Low dose amitriptyline in chronic pain: The gain is modest

35

Pain, 42 (1990) 35-42 Elsevier

PAIN 01608

Low dose amitriptyline in chronic pain: the gain is modest F.G. Zitman a, A.C.G. Linssen b, P.M. Edelbroek ’ and T. Stijnen d a Department of PsychiatryCatholic University Ngmegen, 6500 HB Nijmegen (The Netherlandr), b Department of Psychiatry, University Hospital, 2300 RC Leiden (The Netherlandr), ’ Toxicology Laboratory, University Hospital, 2300 RC Leiden (The Netherlands), and d Department of Medical Statistics, University of Leiden, 2300 RC L.&den (The Netherlands) (Received

5 September

1989, revision received

8 January

1990, accepted

30 January

1990)

In the double-blind placebo-controlled study presented here, the effects were investigated of a low dose of amitriptyline (75 mg) in patients with chronic pain of various origins. The active drug was superior to placebo in reducing pain intensity. The reduction was small. In the second treatment week, the amitriptyline treated patients slept longer. No differences between active drug and placebo were found with respect to daily activities or use of analgesics. Based on our data and those of other studies, it is concluded that amitriptyline (and other antidepressants) in low doses does have a positive effect on the intensity and some other aspects of chronic pain, but that the effect is modest. It must be kept in mind that chronic pain is a very treatment-resistant condition. Therefore, even modest positive effects may be worthwhile.

S-

Key words:

Chronic

pain;

Amitriptyline;

Double-blind

Introduction It is now common practice to use low doses of antidepressants to reduce pain in chronic pain patients. Although the effectiveness of this approach has been evaluated in a number of studies, the usefulness of antidepressants in chronic pain is still open to debate. This is partly due to the fact that many of the studies were not carried out as a double-blind trial, lack appropriate pain measurement or have other serious methodological shortcomings. However, if we look at the double-blind, placebo-controlled studies with appropriate pain measurement, the effectiveness still remains to be established. The antidepressant proved to be superior to placebo in 3 out of 5 studies: in the

Correspondence to: Dr. F.G. Zitman, Department of Psychiatry, Catholic University Hospital, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

0304-3959/90/$03.50

0 1990 Elsevier Science Publishers

study by Gringras [7] with imipramine 75 mg in a cross-over study on 55 rheumatic patients; in the study by Watson et al. [14] with amitriptyline 75 mg on 24 patients with post-herpetic neuralgia, and in the study of Goldenberg et al. [6] with amitriptyline 25 mg on patients with fibromyalgia. The last study of a total of 62 patients included a group of patients using nalproxen and a group using nalproxen and amitriptyline. The effect of the antidepressant was equal to that of the placebo in 2 other studies: that by Jenkins et al. [8] who used imipramine 75 mg in a 4 week study on 44 low-back pain patients; and the study by Ganvir et al. [5] who used clomipramine 25 mg in an 8 week trial on 49 arthralgia patients. All 5 studies only included patients in whom the pain syndrome was more or less defined; none used a sample of pain clinic patients with pain of various origins. In this paper we present the results of a 6 week double-blind, placebo-controlled study of low-dose

B.V. (Biomedical

Division)

amitriptyline (75 mg) in a pain clinic population with a follow-up period of 18 weeks. We wanted to replicate the studies mentioned above in a sample of pain clinic patients with pain of various origins. Exploratively, we also wanted to look at the effects of antidepressants on behaviour and on the intake of analgesics. Only Goldenberg et al. [6] looked for influences on sleeping probiems, and Johansson and Von Knorring [9] and Ganvir et al. [5] looked for changes in analgesic intake. Finally, we also wanted to look at the long-term effects by allowing patients to continue with the study for another 6 weeks under double-blind conditions, and after that with a~t~ptyline in an open I2 week foliow-up period.

