Antitussive Effect of Guaifenesin in Young Adults with Natural Colds

Antitussive Effect of Guaifenesin in Young Adults with Natural Colds* Obiective and Subiedive Assessment Jeffery]. Kuhn, B.S.;t ]. Owen Hendley, M.D.;t Katherine F. Adams, R.N.;t ]ens W. Clark;§ and Jack M. Gwaltney, ]r., M.D.t

The efticacy of gaalfenesln In redndnl coup freqaenc:y In YOIIDI aduhl with aclde respiratory clllleMe was evaluated by both an objective coup colllltln& system and a qaesdoDIUifre. A gnaifenesln congb preprll1dlon and the syrnp vehicle were administered In a double-blind manner. Coughs were recorded ou tape over a 24-hour baseUne evalnation period and a 36-bour treatmeut period for 42 patient& A pronoDDCed diurnal variation In co111h frequency was observed. The evaluation of efticacy was baled upou comparilons between eqafvaleut six-hour time periods of mttellllve days. No antlhulllve eft'ect of gaalfenesln was demonstrated. The qaesdoDIUifre was administered to 65 patients, lndud-

Guaifenesin is one of the most widely used ingredients in cough preparations. Its pharmacologic action is supposed to be that of an "expectorant." However, in evaluating cough preparations,

log the 42 whole coughs were recorded. Of 26 patient. with produetfve coup reeetrin& palfenesln, 25 (96 percent) reported a decreale In spatam thicbeas CHIpared to 13 (54 percent) of 24 patient. reeeMna the vehicle (p=O.OOl, Fisher eDd tat). Twenty-three of 26 (88 percent) patients recelvbtt palfenesln allo r. ported reduc:tlou In sputum qaantity compared to 15 of 24 (62.5 percent) receiving the vehicle (p=0.07, Fisher es:act test). 1be dlnrnal variation In coup frequency measured by the tape reeontln& was not apparent from the suhjec:tlve coqb frequency estimates obtained by the questlollllllire.

adults with natural ooids were selected for study since it has been suggested that cough preparations be tested in patients with cough of pathologic origin due to natural disease.1

For editorial comment see paae 662

the Federal Drug Administration's Advisory Panel on Over-the Counter Cold, Cough, Allergy, Bronchodilator, and Anti-asthmatic Products could not determine from available information if guaifenesin was effective as an expectorant 1 Indeed, there have been difficulties in determining what the putative action of an expectorant is and how such activity can be measured in an objective fashion. The current study was done primarily to determine if guaifenesin had a therapeutic action which might indirectly result in a reduction in cough frequency, a parameter which could be measured objectively. A cough preparation containing guaifenesin and the vehicle used as a control substance were tested in a doubl~blind evaluation. Young •From the University of Virginia School of Medicine,

Charlottesville.

t])epartment of Internal Medicine. tl>eparbnent of Pediabics. §Division of Continuing Education. Manuscript received February 22; revision accepted May 13. &print requuts: Dt. ~. Internal. M~~, Un~ ritv of Virginia School of Medicine, C~ !li908

MATERIALS AND METHODS

Populatfon Sixty-five patients, mostly university students, in the age range of 18 to 30 years, were recruited. All signed consent forms which had been reviewed by the Human Investigation Committee of the University of Virginia. AU patients had acute respiratory illness of less than 48 hours' duration with cough. Emphasis was placed on the selection of subjects who were thought to be cooperative and were otherwise healthy and without hypersensitivity to guaifenesin. Patients were instructed to forego any other medication for respiratory tract symptoms during the test period. Only the study medications ( guaifenesin or vehicle), aspirin and/or acetaminophen, and oral contraceptives were allowed after inclusion into the study. The volunteers were instructed to maintain smoking and sleeping habits at the prestudy level throughout the teat. All patients were isolated in a quiet single room of a motel during the 60-hour test period. A trained technician was present at all times to serve as monitor for the study. A tape recording of cough frequency was obtained on 42 patients. An initial 24-hour baseline evaluation wu performed to ensure that a minimum cough frequency wu present in each subject. Patients selected for study bad at least 30 coughs recorded during the first 24-bour observation period. CHEST I 112 I 8 I DECEMBER, 11112

711

Patients were allocated at random to one of two treatment groups. The study was conducted in a double-blind manner. One group received a total of 2,400 mg of guaifenesin in a syrup vehicle, while the other group received the vehicle. The vehicle contained 95 percent alcohol (0.2 ml/5 ml), glucose ( 1.76 g/5 ml), fructose ( 1.95 g/5 ml), and coloring and flavoring agents. Quinine ( 2.5 mg/5 ml) was added to the vehicle to match the bitter taste of guaifenesin. After the initial 24-hour baseline evaluation period, each patient was instructed to take the assigned medication in 30 ml doses every six hours for 30 hours. Medication doses were administered under direct observation of the study monitor on Saturday at 6:00 PM and midnight and Sunday at 6:00 AM, noon, 6:00 PM, and midnight.

