Management of medication overuse headache: 1-year randomized multicentre open-label trial

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Cephalalgia

http://cep.sagepub.com/content/29/2/221The online version of this article can be found at:

DOI: 10.1111/j.1468-2982.2008.01711.x

2009 29: 221CephalalgiaK Hagen, C Albretsen, ST Vilming, R Salvesen, M Grøning, G Helde, G Gravdahl, J-A Zwart and LJ Stovner

Management of Medication Overuse Headache: 1-Year Randomized Multicentre Open-Label Trial

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Management of medication overuse headache: 1-yearrandomized multicentre open-label trial

K Hagen1,2, C Albretsen3, ST Vilming4, R Salvesen5,6, M Grønning7, G Helde1,2, G Gravdahl1,2,J-A Zwart1,2,4 & LJ Stovner1,2

1Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology and 2Norwegian National HeadacheCentre, Section of Neurology, St Olavs Hospital, Trondheim, 3Department of Neurology, Tromsø University Hospital and 6Institute of ClinicalMedicine, University of Tromsø, Tromsø, 4Department of Neurology, Ullevaal University Hospital, University of Oslo, Oslo, 5Department ofNeurology, Nordland Hospital, Bodo, and 7Department of Neurology, Haukeland University Hospital, Bergen, Norway

Hagen K, Albretsen C, Vilming ST, Salvesen R, Grønning M, Helde G, GravdahlG, Zwart J-A & Stovner LJ. Management of medication overuse headache: 1-yearrandomized multicentre open-label trial. Cephalalgia 2009; 29:221–232. London.ISSN 0333-1024

It is a general belief that patients with medication overuse headache (MOH) needwithdrawal of acute headache medication before they respond to prophylacticmedication. In this 1-year open-labelled, multicentre study intention-to-treatanalyses were performed on 56 patients with MOH. These were randomlyassigned to receive prophylactic treatment from the start without detoxification,undergo a standard out-patient detoxification programme without prophylactictreatment from the start, or no specific treatment (5-month follow-up). Theprimary outcome measure, change in headache days per month, did not differsignificantly between groups. However, the prophylaxis group had the greatestdecrease in headache days compared with baseline, and also a significantlymore pronounced reduction in total headache index (headache days/month ¥ headache intensity ¥ headache hours) at months 3 (P = 0.003) and 12(P = 0.017) compared with the withdrawal group. At month 12, 53% of patientsin the prophylaxis group had � 50% reduction in monthly headache dayscompared with 25% in the withdrawal group (P = 0.081). Early introduction ofpreventive treatment without a previous detoxification programme reduced totalheadache suffering more effectively compared with abrupt withdrawal. (Clini-calTrials.gov number, NCT00159588). �Medication overuse headache, prophylactictreatment, discontinuation

Knut Hagen, MD, PhD, Norwegian National Headache Centre, Department ofNeurology, St Olavs Hospital, 7006 Trondheim, Norway. Tel. + 47 7359-8779,fax + 47 7359-8795, e-mail knut.hagen@ntnu.no Received 14 January 2008, accepted24 May 2008

Introduction

Medication overuse headache (MOH) is believed toaffect 1% of the adult general population world-wide (1–6), and approximately one out of fourpatients referred to a neurologist for headachesuffers from this condition (7). To fulfil the diag-nostic criteria of MOH the patients should have� 15 headache days/month, regular overuse ofacute headache medication for at least 3 months,and the headache should have developed or mark-edly worsened during medication overuse (8).

It is generally accepted that the treatment ofchoice in patients with MOH is discontinuation ofthe overused drug(s). Previous studies have notevaluated the long-term course of patients withMOH without specific treatment, i.e. these studieshave not included an adequate control group. It hasbeen a general belief that patients with MOH rarelyrespond to preventative medications while overus-ing acute medication, which is also stated in theInternational Classification of Headache Disorders,2nd edn (ICHD-II) and a revised version of thesespecific criteria (9, 10). However, many headache

doi:10.1111/j.1468-2982.2008.01711.x

221© Blackwell Publishing Ltd Cephalalgia, 2008, 29, 221–232

experts introduce prophylactic treatment early inthe management of MOH (11), but randomizedstudies evaluating the effect of early start of pro-phylactic medication are lacking.The aim of this randomized, prospective, multi-

centre study was to evaluate the effect of earlyintroduction of prophylactic treatment comparedwith abrupt withdrawal and with a control groupin patients with MOH.

