Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache

Transcription

1 Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache Lars Bendtsen, MD, PhD; and Rigmor Jensen, MD, PhD Abstract Background: The tricyclic antidepressant amitriptyline is the only drug with prophylactic efficacy for chronic tension-type headache. However, amitriptyline is only moderately effective, with headache reduction of approximately 30%, and treatment is often hampered by side effects. Mirtazapine is a relatively new so-called noradrenergic and specific serotonergic antidepressant, which is more specific and therefore generally better tolerated. Objective: To evaluate the efficacy of mirtazapine. Methods: Twenty-four nondepressed patients with chronic tension-type headache were included in a randomized, double-blind, placebo-controlled, crossover trial. All patients had tried numerous other treatments. Mirtazapine 15 to 30 mg/day or placebo was each given for 8 weeks separated by a 2-week wash-out period. Results: Twenty-two patients completed the study. The primary efficacy variable, area-under-the-headache curve (AUC; duration intensity), was lower during treatment with mirtazapine (843) than during treatment with placebo (1,275) (p 0.01). Mirtazapine also reduced the secondary efficacy variables headache frequency (p 0.005), headache duration (p 0.03), and headache intensity (p 0.03) and was well tolerated. Conclusions: Mirtazapine reduced AUC by 34% more than placebo in difficult-to-treat patients. This finding is clinically relevant and may stimulate the development of prophylactic treatments with increased efficacy and fewer side effects for tension-type headache and other types of chronic pain. NEUROLOGY 2004;62: Chronic tension-type headache both is prevalent and has an impact on quality of life. 1 The disorder is responsible for substantial socioeconomic expenses, 2 and it is one of the primary headaches most difficult to treat. 3 Prophylactic pharmacologic therapy should be considered if nonpharmacologic management is inadequate. The tricyclic antidepressant amitriptyline is the only drug with prophylactic efficacy for chronic tension-type headache. 4,5 However, amitriptyline is only moderately effective, with a reduction of headache index of approximately 30% compared with placebo, and the treatment is often hampered by side effects. 6 The exact mechanism(s) by which amitriptyline exerts its analgesic effect is unknown. In addition to several other actions, amitriptyline blocks the neuronal reuptake of serotonin (5-hydroxytryptamine [5-HT]) and noradrenaline, thereby increasing the concentration of these transmitters in the neuronal synapse. 6 This has been assumed to play an essential role for the analgesic effect of amitriptyline. The selective 5-HT reuptake inhibitors (SSRIs) have been tested in various chronic pain conditions including tension-type headache, 4,7 mainly because of their favorable side effect profile. These trials have convincingly demonstrated that the SSRIs have no or only limited analgesic effect. 6,8,9 It is therefore likely that increased activity of both 5-HT and noradrenaline is needed to obtain a clinical relevant analgesic effect. Mirtazapine is a relatively new so-called noradrenergic and specific serotonergic antidepressant. 10 Mirtazapine blocks 2 -adrenergic receptors on noradrenergic and serotonergic presynaptic neurons, which results in increased serotonergic and noradrenergic neurotransmission. 11 The drug is more specific and therefore generally better tolerated than the tricyclic antidepressants. 12 In a pilot study, we found mirtazapine to be effective in tension-type headache with only few adverse events (unpublished data). We sought to evaluate the prophylactic effect of mirtazapine in patients with chronic tension-type headache. Methods. Patients. Twenty-four patients with chronic tensiontype headache diagnosed according to the criteria of the International Headache Society 13 were recruited from the outpatient headache clinic at the Danish Headache Center, Glostrup Hospital, University of Copenhagen, Denmark (figure 1). Patients were recruited between February 2002 and July 2002, and the trial was completed on November 6, The patients underwent a general and a neurologic examination, including 12-channel EKG, and completed a diagnostic headache diary 14 during a 4-week run-in period. The inclusion criteria were a diagnosis of chronic tension-type headache and age between 18 and 65 years. Women of childbearing potential had to use adequate contraceptive measures throughout the study. The exclusion criteria were history of migraine of 1 day/month during the last year, serious somatic or psychiatric diseases including depression (Hamilton Depression Scale score of 17), 15 previous treatment with mirtazapine, abuse of simple analgesics (corresponding to 50 g of aspirin/month), regular intake of opiates or benzodiazepines, and intake of pro- From the Danish Headache Center, University of Copenhagen, and Department of Neurology, Glostrup University Hospital, Copenhagen, Denmark. Received June 16, Accepted in final form February 27, Address correspondence and reprint requests to Dr. L. Bendtsen, Danish Headache Center, University of Copenhagen, and Department of Neurology, Glostrup University Hospital, DK-2600 Glostrup, Copenhagen, Denmark; bendtsen@dadlnet.dk 1706 Copyright 2004 by AAN Enterprises, Inc.

