hospital headache centers of Piemonte Liguria Valle d'aosta. This protocol was followed by a 6-month follow-up. Patients and Methods Seventy patients, 58 females (82.9%) and 12 males (17.1%), mean age at observation ± years (range years), affected by MOH following IHS diagnostic revised criteria, underwent a withdrawal and detoxification therapeutic regimen as inpatients (40, 57.1%) or in Day Hospital (30, 42.9%) between 2003 and The patients were observed and treated by the following Hospitals: Ospedale Mauriziano, Torino (22 cases), and Ospedale SS. Antonio e Biagio, Alessandria (14 cases), Ospedale S. Croce e Carle, Cuneo (9 cases), Ospedale S. Corona, Pietra Ligure (8 cases), Ospedale S. Martino, Genova (7 cases), Ospedali Riuniti del Canavese, Ivrea (5 cases), Ospedale Regionale, Aosta (3 cases), and Ospedale degli Infermi, Biella (2 cases). Inclusion criteria were: age 18 years; diagnosis of MOH; Headache Index (HI) 0.7 (days with headache divided by days observed); [10] Daily Drug Intake (DDI) 1 (number of tablets or suppositories consumed every day); [10] the above conditions having lasted for at least 6 months; verbal informed consent. Exclusion criteria were listed as follows: age <18 years; altered neurological examination; diagnosis of secondary headache as cause of MOH; pregnancy or lactation; 2 of 10 8/11/10 10:42 AM

3 5. severe systemic pathologies associated to headache; 6. major psychiatric disorders such as major depression or psychosis; 7. contraindication to use of steroids. The patients were enrolled after a clinical neurological evaluation by an experienced headache specialist including time pattern of the previous headache, comorbidity, overused drug, previous prophylaxes, and neurological examination. HI and DDI were used for evaluating the severity of headache and medication overuse within a 1-month period (T0). These data were collected during the interview or with an headache diary. Clinical characteristics of the population at observation are shown in Table 2. Table 2. Patients' Characteristics at Observation Inpatients Day hospital Total Males, n Females, n Mean age at observation, years (range) 50.0 ± (24 74) 52.4 ± (29 76) ± (24 76) Duration of overuse, years (range) 3.4 ± 6.55 (0.5 30) 2.6 ± 3.40 (0.5 15) 3.0 ± 5.38 (0.5 30) Headache Index 0.95 ± ± ± 0.13 Daily Drug Intake 3.09 ± ± ± 1.90 Data are expressed as means ± SD (range) except otherwise indicated. Patients were admitted as inpatients or in a day hospital, according to severity of the headache, amount and type of the abused medication, and preference of the patient (ie, distance between the center and their place of residence). According to the data listed in Table 2, we observed a trend to higher severity of both HI and DDI between inpatients, even these parameters did not reach statistical significance. Table 2. Patients' Characteristics at Observation Inpatients Day hospital Total Males, n Females, n Mean age at observation, years (range) 50.0 ± (24 74) 52.4 ± (29 76) ± (24 76) Duration of overuse, years (range) 3.4 ± 6.55 (0.5 30) 2.6 ± 3.40 (0.5 15) 3.0 ± 5.38 (0.5 30) Headache Index 0.95 ± ± ± 0.13 Daily Drug Intake 3.09 ± ± ± 1.90 Data are expressed as means ± SD (range) except otherwise indicated. We preferred to admit to Hospital ward rather than Day Clinic patients who abused of medications containing barbiturates (because of the risk of abstinence symptoms and epileptic seizures), ergot-derivatives and triptans. At admission, they underwent a diagnostic protocol including routine blood tests (at admission and discharge) plus dosage of B12 and folic acid. The treatment included: abrupt discontinuation of all abused drugs; i.v. fluid replacement ( cc of saline solution); 3 of 10 8/11/10 10:42 AM

