Thorax (1964), 19, 125 Objetive assessment of ough suppressants under linial onditions using a tape reorder system C. R. WOOLF AND A. ROSENBERG From the Respiratory Unit, Sunnybrook Hospital (Department of Veterans Affairs), and the Department of Mediine, University of Toronto, Ontario, Canada The primary funtion of a ough suppressant should be to redue signifiantly the number of times a person oughs. There are two prinipal methods of assessing this effet. One method uses patients with pathologial ough, and its onlusions are based on subjetive impressions (Cass and Frederik, 1953; Woolf and Rosenberg, 1962). The other method uses subjets with indued ough, and onlusions are based on objetive ough ounts (Bikerman and Barah, 1954). The purpose of this paper is to desribe a tehnique whih employs the objetivity of ough ounting to determine the effet of suppressants on pathologial ough. Levo-propoxyphene (CT 132),' elixir of terpin hydrate with heroin, and syrup of odeine have been assessed by this tehnique. TECHNIQUE A hospital room with its own bathroom was used. The room was not sound-proofed, but rubber stripping was plaed around the door to the orridor. A mirophone above the head of the bed (Fig. 1) was onneted through the wall to a tape reorder set at the 'on ' position (Fig. 2). The reording input was onneted to the mirophone in the room and to a devie whih produed a time signal one every hour. The reorder was ontrolled by an eletroni on/off unit whih triggered the reorder into ation only when a signal was reeived from the mirophone or from the time signal sender. When the sound stopped the reorder ontinued to run for five seonds and then stopped. By this means it was possible to reord up to 24 hours of observations on two hours of tape. The time signal sender onsisted of a tape playbak unit and an automati swithing arrangement ativated one every hour by an eletri lok. The playbak unit ontained an endless tape whih, on ativation, announed the hour by means of a pre-reorded voie. As an additional hek on the time an ordinary himing lok was added to the system and this registered both the hours and half-hours. The reordings were played bak on a third tape reorder, and the oughs were ounted on a hand tally ounter. The sound of the ough is learly distinguishable from all other sounds that our throughout the day and night in the patient's room. Counts made by two independent observers during 15 hours of oughing from five different patients revealed no signifiant observer error (Fig. 3). Eli Lilly and Co. METHOD.,,_,,...@; t! R _ A patient with hroni ough was plaed in the * s M groom s where he spent four days from Monday afternoon to Friday afternoon. He knew in advane that :~.::i~s~ all sounds in his room would be reorded but he was unaware that a ough suppressant was being tested. He was told, and seemed to aept, that we were investigating the influene of peae and quiet on ~- hest disease and that the reording system would monitor the noise level in his room. He was enouraged to behave as usual. It was deided not to ~~~~~~~~interfere with his normal smoking habits. If smoking had been stopped, one would have been unertain whether hanges in ough were related to alteration in igarette onsumption or to the effets of the mediation. The number of igarettes per day was not ounted as it is diffiult to do so without unduly influening the fairly onstant daily igarette onsump- FIG. 1. Mirophone in position above the head of the bed. tion of the regular smoker. The patient was supplied 125
126 C. R. Woolf and A. Rosenberg A. 3/ 25 w 2 i,. o 5 5 1 15O 2 25 3 number of oughs- observer B FIG. 3. Comparison of ough ounts by two independent observers. Thirty-six omparisons where the number of oughs per hour was greater than 3 but less than 3. with reading matter and a radio with earphones (Fig. 1). Finally he was told that during the last three days in the room he would be given some mediine that might or might not help his hest trouble. On the first day, whih served as a ontrol day, the patient reeived no ough mediine. On the seond and third days he reeived a preparation whih resembled but did not ontain the test drug. On the fourth and final day he reeived the test drug. In the assessment of levo-propoxyphene reording was started at 6 p.m. eah day and ontinued until 5 p.m. on the following day. In the assessment of elixir of terpin hydrate with heroin and of syrup of odeine reording was started at 6 p.m. eah day and ontinued until 4 p.m. on the following day. Reording was disontinued eah day during visiting hours (7 p.m. to 8.3 p.m.) when the mirophone was removed from the room. FIG. 2. Tape reorder system: A, main tape reorder; B, eletroni onloff unit; C, playbak unit with pre-reorded