2 Figure 1. Flow of participants through the study. phylactic headache medication. Thus, prophylactic headache medication was not taken at least 8 weeks before recording of the efficacy variables. All patients gave written informed consent to participate in the study, which was approved by the regional ethics committee and National Board of Health and conducted in accordance with the Declaration of Helsinki. The patients were informed that the study included placebo periods, but no further information about the study design was given. Study design and medication. The study was designed as a double-blind, placebo-controlled, crossover trial. Following a 4-week run-in period, the patients were randomly allocated to start treatment with either active drug or placebo. The allocation sequence was generated by the Central Pharmacy in Copenhagen County. Randomization was done in blocks of six patients. Active drug and placebo were each given for 8 weeks, and the treatment periods were separated by a 2-week wash-out period (figure 2). The study medication was tablets containing 15 mg of mirtazapine (Remeron; Organon, Skovlunde, Denmark) and placebo. In the first week of treatment with mirtazapine, the patients received 1 tablet of active drug and 1 placebo tablet, and in weeks 2 to 8, they received 2 mirtazapine tablets corresponding to a daily dose of 30 mg. During the 8 weeks of treatment with placebo and during the wash-out periods, the patients received a daily dose of 2 placebo tablets. However, the patients were allowed to take only 1 tablet daily if they experienced intolerable side effects. The patients thus received 1 or 2 tablets daily during all 18 weeks of treatment. All tablets had identical look and taste, and the patients were told to take the tablets 2 to 3 hours before bedtime. Figure 2. Study design of the 18-week, double-blind, placebo-controlled, crossover trial. Each patient was randomly allocated to one of the two possible treatment sequences. Clinical visits are indicated with squares. Recording of efficacy variables. Throughout the study, the patients kept a headache diary with recordings of headache intensity, headache duration, intake of analgesics, and side effects. Intensity was recorded on an 11-point verbal rating scale (0 to 10), where 0 indicated the headache-free condition, 5 indicated a moderate headache, and 10 indicated the worst headache imaginable. In addition, localization and quality of the headache, whether the headache was aggravated by physical activity, and presence or absence of nausea, photophobia, and phonophobia were recorded. Clinical visits. Follow-up visits were performed at 4- to 5-week intervals (see figure 2). At each visit, the headache diary was checked, medication supplies were handed over, side effects reported by the patients were recorded, and compliance was tested by a check of the returned packages and by counting the returned tablets, if any. Evaluation of efficacy. The efficacy variables were determined in advance. The primary efficacy variable was the areaunder-the-headache curve (AUC) recorded in the last 4 weeks of each treatment period. AUC was calculated as the sum of the daily recordings of headache duration headache intensity. To evaluate the time course of headache improvement, the improvement in AUC compared with baseline was calculated for each week of treatment as (mean AUC for the 4 weeks of run-in [baseline]) (AUC for each of the 8 weeks of mirtazapine and placebo treatment). The efficacy of mirtazapine compared with placebo was calculated as follows: efficacy (1 AUC mirtazapine / AUC placebo ) 100%. As previously, 16,17 patients were defined as responders if the AUC was decreased by at least 30% during the last 4 weeks of active treatment compared with placebo; in other words, if efficacy was at least 30%. Secondary efficacy variables were 1) headache frequency in the last 4 weeks of each treatment period, 2) headache duration in the last 4 weeks of each treatment period, 3) mean headache intensity per headache day in the last 4 weeks of each treatment period, and 4) number of analgesics doses, equivalent to 500 mg of aspirin, consumed in the last 4 weeks of each treatment period. In addition, the number of patients reporting side effects in each treatment period was recorded. Statistics. Sample size calculations were based on an expected standard deviation of the primary efficacy variable of 40%, whereas 25% was considered a clinically relevant difference between active and placebo treatment. With 80% power and 5% level of significance, sample size was calculated to 20 patients. 