Methods

An open-label, randomized, multicentre trial wasconducted over a 4-year period, and the study wasapproved by the Regional Committee for Ethics inMedical Research, the Norwegian Data Inspec-torate, the Norwegian Medicines Agency, and wasregistered at ClinicalTrials.gov before 13 September2005 (ClinicalTrials.gov number, NCT00159588).Each patient signed a written informed consent.The study was conducted in accordance with GoodClinical Practice (12). An audit by the NorwegianData Inspectorate evaluated the way data wererecorded and stored. Data from the clinical reportforms and headache diaries were entered into a rawdata file by a study nurse (G.G.) who did notparticipate in the data analyses, and this raw datafile was saved unchanged in case of an externalaudit of the study result.

Patients

From 1 January 2004 to 31 December 2006 patientsfrom the out-patient clinics of the neurologicaldepartments at five University Hospitals in Norwaywere included. Patients with suspected MOHaccording to the physician referral letter weremailed a headache diary to be completed for atleast 3 months before attending the first visit. Thisperiod served as a baseline.The inclusion criteria were: (i) age between 18

and 70 years, (ii) MOH defined as headache � 15days/month for at least 3 months combined withintake of ergots, triptans, opioids and/or combina-tion medication (simple analgesics combined withcaffeine) for � 10 days/month, or of simple anal-gesics � 15 days for a minimum of 3 months (7).Patients were excluded if (i) there were contraindi-cations for all types of prophylactic drugs, (ii) therehad been no improvement of the headache at pre-vious trials to stop overused medication for at least3 weeks, (iii) the patient had a history of hemi-crania continua, chronic paroxysmal hemicrania or

cluster headache, (iv) the patient used analgesicsfrequently for other complaints than headache, or(v) the patient was pregnant, breastfeeding or notusing effective contraception.

Randomization and treatment

Computer-generated randomization with randomlypermuted blocks stratified by centre and genderwas used, administrated by the Unit for AppliedClinical Research at the Norwegian Universityof Science and Technology, Trondheim, Norway.Patients recruited from St Olav’s Hospital werestratified by primary diagnosis because we ex-pected less favourable prognoses for individualswith tension-type headache (TTH) than for thosewith migraine.All groups used the same headache diary

throughout the study, and all received at the startthe same written general information about MOH,informing them among other things that with-drawal of acute attack medication was the standardtreatment. The patients were randomly assigned tothree different groups.The withdrawal group underwent a standard

out-patient detoxification programme consisting of:(i) advice to withdraw abruptly the overusedmedication, (ii) written information about potentialwithdrawal symptoms and (iii) telephone call fromthe doctor after 2 weeks. If necessary, they were: (i)allowed to use rescue medication up to 2 days/week [10–25 mg amitriptyline (if lack of sleep),50 mg diclofenac or 500 mg naproxen orally, and/or20 mg metoclopramide] (16); (ii) offered a sick leavefor up to 2 weeks; (iii) offered in-patient detoxifi-cation if they failed to complete the out-patientdetoxification programme; and (iv) offered to startwith preventive treatment after 3 months.The prophylaxis group was not explicitly advised

to withdraw the overused medication. Preventivetreatment was started on day 1, based on a prioritylist of medicines. For each patient the preventiveagent was chosen on the basis of a list of specifi-cations, taking into consideration the primaryheadache diagnosis, the drug’s side-effect profile,coexisting conditions and, in addition, the patient’spreferences and what they had tried before(Table 1).The control group did not get a new preventive

medication or direct advice to stop using analgesicsor medication prescribed by their physician. Thecontrols finished the study period after 5 months’observation, but were then offered the treatmentconsidered to be optimal for them (withdrawal or

222 K Hagen et al.

prophylactic treatment) and further follow-upvisits.After inclusion, patients in all groups underwent

blood screening tests and brain imaging (computedtomography or magnetic resonance imaging) forthose who had not undergone imaging during thepast 2 years.

Study procedure

Follow-up visits were scheduled at months 1, 3, 5and 12 after inclusion, and a telephone call wasscheduled at month 2. A telephone call from thedoctor was also scheduled after 2 weeks for patientsin the withdrawal group.At inclusion, at month 5 and at month 12 (only

the withdrawal group and the prophylaxis group)the patients were asked to fill in the HospitalAnxiety and Depression Scale (HADS) and ahealth-related quality of life-questionnaire (HRQoL)using the Short Form (SF)-12 (13, 14). The SF-12measures HRQoL in two main domains, a mentalhealth component score (MCS-12) and a physicalhealth component score (PCS-12).