4 3. i.v. anxyolitic therapy (ie, clordemetildiazepam 1 3 mg daily or diazepam 5 15 mg daily); 4. i.v. dexhamethasone (8 mg daily); 5. i.v. metoclopramide (10 mg daily). In case of very severe headache, only single drugs were allowed as rescue medications (triptans, 1 cp. daily; or lysine acetylsalicylate, 1000 mg i.v. daily), and always different from the abused drug. When necessary, symptomatic treatment for gastrointestinal disturbances because of dexhamethasone was provided. Nine patients (12.9%) took butalbital-containing preparations (mean daily dose mg), but none of them presented symptoms of dependence with need of phenobarbital therapy. Duration of treatment could vary from 7 to 15 days. Prophylaxis was continued if present at the beginning of treatment; if not, it was immediately started (using preferably antiepileptic drugs as sodium valproate mg, or topiramate 100 mg, or, alternatively, flunarizine 5 mg). All patients were instructed about the positive effects of behavioral modifications. Follow-up data were collected by means of a headache diary. Patients were evaluated before (T0) and after (T10) the therapeutic regimen. They underwent follow-up controls 1 (T30), 3 (T90), and 6 months (T180) after discharge. In these visits, on the basis of headache diary, both HI and DDI were evaluated. Statistical evaluation was carried out using Repeated Measures ANOVA Report with Tukey-Kramer Multiple-Comparison Test. Level of statistical significance was chosen at alpha = Results Diagnosis The initial diagnosis was MOH following IHS revised criteria in all patients. The original headache was classified as: Unclassified Chronic Headache in 25 cases, Migraine without Aura in 19 cases, Transformed Migraine in 14 cases, Chronic Migraine in 11 cases, and Chronic Tension Headache in 1 case. The mean duration of medication overuse was 3.0 ± 5.38 years (range 6 months to 30 years). Overused Medications The overused medications were nonsteroidal anti-inflammatory drugs (NSAIDs)/analgesics in combination in 26 cases (37.1%), NSAIDs/simple analgesics in 18 cases (25.7%), triptans in association with NSAIDs in 13 cases (18.6%) or alone in 9 cases (12.9%), and ergot derivatives (in combination) in 4 cases (5.7%). Thirty-five (50.0%) of our patients took more than 1 preparation. Twenty-five patients (35.7%) took caffeine-containing preparations. Three patients (4.3%) took low-dose opioid-containing preparations. Among these patients, we observed a group of 17 patients with severe drug overuse (DDI 4), all females, who mainly took drugs in combination or association of NSAIDs with ergots or triptans (13/17, 76.5%). Comorbidity and Previous Treatments Comorbidity included anxious depression in 31 cases (44.3%), arterial hypertension in 10 cases (14.3%), obesity in 3 cases (4.3%), and gastric disorders in 3 cases (4.3%). We did not observe differences in overused drugs between patients with or without comorbidity. Interestingly, 5 patients with arterial hypertension overused triptans or ergot derivatives. Previous prophylactic treatments were: tryciclic antidepressants in 28 cases; calcium antagonists in 24 cases; beta-blockers in 20 cases; antiepileptic drugs in 16 cases; selective serotonin reuptake inhibitor (SSRI) in 10 cases; pizotifen in 6 cases; other pharmacological prophylaxes in 7 cases; nonpharmacological treatments in 4 cases (in 34 cases multiple pharmacological treatments were reported). Eighteen patients did not report any prophylaxis. These data are also reported in Table 3. Table 3. Patients' Characteristics at Observation [2] Original headache Patients, n (%) Gender, n (%) 4 of 10 8/11/10 10:42 AM

5 Male Female Unclassified 25 (35.7) 5 (20.0) 20 (80.0) Migraine without aura 19 (27.2) 3 (15.8) 16 (84.2) Transformed migraine 14 (20.0) 14 (100) Chronic migraine 11 (15.7) 4 (36.4) 7 (63.6) Chronic tension headache 1 (1.4) 1 (100) Overused medications NSAIDs/analgesics in combination 26 (37.1) 1 (3.8) 25 (96.2) NSAIDs/analgesics 18 (25.7) 5 (27.8) 13 (72.2) Triptans+NSAIDs 13 (18.6) 2 (15.4) 11 (84.6) Triptans 9 (12.9) 3 (33.3) 6 (66.7) Ergot derivatives in combination 4 (5.7) 1 (25.0) 3 (75.0) Severe abusers (DDI 4) 17 (24.3) 17 (100) Comorbidity Anxious depression 31 5 (16.1) 26 (83.9) Arterial hypertension 10 3 (30.0) 7 (70.0) Hypothyroidism 4 4 (100) Obesity 3 3 (100) Gastric disorders 3 3 (100) Other pathologies 8 5 (62.5) 3 (37.5) (Some patients presented more than 1 comorbid pathology.) Previous prophylactic treatments Tricyclic antidepressants 28 4 (14.3) 24 (85.7) Calcium antagonists 24 5 (20.8) 19 (79.2) Beta-blockers 20 6 (30.0) 14 (60.0) Antiepileptic drugs 16 3 (18.8) 13 (81.2) SSRI 10 1 (10.0) 9 (90.0) Pizotifen 6 1 (16.7) 5 (83.3) Other pharmacological prophylaxes 7 1 (14.3) 6 (85.7) Nonpharmacological treatments 4 4 (100) No prophylaxis 18 2 (11.1) 16 (88.9) (Some patients took more than 1 prophylaxis.) DDI = Daily Drug Intake; NSAIDs = nonsteroidal anti-inflammatory drugs; SSRI = selective serotonin reuptake inhibitor. Clinical Tests 5 of 10 8/11/10 10:42 AM

