Ephedrine Sulphate. Peter Thackray," MB, BS, D Obst, RCOG, Medical Director, Vick International Division of Richardson-Merrell Ltd.

Transcription

1 J Int Med Res (1978) 6,161 A Double-Blind, Crossover Controlled Evaluation of a Syrup for the Night-Time Relief ofthe Symptoms of the Common Cold, Containing Paracetamol, Dextromethorphan Hydrobromide, Doxylamine Succinate and Ephedrine Sulphate Peter Thackray," MB, BS, D Obst, RCOG, Medical Director, Vick International Division of Richardson-Merrell Ltd., Slough, England Seventy subjects suffering from the common cold were recruited at general practitioner surgeries and were treated with an evening dose of a syrup't containing 600 mg paracetamol, 15 mg dextromethorphan hydrobromide, 8 mg ephedrine sulphate, 7 5 mg doxylamine succinate per 30 ml or an identical-appearing and flavoured control syrup without the active ingredients, in a double-blind crossover design study, lasting two days. Subjects were randomly allotted to two equal groups. One group took active formulation the first evening followed by the control formulation the second evening. The second group took the two formulations in the reverse order. Evaluation of symptomatic relief on a 6-point rating scale against eight major cold symptoms was carried out by each subject at 10 a.m.following the administration of active or control formulation the previous evening. Following combination of data for the two groups, results showed a significant degree of relief provided by the active formulation compared to control for thefollowing symptoms, cough, nasal congestion, nasal discharge, sneezing, generally feeling unwell, headache, sore throat, disturbed sleep, the difference between the two preparations in reliefofcough being highly significantly in favour of the "active" preparation. A dditionally, a highly significant number of the subjects expressed a preference for the global symptomatic relief provided by the active formulation as compared to control. These results have demonstrated that the "active" formulation provides effective therapy for night-time symptomatic reliefofthe eight major symptoms ofthe common cold. *Address for reprints: Dr. Peter Thackray, MB, BS, D Obst, RCOG, Medical Director, Vick International, U.K. Research & Development Labs., 250 Bath Road, Slough, Berks, U.K. tvicks MEDINITE Supplied by Richardson-Merrell Ltd., Slough, U.K. Introduction The treatment of the common cold in the normal, previously healthy subject remains essentially symptomatic in the absence of available specific antiviral therapy. Sleep disturbance, principally due to nasal congestion, cough and malaise appears to be a significant disabling feature of the average

2 162 cold, producing fatigue and increased malaise the following day. The formulation under study was therefore designed specifically to reduce sleep disturbance by relieving significant cold symptoms at night and thus allow the subject to achieve a reasonable duration and quality ofsleep. Four well-known active ingredients were chosen, known to be effective in relieving the relevant symptoms, and were incorporated in a flavoured hydroalcoholic vehicle. The purpose of the present study is to demonstrate that the formulation described provides effective relief of cold symptoms at night, thus allowing adequate quality and duration of sleep. Materials and Methods Seventy subjects of both sexes between the ages of 18 and 60 years suffering from the common cold were recruited to the study on presentation at 21 doctors' surgeries in Hull during the winter of Informed consent to taking part in the study was given by each subject. Entry data recorded by the physician included age, sex, date and duration of cold of each subject together with a 6-point rating scale assessment of symptom severity, on admission, on the following scale. Absent (0), Very Slight (1), Slight (2), Moderate (3), Fairly Severe (4), Severe (5) of each of the symptoms cough, nasal congestion, nasal discharge, malaise, headache, sore throat, disturbed sleep. Patients were allotted by a random number code to a Treatment Group A or B. Each was given two bottles (with 30 ml dose-caps) indistinguishable except for the labelling "First Night Medicine" and "Second Night Medicine", a questionnaire in the form of a Clinical Trial Diary and an instructions sheet. Each subject was asked to take a 30 ml dose of the "First Night Medicine" the first evening shortly before retiring and the following morning at 10 a.m. to complete a 6-point rating scale assessment of efficacy of that formula against each of the cold symptoms listed. The second night they were asked to repeat the procedure with a 30 ml dose from the second bottle labelled "Second Night Medicine" followed by a further rating The Journal ofinternational Medical Research assessment. The second morning they were asked to state which formulation they found to be more effective at relieving global cold symptoms and also to record any unwanted side-effects experienced from either formulation. They were warned in the instructions sheet that one formulation may be more effective than the other. Formulae '~ctive"formula contained (per 30 ml dose): *Dextromethorphan HBr. 15 mg (antitussive) *Ephedrine sulphate 8 mg (nasal decongestant) *Doxylamine succinate 7 5 mg (antihistamine and nasal decongestant) *Paracetamol 600 mg (analgesic and antipyretic) in a flavoured hydro-alcoholic vehicle. "Control" formula was identical but without the actives", matched for colour, odour, appearance and taste (by the addition of Bitrex). The rating scale used each morning was as an estimate ofrelief: Useless (0) Almost useless (1) Not very good (2) Good (3) Very good (4) Excellent (5) against the following symptoms: Cough Nasal congestion Nasal discharge Sneezing Generally feeling unwell Headache Sore throat Sleep disturbance Homogeneity oftreatment Groups Treatment Group A (" Active" first night, "Control" second night) There were 35 subjects, 16 male, 19 female, of average age 33 2 years and average symptom severity on admission 2 2.