Headache diary

In the headache diary, which was applied bothduring the baseline period and after randomization,patients recorded daily whether they had headacheor not. They were asked to record the duration ofheadache when awake, if they had nausea, thebrand name and number of doses taken, andabsence from work. The headache severity wasscored on a three-point scale from 1 to 3, explainedin the diary as: 1, mild (does not inhibit work orother activities); 2, moderate (inhibits but does notexclude work or other activities); 3, severe (excludeswork or other activities).Some patients did not indicate headache duration

in hours, but used descriptions. ‘The whole day’

was stipulated to be 16 h, whereas ‘morning’,‘lunchtime’, ‘afternoon’ and ‘evening’ were stipu-lated as 4 h each. A headache day was defined as aday with headache lasting > 30 min.

Outcome measures

The primary outcome measures were the change innumber of headache days, compared with thebaseline period, during month 3 and month 5 (allgroups), and month 12 (the withdrawal group andprophylaxis group only). Change at month 3 wasthe major primary outcome measure because up tothis point the treatment differed markedly betweenthe groups. After 3 months the withdrawal groupcould receive preventive treatment if necessary.The secondary outcome measures included:

change from baseline in days with use of acuteheadache medication per month, change from base-line in headache hours, change from baseline in‘headache index’ (HI) per month calculated by thesum of the products of ‘headache days/month’combined with ‘mean daily hours with headache’and ‘mean daily headache severity’ on days withheadache, change from baseline in sick leavedays per month, change from baseline in anxietyand depression measured by HADS, and changefrom baseline in SF-12 measured by the twomain domains MCS-12 and PCS-12. In addition,responder rates in the three groups were compared.A responder was defined as being without medica-tion overuse and with � 50% reduction in monthlyheadache days compared with baseline.

Power calculation

The main efficacy variable was the number of head-ache days per month. In a previous Swedish studythe mean number of headache days/month atinclusion was 26.9 with a standard deviation (S.D.)of 4.0 days/month (15). We assumed that the mean

Table 1 Priority list of preventive medication* for different primary headache diagnoses

Migraine with or without aura coexistingwith tension-type headache Tension-type headache Unclassified headache

1. Angiotensin II blockers 1. Tricyclic antidepressants 1. Tricyclic antidepressants2. b-Blockers 2. Valproate 2. Valproate3. Valproate 3. Gabapentin 3. Angiotensin II blockers4. Tricyclic antidepressants 4. Gabapentin

*Topiramate was not approved by the Norwegian Medicines Agency for migraine prophylaxis when this study was plannedand approved.

Treatment of medication overuse headache 223

number of headache days/month after end offollow-up would have a somewhat greater varianceand estimated S.D. to be 5.0 days/month. Theminimum difference of clinical interest between thegroups was considered to be 20% or five headachedays per month. With these figures, using a powerof 0.9 and a significance level of 5%, a minimum of21 patients per group was required. Because weexpected drop-outs, we wanted a minimum of 25patients per group and in total a minimum of 75patients included. In a 2-year perspective we esti-mated that 35 patients were likely to be includedat the Norwegian National Headache centre at StOlav’s University Hospital, and that the other fourhospitals were likely to include a total of 40 patients(10 patients from each centre). The inclusion periodwas 1 year longer than planned because of a slowerinclusion rate than expected at three of the hospi-tals, and in the end of 2006, 42 (66%) were includedat St Olav’s Hospital, whereas a total of 22 (34%)were included from the other hospitals. At St Olav’sHospital on average 13% of those referred withsuspected MOH were included in the study.

Statistics

Non-parametric tests were used for comparisonsbetween groups (Kruskal–Wallis test, Mann–Whitney U-test and c2 test) and within groups(Wilcoxon test) because of skewed distribution ofdata. If statistical significance at the 0.05 level usingKruskal–Wallis test was achieved, Bonferroni cor-rection was used for post hoc comparisons of pairsof groups (P < 0.017). Because Bonferroni-type cor-rections can be associated with type II errors, andbecause the Bonferroni adjustment, even whenapplicable, is too conservative when variablesco-vary, no further adjustments were made formultiple comparisons (16, 17).The efficacy analysis was carried out for those

who met the inclusion criteria and had at least onepost-baseline observation (at least 1 month’s follow-up) (intension to treat population). For drop-outsafter this stage, missing data were filled in using themethod ‘last post-randomized measurement carriedforward’. Analyses were carried out using SPSSversion 14.0 for windows (SPSS Inc., Chicago, IL,USA).