18 To obtain this, 24 patients were included. The Shapiro Wilk test was used to determine whether the data were normally distributed. Data that were not normally distributed were presented as median values with quartiles in parentheses and tested with nonparametric statistics. Data that were normally distributed were presented as means and tested with parametric statistics. Patients who dropped out of the study were excluded from the analyses except when calculating side effects. Wilcoxon signed rank test was used to test for differences between active treatment and placebo. Migraine days were excluded from the analyses. A possible carry-over effect was tested for by comparing mean AUC recorded in periods where mirtazapine was followed by placebo with mean AUC in periods where placebo was followed by mirtazapine by means of Mann Whitney U test. 18 A possible time period effect was tested for by comparing the difference in AUC in periods where mirtazapine was followed by placebo with the negative difference in AUC in periods where placebo was followed by mirtazapine. 18 Comparison of the number of patients reporting side effects was done by McNemar test. Spearman test was used for calculation of correlation coefficients (R). Twosided p values were calculated, and significance was accepted at the 5% level. Results. Study population. Twenty-four patients were included (see figure 1). Four patients reported coexisting infrequent migraine ( 1 day/month) during the last year, whereas 20 patients never had had migraine. All patients had previously tried numerous treatments for tension-type headache and had experienced frequent headaches for many years. Ten patients had previously been treated with amitriptyline without effect. By coincidence, as many men as women were included, contrary to what is usually seen. May (2 of 2) 2004 NEUROLOGY

3 Table 1 Characteristics of patients No. of patients 22 Sex, F/M 10/12 Age, y 45 (37 52) Area-under-headache curve 1,477 (965 1,988) Headache duration, h/4 wk 332 ( ) Headache intensity, mm VAS/headache d 4.8 ( ) Headache frequency, d/4 wk 28.0 ( ) Analgesics, doses/4 wk 6.5 ( ) Hamilton Depression Scale score 2.0 ( ) Years with headache 20.0 ( ) Data for the 22 patients who completed the study are presented, taken from history and from headache diary completed before enrollment in the trial. Median values with quartiles in parentheses are given. VAS Visual Analogue Scale. During 8 weeks of treatment with active drug, four patients had from 2 to 5 days with migraine, and during placebo, the same four patients had from 1 to 4 days with migraine. Two women ages 39 and 49 dropped out during active treatment because of side effects (see below). Because of side effects, two patients took only 1 tablet daily for some of the days during both active and placebo treatment, whereas one patient took only 1 tablet daily for a few days during placebo treatment only. Thus, 20 patients took 30 mg of mirtazapine daily and 2 patients took 15 to 30 mg of mirtazapine daily during weeks 2 to 8. The codes were not broken before complete data analysis. Detailed clinical information about the 22 patients who completed the study is presented in table 1. Treatment efficacy: primary variable. The AUC in the last 4 weeks of treatment was 34% lower during treatment with mirtazapine (843 [402 to 2,043]) than during placebo (1,275 [748 to 1,907]) (p 0.01, Wilcoxon signed rank test). Figure 3 shows the improvement of AUC over time for active and placebo treatments. There was no carry-over effect (p 0.54, Mann Whitney U test) or time period effect (p 0.92, Mann Whitney U test). During the last 4 weeks of treatment with mirtazapine, 10 of 22 patients improved by at least 30% compared with placebo; that is, 45% could be termed responders. Two of the four patients who also had migraine were responders; that is, the presence or absence of migraine did not seem to influence efficacy. There was no