Opipramol and Trifluoperazine in the Treatment of Anxiety and Tension

Home , Opipramol, Perphenazine, Trifluoperazine

A COMPARATIVE STUDY OF TWO ANTIHISTAMINES 395 In table VI are given the results of a question directed at discovering how effective the preferred treatment was compared to any other antihistamine used. Fifteen patients only were able to give this information but the results are interesting. Discussion TABLE VI The design of this study was very simple as COMPARISON WITH PREVIOUSLY USED ANTIHISTAMINE such studies must be if they are to be completed under the conditions of a busy general practice. In a condition such as hay fever where anti- Worse As good Better Total histamines are known to be etfective and where fairly rapid symptomatic relief is needed by the 2 4 9 15* patient, we did not feel justified in including a placebo. The results of the study seem fairly *In the majority of patients the previously used clear-cut that if patients are offered the choice antihistamine was the chemically related chlor- of a plain form of this antihistamine or a long- pheniramine maleate B.P. acting form more will choose the latter. Ofthose that do so, however, only about a third find a single tablet at night completely effective, the remainder have to take one further tablet during the day. Both forms of antihistamine are effective and where a retrospective comparison can be made this effectiveness is considered greater or equal to that of previously administered anti-histamines. Summary A simple comparative study under general-practice conditions of two formulations of pheniramine is described. Sixty-one per cent of patients preferred the long-acting form of this antihistamine. The dosages and side-effects of the two formulations are described. Acknowledgements We are grateful to Hoechst Pharmaceuticals Ltd. for generous supplies of Daneral and Daneral S.A. tablets.