6 We found altered values of blood tests at the first visit only in a minority of patients: high cholesterol levels in 8 cases, alteration of hepatic enzymes in 2 cases, low folate values in 2 cases, and mild hyperglycemia in 1 case. No significant changes in blood test values before and after the treatment were found. Follow-up The withdrawal protocol was well-tolerated. Data were collected from 59 patients after 1 month, 56 after 3 months, and 42 after 6 months. No significant differences in clinical history were found between the patients included in the analysis and those lost to follow-up. The suggested prophylaxis was: sodium valproate (n = 30), propranolol (n = 9), topiramate (n = 9), amitriptyline (n = 7), flunarizine (n = 7), SSRI (n = 7), and other prophylaxes (n = 8). In 15 cases, we suggested a combined prophylaxis. The time course of HI and DDI are shown in the Figure. Figure 1. Time course of HI and DDI. DDI = Daily Drug Intake; HI = Headache Index. Statistical evaluation of HI and DDI data are shown in Table 4. Table 4. Statistical Evaluation (Repeated Measures ANOVA Report Tukey-Kramer's Simultaneous Confidence Intervals for Multiple Comparisons of All Pairs) of HI on 42 Patients at T0, T10, T30, T90, and T180 HI 6 of 10 8/11/10 10:42 AM

7 Comparison test groups result Mean Lower 95.0% simultaneous CI Mean difference Upper 95.0% simultaneous CI T T T T T Level of statistical significance vs T0 < HI = Headache Index. Statistical Evaluation (Repeated Measures ANOVA Report Tukey-Kramer's Simultaneous Confidence Intervals for Multiple Comparisons of All Pairs) of DDI on 42 Patients at T0, T10, T30, T90, and T180 DDI Comparison test groups result Mean Lower 95.0% simultaneous CI Mean difference Upper 95.0% simultaneous CI T T T T T Level of statistical significance vs T0 < DDI = Daily Drug Intake. We evaluated the response to treatment in terms of reduction of drug intake at baseline and we were able to single out a group of 48/56 (85.7%) "responders" patients who at T90 significantly reduced drug intake (below one-half of the initial daily intake) and 7/56 (12.5%) "relapsers" patients. More in general, at T180 29/42 patients (69.0%) experienced a significant relief from headache (below one-half of the initial frequency), 37/42 (88.1%) significantly reduced drug intake, and 5/42 (11.9%) were therapeutic failures (no one of the above). Therefore, some patients did not benefit from lowering drug intake in term of significant reduction of attacks frequency. No patient changed prophylactic therapy during the follow-up. Dropouts We observed a significant number of patients (28/70, 40.0%) lost to follow-up at T180. This could be a major limitation of the results of our study. Therefore, an intention-to-treat analysis was performed, showing that at T180 29/70 patients (41.4%) experienced at least 50% of headache reduction and 37/70 (52.9%) reduced more than 50% drug intake. These results, even not significant as those obtained on the 42 patients seen at T180, confirmed the clinical efficacy of the protocol. We are unable to state if these patients dropped out because of early or late relapse of the medication overuse, or because of side effects of the prophylactic medication, or for other reasons. Discussion 7 of 10 8/11/10 10:42 AM