Results

Three out of 64 randomized patients were excludedbecause they had had < 15 headache days/month atbaseline (Fig. 1). Of the 61 who met the inclusion

criteria, five did not deliver a post-baseline head-ache diary and were excluded from the efficacyanalyses. A total of 13 patients (21%) did not com-plete the study according to the protocol (Fig. 1).The drop-out rate tended to be somewhat higherfor patients in the withdrawal group. At month 5 itwas 18% in the withdrawal group (compared with10% in the two other groups, P = 0.38), and after12 months it was 36% (compared with 16% in theprophylaxis group, P = 0.14). During the studyperiod the drop-out rate was lower among patientsincluded at St Olav’s Hospital (10%) than for thoseincluded at the four other centres (47%) (P = 0.001).The reasons given for dropping out were: did nottolerate abrupt withdrawal (two in the withdrawalgroup), worsening of gonarthritis when not usingnon-steroidal anti-inflammatory drugs (one in thewithdrawal group), suicide (one in the withdrawalgroup, but not related to headache according tothe patient’s general practitioner), hospitalized forother reasons (one in the prophylaxis group), suc-cessful withdrawal that gave few headache attacks(one control who himself decided to withdraw),and no specific reason given (four in the with-drawal group, two in the prophylaxis group, andone control).Table 2 presents the demographic and clinical

characteristics of the remaining 56 subjects whowere randomized to the three different groups. Nosignificant differences emerged between the threegroups with regard to sociodemographic variables,headache type, number of headache days permonth, number of analgesic days per month or typeof overused medication.None of the patients in the withdrawal group

was detoxified as an in-patient. At the 3-monthfollow-up, individuals in the withdrawal groupwere offered prophylactic treatment, and 13 out of18 individuals (72%) who attended the 3-monthvisit accepted. Of the five subjects who did not startwith preventive medication, three improved consid-erably during the withdrawal period and did notneed preventive medication, and two did notwant it.Among the 30 individuals (13 in the withdrawal

group and 17 in the prophylaxis group) whoreceived prophylactic treatment, 18 tried one typeduring the follow-up, five tried two types, whereasthe remaining seven subjects tried three to fivetypes due to either intolerance or lack of effect ofthe first attempts. During the follow-up a total of53 attempts with preventive medication were per-formed; angiotensin II blocker (candesartan) wastried 17 times, amitriptyline 15 times, gabapentin

224 K Hagen et al.

10 times, valproate seven times and b-blockers fourtimes. At the end of follow-up, 24 participants wereon medical preventive treatment, the most commondrug was angiotensin II blocker (n = 9), followed byamitriptyline (n = 8), gabapentin (n = 3), valproate(n = 3) and a b-blocker (n = 1).

Headache days

The prophylaxis group had the most consistentreduction in headache days/month compared withbaseline (Fig. 2), being 7.2 days at month 3(P = 0.002), 7.3 at month 5 (P = 0.009) and 10.3 at

64 subjectsrandomized

Fulfilledinclusioncriteria

61 (95.3%)

< 15 headache

days/month 3 (4.7%)

Abruptwithdrawal:22 subjects

Prophylaxisfrom the

start 19 subjects

Controls20 subjects

20completed 1-month

2 dropouts17

completed 1-month

2 dropouts 19

completed 1-month

1 dropout

19completed 3-month

1 dropout 17

completed 3-month

0 dropouts18

completed 3-month

1 dropout

18completed 5-month

0 dropouts17

completed 5-month

0 dropouts18

completed 5-month

1 dropout

14completed 12-month

4 dropouts 16

completed 12-month

1 dropout

Figure 1 Study flow chart.

month 12 (P = 0.001). The corresponding figuresfor the withdrawal group were 4.1 (P = 0.005), 4.7(P = 0.064) and 5.1 (P = 0.035), whereas for controlsthe reduction in mean headache days/month was1.6 at month 3 (P = 0.46) and 2.1 at month 5 (P = 0.41).Change in headache days per month did not differsignificantly between groups during the follow-up(Table 3).Overall, the reduction in monthly headache days

was most pronounced for the 39 individuals whohad tried none or only one prophylactic drug beforeinclusion in the study compared with 17 patientswho had tried two or more, e.g. at month 5, respec-tively 6.1 days and 1.3 days (P = 0.022). This wasmost pronounced for the prophylaxis group, with areduction in monthly headache days at the end of

follow-up of 12.6 days for individuals who hadtried fewer than two preventive drugs at baselinecompared with 2.7 days for those who had triedtwo or more (P = 0.032).The patients who were considered to have had

‘pure’ migraine before they developed MOH hadfewer monthly headache days at baseline than thosewith TTH or mixed headache (20.7 days vs. 27.6days, P < 0.001). However, the headache type did notinfluence prognosis (change in monthly headachedays from baseline) in the three different groups.