Opipramol and trifluoperazine in the treatment of anxiety and tension

J. M. BARRITT, M.R.C.S., L.R.C.P. B. W. McGuINNEss, M.D., D.Obst.R.C.O.G., D.C.H. General practitioners, Bridgnorth and G. BEAUMONT, M.B. M.R.C.S., D.Obst.R.C.O.G., D.C.H. Medical Adviser, Geigy (U.K.) Limited, Pharmaceuticals Division OPIPRAMOL (INSIDON GEIGY) IS AN iminostilbene derivative and belongs to the dibenzazepine group developed by Schindler and Blattner (Schindler and Blattner 1961). The nucleus is similar to that of imipramine and the attached side chain is a piperazine group identical to that of perphenazine. J. ROY. COLL. GEN. PRACTIT., 1969, 17, 395 396 J. M. BARRuTT, B. W. MCGUINNESS AND G. BEAUMONT By virtue of this chemical struc- ture opipramol has both anxiolytic , and antidepressive properties. The [ | action of opipramol is said to be N/N ,, / ,/ CH3 biphasic in that initially there is c"L C lI4k-W NC) prompt improvement of tension, \ C"a anxiety and insomnia noticeable early in treatment followed by a gradual 5 elevation of mood. Opipramol is, therefore, a tranquillizer with a thymoleptic component (Poldinger Th 1961). §"-z- Ha-_ NO- ^- " OH In this study opipramol was compared with trifluoperazine (Stela- zine; Smith, Kline and French) a s tranquillizer which has been exten- r l sively used and is claimed to have a CF5 powerful tranquillizing action, an in- l valuable alerting effect and a low c.1-C-a4 CAP- N 4 -C-Hp.2tic.1 incidence of side effects (Goddard 1959, May 1959). The primary purpose of the NC study was to compare the effect of the two drugs in the treatment of -K anxiety and tension but since some element of depression frequently - CH;a 1- CH;.7 N(" jN..CHa.CMLOH. aXMc. accompanies these symptoms the effect on co-existent depression was also taken into account. In a small series of psychoneurotic patients treated with opipramol, Wechsler (1964) found improvement in 48 per cent of patients suffering from mild anxiety states and neurotic depressions. Kristof, Macpherson and Brown (1962) administered opipramol to a small series of depressed patients and found a small but noticeable decrease in manifest anxiety following administration of the drug. Azima, Silver and Arthurs (1962) considered opipramol to be effective in treating neurotic depressive states. Kirkham and Kinross Wright (1962) concluded that opipramol was an antidepressant with tranquillizing properties. Kiloh, Roy and Carney (1963) however, found opipramol to be more effective in the treatment of endogenous depression rather than reactive depression. Grosser and Ryan (1965) conducted a double-blind cross-over study comparing the efficacy of opipramol and chlordiaze- poxide in the treatment of patients suffering from non-psychotic psychiatric conditions charac- terized or significantly accompanied by anxiety features. The method of evaluation used suggested that both drugs were of equal efficacy in the treatment of the described conditions. Carney and Maxwell (1967) reported on a sequential double-blind, controlled trial of opipramol in anxiety neurosis. Despite a failure to reach a definite result with the sequential diagram they thought it probable from their findings that opipramol was effective in the treatment of anxiety states. In a double-blind trial comparing opipramol with placebo in two groups of patients suffering from anxiety and mild depression, Shepherd (1965) reported that his study indicated a small advantage for opipramol but this did not reach statistical significance. In a double-blind trial comparing opipramol with desipramine, Rogers and Davies found no significant difference between the two drugs in the treatment ofdepression, but anxiety scores ofpatients on opipramol showed a higher percentage improvement which was statistically significant. Rowell and Segall (1960) reported on a series of 48 patients suffering from anxiety states and related conditions treated in general practice with trifluoperazine and found a good to excellent response in 40 cases. Bram (1960) reported on 102 patients suffering from psycho- somatic conditions and found tension, restlessness and panic attacks improved by trifluoperazine OPIPRAMOL AND TRIFLUOPERAZINE IN THE TREATMENT OF ANXIETY AND TENSION 397 and again (1962) on 114 patients in which trifluoperazine was effective in relieving the symptoms of tension. Stoll (1960) found tension quickly lessened on a series of 50 patients treated with trifluoperazine and May (1959) in a double-blind, controlled trial against placebo in which patients dis- playing tension irrespective of diagnosis were treated, found that relaxation and amelioration of symptoms was achieved without sedation with trifluoperazine. Kolodny (1961) treated 73 patients with anxiety reactions, 30 of which responded satisfactorily and a further 15 showed a complete return to their former levels of well being. Method Patients ofeither sex aged 16 years or over, who were considered to be suffering from anxiety or tension either alone or in association with other symptoms, were admitted to the trial. Patients were seen by one of six doctors practising in a group practice. Patients considered suitable for admission to the trial, were rated at their first attendance at the surgery for the following symptoms-anxiety, tension, irritability, inability to concentrate, insomnia, drowsiness, loss of energy, depression, digestive disturbance, anorexia and headache-the severity was recorded as 0, 1, 2 or 3. 0 indicates the symptom was absent, 1 that it was present in mild degree, 2 that it was moderately severe and 3 that it was severe. These ratings were then summated to give an overall score. After two weeks treatment, the patients were reassessed on the same basis. At the first interview a brief history was recorded, together with past history and details of any previous treatment received. At the second interview any volunteered side- effects occurring during the two weeks treatment were recorded and a clinical summary in addition to the symptom rating. Patients were given either opipramol 50 mg three times daily or trifluoperazine 1 mg three times daily. Treatment was allocated at random on a double-blind basis and continued for 14 days. Results Fifty-six patients were admitted to the trial. Twenty-eight were treated with opipramol and 28 with trifluoperazine. Nine opipramol records and four trifluoperazine records were unsuitable as a result of patients defaulting or improper recording. An analysis of the sex, age and initial diagnosis of the two groups of patients is shown in table I. This shows the two TABLE I SEX, AGE AND INITAL DIAGNOSIS OF PATIENTS TREATED

Opipramol Trifluoperazine Total number of patients treated: ...... 19 24 Males ...... 1 5 Females ...... 18 19 Age: Males ...... 35 26 to 34 (mean 28.8) Females ...... 20 to 57 17 to 51 (mean 32.27) (mean 30.27) Initial diagnosis: Anxiety depression state 13 9 Anxiety state .. .. 4 6 Chronic anxiety state .. 1 4 Depression .. .. 2 Reactive depression .. 1 Post influenzal debility 1 Unclassified .. .. 2 groups reasonably well balanced for age and sex and therefore suitable for comparison. The initial diagnosis in the two groups also shows a similar distribution. Table It shows an analysis of factors which were thought to be of importance in the cases treated and the response to treat- 398 J. M. BARRITT, B. W. MCGUINNESS AND G. BEAUMONT ment in the sub-groups in which these factors were operative. This shows a wide diversity of precipitating factors and yet having a similar 'theme' in the two groups. The frequency of presenting symptoms in the two main groups is shown in table III which indicates a predominance of depression, tiredness, tension, insomnia, anxiety and headaches as presenting symptoms (16 TABLE II PRECIPITATING FACTORS AND RESPONSE TO TREATMENT

