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Amitriptyline, a combined serotonin and noradrenaline re-uptake inhibitor, reduces exteroceptive suppression of temporal muscle activity in patients with chronic tension-type headache
ELSEVIER
Electroencephalographyand clinical Neurophysiology101 (1996) 418-422
Amitriptyline, a combined serotonin and noradrenaline re-uptake inhibitor, reduces exteroceptive suppression of temporal muscle activity in patients with chronic tension-type headache L. B e n d t s e n * , R. J e n s e n , J. O l e s e n Department of Neurology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Denmark
Accepted for publication: 26 April 1996
Abstract Although reflexes in human jaw muscles have been extensively studied, the neurotransmitters involved in the regulation of these reflexes are not well known. The aim of the present study was to investigate whether amitriptyline, a combined serotonin and noradrenaline re-uptake inhibitor, modulates the late exteroceptive suppression period (ES2) of temporal muscle activity in chronic tension-type headache. ES2 was recorded with a previously evaluated method and assessed by a blinded observer in 35 patients with chronic tension-type headache. Thereafter, ES2 was recorded in 27 of these patients during a double-blind, placebo-controlled, 3-way crossover trial investigating the prophylactic effect of amitriptyline, the selective serotonin re-uptake inhibitor citalopram, and placebo. ES2 duration was significantly shorter during treatment with amitriptyline than during placebo, P = 0.02, while ES2 duration only tended to be shorter during treatment with citalopram, P = 0.34. ES2 was not significantly correlated to the prophylactic effect of amitriptyline or to a range of clinical and experimental pain parameters. Our results demonstrate that amitriptyline reduces ES2 and indicate that ES2 is modulated by serotonergic as well as noradrenergic neuronal pathways. Keywords: Amitriptyline; Exteroceptive suppression; Serotonin; Silent period; Tension-type headache
I. Introduction Reflexes in jaw muscles have been used extensively in investigations of pain mechanisms (Mason et al., 1986), motor control (Yemm, 1972; Godaux and Desmedt, 1975), trigeminal nerve function (Cruccu et al., 1987) and orofacial pain disorders (De Laat, 1987). In 1987 Schoenen et al. (Schoenen et al., 1987) reported that the duration of the late exteroceptive suppression period (ESz), also known as the second silent period SP2, of temporal muscle activity was reduced in patients with chronic tension-type headache. This finding has later been confirmed by other research groups (Nakashima and Takahashi, 1991; Wallasch et al., 1991), while recent studies by Zwart and Sand (1995) and our group (Bendtsen et al., 1996a) found normal ES2 durations in chronic tension-type headache. *Corresponding author. Tel.: +45 43964333, ext. 6117; fax: +45 43423570.
Serotonergic neuronal pathways play an important role in the regulation of jaw reflexes (Mason et al., 1986), and ES2 may therefore be a valuable tool for assessing serotonergic neurotransmission in the brain-stem (Maertens de Noordhout et al., 1995). Amitriptyline has been reported to be effective in the prophylactic treatment of chronic tension-type headache in most studies (Lance and Curran, 1964; Diamond and Baltes, 1971; Ben&sen et al., 1996b), while one study has been negative (Pfaffenrath et al,, 1994). Amitriptyline is a combined serotonin and noradrenaline re-uptake inhibitor, but has also several other pharmacological effects, e.g. effects on serotonergic, adrenergic, cholinergic, and histaminergic receptors (Bendtsen et al., 1996b). The mechanisms behind the effect of amitriptyline in tension-type headache are not known, but it is likely that modulation of serotonergic neuronal pathways plays an important role. The primary aim of the present study therefore was to investigate whether amitriptyline modulates ES2.