Medication intake

All three groups had a significant (P < 0.009) reduc-tion in days with use of acute headache medication

Table 2 Study population characteristics at baseline

Abrupt withdrawal(n = 20)

Prophylaxis from the start(n = 17)

Controls(n = 19) Statistics

Sex, female (%) 65 59 58 0.89*Age in years, mean (median) 42.1 (44.5) 41.6 (43.0) 38.7 (39.0) 0.55†Education > 12 years (%) 60 41 37 0.39*Employed, full-time or part-time (%) 75 71 63 0.37*HADS-Total, mean (median) 9.9 (9.0) 10.7 (11.0) 10.8 (10.0) 0.81†MCS-12, mean (median) 41.8 (45) 42.9 (50) 44.2 (50) 0.93†PCS-12, mean (median) 48.1 (45.8) 52.7 (45.8) 43.4 (45.8) 0.62†Days with sick leave/month, mean(median) (n = 35)

5.1 (1.3) 10.3 (1.3) 4.8 (2.7) 0.49†

Tension-type headache withoutmigrainous features (%)

25 35 32 0.98*

Had tried at least one type ofprophylactic drug before (%)

60 41 63 0.36*

Number of prophylactic drugs triedbefore, mean (median)

1.2 (1.0) 0.9 (0) 1.3 (1.0) 0.47†

Type of drugs overusedTriptans (%) 40 41 11 0.07*Simple analgesics (%) 40 24 32 0.56*Combination analgesics (%) 10 12 16 0.86*Opioids (%) 10 23 42 0.07*

Number of HDs/month, mean(median)

24.1 (23.2) 25.2 (29.3) 26.8 (29.7) 0.63†

IH/day, mean (median) 2.0 (2.0) 1.9 (2.0) 1.9 (2.0) 0.87†HHs/day, mean (median) 8.2 (6.7) 9.1 (7.5) 6.6 (6.1) 0.44†Number of days with analgesics, mean(median)

22.9 (22.5) 23.5 (24.7) 23.7 (24.0) 0.99†

Headacheindex = (HDs/month) ¥ (IH/day) ¥ (HHs/day),mean (median)

436 (267) 492 (299) 383 (291) 0.80†

Recruited at St Olav’s Hospital (%) 75 82 68 0.63*

*Chi-squared test.†Krusal–Wallis test.HDs, headache days; IH, intensity of headache; HHs, headache hours; HADS, Hospital Anxiety and Depression Scale;

MCS, mental health component score; PCS, physical health component score.

226 K Hagen et al.

per month compared with baseline during thefollow-up (Fig. 3). Change in acute headachemedication per month was significantly more pro-nounced in the withdrawal group compared withcontrols at months 3 and 5 (P < 0.001), whereaspairwise comparisons between controls and theprophylaxis group, and between the prophylaxisand withdrawal groups did not achieve Bonferroni-adjusted significance level at months 3 and 5(P � 0.04). Among the controls, five out of 19 (26%)actively performed withdrawal of acute attackmedication on their own.

Headache hours

The withdrawal group had a significant (P < 0.009)increase in headache hours compared with baselineat months 3 and 5 (Table 3). At month 5 the with-drawal group had an increase of 1.4 headachehours, whereas the prophylaxis group had adecrease of 0.1 h (P = 0.017).

Headache index

Regarding change in HI/month from baseline, theprophylaxis group had a significantly (P = 0.003)more pronounced reduction at month 3 comparedwith the withdrawal group (Table 3). As demon-strated by Fig. 4, the withdrawal group had anincrease in HI/month during the first 5 months of

follow-up compared with baseline. At month 12 theprophylaxis group had a reduction of HI with anaverage of 201 per month (41% reduction frombaseline), whereas the withdrawal group had adecrease of only 20 (5% reduction from baseline)(P = 0.017).

Disability

The prophylaxis group had the most prominentreduction in sick leave days/month compared withbaseline, being 9.8 days at month 3 (P = 0.008), 10.0days at month 5 (P = 0.028) and 10.3 days at month12 (P = 0.008). During the whole follow-up, thenumber of days with sick leave/month was higherin the withdrawal group than in the prophylaxisgroup at months 3 (P = 0.016), 5 (P = 0.007) and 12(P = 0.007) (Table 3).The prophylaxis group had also the most promi-

nent increase in physical health component score(PCS-12) compared with baseline: 15.2 at month5 (P = 0.018) and 20.2 at month 12 (P = 0.012). Thecorresponding figures for the MCS-12 were 13.2 atmonth 5 (P = 0.024) and 13.9 at month 12 (P = 0.039)(Table 3). The withdrawal group had a significantincrease in MCS-12 at month 12, being 14.6(P = 0.001) (Table 3). No significant difference wasfound between the groups regarding PCS-12 andMCS-12.At month 12 the prophylaxis group had a

decrease in total anxiety and depression scoresmeasured by HADS of 2.9 compared with baseline(P = 0.049), whereas the withdrawal group had anincrease of 0.6 (group comparison: P = 0.058).