Opipramol Trifluoperazine Previous history of: 'Nervous illness' .. .. 8 14 Response: Improved .. 7 10 Not improved 1 4 Precipitating factor considered important ...... 10 8 Newly wed; living with in-laws; Recent influenza (2); recent renal family illness; removal; ectopic colic; recent fracture; domestic pregnancy; recent fracture; worries (2); complex marital recent influenza; hypertension; situation; occupational failure handicapped child; domestic tension; additional housework; bereavement Response: Improved 8 6 Not improved 2 2 Previous history of nervous illness in those patients considered to have a precipitating factor ...... 3 4

TABLE III PRESENTING SYMPTOMS

Opipramol Trifluoperazine Opipramol Trifluoperazine Depression .. 9 9 Skeletal pain .. 1 Tension .. .. 6 5 Dysmenorrhoea .. 1 Tiredness .. .. 4 10 Irritability .. .. 1 6 Indigestion .. 3 1 Trembling .. .. 1 Insomnia .. .. 3 4 Inability to Anxiety .. .. 2 4 concentrate .. 1 1 Headache .. .. 2 4 Short tempered .. 1 Prone to tears .. 2 2 Nervousness .. 1 Functional throat Nightniares .. 1 symptoms .. 1 1 Frustration .. Functional bladder Giddiness .. .. symptoms .. 1 - Panic attacks .. Nausea .. .. I I Flushing .. .. Anorexia .. .. 1 2 Palpitation... . - Gastro-intestinal pain full opipramol case histories and 20 trifluoperazine were recorded in detail; three opipramol and four trifluoperazine records could not be included on account of insufficient detail). As distinct from these presenting symptoms the patients were rated by the examining physician for the 11 target symptoms already described on a 0-3 basis. According to the summated scores 15 out of the 19 patients treated with opipramol and 17 of the 24 patients treated with trifluoperazine were found to have improved after two weeks treatment. The initial mean score of the opipramol group was 15.9 and the trifluoperazine group 16.25. Using the value as OPIPRAMOL AND TRIFLUOPERAZINE IN THE TREATMENT OF ANXIETY AND TENSION 399 an index of improvement 'd' where 'd' =x1-x2 (xl and x2 being the total rating score before and after treatment) the mean value of 'd' for opipramol was 6.5 (range 2-14) and for trifluoperazine 5.2 (range 9-16). In both cases the mean score was significantly different from zero (P <0.005 in each case) indicating both drugs to be ofvalue in treatment. The difference between the mean values of 'd' however, is not significant (Pc0.6). The ratings for each individual symptom before and after treatment for two weeks with each drug and the total improvement for all patients in each group expressed as a percentage of the total possible improvements are shown in table IV. The opipramol group showed a higher percentage improvement in anxiety, tension, TABLE IV TOTAL IMPROVEMENT EXPRESSED ON PERCENTAGE OF MAIN SYMPTOMS