3 P Thackray Treatment Group B ("Control" first night, "Active" second night) Contained 35 subjects, 11 male, 24 female, of average age 34 7 years and average symptom severity on admission Following analysis of initial entry data of subjects in each group (by Analysis of Variance method) it was considered that the two groups were homogeneous and that the efficacy assessments for the two groups could be legitimately combined. Results Before the trial was carried out it was decided that the criterion of acceptable symptomatic relief from each symptom would be a rating by the subject of Good, Very good, or Excellent. (Only those subjects who had a symptom present on both nights were included in the evaluation of response to therapy for that symptom). Formulation Preference Subjects were asked to state at the conclusion of the study which formulation they believed to be more effective at relieving their cold symptoms. The stated preferences (after decoding) were found to be as follows: Group A (" Active" first night, "Control" second night) Preferred "Control" (60 0%) (34 3%) (5 7%) Totals Preferred "Contro!" Group B ("Contro!" first night, "Active" second night) Preferred "Contro!" (71 4%) (22 9%) (5 7%) (65 7%) 20 (28 6%) 4 (5 7%) 70 This demonstrates an interesting potential bias of second product preference, equal to a swing from the true mean of 5 7%. (This bias is eliminated by the crossover design). Table 1 Subjects who rated formulation as "good", "very good", or "excellent" (Groups A and B combined) Significance" Symptom No. ofsubjects ''Active'' "Control" p= Cough (57-6%) 19 (32 2%) <0 01 Nasal congestion (69 8%) 29 (46 0%) <0 05 Nasal discharge (63 6%) 21 (38 2%) <0 05 Sneezing (83 3%) 20 (66 7%) N.S. Generally feeling unwell (60 4%) 25 (43 1%) <0 05 Headache (75 0%) 23 (52 3%) <0 05 Sore throat 45 30(66 7%) 19 (42 2%) <0 05 Disturbed sleep (75 5%) 27 (50 9%) <0 05