0924-980X/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PI1 S0921-884X(96)96532-7
EEM 96532
419
L. Bemltsest et al. / Electroencephalography and clinical Neurophysiolow I01 t1996i 41S 422
2. Patients and methods
Table 1 Clinical characteristics of tension-type headache patienis
2.1. Patienl,s
Forty patients with chronic tension-type headache diagnosed according to the criteria of the International Headache Society (Headache Classification Committee, 1988) were included in a study (Bendtsen et al., 1996b) of the prophylactic effect of amitriptyline and of citalopram in chronic tension-type headache. Seven patients with coexisting infrequent migraine (<1 day/month) were accepted. The patients were recruited from the outpatient headache clinic at Glostrup University Hospital, Copenhagen, Denmark. The inclusion criteria were a diagnosis of chronic tension-type headache and age between 18 and 65 years. The exclusion criteria were migraine more than 1 day/ month, serious somatic or psychiatric diseases including depression (Hamilton Depression Score (Hamilton, 1960) _>17). intake of prophylactic medications for tension-type headache, abuse of simple analgesics (corresponding to more than 2 g of aspirin/day), regular intake of opiates or benzodiazepines and previous treatment with antidepressants. All patients underwent a general physical and a neurological examination and completed a diagnostic headache diary (Russell et al.. 1992) during a 1 month run-in period. The trial was designed as a 32 week, double-blind, placebo-controlled. 3-way crossover study and has previously been described in detail (Bendtsen et al., 1996b). Briefly, each drug was given in random order for 8 weeks, separated bv 2 week wash-out periods. The drugs were administered in a dose-increasing regimen. In the last 6 weeks of the treatment periods, the daily dose of amitriptyline was 75 mg and of citalopram 20 mg. Thirty-five of the 40 patients were included in the present study (Table 1 i. Four women did not want to participate and one woman was excluded because of dentures. The patients were not allowed to take analgesics on the days of examinatkm. All patients gave written informed consent to participate in the study, which was approved by the regional ethics committee. a..c. "~ ~ M e t h o d s
The recordings were performed in a standardized manner by the same investigator, a trained technician (HA), throughout the study. In the run-in period, the patients were examined during a typical episode of tension-type headache. During the trial, we examined the patients irrespective of their headache state, since ES 2 does not differ on days with headache compared with days without headache (Bendtsen et al.. 1996a). The recordings were perlk~rmed in the last week of each of the three 8 week treatment periods, i.e. during treatment with 75 mg amitriptyline daily,, during treatment with 20 mg citalopram daily and during placebo. Exteroceptive suppression was recorded according to a
Number Sex (females/males) Age(years) Headache days/4 weeks Years with headache
Patients included
Patients who Colnplctcd Ihc stud}
35 20115 39.3 122 571 24.9 (16 28} 12.6(I 33)
"7 161 3%0i22-56i 25.0 (16-28) !2.{,11--361
Mean values are given. ~ iih range m brackc~,,.
previously described method (Bendtsen el al.. 1993). Briefly, electromyographic (EMG) activity of the left temporal muscle was recorded with surface electrodes and the EMG signals were stored for off-line analysis. A bipolar surface stimulation electrode was placed with the stimulation tips on either side of the left labial commissure. The sensory detection threshold, i.e. ihe weakest stimulus detectable by the subject, and the pain detection threshokl, i.e. the weakest stimulns perceived as painful by the subject, were measured at the beginning of each recording series. Thereafter, single electrical rectangular stimuli with an intensity' of 20 mA and a dilration ol (}.5 ms were delivered during 2 - 3 s of nmxirnum voluntar 3 jaw occlusion. Sixteen stimuli were delivered at 15 s intervals in each recording series. Signals from one recording series were rectified and averaged by means of a purpose-made computer program. Reduction of mean EMG amplitude below 50% of pre-stimulus activity \~as delined as exteroceptive suppression. ES~ durations were measured by means of vertical cursors placed at the interceptions of the averaged curve and a 5()~/< amplitude cursor. This method has previously proved to be reliable IBendtsen et al., 1993). All recordings were coded b\ an assistant before the analyses. Thereafter. one observer (LB), who was blinded to any information about the recordings, analysed the ES: periods. In addition to recordings of ES:. ~arious pain parameters were recorded in the run-in period. The procedures and results have been presented in a pre~ ious paper (Bendtsen el al.. 1996c). Briefly. the patients recorded their actual headache intensity on a 100 mm visual atlalogue scale, tenderness of pericranial myohtcial lissues was recorded by manual palpation according to the Total Tenderness Scoring system, and pressure pain thresholds and tolerances were recorded in the temporal region and in the finger with an electronic pressure algometer. The reduction in ES~ duration during treatment with amitriptyline compared with placebo was calculated as: ES= reduction = (1 - ES=,,,i~ip~>l,,,d'ES?pl~<,,~7o)>: 100%. The reduction in ESe duration during treatment with citalopram compared with placebo was calculated as: ES2 reduction = (1 - ES2citaiop,am/ES2plac,,,) >: 10()~}~. The reduction in headache during treammnl with amitriptyline compared with placebo was calculated as: headache reduc-
L. Bendtsen et al. / Electroencephalography and clinical Neurophysiology 101 (1996)418-422
420
tion = (1 AUCamitriptyline/AUCplacebo)X 100%. AUC was defined as the area under the headache curve (headache duration x headache intensity). -
40 A
2.3. Statistics
30 f-
Results are presented as mean + SD. Recordings without a detectable ES2 period were defined as having an ES2 duration of 0 ms. Wilcoxon's rank sum test was used for paired observations, i.e. testing results within patients on different days. Spearman's test was used for calculation of coefficients of correlation, R. Significance was accepted at the 5% level.
.c, -i "O
20
10
Amitriptyline
Cltalopram
Placebo
3. Results 3.1. Run-in period (n = 35) The duration of ES2 recorded in the run-in period was 33.0 +_ 16.8 ms. Three patients had no detectable ES2 period.
3.2. Drop-outs Twenty-seven of the 35 patients completed the study (Table 1). Six patients dropped out of the trial for various reasons (Bendtsen et al., 1996b) unrelated to the present study, one patient did not want to participate in the present study during the trial, and one patient was excluded because of technical problems. In total, 4 women and 4 men with a mean age of 40.5 years (range 2 5 - 5 7 years) did not complete the study.