Opipramol Trifluoperazine Improvement Improvement as a as a Symptom Before After percentage of Before After percentage of possible possible improvement improvement Anxiety ...... 30 19 36.6 34 24 29.4 Tension ...... 37 22 40.5 43 33 23.25 Irritability...... 37 23 37.8 44 31 29.5 Inability to concentrate .. 30 20 33.3 37 26 29.7 Insomnia ...... 16 11 31.2 35 24 31.4 Drowsiness .. .. 23 17 26.8 42 16 57.1 Loss of energy .. .. 40 26 35 57 36 36.8 Depression ...... 41 24 41.2 34 22 35.29 Digestive disturbance .. .. 19 10 48.2 12 6 50 Anorexia ...... 13 9 30.7 21 13 38.09 Headache...... 17 8 48.2 30 17 43.3 Overall ...... 303 189 37.6 390 251 35.64 irritability, inability to concentrate, depression and headache. The trifluoperazine group showed a better response for insomnia, drowsiness, loss of energy and digestive disturbance. None of these differences were statistically significant. Very few side effects were recorded. In the opipramol group, one patient complained of a 'muzzy head' and one of nausea and vomiting and drowsiness. In the trifluoperazine group, one patient complained of increased headache and one of 'feeling sleepy'. One patient became more agitated on trifluoperazine. Discussion The choice of trifluoperazine as a yard stick to assess the newer preparation opipramol, was based on the fact that trifluoperazine had been a favourite prescription as a tranquillizer for cases of mild to moderate anxiety for several years in this practice. Patients who were considered to be primary cases of depression were not included in the trial as trifluoperazine is not claimed to have a thymoleptic action and, in fact, may have an adverse effect in depressive illness. There was, therefore, no real test of opipramol's effect in the treatment of true depression. As far as depression as a symptom was concerned, there was no significant difference in the relief afforded by the two drugs but a wider selection of cases might have produced an improvement in the response to opipramol. A prominent factor was the high defaulting rate, perhaps inevitable in this type of trial. Patients were asked at their first attendance to return in two weeks so that progress could be assessed but no attempt was made to approach those who failed to report. However, approximately 12 months after the trial the medical records ofdefaulters were examined to discover their subsequent progress. Out of nine on opipramol, six had no further attendances connected with psychogenic 400 J. M. BARRITT, B. W. McGUINNESS AND G. BEAUMONT symptoms and three had continued to seek medical advice (one on 13 occasions) with minor complaints probably functional in nature. Two of the three trifluoperazine defaulters continued to have repeated attendances for anxiety symptoms. It is difficult to account for the marked difference in the defaulter rate between opipramol and trifluoperazine but there was no evidence that side effects were likely to have produced this result. The large number of opipramol defaulters who subsequently had satisfactory psychiatric histories would suggest that they probably attended with an acute emotional problem, were reassured and subsequently took the tablets for a short time or possibly not at all. Summary Opipramol and trifluoperazine were compared in the treatment of anxiety and tension in patients attending their general practitioner. Both drugs appeared to be effective in the doses employed over a period of 14 days. There were no statistically significant differences between either in overall effect or in their effect on specific symptoms. Acknowledgements We would like to thank Dr A. W. Galbraith of Geigy (U.K.) Ltd, and Dr H. D. Darcus of Smith, Kline and French Laboratories Ltd, who were responsible for initiating this study, Mr J. V. Smart of Smith, Kline and French Laboratories Ltd, for statistical analysis and Geigy (U.K.) Ltd and Smith, Kline and French Laboratories Ltd for supplies of trial compounds. REFERENCES Azima, H., and Silver, A. (1962). Amer. J. Psychiat. 119, 465. Bram, G. (1960). Brit. J. clin. Pract. 14, 107. Bram, G. (1962). Brit. J. clin. Pract. 16, 143. Carney, M. W. P., and Maxwell, C. (1967). Int. J. Neuropsychiat. 3, 6. Goddard, E. S. (1959). Canad. med. Ass. J. 81, 467. Grosser, H. H., and Ryan, E. (1965). Brit. J. Psychiat. 3, 471. Kiloh, L. G., Roy, J. R., and Carney, M. W. P. (1963). Int. J. Neuropsychiat. 5, 18. Kirkham, J. E. Jnr., and Kinross Wright, J. (1962). Psychosomatics. 3, 464. Kolodny, A. L. (1961). Dis. nerv. Syst. 22, 151. Kristof, F. E., Macpherson, A. S., and Brown, M. (1962). Amer. J. Psychiat. 118. May, A. R., et al. (1959). J. ment. Sci. 105, 1059. Poldinger, W. (1961). Third World Congr. Psychiatry. Montreal. Rogers, S. C., and Davies, F. J. (Unpublished). Rowell, S. S., and Segall, M. L. J. (1960). Practitioner. 184, 225. Schindler, W., and Blattner, H. (1961). Helv. chim. Acta. 44, 753. Shepherd, F. S. (1965). Practitioner. 195, 92. Stoll, L. J. (1960). Med. Press. 243, 578. Wechsler, Z. (1964). The general practitioner. 35, 292.

PERSONAL POINT OF VIEW What constitutes workload K. G. DICKINSON, M.B., Ch.B., D.P.M. Birmingham THIS PAPER PRESENTS AN EVALUATION of the work performed by a full-list, single-handed general practitioner working in the industrial part of Birmingham with a practice predominantly in the Registrar General Classes III and IV. Approximately 30 per cent of the patients are of West Indian stock. Method The analysis was carried out on a series of prepared cards during surgery sessions for a J. ROY. COLL. GEN. PRACTIT., 1969, 17, 400