Responders

The proportion of responders without medicationoveruse combined with � 50% reduction inmonthly headache days tended to be highest for theprophylaxis group during the follow-up, being sig-nificantly higher at month 5 for prophylaxis groupthan for the controls (41% vs. 5%, P = 0.010, Fig. 5).At month 12, 53% of the patients in the prophylaxisgroup had � 50% reduction in monthly headachedays compared with 25% in the withdrawal group(P = 0.081, Fig. 5).

Change in headache diagnosis

The results of blood screening tests and brainimaging had no influence on the suggested head-ache diagnosis. Individuals with unclassified head-ache at the first screening visit were all classified as

0 1 2 3 4 5 6 7 8 9 10 11 12

Months

thControls

Abrupt withdrawal

Prophylaxis from the start

Figure 2 Headache days per month.

having an original migraine, TTH, or migrainecoexisting with TTH during the follow-up visits.After the end of the follow-up period, the headachediagnosis was revised in one case because the head-ache did not improve despite withdrawal of anal-gesics (from MOH to cervicogenic headache).

Discussion

The main finding in this randomized, open-label,1-year follow-up study of patients with MOH wasthat early introduction of prophylactic medicationwithout a detoxification programme was an effec-tive way to reduce headache days and total head-ache burden during the first 3 months, and theimprovement was sustained during the wholefollow-up period. The effect was most pronouncedin individuals who had previously tried no morethan one type of preventive medication.The optimal way to evaluate new treatment strat-

egies is to perform a randomized, double-blind,placebo-controlled trial, but so far no blindedplacebo-controlled trials involving withdrawal

therapy among patients with MOH havebeen performed. To the best of our knowledge,this is the first randomized study evaluating theefficacy of early introduction of preventive medi-cation compared with the traditional withdrawaltherapy. Although we could not include as manypatients as intended, power calculations indicatethat the study should be able to detect a differencein treatment effect between the groups of clinicalinterest.The reduction in days with use of acute headache

medication per month was most pronounced in thewithdrawal group, but the group who receivedprophylactic treatment at the start also had > 50%reduction of days with acute headache medicationduring the first 3 months. The prophylaxis groupwas not explicitly advised to withdraw the over-used medication. However, the general writteninformation stated that abrupt withdrawal was thestandard treatment of MOH. This information mayhave influenced both patients in the prophylaxisgroup and controls to be more restrictive in theiruse of acute attack medication. This may explain

Table 3 Change from baseline with 95% confidence intervals for efficacy variables for each group at months 3, 5, and 12

Abrupt withdrawal(n = 20)

Prophylaxis from the start(n = 17)

Controls(n = 19) P-value

Month 3Headache days -4.2 (-3.3, -7.4)** -7.2 (-2.7, -11.8)** -1.6 (1.8, -5.1) 0.056†Days with acute headachemedication

-19.1 (-14.9, -23.3)*** -13.2 (-7.6, -18.8)*** -6.9 (-2.0, -11.8)** 0.002†

Headache hours 1.65 (2.75, 0.54)** -0.53 (0.66, -1.73) 0.04 (0.82, -0.74) 0.030†Headache index 33 (142, -76) -169 (-89, -248)*** -36 (50, -122) 0.012†Days with sick leave 0.1 (2.1, -1.9) -9.8 (3.0, -22.7)** -2.8 (-0.4, -5.7)* 0.033†

Month 5 of follow-upHeadache days -4.8 (-1.3, -8.2) -7.3 (-2.7, -12.0)** -2.1 (0.8, -5.2) 0.184†Days with acute headachemedication

-18.5 (-14.2, -22.7)*** -11.6 (-6.4, -16.9)*** -6.1 (-1.4, -10.7)** 0.001†

Headache hours 1.41 (2.35, 0.46)** -0.07 (1.77, -1.91) -0.03 (0.8, -5.2) 0.016†Headache index 33 (149, -83) -155 (-31, -279)* -19 (62, -101) 0.090†Days with sick leave 1.1 (3.0, -0.7) -10.1 (3.3, -23.8)* -3.5 (-0.1, -6.8)* 0.007†Mental health component (MCS-12) 5.8 (-2.3, 13.8) 13.2 (3.1, 23.4)* 6.1 (0.3, 11.8) 0.281†Physical health component (PCS-12) 8.9 (-1.5, 19.0) 15.2 (3.6, 26.8)* 5.5 (-2.2, 13.1) 0.418†