3.3. Modulation of ES 2 by amitriptyline (n = 27) The duration of ES2 during treatment with amitriptyline was 31.7 +_ 14.3 ms, which was significantly shorter than the duration during placebo (36.1 _+ 15.5 ms, P = 0.02) (Fig. 1). ES2 was present in all patients during all 3 treatments, except for one woman who did not have a detectable ES2 period during any of the 3 treatments.
3.4. Modulation of ES2 by citalopram (n = 27) The duration of ES2 during treatment with citalopram was 34.3 _+ 13.0 ms and not significantly different from the duration during placebo (36.1 +_ 15.5 ms, P = 0.34) (Fig. 1).
3.5. Relation between modulation of ES2 by amitriptyline and modulation of ES2 by citalopram (n -- 27) The reduction in ES 2 duration during treatment with amitriptyline was significantly correlated to the reduction in ES2 duration during treatment with citalopram (R = 0.54, P = 0.006).
Fig. 1. ES2 durations in 27 patients with chronic tension-typeheadache during treatment with amitriptyline, citalopram and placebo. Columns represent mean values, bars represent 1 SD. *P -: 0.02; NS, not significant.
3.6. Relation between reduction in ES2 duration and reduction in headache (n = 27) Amitriptyline reduced headache significantly more than placebo (Bendtsen et al., 1996b). However, the reduction in ES2 duration during treatment with amitriptyline was not significantly correlated to the headache reduction (R = 0.09, P = 0.66). There was no significant effect on headache during treatment with citalopram (Bendtsen et al., 1996b).
3.7. Relation to clinical characteristics and pain parameters (n = 35) The duration of ES2 in patients was not significantly correlated to usual frequency of headache (R = 0.03, P = 0.86); actual headache intensity (R = 0.01, P = 0.94); age (R = 0.05, P = 0.75); years with headache (R =0.04, P = 0 . 8 6 ) ; pericranial muscle tenderness (R = - 0 . 2 0 , P =0.23); electrical sensory detection threshold (R = 0.07, P = 0.66); electrical pain threshold (R = - 0.01, P = 0.96); pressure pain detection threshold in the finger (R = 0.16, P = 0.35); pressure pain tolerance threshold in the finger (R = 0.13, P = 0.44); pressure pain detection threshold in the temple (R = 0.11, P = 0.54); or pressure pain tolerance threshold in the temple (R = 0,13, P = 0.43).
4. Discussion Although reflexes in human jaw muscles have been extensively studied, the neurotransmitters involved in the regulation of these reflexes are not well known. However, it is generally agreed that the late exteroceptive suppression period (ES2) of jaw-closing muscle activity is mediated via inhibitory brain-stem interneurons (Cruccu et al., 1984), and that ES2 is partly controlled by seroto-
1.. BendtseH et al.
Electroencephaloeraphy and clinical Ncur.l~hvsiolog, y I01 ! I79~i 418' 422
nergic neuronal pathways (Schoenen, 1993). This makes drug-induced modulation of ES, an interesting, non-invasive method for studying serotonergic neurotransmission in the central nervous system. However, because of the complexity of the neuronal pathways investigated, such studies cann()t show the exact location of the pharmacological modulation (Maertens de Noordhout et al., 1995). Previous studies on modulation of ES2 by serotonergic drugs have given conflicting results. In a preliminary study. Schoenen el al. (1991b) investigated the modulation of ES2 in healthy volunteers following administration of various serotonergic drugs. It was found that metysergide, a serotonin antagonist, prolonged ES2, that fluoxetine, a serotonin re-uptake inhibitor, reduced ES2, and that sumatriptan, a serotonin agonist, had no significant effect on ES2, These data indicate that drugs which increase serotonin levels tend to decrease ES3. while drugs which block serotonin receptor,+ tend to increase ES,. In contrast to this, Gobel el al. (1994a) could not detect any difference in ES~ before and after treatment with amitriptyline, a combined serotonm and noradrenaline inhibitor, in patients with chronic tension-type headache. In another study, where ihe ES_+ periods were analysed by a blinded observer, G6bel et al~ 11994b) demonstrated that sumatriptan increased ES, in patients with migraine during a migraine attack. The reason for these discrepancies remains obscure, but they may be caused by differences in the methods used for recording and analysing ES2, or it might be thai healthy controls, patients with migraine and patients with tension-type