difference in efficacy between the 10 patients who previously had been treated and the 12 patients who never had been treated with amitriptyline for headache (p 0.51, Mann Whitney U test), and there was no difference in efficacy between women and men (p 0.77, Mann Whitney U test). There was no correlation between Hamilton Depression Scale score and efficacy of mirtazapine (R 0.05, p 0.81, Spearman test). Treatment efficacy: secondary variables. Table 2 presents the secondary efficacy variables. Mirtazapine reduced headache frequency (p 0.005), headache duration (p 0.03), and headache intensity (p 0.03) significantly more than placebo (Wilcoxon signed rank test). There was no difference in intake of analgesics between mirtazapine and placebo NEUROLOGY 62 May (2 of 2) 2004 Figure 3. Improvement in area-under-the-headache curve (AUC) values in 22 patients with chronic tension-type headache during 8 weeks of treatment with mirtazapine and placebo. Values are calculated as (mean AUC for the 4 weeks of run-in [baseline]) (AUC for each of the 8 weeks of treatment). Negative values (week 8 for placebo) represent increase in AUC compared with run-in. *p 0.05, **p (paired samples t-test). Triangles mirtazapine; circles placebo. Side effects. Two patients dropped out during active treatment because of side effects (see figure 1). One woman dropped out in week 1 because of drowsiness and dizziness, and one woman dropped out in week 7 because of weight gain. More patients reported drowsiness, dizziness, and weight gain during treatment with mirtazapine than placebo, as expected, whereas more patients on placebo had irritability (table 3). The differences in reports of side effects between active and placebo treatments did not reach significance. Discussion. The most important finding of the current study was that mirtazapine had a significant effect in the prophylactic treatment of chronic tension-type headache. Mirtazapine reduced the primary efficacy variable, AUC, by 34% compared with placebo; that is, the therapeutic gain was 34%. Mirtazapine also significantly reduced most of the secondary efficacy variables, namely, headache frequency, headache duration, and headache intensity. Intake of analgesics was very low in the examined patients, with no significant difference between active and placebo periods. The patients were not depressed, were all treatment resistant (including treatment with amitriptyline for nearly half of the patients), and had had chronic tension-type headache for many years. In this difficult-to-treat group, the treatment response is considered satisfactory, clinically relevant, and highly interesting. To our knowledge, this is the first randomized, placebo-controlled, double-blind trial of mirtazapine

4 Table 2 Treatment efficacy: secondary variables Variables Mirtazapine Placebo p Value Headache frequency, d/4 wk 25.5 ( ) 28.0 ( ) Headache duration, h/4 wk 210 ( ) 288 ( ) 0.03 Headache intensity, VRS/headache d 4.2 ( ) 4.3 ( ) 0.03 Analgesics, doses/4 wk 1.0 ( ) 0.0 ( ) 0.46 The p values are given from Wilcoxon signed rank test of differences between treatment with mirtazapine and placebo (n 22). Median values with quartiles in parentheses are presented. VRS Verbal Rating Scale (0 10). in headache prophylaxis and in the treatment of any chronic pain condition. Mirtazapine has been reported effective in open trials in patients with chronic tension-type headache and concomitant depression (I.B. Kulaksizoglu et al., unpublished data, 2003) and in patients with cancer pain. 19 Case reports of patients with migraine, 20 cluster headache, 21 and low back pain 22 have also suggested mirtazapine to be effective. The efficacy of mirtazapine found in the current study was of the same magnitude as that reported for amitriptyline. 6 Thus, the therapeutic gain was approximately 30% in the two most recent prophylactic trials of amitriptyline in chronic tension-type headache. 