Methods Patient

selection

The patients included in this study had to fulfill the following criteria: (1) chronic pain for more than 6 months (no selection on organic or psychogenic aetiology); (2) pain is refractory to treatment; (3) out-patients referred by the pain clinic; (4) age between 30 and 60 years; (5) no serious mental disease requiring other medication and/or higher doses of antidepressants (e.g., major depression with melancholia DSM III 296.x3 [l]); (6) no organic disease in which antidepressants are contr~ndicat~: epilepsy, glaucoma, hypertension, prostate dysfunction, renal, hepatic and cardiac disorders; no malignant disease or post-herpetic neuralgia; (7) no antidepressants, phenothiazines or other enzyme-inducing drugs. All patients underwent a medical examination in the pain clinic and a psychiatric examination in the Department of Psychiatry before entering the study. The placebo was called a non-specific acting drug. All patients gave informed consent. The Medical Ethics Committee of the hospital approved the protocol. Baseline, treatment and follow-up procedure

A baseline period of 1 week was followed by a treatment period of 6 weeks. There was a follow-up period of 18 weeks. After the first 6 weeks of the follow-up period (in which double-bled condi-

tions were maintained), short-term follow-up determinations were carried out. In the rern~~ng 12 weeks the patients could choose between normally prescribed amitriptyline, another treatment or no treatment. At the end of this 12 week period long-term follow-up determinations were performed. At the beaning of the treatment, the patients were randomly assigned, double-blind, to either placebo or amitriptyline. They started with 1 tablet. Every other day, a tablet was added to a maximum of 3 tablets. The tablets were always taken in a single dose at 10 p.m. The tablets contained either a~t~ptyline 25 mg and riboflavin 5 mg or riboflavin 5 mg alone (placebo). Riboflavin was added to check compliance [2]. At the beginning of the baseline period and on days 1,4, 8, 22, 43, 85 and 169, the patients visited the Department of Psychiatry. During the first visit, demo~ap~c data were gathered and the NPV (Nederlandse Persoonlijkheids Vragenlijst, a Dutch personality inventory [ll]) and the STAI (the State-Trait Anxiety Inventory, Dutch version [13]) were administered. The 20-item Zung depression scale (151 was administered at the beginning of the baseline period and on days 22, 43 and 85. During each visit the patients had a 30 min session with a resident in psychiatry who gave verbal reinforcement to continue the therapy. The appointments were arranged in such a way that it was not possible for the patients to meet each other more than once. In this way we hoped to minimize the risk of the patients influencing each other’s opinion about the drug effects. The patients had to record, on an hourly basis, the following parameters: their pain intensity on a numerical scale (0 = no pain, 10 = unbearable pain), their drug use, and their activities (sitting, standing and walking, reclining and sleeping). They noted these data in a diary adapted from Fordyce [4] on the following days: on day 6,4 and 1 before treatment (baseline), 9, 11 and 13 days (2nd treatment week), 34, 37, and 42 days (6th treatment week), 7.5, 78 and 81 days (short-term follow-up) and 159, 163 and 167 days (long-term follow-up) after initiation of therapy. The scores of days 6, 4 and 1 before treatment were used to calculate the mean 24 h, the mean night and the

31

mean day pain scores in the baseline period. Comparable calculations were performed using the scores in the other weeks during which the patients kept their diaries. Night was defined as the hours spent in bed at night. Because we also wanted the patients to record daily activities, we chose a numerical scale instead of a visual analogue scale to record pain intensity: a visual analogue scale (VAS) would have rendered the format of the diaries unmanageable. On day 43 the patients had to answer the following question: ‘If we estimate your pain before treatment as loo%, what is the percentage of your pain now?’ (subjective pain estimation). Patients with a decrease of at least 25% were considered to be responders. The serum levels of amitriptyline and its metabolites were measured on days 4, 8, 22, 43, 63 and 84. Blood samples were drawn into open disposable glass tubes [2] 9-11 h after the intake of the tablets the night before. Serum was separated as soon as possible, frozen immediately and stored at - 20°C until analysed. Amitriptyline

(AT), nortriptyline (NT), total(= E + Z)-lOhydroxyamitriptyline (tot-lo-OH-AT), E-lO-hydroxynortriptyline (E-lo-OH-NT) and Z-lO-hydroxynortriptyline (Z-lo-OH-NT) were measured in 2 ml serum by HPLC. Because the mean steady serum concentrations of tot-lo-OH-AT and of Z-lo-OH-NT were about 9 pg/l, these compounds were not involved in further evaluations. In this paper only the mean steady-state concentrations (calculated as the means of the concentrations at 3 and 6 weeks) of the other 3 compounds will be presented. A detailed analysis of the results is described elsewhere [3]. On each visit during the treatment period, the patients had to bring along a sample of first morning urine to check the presence of riboflavin. Differences were evaluated using the Student’s t test, the Mann-Whitney U test, the Pearson correlation coefficient and an analysis of covariante. The level of significance was P < 0.05 (2tailed).

