Combination of tizanidine and amitriptyline in the prophylaxis of chronic tension-type headache: evaluation of efficacy and impact on quality of life

Abstract

Chronic tension type headache (CTTH) has a strong impact on the Quality Of Life (QOL). We carried out an open-label randomized clinical trial on 18 patients with CTTH in order to compare two different regimens of pharmacological prophylaxis: the first provided for the use of amitriptyline 20 mg/d during 3 months, while in the second we combined amitriptyline with tizanidine (4 mg/d) in the first 3 weeks of treatment. Our hypothesis is that the combination therapy may guarantee an improvement of QOL even in the early stages of treatment. In fact, it's as well-known, there is a delay of 2-3 weeks in the prophylactic effect of amitriptyline, with a consequent persistence, in the first phases of therapy, of the headache and its negative impact. We assessed the following outcome measures: frequency, pain intensity, duration of headache and the Headache Impact Test (HIT) score, used as headache-related QOL measure. The combination therapy was effective since the first month of treatment, with a significant reduction of the headache, greater than one obtained with amitriptyline alone, in terms of frequency (-52,3% vs. -40,7%), intensity (-59,51% vs. -20,39%) and duration (-53,17% vs. -36,16%). This trend was confirmed by the HIT. Our data suggest that the combination of tizanidine with amitriptyline is faster than the amitriptyline alone in providing an improvement in the headache pattern and correlated QOL. [PUBLICATION ABSTRACT]

J Headache Pain (2006) 7:3436

DOI 10.1007/s10194-005-0251-5ORIGINALDiego Bettucci

Lucia Testa

Silvia Calzoni

Paola Mantegazza

Michele Viana

Francesco MonacoCombination of tizanidine and amitriptyline in

the prophylaxis of chronic tension-type

headache: evaluation of efficacy and impact on

quality of lifeReceived: 15 July 2005Accepted in revised form: 7 October 2005

Published online: 15 December 2005Abstract Chronic tension type

headache (CTTH) has a strong

impact on the Quality Of Life

(QOL). We carried out an open-label

randomized clinical trial on 18

patients with CTTH in order to compare two different regimens of pharmacological prophylaxis: the first

provided for the use of amitriptyline

20 mg/d during 3 months, while in

the second we combined amitriptyline with tizanidine (4 mg/d) in the

first 3 weeks of treatment.

Our hypothesis is that the combination therapy may guarantee an

improvement of QOL even in the

early stages of treatment. In fact, its

as well-known, there is a delay of

23 weeks in the prophylactic effect

of amitriptyline , with a consequent

persistence, in the first phases of

therapy, of the headache and its negative impact.We assessed the following outcome

measures: frequency, pain intensity,

duration of headache and the

Headache Impact Test (HIT) score,

used as headache-related QOL measure. The combination therapy was

effective since the first month of

treatment, with a significant reduction of the headache, greater than

one obtained with amitriptyline

alone, in terms of frequency (-52,3%

vs. -40,7%), intensity (-59,51%vs. -20,39%) and duration (-53,17%

vs. -36,16%).This trend was confirmed by the

HIT. Our data suggest that the combination of tizanidine with amitriptyline is faster than the amitriptyline

alone in providing an improvement

in the headache pattern and correlated QOL.Keywords Chronic tension-type

headache Tizanidine Amitriptyline Quality of life ProphylaxisD. Bettucci L. Testa S. CalzoniP. Mantegazza M. Viana F. Monaco

Headache Centre,

Department of Neurology,

University Amedeo Avogadro,

Corso Mazzini 18, I-28100 Novara, Italy

e-mail: [email protected]

Tel.: [phone]

Fax: [phone]IntroductionIt is well known that chronic headaches, of which the tension-type form is the one with the greatest epidemiological prevalence [1], have a strong impact in terms of

Quality Of Life (QOL) and socio-economic costs [2].At present, amitriptyline represents the first choice in

prophylactic therapy of chronic tension-type headache

(CTTH), supported by the highest levels of evidence [3].As is well known, the effectiveness of amitriptyline in

CTTH prophylaxis may be observed only after 23 weeks

of therapy, with a consequent persistence of the headache

and its correlated negative impact on psychophysical conditions in the first phases of treatment. In this respect, a

faster pharmacological treatment would be very useful.Many clinical trials indicate tizanidine as a promising

additional prophylactic agent in chronic headaches, while

currently available data do not justify its use in monotherapy [3, 4]. Tizanidine is an 2 agonist that inhibits the35release and effect of norepinephrine in both the brainstem

(e.g., locus coeruleus) and the spinal cord. It acts as a central muscle relaxant but it also has an antinociceptive

effect that does not involve the endogenous opioid system

and appears to be centrally mediated by 2 adrenoreceptors, with little, if any, interaction with 5-HT, dopamine

and GABA receptors [4].There is not a codified posology for headache prophylaxis with tizanidine. In clinical trials it was used at a

dosage between 2 and 24 mg/day, for periods varying

from 2 to 12 weeks [57]. Unlike amitriptyline, tizanidine

does not have a latency period of clinical effects, neither

as an antispastic nor in the prophylaxis of cephalalgia [4].We carried out an open-label clinical trial in order to

evaluate the effectiveness and the impact on QOL of a combined treatment with tizanidine and amitriptyline in the first

weeks of the pharmacological prophylaxis of CTTH. The

aim of our study was to determine if the combination tizanidine/amitriptyline may have, as expected from a pharmacodynamic standpoint, a faster action than amitriptyline alone

in both reducing the cephalalgical pattern, and consequently, in improving the headache-related QOL.Patients and methodsAll consecutive patients (n=27) who had been diagnosed with

CTTH according to the International Headache Society criteria in

the six months prior to the study were preliminarily evaluated.