voie; D, himing lok with mirophone. In order to ompare the objetive evidene of the tape reorder with the patient's subjetive assessment of the treatment, a questionnaire was ompleted at 5 p.m. eah day. Among a number of irrelevant questions about breathing and sleeping were several questions relating to ough. MATERIAL Three antitussive drugs were investigated. They were made up in standard dosages (see below) and given five times in 24 hours at 6 p.m., 1 p.m., 6 a.m., 1 a.m., and 1 p.m. If a ough suppressant really redues ough, its effet ought to be evident after even one standard dose, and its effet should ertainly be obvious if five doses are given in 24 hours. LEVO-PROPOXYPHENE On the first day the patient reeived no ough mediine. On the seond and third days he reeived a plaebo apsule idential in appearane with the test drug. On the final day he reeived the test drug in the manufaturer's reommended dosage of one 1 mg. apsule. The dosage was giverl five times in 24 hours. ELIXIR OF TERPIN HYDRATE WITH HEROIN On the first day the patient reeived no ough mediine. On the seond and third days he reeived elixir of terpin hydrate alone (eah dose 6 minims). On the final day elixir of terpin hydrate with heroin (1/24 gr.) was given. Mediation was given five times in 24 hours. SYRUP OF CODEINE On the first day the patient reeived no ough mediine. On the seond and third days he reeived a syrup whih resembled syrup of odeine in all respets (eah dose 12 minimns). On the final day syrup of odeine (. gr.) was given. Mediation was given five times in 24 hours. Thirty male in-patients took part in the inivestigation. Ten reeived levo-propoxyphene, 1 reeived elixir of terpin hydrate and heroin, and 1 syrup of odeine. The ages and diagnoses in the three groups are shown in Table I. All patients had had hroni
TABLE I AGE AND DIAGNOSIS Objetive assessment of ough suppressants Levo-propoxyphene Heroin Codeine Age (yr.) Mean Range 66 6-77 54 38-65 64 52-7 Diagnosis (No. of patients) Emphysema 5 6 9 Pulmonary fibrosis I I1 Chroni bronhitis 2 1 Bronhietasis 2 Bronhogeni arinoma 1 Total 1 1 ough for many years and were free of ative infetion. All ough suppressants were disontinued at least 24 hours before the patient entered the room. RESULTS Daily ough urves were onstruted for eah patient by progressively adding the number of oughs reorded every hour. Examples of suh urves are shown in Figs. 4, 5, and 6. The total daily ough ounts were subjeted to an analysis of variane, omparisons being made between the ontrol day, the two plaebo days, and the drug day. The number of oughs reorded from 1 p.m. to midnight, 6 a.m. to 8 a.m., 1 a.m. to noon, and 1 p.m. to 3 p.m. (two hours after eah dose of FIG. 4. Daily ough urves onstruted by progressively adding the number of oughs reorded eah hour. Patient W.G. Test drug levo-propoxyphene. Eah drug dose is indiated by an arrow on the base line. a, ob u mediation) were similarly analysed for the four days. The total daily ough ounts of eah patient were further analysed on the basis of perentage hange, a hange of more than 15 % being arbitrarily onsidered signifiant. LEVO-PROPOXYPHENE Statistial analysis of both the total daily ough ounts and the two-hour post-treatment ounts showed no signifiant differenes between the ontrol day, the two plaebo days, and the drug day (Tables II and III). It was onluded that levo-propoxyphene had no signifiant antitussive effet. ELIXIR OF TERPIN HYDRATE WITH HEROIN Statistial analysis of both the total daily ough ounts and the two-hour post-treatment ounts showed a signifiant redution in ough when heroin was added to elixir of terpin hydrate. There were no signifiant differenes between the ontrol day and the two elixir of terpin hydrate days (Tables II and III). It was onluded that elixir of terpin hydrate with heroin is an effetive ough suppressant. SYRUP OF CODEINE Statistial analysis of both the total daily ough ounts and the two-hour posttreatment ounts showed signifiant redutions in ough when odeine was added to the syrup. o o no treatment *------eplaebo -----. plaebo x- x test drug /O p.m. a.m. 'Ar X> I/ ".XI, p.m 127
128 1 ta 6 o-o no treatment * -- elixir --_ elixir x x elixir and heroin C. R. Woolf and A. Rosenberg p.m. a.m. p.m. FIG. 5. Cough urves. Patient F.G. Test drug heroin. o- o no treatment *---e syrup syrup x -x syrup and odeine /J/ Thorax: first published as 1.1136/thx.19.2.125 on 1 Marh 1964. Downloaded from http://thorax.bmj.om/ FIG. 6. Cough urves. Patient, at P. W. Test drug odeine. 1-9- 8-7- 6-5- 4-3- 2-1* A #1 x/ II x11-11, I,, 11 x X., 11 X-X-X-X-X-X--"Xwoo X-,X-.-x X-X /.. t'..~~~~~ t.....l 6 7 9 1 I1 12 1 2 3 4 5 6 7 8 9 1 II 12 I 2 3 4 p.m a.m. p.m. on 2 Otober 218 by guest. Proteted by opyright.