8 Medication overuse headache still represents a very hard obstacle for clinicians involved the treatment of headaches. This diagnosis is clinically important because generally in these cases, results obtained with pharmacological treatments are considered unsatisfactory. This probably is a consequence of our limited knowledge of multiple mechanisms leading to chronicization of episodic headaches or to medication overuse. In previous studies, various approaches and treatments for MOH were suggested. It is generally accepted that abrupt withdrawal from overused medication(s) is essential for recovery and prophylactic treatments are considered ineffective if given before of this withdrawal. But in a recent study, [17] Hagen et al pointed out that prophylactic medication given during the management of MOH is more effective than abrupt withdrawal with standard outpatient detoxification. For the treatment of withdrawal headache and other related symptoms only a limited number of studies recommend the use of steroids, [9,11,14] but there is not a general consent about the molecule, doses and route of administration (oral or i.v.). These results were not confirmed by Bøe et al in a double-blind, placebo controlled study. [15] The authors tested oral prednisolone for 6 days (60 mg on days 1 and 2, 40 mg on days 3 and 4, and 20 mg on days 5 and 6) vs placebo for 6 days in hospitalized patients with MOH, with no recognizable effect. Krymchantowski and Moreira [14] found unsatisfactory results on headache frequency and intensity between 3 groups of patients taking the same doses of oral prednisolone, naratriptan 2.5 mg twice a day and no therapy, while obtained significant results only on withdrawal symptoms and consuption of rescue drugs in patients taking the 2 treatments in comparison with the "nothing" group. We think that the doses were too low and oral administration not adequate. It might be that treatment of withdrawal symptoms requires high doses of steroids, or i.v. route of administration (as in our study), or using prednisolone in open trials provokes a high placebo response, as hypothesized by Diener. [18] Further, not all studies include i.v. hydration. Relja et al [12] obtained better results on initial symptoms (but only with 3 months' follow-up) using a protocol including i.v. hydration. Timing of introduction of prophylactic treatment was not the same in all examined studies (at the beginning or end of detoxification protocol, or only after few days). Finally, in some studies inpatient setting for detoxification treatment was used, [6,10,15] but without general consent. [11,12,16] It can be concluded that guidelines and consensus about the management of MOH are currently not available and are far to be stated. Our data, even obtained on a limited number of patients and with the biases of an open study, are homogenous and were collected prospectically. The withdrawal protocol was effective, safe, and well-tolerated. Prophylaxis was prescribed mainly on the basis of comorbidity and possible side effects of prophylactic medication, in particular suggesting amitriptyline to patients with anxious depression and avoiding sodium valproate, flunarizine, and amitriptyline in patients with overweight. In general, it was not suggested on the basis of the overused medication. HI and DDI results before and after treatment are statistically highly significant (P <.0001). We also obtained a good rate of positive individual results at 90 and 180 days control visit (69.0% for headache relief and 88.1% for lowering drug intake, for patients seen at T180). No significant differences in clinical outcome were collected on the basis of different overused medications, comorbidity or severity of the initial clinical presentation. Our results are in accordance with previous studies: Baumgartner et al [16] found that 60.5% of their patients experienced significant relief of headache and 76.3% reduced analgesic intake. Pini et al [10] reported an efficacy of 60% for HI and 72% for DDI. Similar figures were obtained also by Rossi et al, [11] with 75.4% of positive results. Suhr et al [15] found positive results in 79.2% of their patients. We stress mainly the opportunity of parenteral fluid replacement therapy and the importance of steroids given intravenously. This therapeutic protocol needs at least Day Hospital setting for its administration. We found no significant differences in the outcome of patients who underwent detoxification as inpatients and those treated in Day 8 of 10 8/11/10 10:42 AM