Table 1--Com,..,UUn o/ c-.la Count. /rom Orqinel MJ.Hour Tape to Corrapmull,.. C_,__, R.eort~~,.. No Coughs from

Time Period (Hours)

No Coughs from Condensed Difference Recording (%)

Original

Tape

0-6

960

889

-7.4

6-12

261

246

-5.7

12-18

43

43

0

18-24

330

311

-5.8

24-30

65

63

-3.1

30-36

5

5

0

Cough Counting Methodology

36-42

260

249

-4.2

Recmding If/Item: A recording system, modified from that of Loudon and Romans. 8 was used to monitor each subject. A lapel microphone was attached to the clothing and connected to either a SX-724 Crown tape recorder (Crown International, Inc, Elkhart, Indiana) or to a Metrotech tape recorder (Ambro-Scully, Newtown, Pennsylvania). The tape recorder contained two channels each. Four single patient rooms were monitored simultaneously. The tape recording system ran continuously during the 60-hour period with marldng of six-hour time intervals. Cough counting procedure: A completed 60-hour tape recording of a single patient was placed on a Crown recorder and run. The ampliBed signal was split and one portion was transmitted undelayed through an RP 2215-R graphic equalizer (Sound Craftsmen, Santa Ana, California) to an M ffT audio ampliJler with an adjustable output which operated as a threshold control for the voice-operated relay (Shure Products, Evanston, lllinois). The signal was then passed to a voice-operated relay (made from separate components by the University of Virginia Radio and Television Center) which was connected to the modified remote control of an A 700 Revox tape recorder (Studer Revox America Inc, Nashville, Tennessee). The other portion of the signal was fed, unfiltered, through a JJ 193 audio delay line (Eventide Clockworks, Inc, New York), and a one-second delayed signal was constantly applied at the record input of the Revox tape recorder. This recorder was switched into the record mode when the voice-operated relay was activated by a cough. The recorder then returned to the ready mode following the cessation of the cough(s). Thus, the Revox tape recorder started one second before each signal, recorded these sounds, and then stopped. The graphic equalizer and the audio ampliBer were tuned to accept all coughs and reject, as much as possible, -extraneous sounds occurring in the patient's room. Since the sound of a cough contains a rather wide spectrum of frequencies (50-13,000 cps) and in order to distinguish cough from extraneous frequency noise, the settings on the graphic equalizer and the audio ampliBer were determined by a procedure of trial and error with each patient. With this system, the 60 hours of recording was condensed onto tapes that toolc from five to ten hours to read, depending upon the patient's cough frequency. The compressed tape recording was monitored by ear on a tape recorder using stereophonic headphones. Cough counts were tallied by investigators unaware of the treatment

42-48

287

272

-5.2

48-54

321

293

-8.7

54-60

40

39

-2.5

Total

2,572

2,410

714

-4.3 Mean difference (%)

status of the patients. When multiple coughs occurred in a burst, each cough was counted as a single event. As the recording on the final tapes were not representative of the total 60-hour time period, it was necessary to mark the tape verbally for each six-hour time interval. The 370

A. 0

Vehicle

• Guailenelin

100

7

a

• 0

...,.

2

___ """ ___ ...,. __

0~~--~~--~--L-~--~~--~~

~

~

~

~

~

~

~

k

k

~

-

F'lcvlm 1. Measurements of cough frequency in young adults with natural colds receiving guaifenesin ( 21 vols) or syrup vehicle ( 21 vols). A. Cough counts obtained by tape recordings. B. Congh frequency estimates from a questionnaire (scale o£0 to 12). Antltu•lve Effect of Gueltenaln (Kuhn et el)

number of coughs exhibited during each six-hour time segment was then used as the primary basis for evaluation. To validate the ef&clency of the system, an original 60hour tape recording was monitored by ear at normal speed, and the number of coughs counted was compared to the number of coughs recorded with the cough discriminator system. The discriminator system had a 95 percent efficiency comoared to monito~ of the entire 60-hour tape (Table 1). Subfectroe e1Jolf.IOtUm: The patient's subjective assessment of treatment was determined by means of a questionnaire on six symptoms including frequency of cough. Cough frequency was scored on a scale of 0 to 12, with 12 being the most severe form of the symptom. The other symptoms evaluated by the same scoring system were cough severity, cough discomfort, chest discomfort, sputum quantity, and sputum thiclcness. The questionnaire was given to the patient prior to entrance into the study, at the end of 24-hour baseline evaluation period, and at subsequent three-hour intervals during the treatment period. The questionnaire was administered by the monitor.