Month 12 of follow-upHeadache days -5.1 (0.9, -9.3)* -10.3 (-5.8, -14.8)*** 0.047‡Days with acute headachemedication

-16.1 (-11.1, -21.1)*** -14.2 (-9.2, -14.1)*** 0.577‡

Headache hours 0.64 (1.91, -0.62) -0.27 (0.89, -1.42) 0.156‡Headache index -19 (112, -151) -201 (-60, -343)** 0.017‡Days with sick leave 0.2 (2.0, -1.5) -10.3 (3.5, -24.2)** 0.007‡Mental health component (MCS-12) 14.6 (6.0, 23.1)*** 13.9 (2.0, 25.8)* 0.976‡Physical health component (PCS-12) 6.5 (-2.5, 15.5) 20.2 (6.1, 34.2)* 0.060‡

Between-group analyses: †Kruskal–Wallis test, ‡Mann–Whitney test.Within-group analyses: *< 0.05; **� 0.01; ***� 0.001.

228 K Hagen et al.

why 26% of the controls markedly reduced intakeof acute medication on their own. However, weconsider it likely that the reduction of days with useof acute medication among the prophylaxis groupwas due, at least in part, to an overall reduction of

headache days/month caused by the prophylacticmedicines and not only to an active effort to reducethe acute medication. Thus, our results do notsupport the tenet that patients with MOH rarelyrespond to prophylactic medications while over-using acute attack medication. This tenet hasalso been challenged in a recent double-blinded,placebo-controlled trial evaluating the efficacy oftopiramate among patients with chronic migraine,of whom the majority had medication overuse (18).In this 16-week trial, topiramate significantlyreduced the mean number of monthly migrainedays compared with placebo, despite the fact thatuse of acute medication did not differ between thegroups (18).The spontaneous long-term course of MOH is

mostly unknown, and no previous prospectivestudies have included a control group receiving noactive treatment or strong advice of withdrawal ofthe overused medication. One may argue that ourcontrol group was not totally unaffected by theintervention, since investigation by a neurologistand participation in a MOH trial (including generalinformation about the condition) is also an inter-vention. Because 26% of the controls tapered off theoveruse of medication on their own, informationalone about the negative effects of medicationoveruse seems to have an impact on the overuse in

0 1 2 3 4 5 6 7 8 9 10 11 12

Months

thControls

Abrupt withdrawal

Figure 3 Days with use of acute headache medication permonth.

0 1 2 3 4 5 6 7 8 9 10 11 12

Months

Controls

Abrupt withdrawal

Figure 4 Headache index (HI) per month.

Month 3 Month 5 Month 12P

Controls

Withdrawal

Figure 5 Responder rates (responder defined as beingwithout medication overuse combined with 50% reductionin headache days per month). *P = 0.010.

some individuals. Previously it has been shownthat advice alone gives a similar success rate toa standardized detoxification programme in a2-month follow-up of patients with the combina-tion of migraine and MOH (19). Conceivably, thespontaneous long-time course of MOH could bedemonstrated in double-blinded placebo-controlledtrials including patients with chronic headache withmedication overuse, but to date such patients havebeen excluded from most trials evaluating the effi-cacy of prophylactic treatment. So far, the placeboresponse in a few studies evaluating the efficacyof topiramate among migraine patients withmediation-overuse has been inconsistent. Nochange in migraine days or days with intake ofacute medication compared with the 4 weeks’ base-line period was reported in the placebo groupduring a 16-week follow-up (18). In another studythe placebo group of 14 subjects had a meandecrease of headache days per month from 24.5 to15.4, with a corresponding reduction in amount ofacute medication taken monthly from 30.8 to 15.4during a 12-week follow-up (20). To make validconclusions about the spontaneous long-termcourse of MOH more double-blinded, placebo-controlled studies are needed on patients withmedication overuse combined with chronic head-ache (TTH included) evaluating prophylactic drugs,or prospective studies without intervention.During the first 3 months only 15% of the indi-