Results TABLE I BASELINE DEMOGRAPHIC DATA FOR TIENTS IN THE DOUBLE-BLIND STUDY Sex Male Female Marital status Married Cohabiting Single Divorced Widowed Main pain location Head Back One half of the body Whole body Other Data missing

Age Duration of pain (years) No. of specialists seen No. of operations

ALL

39 PA-

19 20

32 2 4 0

6 8 12 4 2 N

Mean

S.D.

39 38 38 39

45.2 5.1 4.2 1.3

1.3 3.4 2.3 0.4

(1) Baseline and 6 week treatment period Of 52 patients, screened by the pain clinic and the out-patient Department of Psychiatry and found to be eligible, 3 refused to participate. Eight patients dropped out during treatment: 2 in the AT group (amitriptyline treated group) because of the side-effects and 2 because they did not observe a positive effect of the drug; in the PL group (placebo treated group) 4 patients also dropped out because they did not observe a positive effect of the drug. In addition, another 2 patients in the AT group were excluded because of poor compliance as demonstrated by the riboflavin test. Nineteen patients in the AT and 20 in the PL group completed the 6 week treatment period. The groups did not show statistically significant differences with respect to sex, marital status, level of education, number of patients on compensation, duration and localisation of the pain, number of operations or consumption of analgesics and tranquilizers. Baseline demographic data for all 39 patients are presented in Table I. The number of patients with a DSM III disorder [l] did not differ

3x TABLE

II

PAIN INTENSITY _Week

Baseiine

2 6 12

*

N

24 h

Night

.--

Day

Mean

S.D.

Mean

S.D.

Mean

S.D.

AT

19

3.0

1.5

1.8

1.0

3.9

2.0

PL

20

3.9 *

1.5

2.5

1.6

5.0

I.6

0.9 1.7 1.2 1.8 1.5 2.0

3.5 5.3 ** 3.6 5.3 ** 3.x 4.5

2.1 1.4 2.1 1.5 2.4 2.1

AT

19

2.6

1.5

I .3

PL AT PL AT PL

20 19 20 13 14

4.2 ** 2.7 4.3 ** 2.9 3.3

1.3 1.7 1.4 2.0 1.7

2.6 **

P < 0.05, ** P < 0.01. In both

cases amitriptyline

(AT group)

in a statistically si~ficant way between the two groups. Of the 39 patients entering the trial, 20 had a DSM III axis 1 diagnosis: 14 patients had a psychogenic pain disorder, 3 a substance use disorder (in 2 cases benzodiazepines, in 1 case caffeine}, 2 a dysthymic disorder and I hypochondriasis. Two patients had an axis 2 diagnosis: a histrionic and a mixed personality disorder. As for as the STAI and the Zung Depression Scale are concerned, no statistically significant differences were found. On 2 of the 7 subscales of the NPV. however (the SI and the ZW scale), statistically significant differences were found indicating that on average the patients of the AT group felt more uncomfortable as far as social contact was concerned and were less flexible. These results suggest that the AT group was psychologically somewhat more disturbed. Table II presents the mean pain intensity scores per 24 h and during the night and the day in the baseline period, and in the treatment period (in weeks 2 and 6) for the AT and PL groups. Looking first at the pain intensity scores per 24 h, there are statistically significant differences between the 2 groups in the baseline period (P = 0.049), week 2 and week 6, the AT group having the lowest scores. The statistically significant difference in baseline scores indicates that the differences in week 2 and week 6 cannot as such be considered as differences in effect between AT and PL. To investigate whether the differences in week 2 and week 6 really are differences in effect.