9 Hospital, so we are able to suggest this last treatment setting, at least for the majority of patients, without severe ergots, opiates, or barbiturates overuse. Moreover, Day Hospital setting allows a good saving both in terms of bed engagement and of economic resources. The obtained values tend to remain fairly stable during all observation period. These results induced us to consider our therapeutic regimen as effective in the treatment of MOH, both in term of lowering the frequency of attacks and medications intake, and to continue utilizing it on a larger number of patients in daily practice. Sidebar Statement of Authorship Category 1 a. b. c. Category 2 Conception and Design M. Trucco, P. Meineri, L. Ruiz, M. Gionco Acquisition of Data M. Trucco, P. Meineri, L. Ruiz, M. Gionco, M. Maggio, D. Ferrandi, E. Bottacchi, C. Lia, E. Barbero, M. Fonzari, D. Farinini, D. Santoloci, F. Valguarnera, A. Febbraro, G. Perego Analysis and Interpretation of Data M. Trucco, P. Meineri, L. Ruiz, M. Gionco, R. Melchio a. b. Category 3 Drafting the Article M. Trucco, P. Meineri, L. Ruiz, M. Gionco Revising it for Intellectual Content M. Trucco, P. Meineri, L. Ruiz, M. Gionco a. Final Approval of the Completed Article M. Trucco, P. Meineri, L. Ruiz, M. Gionco References Castillo J, Muñoz P, Guitera V, Pascual J. Epidemiology of chronic daily headache in the general population. Headache. 1999;39: Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. Cephalalgia. 2004;24(Suppl. 1): Silberstein SD, Olesen J, Bousser M-G, et al. The International Classification of Headache Disorders, 2nd Edition (ICHD-II) revision of criteria for 8.2 Medication-overuse headache. Cephalalgia. 2005;25: Headache Classification Committee, Olesen J, Bousser M-G, Diener H-C, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia. 2006;26: Zidverc-Trajkovic J, Pekmezovic T, Jovanovic Z, et al. Medication overuse headache: Clinical features predicting treatment outcome at 1-year follow-up. Cephalalgia. 2007;27: Ghiotto N, Sances G, Galli F, et al. Medication overuse headache and applicability of the ICHD-II diagnostic criteria: 1-year follow-up study (CARE I protocol). Cephalalgia. 2009;29: Zeeberg P, Olesen J, Jensen R. Discontinuation of medication overuse in headache patients: Recovery of therapeutic responsiveness. Cephalalgia. 2006;26: Zeeberg P, Olesen J, Jensen R. Probable medication-overuse headache. The effect of a 2- month drug-free period. Neurology. 2006;66: Pageler L, Katsarava Z, Diener HC, Limmroth V. Prednisone vs placebo in withdrawal therapy following medication overuse headache. Cephalalgia. 2008;28: Pini LA, Bigarelli M, Vitale G, Sternieri E. Headaches associated with chronic use of analgesics: A therapeutic approach. 9 of 10 8/11/10 10:42 AM

10 Headache. 1996;36: Rossi P, Di Lorenzo C, Faroni J, et al. Advice alone vs structured detoxification programmes for medication overuse headache: A prospective, randomized, open-label trial in transformed migraine patients with low medical needs. Cephalalgia. 2006;26: Relja G, Granato A, Bratina A, et al. Outcome of medication overuse headache after abrupt in-patient withdrawal. Cephalalgia. 2006;26: Suhr B, Evers S, Bauer B, et al. Drug-induced headache: Long-term results of stationary vs ambulatory withdrawal therapy. Cephalalgia. 1999;19: Krymchantowski AV, Moreira PF. Out-patients detoxification in chronic migraine: Comparison of strategies. Cephalalgia. 2003;23: Bøe MG, Mygland Å, Salvesen R. Prednisolone does not reduce withdrawal headache. A randomized, double-blind study. Neurology. 2007;69: Baumgartner C, Wessely P, Bingöl C, et al. Longterm prognosis of analgesic withdrawal in patients with drug-induced headache. Headache. 1989;29: Hagen K, Albretsen C, Vilming ST, et al. Management of medication overuse headache: 1-year randomized multicentre open-label trial. Cephalalgia. 2009;29: Diener H-C. How to treat medication overuse headache. Prednisolone or no prednisolone? Neurology. 2007;69: Acknowledgments We thank the following colleagues, members of the Neurological Hospital Interregional Group for the Study of the Headache, who participated in the study: M. Maggio (Ivrea); D. Ferrandi (Alessandria); E. Bottacchi, C. Lia (Aosta); E. Barbero (Biella); M. Fonzari, D. Farinini, D. Santoloci (Genova, S. Martino Hospital); F. Valguarnera (Genova, Sestri Ponente Hospital); A. Febbraro (Torino); G. Perego (Pietra Ligure). Thanks to R. Melchio (Cuneo) for statistical analysis. Conflict of Interest: None Headache. 2010;50(6): Blackwell Publishing 10 of 10 8/11/10 10:42 AM