4,5 However, comparative studies are required to make conclusions about the analgesic efficacy of mirtazapine compared with that of other antidepressants. There was no significant difference between frequency of side effects during active and placebo treatment, but there was a clear tendency to increased occurrence of the well-known side effects of mirtazapine under active treatment, namely, drows- Table 3 Side effects Side effects Mirtazapine Placebo Drowsiness 14 9 Dizziness 6 2 Weight gain 6 1 Dry mouth 5 4 Increased appetite 3 5 Edema in extremities 3 2 Sleep disturbances 2 3 Nausea 2 2 Concentration difficulties 2 1 Irritability 1 5 Various 5 3 No. of patients reporting one or more side effects There were no differences in the occurrence of any of the listed adverse effects (p 0.13), or in the number of patients reporting one or more adverse effects (p 0.39) between treatment with mirtazapine and placebo (McNemar test). n 24. iness, dizziness, and weight gain. The lack of significant difference is probably due to the small number of patients. Only two patients dropped out of the study because of side effects. We consider this very satisfactory compared with other prophylactic headache trials. Three patients chose to take only 1 tablet daily, that is, 15 mg of mirtazapine or placebo, for a limited period, equally distributed between placebo and active periods. It can be concluded that mirtazapine was well tolerated. This study has important clinical implications. Given the convincing evidence of effect of amitriptyline in tension-type headache 6 as well as other chronic pain conditions, 8 amitriptyline should remain the first choice for tension-type headache until the efficacy of mirtazapine has been confirmed by other studies. However, in patients who cannot tolerate or have an insufficient response to amitriptyline, mirtazapine should be the next choice. Mirtazapine has a substantial antihistaminergic effect that may cause sedation, increased appetite, and weight gain. 23 Mirtazapine is considered to have a good tolerability and safety profile 24 and a low propensity for drug interactions. 25 It appears safe in overdose. 26 Its half-life of 20 to 40 hours 27 makes it suitable for once-daily bedtime dosing. 26 Apart from the immediate clinical implications, these results have importance for the understanding of the antinociceptive mechanisms of antidepressants. The many actions of the tricyclic antidepressants, together with the incomplete knowledge of headache 28 and chronic pain pathophysiology, have for decades made their mechanism of action puzzling. 6,8 The analgesic effect of amitriptyline seems unrelated to its antidepressant effect. 3,29 Amitriptyline inhibits the presynaptic reuptake of 5-HT and noradrenaline in the CNS, thus potentiating the activity of these neurotransmitters. Beyond this, amitriptyline is a potent blocker of muscarinic cholinergic receptors, H 1 -histamine receptors, 1 - adrenergic receptors, and several 5-HT receptors (e.g., 5-HT 2A receptors), whereas the affinity for 2 - adrenergic receptors is low. 11,30 With prolonged treatment, amitriptyline may decrease -adrenergic receptor density and may down- or up-regulate several receptor systems, for example, -aminobutyric acid, May (2 of 2) 2004 NEUROLOGY

5 adenosine, and 5-HT receptors. Moreover, amitriptyline potentiates the effect of endogenous opioids 31 and may act as an NMDA receptor antagonist. 32 Of these actions, the effect on central pain pathways via inhibition of 5-HT and noradrenaline reuptake, interaction with 5-HT receptors, and potentiation of endogenous opioids or attenuation of central sensitization via NMDA receptor antagonism have been considered of particular importance for the analgesic effect. 33 In addition, amitriptyline may have peripheral analgesic actions. 16,34 We previously demonstrated that the highly selective 5-HT reuptake inhibitor citalopram has no clinically relevant effect in tension-type headache. 4 As citalopram inhibited 5-HT reuptake more than amitriptyline in these patients, 35 5-HT reuptake inhibition alone cannot explain the analgesic effect of amitriptyline. Assuming that mirtazapine and amitriptyline act through similar mechanisms in headache, the more selective mode of action of mirtazapine makes it possible to narrow the search for the analgesic mechanisms of antidepressants. Mirtazapine does not block amine reuptake but increases noradrenergic and serotonergic neurotransmission via blockade of presynaptic 2 -adrenergic receptors, and mirtazapine selectively blocks 5-HT 2 - and 5-HT 3 -type receptors. 