1.5 3.0 ** 1.5 2.1 compared

with placebo

(PL group),

P 2-sided,

Student’s

-__

I test.

the baseline differences must be taken into account. This was done by means of an analysis of covariance. The analysis was carried out with respect to the baseline data on the one hand, and the data of week 2 and week 6 successively on the other hand. In both cases the differences appeared to be statistically significant (P c 0.02 in both cases) indicating that amitriptyline treatment was more effective than placebo treatment. The results with respect to the mean pain intensity per night and per day are comparable, with the exception of the differences in the baseline data, which do not reach statistical’ significance. Here again, the effect of amitriptyline is maximal in week 2. The subjective pain estimation on day 43 gives results comparable to the data on pain intensity in week 6: in the AT group, the mean of the subjective pain estimations is 78%, in the PL group 102%. In the AT group, 6 patients were responders (data of 1 patient were missing) and in the PL group 1 patient was a responder (no missing data). Data concerning daily activities as recorded in the diaries are presented in Table III. The differences between the groups with respect to the mean baseline scores and the mean scores in the 2nd and 6th treatment week did not show statistically significant differences, with the exception of the number of hours patients slept at night in week 2: in this second treatment week, patients in the AT group generally slept longer than those of the PL group.

39 TABLE III DAILY ACTIVITIES

N

Sleeping

Standing + walking Reclining

Sitting

Week

Mean

S.D.

Mean

S.D.

Mean

S.D.

Night

Day

Mean

S.D.

Mean

S.D.

AT PL

19 20

9.5 9.4

2.8 2.2

4.1 4.2

2.0 2.1

9.8 10.5

1.4 2.5

1.2 6.9

1.3 1.5

0.7 0.6

0.8 0.7

2

AT PL

19 20

8.9 9.7

2.9 2.6

4.8 3.9

2.5 1.2

10.3 10.3

2.1 2.8

1.7 6.6 **

0.9 1.7

0.7 0.4

0.7 0.6

6

AT PL

19 20

9.1 9.7

3.0 2.1

4.9 3.8

2.1 2.1

10.0 10.5

2.4 2.2

7.1 6.2

1.3 2.0

0.8 0.8

1.0 0.9

12

AT PL

13 14

8.7 9.5

2.4 1.3

5.2 4.0

2.0 1.6

10.2 10.4

2.3 1.6

7.4 6.9

1.6 1.6

0.6 0.6

0.5 0.7

Baseline

* * P < 0.01 (2-sided), Student’s t test.

Very many types of analgesics were used. In the AT group 1 patient used pentazocine and APCPC (acetylsalicylic acid, phenacetine, caffeine, phenobarbital and codeine). Other analgesics used (each by 1 patient) were floctafenine, paracetamol alone, paracetamol in combination with caffeine and propyphenazone, and ergotamine combined with caffeine, belladonna alkaloids and butalbital. In the PL group 3 patients used acetylsalicylic acid. A fourth patient used it in combination with paracetamol and caffeine, and a fifth in combination with caffeine and propyphenazone. Other analgesics used (each by 1 patient): paracetamol alone, pentazocine, glafenine, ibuprofen and ergotamine combined with caffeine, belladonna alkaloids and butalbital. Because of these differences we restricted the comparison of analgesic intake to the number of pills, powders, etc., containing analgesics used per 24 h in the baseline period, in week 3 and in week 7 (see Table IV). Although the use of analgesics in the AT group is lower than in the PL group for both weeks, the differences show only borderline significance (P < 0.07, Mann-Whitney U test). We looked for relationships between the changes in time spent sleeping and changes in 24 h pain intensity and the same with respect to analgesic use and 24 h pain intensity. No statistically significant correlations were found.

TABLE

IV

NUMBER Week

Baseline 2 6 12

OF ANALGESICS

PER 24 H

Amitriptyhe

Placebo

N

Mean

SD.

N

Mean

S.D.

19 19 19 13

0.7 0.4 0.6 0.8

1.1 0.9 1.3 1.6

20 20 20 14

1.9 0.9 1.1 1.3

2.4 1.6 1.8 2.5

No statistically significant differences (P 2-sided, MannWhitney U test).

As is shown in Table V, there were no statistically significant differences in Zung depression scores between the 2 groups in the baseline period or on days 22 and 43. Nor did the within-group differences in baseline scores and scores on days TABLE V ZUNG DEPRESSION Day

SCORES

Amitriptyline

Placebo

N

Mean

S.D.

N

Mean

S.D.

Baseline 22 43

19 18 19

44.7 41.1 39.2

10.1 11.1 10.5

20 19 20

44.0 39.7 39.2

10.5 7.8 10.2

85

13

41.3

11.5

14

41.0

11.0

All within- and between-group differences non-significant, P 2-sided, Student’s t test.