Subjects with coexistence of migraine (IHC criteria) and CTTH

were excluded. After an observation period of one month, in

which patients recorded their headache pattern in a baseline standard diary, 18 patients (5M, 13F, mean age 35.211) were enrolled

in the study. All patients had normal neurological examination and

laboratory investigation. They did not show any other health problems, or contraindications to the use of the drugs in question.

Depression had been ruled out at the time of recruitment using the

Zung test. Abortive treatment with a simple analgesic was permitted, but we excluded the abusers (IHC criteria) [8]. The symptomatic drugs used in our population were paracetamol and nonsteroidal anti-inflammatory drugs, with a mean use of abortive

medication of 11.153.49 days/month in the observation period.Patients at the run-in were randomized, via an online random

number generator (http://www.randomizer.org), into two groups of

treatment, each one consisting of 9 patients. The first (A group, 2M,

7F, average age 34.512.2) assumed amitriptyline 20 mg/day for 3

months, while the second (B group, 3M, 6F, mean age 369.8) was

treated with amitriptyline 20 mg/day for 3 months combined with

tizanidine (4 mg/day) in the first 21 days of treatment.Using a standard headache diary/4 weeks, drawn up by the

patient, we collected the following outcome measures: number

of headache days per month, pain intensity with a numerical

score (1, mild headache, easily ignored; 2, moderate, tolerable;

3, very intense pain/intolerable) and duration of headache in

hours. The headache-related QOL was assessed monthly with the

HIT6 questionnaire [9].In both groups, monthly headache frequency, mean intensity,

mean headache duration and HIT scores were assessed using

data from standard headache diary/4 weeks of both pre-treatment

month (T0 period baseline) and two treatment periods (weeks

14 [T1 period] and weeks 912 [T2 period]).For each group of treatment, we assessed the mean per cent

reduction of each variable obtained in T1 and T2 evaluation with

the mean baseline value. Thereafter we compared the results in

the two treatment groups. Statistical evaluation was performed

with the 2-test, deeming a p value <0.05 as significant.ResultsAll 18 patients enrolled completed the study. In our

patients the combination therapy (B group: tizanidine+amitriptyline) was effective from the first month of

treatment, with a significant reduction of symptoms

(>50%) in terms of frequency, intensity and duration of

the headache. This reduction was greater than the one

obtained with amitriptyline alone (A group).In particular, in the first four weeks of treatment we

recorded the following per cent improvement in headache

indexes (Tables 1 and 2): frequency -52.3% in B group vs.

-40.7% in A group (p<0.05), intensity -59.51% vs. -20.39%

(p<0.02), duration -53.17% vs. -36.16% (p<0.05). At the

end of the 90-day treatment period, however, there were no

significant differences (frequency -57.71% in B group vs. -

60.04% in A group; intensity -30.05% vs. -23.81%; and

duration -56.55% vs. -37.55%; all results with p>0.05).Table 1 Results of prophylaxis with amitriptyline aloneGroup A: amitriptyline Mean headache, Mean pain, Mean duration, HIT,

days/4 weeksSD intensitySD hSD 6SDT[phone].953.05 61.262.46T1 12.053.59 1.340.26 4.442.25 53.372.57T2 8.123.63 1.280.51 4.342.36 47.7115.28Mean improvement % (T0T1) -40.70% -20.39% -36.16% -12.88%Mean improvement % (T0T2) -60.04% -23.81% -37.55% -22.11%36Table 2 Results of use of tizanidine in addiction to amitriptylineGroup B: amitriptyline+tizanidine Mean headache, Mean pain, Mean duration, HIT,

days/4 weeksSD intensitySD hSD 6SDT[phone].052.79 62.503.41T1 10.405.89 1.290.37 3.772.00 50.903.54T2 9.227.00 1.280.51 3.492.47 48.006.32Mean improvement % (T0T1) -52.30% -59.51% -53.17% -18.56%Mean improvement % (T0T2) -57.71% -30.05% -56.65% -23.20%This trend of improvement had also been confirmed by

the pattern of HIT scores, which are an indicator of the

headache impact on QOL (-18.56% vs. -12.88% in T1 period, p<0.05; at the 3rd month -23.20 vs. -22.11, p>0.05).Three patients (33.3%) from group A and four patients(44.4%) from group B reported mild to moderate common

adverse events such as somnolence (22.2%, n=2 in A group

and 33.3%, n=3 in B group), asthenia (11.1%, n=1 in A group

and 22.2%, n=2 in B group), dry mouth (2 patients, 22.2% in

A group) and dizziness (only 1 patient, 11.1% in B group).the first phase of treatment provides a more rapid improvement in the headache pattern, compared to the use of

amitriptyline alone. As expected, the faster effectiveness

of combination therapy had an immediate impact on the

headache-related quality of life. Furthermore, the use of

tizanidine in addition to amitriptyline was well tolerated.In our opinion, the high frequency and the remarkable

disability correlated with CTTH suggest the need for a

prophylaxis treatment which is not only effective, but also

as fast as possible in restoring an acceptable QOL from

the first days of treatment.This preliminary study suggests that the combination

of amitriptyline and tizanidine has a promising potential

as a therapeutic option in the preventive treatment of

CTTH. A large double-blind randomised controlled trial

would be needed in order to draw strong evidence on this

issue.DiscussionOur data, although obtained from a small group of patients, suggest that adding tizanidine to amitriptyline inReferences1. Millea PJ (2002) Tension-type

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