headache react differently to seroionergic drugs. The preserli finding of decreased ES2 durations during treatment with amilriptyline was obtained by means of previously evaluated, reliable (Bendtsen et al., 1993) and blinded methods (Bendtsen et al., 1996a). How can we explain the n'duclion in ES3 during treatment with amitriptyline? A, it is known that ES3 is decreased with decreasing stimulus intensities (T/Jrker, 1988), one may suggest that the analgesic properties of amitriptyline (Egbunike and Chaffee, 199{)) lead to decreased painful input from the: periphery and thereby to an ES2 reduction. Howe~er, since the ES+ reduction was not correlated to the reduction in headache during treatment with amitriptyline, and since ES, was not correlated to any of the clinical or experimental pain parameters, this explanation seems unlikely. We find it more likely that amitriptyline modulates ES, ~ia an effect or3 serotonergic neurotransmission in the brain-stem. This was supported by the finding of a highly signilicant correlation between the modulation of ES+ induced by amitriptyline and the modulation of ES3 induced by the selective serotonin re-uptake inhibitor citalopram. However, citalopram only tended to shorten ES2, which indicates that serotonergic as well as noradrenergic neuronal pathways may be involved in the regulation of ES:. Amilriplyline significantly reduced headache while cita-
421
lopram caused only a minor and non-signilicant decrease in headache (Bendtsen et al., 1996b). ]'he mechanisms behind the prophylactic effect of amiiriptyline in chronic tension-type headache are not known. The present finding of a modulation of ES2 by amitriptyline indicates that this drug has a central effect in patients with chronic tension-type headache. However, since the reduction in ES~_ was not correlated to the reduction in headache, this particular central effect is probably not related to the prophylactic effect. The present study, therefore, does not indicate any relevance of ES2 in the monitoring of treatment effects it+, tension-type headache. It has previously been suggested (Schoenen et al., 1987: Nakashima and Takahashi, 1991; Wallasch et al., 1991! that reduced ES3 periods is an important abnonnality in chronic tension-type headache. However. two recent blinded studies (Zwart and Sand. 19o5: Bendlsen et al.. 1996a) were not able to confirm these findings, and the present study demonstrates that amitriptyline reduces E S and yet improves headache. Furthermore, m agreemeni with previous studies (McGrath et al., 1981: Schoenen el al., 1991a; Zwart and Sand, 1995) we lound no significant correlation between ES2 duration and either clinical characterisiics or any of the examined pain parameters. Together, these findings question the importance of ES~ in tension-type headache. In conclusion, the present results suggest thai amitriptyline modulates ES~ via an effect on serotonergic as well as noradrenergic neurotransmission in Ihc brain-stem.
Acknowledgements We would like to thank Mrs. Hanne Andresen for skilful technical assistance. The study ,aas supported bx the Lundbeck Foundation ~145/91 ).
References Bendtsen, L., Jensen, R., Brennum, J., Arendl-Nielsen, l,. and Ole~,en. J. Exteroccptive suppression periods in jaw cJosing muscles: variabiliiy and relation lo experimental pain and suslained mu,,clc contraction. Cephalalgia, 1993, 13:184 1Ol. Bendtsen, L., Jensen, R., Brennum, J., Arendt-Nielsen. L. and Olesen, J. Exteroceplive suppression of lemporalis nluscic acli,+lly is normal in patients with chronic tension-type headach,: arid not related to aclua[ headache stale. Cephalalgia, 1996a. 16:251 256. Bendlsen, L.. Jensen, R. and Olesen, J. A non->,clective (amilriplyline), but not a selective (citalopram), serolonin re-uptake inhibitor is effective in the prophylactic Irealmenl of chronic tcnsion-P~pe headache. J. Neurol. Neurosurg. Ps.'rchiatry, 1996b, in pre~,~. Bendtsen. L., Jcnsen. R. and Olesen. J. Decreased Pare thresholds and tolerances in chronic lension-type headache A~ch Net~rol., ~t)96c, 53: 373-376. Cruccu, G., Agostino, R., Fornarelli. M, lnghiller< M. and Manfredi. M. Recovery cycle of the masseter inhibilor)~ rcllex in :nan. Neurosci. Let/., 1984.49: 63-68. Cruccu, G.. lnghilleri. M.. Fraioli, B,. Guideui. B. and Manfredi, M. Neurophysiologic assessment of trigeminal function ~tilor surgery for irigemmal neuralgia. Neurology, lgg7. 37: !',~i 6~g.