viduals in the withdrawal group had a > 50%reduction in headache frequency. In contrast, thecorresponding success rate of withdrawal therapyhas been reported to be > 70% in several previousstudies (1). However, almost all previous studieshave been based on migraine patients, and lack ofinformation about drop-outs and lack of patientswith TTH in these studies make direct comparisonswith the present study difficult. The relatively lowresponse rate is similar to that in a recently pub-lished Danish study reporting that only 45% ofthose with MOH had at least 1% reduction inheadache frequency after a 2-month drug-freeperiod (11). The low response rate in the Danishstudy was in part caused by the fact that individu-als with TTH had a median relative reduction inheadache frequency of 0%. In the present study,> 30% of the participants had TTH, and this may inpart explain the rather low response rate. Based onthe results of the Danish study and the presentstudy, it is reasonable to assume that definite MOHis less prevalent than previously thought. In thewithdrawal group of the present study 50% had notimproved at the 3-month visit and hence did not

fulfil the original criteria for definite MOH (9).However, the prevalence of definite MOH is influ-enced by the way a responder is defined. There isno universally accepted definition of a ‘responder’for studies evaluating treatment effect of patientswith MOH. In the D criterion of MOH it is statedthat ‘headache reverts to its previous pattern within2 months after discontinuation of the analgesics’ (9).This criterion is difficult to incorporate in a studydefinition of a ‘responder’, because reliable dataregarding the previous headache pattern areusually lacking. According to the ICHD-II criteriathe effect of withdrawal therapy shall be evaluatedafter 2 months, and this is also recommended bysome authors (11). However, there is little evid-ence to support a 2-month withdrawal as beingnecessary or sufficient. In the present study thewithdrawal group had to wait 3 months beforepreventive medication was considered to be abso-lutely certain that withdrawal had been tried suffi-ciently long. As indicated by Fig. 2, the headachefrequency tended to decrease from month 2 tomonth 3, probably illustrating that the 2-monthlimit mentioned in the original ICHD-II criteria wassomewhat arbitrary. During the first 3 months noneof the patients in the withdrawal group started tooveruse attack medication.Until now, abrupt withdrawal of acute attack

medication has been the treatment of choice inpatients with MOH. However, the most commonproblems with such a strategy are the withdrawalheadache and that many patients are not able tocomplete the recommended drug-free period. In thepresent study these problems were reflected in thesomewhat higher overall drop-out rate in thisgroup (36% vs. 16% in the prophylaxis group) andin the increase in overall suffering (high HI in thewithdrawal group). Similarly, 36% of patients withMOH were not able to be drug-free for a 2-monthperiod in the Danish study (11). Problems withwithdrawal headache and high drop-out rates prob-ably explain why many headache experts are reluc-tant to recommend a long drug-free period beforethey introduce prophylactic treatment in the man-agement of MOH (11).During the whole study period it was evident

that those who received preventive medicationfrom day 1 had the lowest number of headachedays, days with sick leave, HI/month and thehighest response rate compared with the two othergroups. The results from the present study do notsupport the tenet that patients with MOH rarelyrespond to prophylactic medications while overus-ing acute medication. On the contrary, it indicates

230 K Hagen et al.

that early introduction of preventive medication isan attractive alternative to abrupt withdrawal ofacute attack medication. In the Danish study, 55%of those who managed to stop use of acute medi-cation had no change in headache frequency or gotworse (21). In the follow-up of these, a 26% reduc-tion in headache frequency was found, at least inpart explained by use of preventive medication. Wesuggest that some of these individuals would haveimproved earlier if preventive medication had beenstarted before. In our study the group who receivedpreventive medication from the start seemed tohave a ‘flying start’, which remained during thewhole study period and which reduced the totalburden of headache and lowered the drop-out risk.In contrast, the withdrawal group continued tohave a high HI during the whole 12-month follow-up. Because headache days/month decrease with5.1 days, the lack of decrease in HI was caused bymore headache hours combined with higher head-ache intensity, probably because of the more restric-tive use of pain killers than in the group receivingpreventive medication from the start.The study has also demonstrated a significant

reduction of headache days per month amongpatients in the withdrawal group during the first3-month withdrawal period. The optimal way totreat these patients may therefore be to recom-mend withdrawal or reduction of analgesics,together with early introduction of prophylacticmedication.In conclusion, this randomized, multicentre,

1-year follow-up trial has shown that prophylactictreatment from the start without abrupt detoxifica-tion was superior to abrupt withdrawal in reducingtotal headache burden. Regarding the decrease inheadache days compared with baseline, our studyhas also demonstrated a significant effect of with-drawal during the first 3-month withdrawal period,but it has also indicated that abrupt withdrawalmay not be necessary before starting with prophy-lactic medications. The notion that patients withMOH need withdrawal of acute medication inorder to respond to prophylactic medication seemsto be incorrect. In future studies on treatment ofMOH it may be advisable to have a group withboth prophylactic treatment and withdrawal ofacute medication from the start.

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