40

22 and 43 reach statistical significance. Furthermore, correlations were computed between the changes in Zung scores and the changes in painintensity scores from day 1 to day 50. These were 0.31 and 0.21 for the AT and the PL group, respectively (both not significant). The mean steady-state serum concentrations of the 19 patients in the AT group were 35 (f 18.3) pg/l for AT, 38 (522.6 pg/l for NT and 45 (+ 19.8) pg/l for E-lo-OH-NT. After 6 weeks of treatment neither the improvement in pain intensity nor in Zung score in comparison with baseline scores correlated significantly with the steady-state levels of AT. NT or E-lo-OH-NT [3]. (2) Short-term follow-up: week 12 and day 85 After day 43, 5 patients in the AT and 5 patients in the PL group dropped out of the trial. A comparison of the 29 continuers and the 10 drop-outs in week 6 revealed no statistically significant differences, although there is a tendency for continuers to have had more pain relief (P < 0.10) and to have slept better (P -c 0.10) during treatment than the drop-outs. In Table II, data are also presented concerning pain intensity scores in week 13 of the continuers. There are no statistically significant differences between the AT and PL groups. The same is true with respect to the Zung depression scores on day 85 (Table V).

TABLE

VI

MEAN 24 H PAIN INTENSITY PER WEEK pain diaries each week) IN 7 AMITRIPTYLINE weeks)

(based on 3 USERS (24

Week 12

Week 24

2.7 2.8 1.6 5.1 3.7

2.1 3.5 1.5 4.9 3.6

Amitriptyline 75 mg after week I2 150 ml: 1 3.2 2.0 1.2 0.9 54 2.3 1.1 0.4 0.1

0.6 *

Week 2

Week 6

Patient “0.

Baseline

Amitriptyline 10 17 52 60 63

75 mg until week 24 4.0 2.5 2.9 3.0 2.9 3.2 2.3 1.9 1.8 4.4 4.1 3.7 3.1 2.4 3.8

* Missing

data.

(3) Long-term follow-up: week 24 and day 169 After day 85. the patients could continue (in the AT group) or start (in the PL group) with amitriptyline in an open treatment. Of the AT group 5 patients were still using amitriptyline at a dose of 75 mg in week 24, only 2 patients wanted to change to a dose of 150 mg. Table VI presents the 24 h pain-intensity scores of these patients during baseline, treatment and follow-up. On day 169, 3 patients still using 75 mg reported a positive effect of the drug on their pain. Of the other 2 users of 75 mg, patient no. 10 reported a negative effect and for patient no. 60 we have no information concerning this question. The 2 patients using 150 mg also reported a positive effect although, subjectively, no greater than during the first 12 weeks. These data suggest that the long-term effects are uncertain.

Discussion The main finding of this double-blind comparison of low-dose amitriptyline and placebo in chronic pain is that amitriptyline has a statistically significant analgesic effect. This effect is small. Looking at the mean pain-intensity scores per 24 h, the pain in week 6 is 0.9 times the baseline scores in the AT group and 1.1 times the baseline scores in the PL group. In Table VII, these data are presented together with comparable data derived from the studies using a visual analogue scale. Unfortunately, the way in which Watson et al. [14] provided their data made inclusion in this table impossible. Of course, the data must be interpreted with caution because of differences in study design. Nevertheless, the table illustrates the point that when measured with visual analogue or numerical scales, the mean effects of low-dose antidepressants on pain are small in all these studies. What about the effect on pain of antidepressants when given in higher antidepressive doses? Table VII includes the results of the only 2 double-blind placebo-controlled studies using visual analogue scales, in which higher doses were given. In the study by Johansson and Von Knorring [9] with zimelidine 200 mg on 40 patients with

41

TABLE

VII

REDUCTION NUMERICAL

IN PAIN INTENSITY, REVIEW SCALES FOR PAIN INTENSITY

A = visual analogue

scale O-100 mm; B = visual analogue Duration (weeks)

Ganvir [5], clomipramine

25 mg

Goldenberg et al [6], amitriptyhne Gringras [7], imipramine

OF PLACEBO-CONTROLLED

25 mg

75 mg

Scale

Johansson and Von Knorring [9], zimehdine 200 mg Pilowsky et al. [12], amitriptyline 150 mg

USING

VISUAL

8

B

6

B

4

A

Post

Post/

Pre

Post

44

0.8

1.3

5.4

0.7

64 *

51 *

0.8

Post/ pre

41 1.6 * 65 *

44 1.3 * 48 *

0.9 1.0 0.7

study)