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L. Bendtsen et al. / Electroencephalography and clinical Neurophysiology 101 (1996) 418-422
De Laat, A. Reflexes elicitable in jaw muscles and their role during jaw function and dysfunction: a review of the literature, part IlI, reflexes in human jaw muscles during function and dysfunction of the masticatory system. Cranio, 1987, 5: 333-343. Diamond, S. and Baltes, B.J. Chronic tension headache treated with amitfiptyline: a double-blind study. Headache, 1971, 11: 110-116. Egbunike, I.G. and Chaffee, B.J. Antidepressants in the management of chronic pain syndromes. Pharmacotherapy, 1990, 10: 262-270. Godaux, E. and Desmedt, J.E. Exteroceptive suppression and motor control of the masseter and temporalis muscles in normal man. Brain Res., 1975, 85: 447-458. G6bel, H., Hamouz, V., Hansen, C., Heininger, K., Hirsch, S., Lindner, V., Heuss, D. and Soyka, D. Chronic tension-type headache: amitriptyline reduces clinical headache-duration and experimental pain sensitivity but does not alter pericranial muscle activity readings. Pain, 1994a, 59: 241-249. G6bel, H., Krapat, S., Dworschak, M., Heuss, D., Ensink, F.B. and Soyka, D. Exteroceptive suppression of temporalis muscle activity during migraine attack and migraine interval before and after treatment with sumatfiptan. Cephalalgia, 1994b, 14: 143-148. Hamilton, M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry, 1960, 23: 56-62. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia, 1988, 8 (Suppl. 7). Lance, J.W. and Curran, D.A. Treatment of chronic tension headache. Lancet, 1964, 1: 1236-1239. Maertens de Noordhout, A., Wang, W. and Schoenen, J. Clinical neurophysiology and neurotransmitters. Cephalalgia, 1995, 15: 301-309. Mason, P., Strassman, A. and Maciewicz, R. Intracellular responses of raphe magnus neurons during the jaw-opening reflex evoked by tooth pulp stimulation. Brain Res., 1986, 379: 232-241. McGrath, P.A., Sharav, Y., Dubner, R. and Gracely, R.H. Masseter inhibitory periods and sensations evoked by electrical tooth pulp stimulation. Pain, 1981, 10: 1-17. Nakashima, K. and Takahashi, K. Exteroceptive suppression of the mass-
eter, temporalis and trapezius muscles produced by mental nerve stimulation in patients with chronic headaches. Cephalalgia, 1991, 11: 23-28. Pfaffenrath, V., Diener, H.C., Isler, H., Meyer, C., Scholz, E., Taneri, Z., Wessely, P., Zaiser Kaschel, H., Haase, W. and Fischer, W. Efficacy and tolerability of amitriptylinoxide in the treatment of chronic tension-type headache: a multi-centre controlled study. Cephalalgia, 1994, 14: 149-155, Russell, M.B., Rasmussen, B.K., Brennum, J., Iversen, H.K., Jansen, R.A. and Olesen, J, Presentation of a new instrument: the diagnostic headache diary. Cephalalgia, 1992, 12: 369-374. Schoenen, J. Exteroceptive suppression of temporalis muscle activity in patients with chronic headache and in normal volunteers: methodology, clinical and pathophysiological relevance. Headache, 1993, 33: 3-17. Schoenen, J., Jamart, B., Gerard, P., Lenarduzzi, P. and Delwaide, P.J. Exteroceptive suppression of temporalis muscle activity in chronic headache. Neurology, 1987, 37: 1834-1836. Schoenen, J., ( ~ a r d , P., De Pasqua, V. and Sianard Gainko, J. Multiple clinical and paraclinical analyses of chronic tension-type headache associated or unassociated with disorder of pericranial muscles. Cephalalgia, 1991a, 11: 135-139. Schoenen, J., Raubuchl, O. and Sianard, J. Pharmacological modulation of temporalis exteroceptive silent periods in healthy volunteers. Cephalalgia, 1991b, 11 (Suppl. 11): 16-17. Tiirker, K.S. A method for standardization of silent period measurements in human masseter muscle. J. Oral Rehabil., 1988, 15: 91-101. Wallasch, T.M., Reinecke, M. and Langohr, H.D. EMG analysis of the late exteroceptive suppression period of temporal muscle activity in episodic and chronic tension-type headaches. Cephalalgia, 1991, 11: 109-112. Yemm, R. Reflex jaw opening following electrical stimulation of oral mucous membrane in man. Arch. Oral Biol., 1972, 17: 513-523. Zwart, J.A. and Sand, T. Exteroceptive suppression of temporalis muscle activity: a blind study of tension-type headache, migraine, and cervicogenic headache. Headache, 1995, 35: 338-343.
Electroencephalographyand clinical Neurophysiology101 (1996) 418-422
Amitriptyline, a combined serotonin and noradrenaline re-uptake inhibitor, reduces exteroceptive suppression of temporal muscle activity in patients with chronic tension-type headache L. B e n d t s e n * , R. J e n s e n , J. O l e s e n Department of Neurology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Denmark
Accepted for publication: 26 April 1996
Abstract Although reflexes in human jaw muscles have been extensively studied, the neurotransmitters involved in the regulation of these reflexes are not well known. The aim of the present study was to investigate whether amitriptyline, a combined serotonin and noradrenaline re-uptake inhibitor, modulates the late exteroceptive suppression period (ES2) of temporal muscle activity in chronic tension-type headache. ES2 was recorded with a previously evaluated method and assessed by a blinded observer in 35 patients with chronic tension-type headache. Thereafter, ES2 was recorded in 27 of these patients during a double-blind, placebo-controlled, 3-way crossover trial investigating the prophylactic effect of amitriptyline, the selective serotonin re-uptake inhibitor citalopram, and placebo. ES2 duration was significantly shorter during treatment with amitriptyline than during placebo, P = 0.02, while ES2 duration only tended to be shorter during treatment with citalopram, P = 0.34. ES2 was not significantly correlated to the prophylactic effect of amitriptyline or to a range of clinical and experimental pain parameters. Our results demonstrate that amitriptyline reduces ES2 and indicate that ES2 is modulated by serotonergic as well as noradrenergic neuronal pathways. Keywords: Amitriptyline; Exteroceptive suppression; Serotonin; Silent period; Tension-type headache
I. Introduction Reflexes in jaw muscles have been used extensively in investigations of pain mechanisms (Mason et al., 1986), motor control (Yemm, 1972; Godaux and Desmedt, 1975), trigeminal nerve function (Cruccu et al., 1987) and orofacial pain disorders (De Laat, 1987). In 1987 Schoenen et al. (Schoenen et al., 1987) reported that the duration of the late exteroceptive suppression period (ESz), also known as the second silent period SP2, of temporal muscle activity was reduced in patients with chronic tension-type headache. This finding has later been confirmed by other research groups (Nakashima and Takahashi, 1991; Wallasch et al., 1991), while recent studies by Zwart and Sand (1995) and our group (Bendtsen et al., 1996a) found normal ES2 durations in chronic tension-type headache. *Corresponding author. Tel.: +45 43964333, ext. 6117; fax: +45 43423570.