TABLE II COUGH COUNT ANALYSIS Objetive assessment of ough suppressants Average No. of Total Daily Coughs Average No. of 2-Hour Post-treatment Coughs,Control day 628 47 'Plaebo 7 57 Levo-propoxyphene 686 57 Control day 761 61 Elixir of terpin hydrate 765 74 Elixir of terpin hydrate with heroin 579 38 Control day 64 56 Simple syrup 513 51 Simple syrup with odeine 359 27 TABLE III STATISTICAL ANALYSIS OF COUGH COUNT DATA Comparison Level of Signifiane Two-hour Total Coughs Coughs Plaebo and ontrol N.S.D. N.S.D. Levo-propoxyphene and ontrol N.S.D. N.S.D. Levo-propoxyphene and plaebo N.S.D. N.S.D. Elixir and ontrol N.S.D. N.S.D. Elixir + heroin and ontrol 5%.5% Elixir + heroin and elixir 1% -1% Syrup and ontrol N.S.D. N.S.D. Syrup + odeine and ontrol 5% -5% Syrup + odeine and syrup 5%.5% N.S.D. = No signifiant differene There were no signifiant differenes between the ontrol day and the two simple syrup days (Tables II and III). It was onluded that syrup of odeine is an effetive ough suppressant. DISCUSSION The first drug to be assessed by the tape reorder tehnique was levo-propoxyphene. Although this had given evidene of a ough suppressant effet in both itri aid aerosol and linial trials (Gruber and Carter, 1961; Calesnik, Christensen, and Munh, 1961), a reent publiation suggested that more objetive studies were required (The Medial Letter on Drugs and Therapeutis, 1962). Using the tape reorder system we have been unable to demonstrate the effetiveness of this drug. Sine the itri aid aerosol tehnique and the tape reorder tehnique both base their onlusions on objetive ough ounts, the disrepany in the results might be due to the possibility that ough indued by irritating agents and pathologial ough respond differently to the ation of some suppressants. The failure of the tape reorder to onfirm the results of linial trials is probably due to the differene in tehnique. 129 The next drug to be assessed was elixir of terpin hydrate with heroin. Previous double-blind studies by Woolf and Rosenberg (1962) had suggested that heroin had little ough suppressant effet in the dosage used and that elixir of terpin hydrate alone was the effetive element in the preparation. The tape reorder tehnique reversed these onlusions. It is now onluded that heroin, in the same dosage as previously, is signifiantly effetive in suppressing ough and that elixir of terpin hydrate alone is of little value. The disrepany between the results of the double-blind studies and the tape reorder tehnique is in all probability due to the small number of patients used in the double-blind trial. Most patients do not aurately appreiate the day-to-day variation of their ough (see below), and linial studies ought to deal with very large numbers of patients to overome the unreliability of personal opinion. An advantage of the tape reorder tehnique is that it is possible to base onlusions on the results of a relatively small number of patients. The third drug to be assessed was syrup of odeine. The tape reorder results supported the evidene of other investigations that odeine is an effetive ough suppressant. By reording the number of oughs eah day it was possible to ompare the patient's opinion as to whether his ough had hanged with the objetive evidene of the reorder. It was arbitrarily deided that a 15% hange in the daily ough ount would be large enough to make the patient aware of an inrease or a derease in his ough as ompared with the previous day. Ninety omparisons were made between hange in the ough ount and the statements of the patients. The patient's assessment agreed with the ough ount in only 39 instanes. These agreements were evenly distributed over the three series, there being 13 agreements out of 3 omparisons for eah of the levo-propoxyphene, elixir of terpin hydrate with heroin, and syrup of odeine groups. It was then onsidered that a 15% hange in the daily ough ount might not be suffiient for the patient to notie, and the omparisons were therefore made again, but this time on the basis of a 5% hange in the ough ount. The patient's assessment agreed with the reorder in only 36 of the 9 omparisons. It may be onluded that the majority of patients do not appreiate the extent to whih their ough varies from day to day and that they are frequently unaware of the effets of antitussive preparations. Just as the double-blind trial has to ontend with random impressions so must the reorder tehnique overome the 'normal' flutuations of