4

B

4

A

65

47

0.7

45

48

1.1

12

A

55

51

0.9

55

53

1.0

6

C

OR

Placebo

Active drug

55

ANALOGUE

scale O-10.

pre

(data both parts cross-over Zitman et al. [this study] amitriptyhne 75 mg

scale O-10 cm; C = numerical

Pre

(data first part cross-over Jenkins et al. [8], imipramine 75 mg

STUDIES

4.7 *

3.7 *

0.8

4.8 *

3.8 *

0.8

study) 3.0

2.7

0.9

3.9

4.3

1.1

* Data based on graphics.

chronic pain of various origins, the antidepressant was superior to placebo. Pilowsky et al. [12] did a cross-over study with amitriptyline 150 mg and placebo in 18 patients with pain of various origins. Amitriptyline proved superior in the 2nd and 4th weeks, but not in the 6th week. Hence, normal dose antidepressant therapy also leads to contradictory results. Moreover, in both studies the mean effects on pain are also small. They support the clinical impression that higher doses do not give better results. Pain influences behaviour. It is conceivable that antidepressants have a more pronounced effect on the behaviour of the pain patients than on their experience of pain intensity. We attempted to record behaviour in general by means of the pain diaries. The only statistically significant change found by us during treatment with amitriptyline was that the patients in general slept longer during the second treatment week. Goldenberg et al. [6] found a statistically significant decrease of sleep difficulty at the end of their 6 week trial. These effects on sleep are probably a result of the seda-

tive properties of amitriptyline. From the absence of other statistically significant effects on the number of hours spent sitting, walking and standing, and reclining in our study, one cannot make a general statement as to the effect of amitriptyline on the behaviour of the pain patients, but it makes dramatic changes improbable. In the studies listed in Table VII apart from the one of Goldenberg et al. [6], (aspects of) pain behaviour was not measured. The intake of analgesic drugs can be seen as an aspect of pain behaviour in the broader sense of the word. In our study, the intake of analgesic drugs was reduced during treatment in the AT as well as in the PL group, but the reduction was not statistically significantly different in either group. The reduced intake of analgesics might be a means of compensating for the rise in the total number of pills patients had to ingest during the trial. Johansson and Von Knot-ring [9] did not find differences in effect between zimelidine and placebo on analgesic consumption and Ganvir et al. [5] did not find any changes in analgesic intake.

42

In the other studies analgesic use was not measured or was kept constant. A complication of changes in analgesic intake is that those changes can influence ratings of pain intensity. In our study a stable level of analgesic intake might have led to a more pronounced effect of AT on pain intensity and might have prevented the rise in pain-intensity ratings in the PL group. This hypothesis is refuted by the fact that we did not find a statistically significant correlation between changes in pain-intensity ratings and changes in the use of analgesics. It can be argued that the instruments we used to record effects of amitriptyline in chronic pain were not completely appropriate: pain intensity is only a part of the experience of pain, and with a numerical scale the measurement of pain intensity is defective; with the pain diaries only some aspects of pain behaviour (intake of analgesics included) are recorded by the patient, thus in a subjective way. An extensive discussion of the problems of pain measurement is beyond the scope of this article. It is more appropriate here to go back to the overall clinical impression of the effects of amitriptyline (and other antidepressants) on chronic pain in a pain clinic population. That clinical impression concurs with the results of this study: in general only modest effects are seen. By definition, chronic pain is a very treatment-resistant condition. For that reason, even a small gain is important. Because of the modest gain obtained so far with antidepressants in chronic pain, future research will have to be directed at increasing the effects. How could this be done? Firstly, it could be obtained by allowing patients to find their own optimal dose. Such a flexible dose regimen was not used in the studies published to date. Secondly, it might be worthwhile looking for differences in response between pain patients (and pain syndromes) who respond well and those who do not respond to treatment with antidepressants. We have described such an analysis for the patients in our study elsewhere [3]. Thirdly. it might also be worthwhile looking at patients who can have long-lasting effects, because, as our data sug-

gest, not all patients can have long-term profits from amitriptyline. Fourthly, a fruitful way might he to investigate the effects of the combination of antidepressants with neuroleptics [lo].

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2

3

4 5

6

7

X

9

10 11

12

13

14

15

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