Serotonergic neuronal pathways play an important role in the regulation of jaw reflexes (Mason et al., 1986), and ES2 may therefore be a valuable tool for assessing serotonergic neurotransmission in the brain-stem (Maertens de Noordhout et al., 1995). Amitriptyline has been reported to be effective in the prophylactic treatment of chronic tension-type headache in most studies (Lance and Curran, 1964; Diamond and Baltes, 1971; Ben&sen et al., 1996b), while one study has been negative (Pfaffenrath et al,, 1994). Amitriptyline is a combined serotonin and noradrenaline re-uptake inhibitor, but has also several other pharmacological effects, e.g. effects on serotonergic, adrenergic, cholinergic, and histaminergic receptors (Bendtsen et al., 1996b). The mechanisms behind the effect of amitriptyline in tension-type headache are not known, but it is likely that modulation of serotonergic neuronal pathways plays an important role. The primary aim of the present study therefore was to investigate whether amitriptyline modulates ES2.
0924-980X/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PI1 S0921-884X(96)96532-7
EEM 96532
419
L. Bemltsest et al. / Electroencephalography and clinical Neurophysiolow I01 t1996i 41S 422
2. Patients and methods
Table 1 Clinical characteristics of tension-type headache patienis
2.1. Patienl,s
Forty patients with chronic tension-type headache diagnosed according to the criteria of the International Headache Society (Headache Classification Committee, 1988) were included in a study (Bendtsen et al., 1996b) of the prophylactic effect of amitriptyline and of citalopram in chronic tension-type headache. Seven patients with coexisting infrequent migraine (<1 day/month) were accepted. The patients were recruited from the outpatient headache clinic at Glostrup University Hospital, Copenhagen, Denmark. The inclusion criteria were a diagnosis of chronic tension-type headache and age between 18 and 65 years. The exclusion criteria were migraine more than 1 day/ month, serious somatic or psychiatric diseases including depression (Hamilton Depression Score (Hamilton, 1960) _>17). intake of prophylactic medications for tension-type headache, abuse of simple analgesics (corresponding to more than 2 g of aspirin/day), regular intake of opiates or benzodiazepines and previous treatment with antidepressants. All patients underwent a general physical and a neurological examination and completed a diagnostic headache diary (Russell et al.. 1992) during a 1 month run-in period. The trial was designed as a 32 week, double-blind, placebo-controlled. 3-way crossover study and has previously been described in detail (Bendtsen et al., 1996b). Briefly, each drug was given in random order for 8 weeks, separated bv 2 week wash-out periods. The drugs were administered in a dose-increasing regimen. In the last 6 weeks of the treatment periods, the daily dose of amitriptyline was 75 mg and of citalopram 20 mg. Thirty-five of the 40 patients were included in the present study (Table 1 i. Four women did not want to participate and one woman was excluded because of dentures. The patients were not allowed to take analgesics on the days of examinatkm. All patients gave written informed consent to participate in the study, which was approved by the regional ethics committee. a..c. "~ ~ M e t h o d s
The recordings were performed in a standardized manner by the same investigator, a trained technician (HA), throughout the study. In the run-in period, the patients were examined during a typical episode of tension-type headache. During the trial, we examined the patients irrespective of their headache state, since ES 2 does not differ on days with headache compared with days without headache (Bendtsen et al.. 1996a). The recordings were perlk~rmed in the last week of each of the three 8 week treatment periods, i.e. during treatment with 75 mg amitriptyline daily,, during treatment with 20 mg citalopram daily and during placebo. Exteroceptive suppression was recorded according to a
Number Sex (females/males) Age(years) Headache days/4 weeks Years with headache
Patients included
Patients who Colnplctcd Ihc stud}
35 20115 39.3 122 571 24.9 (16 28} 12.6(I 33)
"7 161 3%0i22-56i 25.0 (16-28) !2.{,11--361
Mean values are given. ~ iih range m brackc~,,.