13 C. R. Woolf and A. Rosenberg ough from day to day. Using the present tehnique, it has been possible to show that some mediations redue ough signifiantly in a group of patients. It is muh more diffiult to demonstrate the effet of a drug on an individual patient. It has not been possible to assess the individual patient in the present investigation as the day-today variation is too great to allow statistial analysis if only three ontrol or plaebo days are used. It would probably be neessary to follow the daily flutuation of untreated ough for at least 1 days to be reasonably sure that any redution in ough on the final drug day or days is due to the effet of the drug and does not represent some hane variation in the state of the ough. There are no figures available as to how frequently the patient must ough to be lassified as having a hroni ough. In the present series the average number of daily oughs varied from 628 to 761 for the ontrol days. No patient had a daily ough ount of less than 233 oughs, and the highest ount was 2,663. The reorder tehnique has proved useful in examining plaebo effet. A true plaebo was used only in the levo-propoxyphene series. There were seven laims of improvement after a plaebo day, but in only two of these instanes was there a greater than 15 % redution in ough. These findings suggest that plaebos may influene the patient's attitude towards his ough without produing a real redution in ough. Gravenstein, Devloo, and Beeher (1954) assessed the antitussive effet of heroin and odeine by objetive ough ounting. A diret writing system was used to reord all sounds in the patient's room. The tehnique was found to be 'tedious' as one of the investigators was obliged to sit outside the room and personally note whih sounds were oughs. These workers posed the question: Do opiates really redue the number of oughs or do they merely make the patient less aware of his ough? They were unable to demonstrate that opiates produed a redution in ough. In our series there was learly a signifiant redution in the number of oughs when heroin or odeine was administered. The way in whih opiates produe this effet is not known, but a sedative ation may play a part. Levopropoxyphene was perhaps ineffetive simply beause it laked this sedative effet, and it may well be that no non-additing preparation will be as effetive as the opiates. The tape reorder system supplies data for statistial analysis using only a small number of patients and is useful in the objetive assessment of ough suppressants under linial onditions. SUMMARY An objetive method of assessing ough suppressants under linial onditions by a tape reorder system is desribed. The tehnique is based on the prinipal of ounting ontinuously reorded ough. Levo-propoxyphene, elixir of terpin hydrate with heroin, and syrup of odeine were the three drugs assessed. Thirty male inpatients with hroni ough took part in the investigation. It was shown that levo-propoxyphene produed no signifiant redution in ough and that both elixir of terpin hydrate with heroin and syrup of odeine were effetive ough suppressants. In spite of laims of subjetive improvement, no real redution in ough ourred after the use of a plaebo. A omparison was made between the objetive evidene of the reorder and the subjetive observations of the patient. It was shown that patients are largely unaware of onsiderable hanges in the state of their ough and that linial trials whih base their onlusions on subjetive impressions are open to ritiism on this aount. The tape reorder system provides a pratial means of assessing ough suppressants objetively under linial onditions. We wish to thank the following: Mr. S. Baso, Respiratory Unit tehniian. Sunnybrook Hospital, without whose enthusiasm this investigation would not have been possible; Mr. R. Tompson, Head Pharmaist, Sunnybrook Hospital, who prepared the mixtures; Tele-Teh Eletronis Ltd., 1947 Avenue Road, Toronto 12, who designed the tape reorder system. The work was supported by Department of Veterans Affairs Researh Grant 27-57 and by a grant from Eli Lilly and Company. REFERENCES Bikerman, H. A., and Barah, A. L. (1954). The experimental prodution of ough in human subjets indued by itri aid aerosols. Preliminary studies on the evaluation of antitussive agents. Amer. J. med. Si., 228, 156. Calesnik, B., Christensen, J. A., and Munh, J. C. (1961). Antitussive ation of L-propoxyphene in itri aid-indued ough response. Ibid., 242, 56. Cass, L. J., and Frederik, W. S. (1953). Evaluation of a new antitussive agent. New Engl. J. Med., 249, 132. Gravenstein. J. S., Devloo, R. A., and Beeher, H. K. (1954). Effet of antitussive agents on experimental and pathologial ough in man. J. appl. Physiol. 7, 119. Gruber, C. M. Jr., and Carter, C. H. (1961). A measure of the effetiveness of propoxyphene antitussives in hildren. Amer. J. med. Si.. 242, 443. The Medial Letter on Drugs and Therapeutis (1962). 4, 77 [No. 2]. (Amer. ed.) Woolf, C. R., and Rosenberg, A. (1962). The ough suppressant effet of heroin and odeine: A ontrolled linial study. Canad. med. Ass. J., 86, 81.