4 164 The Journal ofinternational Medical Research Table 2 Intrapatient comparisons (all ratings) Number Number Number who Significance No. of rating rating rated ofdifference subjects "Active" "Control" formulations between with higher than higher than equally columns Symptom symptom "Control" "Active" 1 and 2 Cough (54 2%) 9 (15 3%) 18 (30 5%) p ~ <0 01 Nasal congestion (49 2%) 14 (22 2%) 18 (28 6%) P <0 02 Nasal discharge 55 30(54 6%) 10(18 2%) 15(27-3%) P = <0 01 Sneezing (36 7%) 3 (10 0%) 16 (53 3%) p.~ <0 02 Generally feeling unwell (48 3%) 11 (19 0%) 19 (32-8%) p= <0 02 Headache (43 2%) 6 (13 6%) 19 (43 2%) p= <0 01 Sore throat (48 9%) 7 (15 6%) 16 (35 6%) p = <0 01 Disturbed sleep (54 7%) 8 (15 1%) 16 (30 2%) p -= <0 01 (*sign test) Reported Possible Adverse Reactions Nineteen subjects reported possible sideeffects, 11 being related to each formulation, most were attributable to the underlying cold, the remainder being distributed equally between "active" and "control" formulations. Giddiness/drowsiness was reported by 7 subjects for"active" and by 4 subjects for the "Control" formulation. Discussion (a) The clinical trial methodology Many of the short-term pathological changes occurring during the common cold and the effects of therapy can be objectively measured. For example, cough frequency may be measured by voice-actuated tape-recorder and subsequent counting (Sevelius & Colmore 1966), nasal congestion may be measured by nasal rhinorheometric studies (Martins 1966), nasal discharge by weighing paper tissues (Kravetz et al 1961) and sleep disturbance by kinetic bed studies (Crisp, Stonehill & Eversden 1970). Nevertheless, there remain some features which cannot yet be objectively quantified malaise, headache, sore throat) and in addition, there is the possibility that data produced objectively (e.g. nasal airway resistance) may not correlate exactly with subjective experiences of relief (nasal congestion) because the variable measured may be only one feature of a complex involving peripheral change and the central (or cerebral) analysis and interpretation of that change. Historically the subjective assessment of relief provided from the symptoms of the common cold has been carried out using rating scale assessment on comparative subject groups, one group using test formulation, the other using an inactive control or alternatively no treatment. Underlying this procedure was the belief that the variation in symptom severity within the same subject from one day to the next was greater than the variation between one subject and another on the same day. This author does not believe this to be the case and if accepted, leads to the possibility of conducting an intrapatient double-blind crossover study, which apart from the significant advantage of economy in terms of subject numbers required, offers a further specific advantage.

5 PThackray Rating scale evaluation is quite arbitrary. The scales used can be defined but the accuracy of placement depends totally on the observers' personal interpretation of scaledivision boundaries. This can vary immensely from one subject to another. Some rate consistently highly whatever formulations are used, others the reverse. Intrapatient comparison utilizes a consistent personally-interpreted defined scale and therefore allows meaningful "difference" evaluations to be made between two (or more) formulations. (b) The present study The present study has demonstrated that it is reasonable to use the double-blind crossover controlled design in short-duration conditions with rating scale assessment of symptomatic relief. The results show that a formulation containing dextromethorphan hydrobromide 15 mg, paracetamol 600 mg, ephedrine sulphate 8 mg, and doxylamine succinate 7 5 mg was significantly more effective than control syrup lacking those ingredients in the relief of the following symptoms of the common cold at night, namely, cough, nasal congestion, nasal discharge, sneezing, generally feeling unwell, headache, sore throat and disturbed sleep. 165 Acknowledgements The author wishes to acknowledge the assistance of the following general practitioners from the Hull area of England who took part in this study: Dr A T Barwood, Dr T Bolton, Dr A K Brahmachari, Dr M Dalton, Dr N F Denetto, Dr J H Earnshaw, Dr G Elsworth, Dr M C Flasher, Dr R Gamble, Dr P Heylings, Dr I 0 Innes, Dr B Kell, Dr P Kundu, Dr K Kutte, Dr R Lurie, Dr J Mullin, Dr T Oglesby, Dr M Sanders, Dr N Somerville, Dr G Staley and Dr M Wilkinson. REFERENCES Crisp A H, Stonehill E & Eversden I D (1970) The design of a motility-bed including its calibration for the subjects weight. Medical and Biological Engineering 8,455 Kravetz H M, Knight V, Chanoek R M, Morris J A, Johnson K M, Rifkind D & Utz J P ( 1961) Respiratory syncytial virus - III production of illness and clinical observations in adult volunteers. Journal ofthe American Medical Association 176,657 Martins J (1966) Rhinometric evaluation of a nasal decongestant spray. Clinical Medicine 73, 70 Sevelius H & Colmore J P (1966) Objective assessment of antitussive agents in patients with chronic cough. The Journal ofnew Drugs 6,216