previously described method (Bendtsen el al.. 1993). Briefly, electromyographic (EMG) activity of the left temporal muscle was recorded with surface electrodes and the EMG signals were stored for off-line analysis. A bipolar surface stimulation electrode was placed with the stimulation tips on either side of the left labial commissure. The sensory detection threshold, i.e. ihe weakest stimulus detectable by the subject, and the pain detection threshokl, i.e. the weakest stimulns perceived as painful by the subject, were measured at the beginning of each recording series. Thereafter, single electrical rectangular stimuli with an intensity' of 20 mA and a dilration ol (}.5 ms were delivered during 2 - 3 s of nmxirnum voluntar 3 jaw occlusion. Sixteen stimuli were delivered at 15 s intervals in each recording series. Signals from one recording series were rectified and averaged by means of a purpose-made computer program. Reduction of mean EMG amplitude below 50% of pre-stimulus activity \~as delined as exteroceptive suppression. ES~ durations were measured by means of vertical cursors placed at the interceptions of the averaged curve and a 5()~/< amplitude cursor. This method has previously proved to be reliable IBendtsen et al., 1993). All recordings were coded b\ an assistant before the analyses. Thereafter. one observer (LB), who was blinded to any information about the recordings, analysed the ES: periods. In addition to recordings of ES:. ~arious pain parameters were recorded in the run-in period. The procedures and results have been presented in a pre~ ious paper (Bendtsen el al.. 1996c). Briefly. the patients recorded their actual headache intensity on a 100 mm visual atlalogue scale, tenderness of pericranial myohtcial lissues was recorded by manual palpation according to the Total Tenderness Scoring system, and pressure pain thresholds and tolerances were recorded in the temporal region and in the finger with an electronic pressure algometer. The reduction in ES~ duration during treatment with amitriptyline compared with placebo was calculated as: ES= reduction = (1 - ES=,,,i~ip~>l,,,d'ES?pl~<,,~7o)>: 100%. The reduction in ESe duration during treatment with citalopram compared with placebo was calculated as: ES2 reduction = (1 - ES2citaiop,am/ES2plac,,,) >: 10()~}~. The reduction in headache during treammnl with amitriptyline compared with placebo was calculated as: headache reduc-
L. Bendtsen et al. / Electroencephalography and clinical Neurophysiology 101 (1996)418-422
420
tion = (1 AUCamitriptyline/AUCplacebo)X 100%. AUC was defined as the area under the headache curve (headache duration x headache intensity). -
40 A
2.3. Statistics
30 f-
Results are presented as mean + SD. Recordings without a detectable ES2 period were defined as having an ES2 duration of 0 ms. Wilcoxon's rank sum test was used for paired observations, i.e. testing results within patients on different days. Spearman's test was used for calculation of coefficients of correlation, R. Significance was accepted at the 5% level.
.c, -i "O
20
10
Amitriptyline
Cltalopram
Placebo
3. Results 3.1. Run-in period (n = 35) The duration of ES2 recorded in the run-in period was 33.0 +_ 16.8 ms. Three patients had no detectable ES2 period.
3.2. Drop-outs Twenty-seven of the 35 patients completed the study (Table 1). Six patients dropped out of the trial for various reasons (Bendtsen et al., 1996b) unrelated to the present study, one patient did not want to participate in the present study during the trial, and one patient was excluded because of technical problems. In total, 4 women and 4 men with a mean age of 40.5 years (range 2 5 - 5 7 years) did not complete the study.
3.3. Modulation of ES 2 by amitriptyline (n = 27) The duration of ES2 during treatment with amitriptyline was 31.7 +_ 14.3 ms, which was significantly shorter than the duration during placebo (36.1 _+ 15.5 ms, P = 0.02) (Fig. 1). ES2 was present in all patients during all 3 treatments, except for one woman who did not have a detectable ES2 period during any of the 3 treatments.
3.4. Modulation of ES2 by citalopram (n = 27) The duration of ES2 during treatment with citalopram was 34.3 _+ 13.0 ms and not significantly different from the duration during placebo (36.1 +_ 15.5 ms, P = 0.34) (Fig. 1).
3.5. Relation between modulation of ES2 by amitriptyline and modulation of ES2 by citalopram (n -- 27) The reduction in ES 2 duration during treatment with amitriptyline was significantly correlated to the reduction in ES2 duration during treatment with citalopram (R = 0.54, P = 0.006).
Fig. 1. ES2 durations in 27 patients with chronic tension-typeheadache during treatment with amitriptyline, citalopram and placebo. Columns represent mean values, bars represent 1 SD. *P -: 0.02; NS, not significant.
3.6. Relation between reduction in ES2 duration and reduction in headache (n = 27) Amitriptyline reduced headache significantly more than placebo (Bendtsen et al., 1996b). However, the reduction in ES2 duration during treatment with amitriptyline was not significantly correlated to the headache reduction (R = 0.09, P = 0.66). There was no significant effect on headache during treatment with citalopram (Bendtsen et al., 1996b).
3.7. Relation to clinical characteristics and pain parameters (n = 35) The duration of ES2 in patients was not significantly correlated to usual frequency of headache (R = 0.03, P = 0.86); actual headache intensity (R = 0.01, P = 0.94); age (R = 0.05, P = 0.75); years with headache (R =0.04, P = 0 . 8 6 ) ; pericranial muscle tenderness (R = - 0 . 2 0 , P =0.23); electrical sensory detection threshold (R = 0.07, P = 0.66); electrical pain threshold (R = - 0.01, P = 0.96); pressure pain detection threshold in the finger (R = 0.16, P = 0.35); pressure pain tolerance threshold in the finger (R = 0.13, P = 0.44); pressure pain detection threshold in the temple (R = 0.11, P = 0.54); or pressure pain tolerance threshold in the temple (R = 0,13, P = 0.43).