11 The result is a selective stimulation of the postsynaptic 5-HT 1 -type receptors. Moreover, mirtazapine has a high affinity for histamine H 1 receptors and may modulate the opioid system. The antihistaminergic effect of mirtazapine may play a role by improving sleep. 23 A recent animal study reported an antinociceptive effect of mirtazapine in the hotplate test mediated through serotonergic, noradrenergic, and opioid mechanisms. 36 Other important questions, for example, whether mirtazapine may counteract central sensitization or have a peripheral analgesic effect, have, to our knowledge, not been investigated. It is hoped that the positive result of this study will stimulate more basic animal and human studies to clarify the analgesic mechanisms of mirtazapine. This may lead to new treatments with increased efficacy and fewer adverse events. The major limitation of the current study was the limited number of patients examined. The crossover design provides an acceptable power, but the generalization of the results would be improved by examining more patients. Therefore, more studies are needed, preferably from other headache centers, to finally conclude that mirtazapine is effective in tension-type headache. This study does not reveal the optimal dose of mirtazapine or the duration of treatment before efficacy can be seen. Figure 3 indicates that the difference between mirtazapine and placebo became clinically significant from week 4, that is, after 2 weeks on the final dose of mirtazapine, but it was not the primary efficacy variable in this study. Moreover, the long-term efficacy of mirtazapine should be investigated NEUROLOGY 62 May (2 of 2) 2004 Acknowledgment The authors thank Ms. Hanne Andresen for technical assistance, Prof. Jes Olesen and Dr. Messoud Ashina for their comments on the manuscript, and Rolf Gideon, Liudmila Babenko, and Merete Christensen for their participation in recruitment of the patients. References 1. Rasmussen BK, Jensen R, Olesen J. 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6 31. Botney M, Fields HL. Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system. Ann Neurol 1983;13: Watanabe Y, Saito H, Abe K. Tricyclic antidepressants block NMDA receptor-mediated synaptic responses and induction of long-term potentiation in rat hippocampal slices. Neuropharmacology 1993;32: Bendtsen L. Sensitization: its role in primary headache. Curr Opin Invest Drugs 2002;3: Sawynok J, Reid AR, Esser MJ. Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. Pain 1999;80: Ashina S, Bendtsen L, Jensen R. Antinociceptive effect of amitriptyline is not directly related to serotonin reuptake inhibition. Pain 2004;108: Schreiber S, Rigai T, Katz Y, Pick C. The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms. Brain Res Bull 2002;58: PUBLIC SERVICE ANNOUNCEMENT: NATIONAL PRION DISEASE PATHOLOGY SURVEILLANCE CENTER The National Prion Disease Pathology Surveillance Center (NPDPSC) is funded by the United States Congress through the Centers for Disease Control and Prevention (CDC) to monitor the possible occurrence in the United States of variant Creutzfeldt-Jakob disease (vcjd) and other emerging prion diseases. The need of prion surveillance in the USA has recently been further underlined by the discoveries of bovine spongiform encephalopathy (BSE) in North America, the probable transmission of vcjd by blood transfusion, and the report of a second strain of BSE in Italy. The Surveillance Center performs (free of charge) histopathological and immunohistochemical Western blot and protein gene examinations in autopsy and biopsy tissues. The Center is fully compliant with HIPAA regulations and can receive information even without patient consent ( It also assists physicians in obtaining autopsies and consent forms (see also Based on the reported incidence (about 1 case per million of the general population per year), the Surveillance Center examines only about 50% of the cases of prion diseases. It is critically important that this percentage be increased. Therefore, as soon as you observe a case of suspected CJD or other suspected prion disease, inform your health department and the NPDPSC at phone , fax , cjdsurv@case.edu, address Case Western Reserve University, 2085 Adelbert Road, Room 419, Cleveland, OH May (2 of 2) 2004 NEUROLOGY