4. Discussion Although reflexes in human jaw muscles have been extensively studied, the neurotransmitters involved in the regulation of these reflexes are not well known. However, it is generally agreed that the late exteroceptive suppression period (ES2) of jaw-closing muscle activity is mediated via inhibitory brain-stem interneurons (Cruccu et al., 1984), and that ES2 is partly controlled by seroto-
1.. BendtseH et al.
Electroencephaloeraphy and clinical Ncur.l~hvsiolog, y I01 ! I79~i 418' 422
nergic neuronal pathways (Schoenen, 1993). This makes drug-induced modulation of ES, an interesting, non-invasive method for studying serotonergic neurotransmission in the central nervous system. However, because of the complexity of the neuronal pathways investigated, such studies cann()t show the exact location of the pharmacological modulation (Maertens de Noordhout et al., 1995). Previous studies on modulation of ES2 by serotonergic drugs have given conflicting results. In a preliminary study. Schoenen el al. (1991b) investigated the modulation of ES2 in healthy volunteers following administration of various serotonergic drugs. It was found that metysergide, a serotonin antagonist, prolonged ES2, that fluoxetine, a serotonin re-uptake inhibitor, reduced ES2, and that sumatriptan, a serotonin agonist, had no significant effect on ES2, These data indicate that drugs which increase serotonin levels tend to decrease ES3. while drugs which block serotonin receptor,+ tend to increase ES,. In contrast to this, Gobel el al. (1994a) could not detect any difference in ES~ before and after treatment with amitriptyline, a combined serotonm and noradrenaline inhibitor, in patients with chronic tension-type headache. In another study, where ihe ES_+ periods were analysed by a blinded observer, G6bel et al~ 11994b) demonstrated that sumatriptan increased ES, in patients with migraine during a migraine attack. The reason for these discrepancies remains obscure, but they may be caused by differences in the methods used for recording and analysing ES2, or it might be thai healthy controls, patients with migraine and patients with tension-type headache react differently to seroionergic drugs. The preserli finding of decreased ES2 durations during treatment with amilriptyline was obtained by means of previously evaluated, reliable (Bendtsen et al., 1993) and blinded methods (Bendtsen et al., 1996a). How can we explain the n'duclion in ES3 during treatment with amitriptyline? A, it is known that ES3 is decreased with decreasing stimulus intensities (T/Jrker, 1988), one may suggest that the analgesic properties of amitriptyline (Egbunike and Chaffee, 199{)) lead to decreased painful input from the: periphery and thereby to an ES2 reduction. Howe~er, since the ES+ reduction was not correlated to the reduction in headache during treatment with amitriptyline, and since ES, was not correlated to any of the clinical or experimental pain parameters, this explanation seems unlikely. We find it more likely that amitriptyline modulates ES, ~ia an effect or3 serotonergic neurotransmission in the brain-stem. This was supported by the finding of a highly signilicant correlation between the modulation of ES+ induced by amitriptyline and the modulation of ES3 induced by the selective serotonin re-uptake inhibitor citalopram. However, citalopram only tended to shorten ES2, which indicates that serotonergic as well as noradrenergic neuronal pathways may be involved in the regulation of ES:. Amilriplyline significantly reduced headache while cita-
421
lopram caused only a minor and non-signilicant decrease in headache (Bendtsen et al., 1996b). ]'he mechanisms behind the prophylactic effect of amiiriptyline in chronic tension-type headache are not known. The present finding of a modulation of ES2 by amitriptyline indicates that this drug has a central effect in patients with chronic tension-type headache. However, since the reduction in ES~_ was not correlated to the reduction in headache, this particular central effect is probably not related to the prophylactic effect. The present study, therefore, does not indicate any relevance of ES2 in the monitoring of treatment effects it+, tension-type headache. It has previously been suggested (Schoenen et al., 1987: Nakashima and Takahashi, 1991; Wallasch et al., 1991! that reduced ES3 periods is an important abnonnality in chronic tension-type headache. However. two recent blinded studies (Zwart and Sand. 19o5: Bendlsen et al.. 1996a) were not able to confirm these findings, and the present study demonstrates that amitriptyline reduces E S and yet improves headache. Furthermore, m agreemeni with previous studies (McGrath et al., 1981: Schoenen el al., 1991a; Zwart and Sand, 1995) we lound no significant correlation between ES2 duration and either clinical characterisiics or any of the examined pain parameters. Together, these findings question the importance of ES~ in tension-type headache. In conclusion, the present results suggest thai amitriptyline modulates ES~ via an effect on serotonergic as well as noradrenergic neurotransmission in Ihc brain-stem.
Acknowledgements We would like to thank Mrs. Hanne Andresen for skilful technical assistance. The study ,aas supported bx the Lundbeck Foundation ~145/91 ).
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