Table

~b}eetlt~e

fu:suLTS Cough Counts from Recordings Cough counts for the six-hour intervals ranged from 0 to 1,334 for individuals in the guaifenesin group, and 0 to 889 for individuals in the control group (Table 2). Due to the extreme variation in cough frequency among patients, median instead of mean cough frequencies were used for analysis of the data. The median cough frequency for the sixhour intervals ranged from 17 to 310 for the vehicle group and from 12 to 377 counts for the guaifenesin group (Table 2, Fig 1A). The median pre-treatment cough counts (periods 1 through 4) were higher for the guaifenesin group ( 41 to 377) than the vehicle group ( 33 to 310). The median cough counts during the treatment periods 6 through 10

Cou•la Coanu from I'oa,.. .4d_,. IIIith .4eww Re.pi,..,ory mReeeilliq GfUIJ/enain or Y elaiele

Vehicle Patient No

1

6

363

Guaifenesin

Six-Hour Time Intervals 3 4 5 6 7 8

2

94 182

52

16

31 153 169

Patient No

Six-Hour Time Intervals 3 4 5 6 7 8

9

10

7

0

11

1334 503 714 1245 796 224

50

2

9

10

77 214 241 114

10

386 109

94 247 170 175

40

65

87

14

511 214 160 505 253 192

10

27 101

4

16

313 296 141 404 375 197

76

51 112 157

18

152

15 125 149

20

17

889 246

39

19

407

20

595

28 329 374 258

37

22

21

884

24

50 267 359 266

25

497

47

81 214 211

63

3

0

0

28

~

29

~

1~

~

~

0

40

33

234

33

91

73

98

45

27

35

~

114

33 398 190

3

14

44

279

48

172

92

46 272

49

155

36

52

473

33 190 245

54

90

55

43 311

63

5 249 272 293

8

17 364 236

73

41 202 255 190

22

34 178

19

412 225 187 471 487 140

20 127 134

12

23

110

46

21

52

0

26

570

81 114 581 402 225

74 182 343 159

~

4

27

443

11 237

23

82

70

11

30

229

29

6

0

34

18

25 192 285 119

50

36

46

10

5

15

20

11

38

32 299 115

69

35

93

65

23

41

96

90

88

54 326

85

30

45

294

65

17

34

29

1

826

33 223 364 405

52

33 145 110

58

553

56 234 329 116

4

59

108

14

37

61

139

27

38 100

64

171

46 161 155 238

67

310

Mean 371 Median 310

7 542 365 310

5 243 319

0

78

5 206

7

70

37

64

88 156 424 429

7

251

95

36

5

9

13

0

~

2

~

42

~

1~

44

1024 221 265 492 530 116 160 138

65

4

27 140

1~

213

14

11 146 122

58

43

78

79

46

26

56

591 120 151 192

52

22

1

38

28

3

10

57

704

40 245 532 417

41

1~

367 363

16

11

25

2

10

10

12

8

263

32 240 284

93

42

70

72

53

1

63

377

34 265 299 204

28

57 116 133

6

19

66

442

86 161 150 355 364

39

2

~

362

17

50 117

84

38

Mean 420

33

64

17

Median 377

78

12

8

30

23

0

62

43 109

25

35

36

17

~

19 231 135

58

27

36

95

65 121 250 147

~

91 247

45

98

65 125

14

59 182 273

60

33

50

200

14 194 176 141

32

6 255 144

82

93 279 355 514

~

18

49

0

112

69

61

1

0 119

73

7 160 118

3

82

3

1

0

90

17

82

12

3

7

24

1

44

17

90 174 320 257

89

60 115

41 161

53

42

54

~

200

136 25

79 101

CHEST I 12 I 8 I DECEMBER, 1812

12 711

Table J..-rropordon o/ P,_,. fa Grud/.,._,n . COWirol c,_,_ Fltlll. . ..46oH .M IJel4. r1ae II.._ Pfll'eenl in C-.la ,,.,.._,. /or Cf1rrW,_,.. . ~.ad TN8Imelll Perloa

c._..

Six-Hour Time Intervals

% Change

2and6

Treatment Group


+24.5

Guaifenesin Vehicle

13 61.9 8 38.1 8 38.1 13 61.9

3and 7

-57.5

Guaifenesin Vehicle

12 57.1 9 42.9 9 42.9 12 57.1

4and8

-68.8

Guaifenesin Vehicle

9 42.9 12 57.1 12 57.1 9 42.9

1 and 9

-79.2

Guaifenesin Vehicle

11

Guaifenesin Vehicle

9 42.9 12 57.1 12 57.1 9 42.9

2 and 10

-66.7

10 47.6 11 52.4 52.4 10 47.6

were similar for the two groups with ranges of 17 to 82 and 12 to 101 for the guaifenesin and vehicle groups, respectively. Although cough frequency diminished over the 60-hour period, the decline was not steady, but was characterized by a pattern of increased daytime cough activity and marked reduction in cough frequency during the evening. Cough frequency tended to be highest between noon and 6:00 PM and lowest between midnight and 6:00 AM. Because of the marked diurnal variation in cough frequency, each six-hour pre-treatment time interval was compared to the corresponding six-hour treatment period ( ie, the median cough frequency during the time interval from midnight Friday to 6:00 AM Saturday was compared to that of the time interval from midnight Saturday to 6:00 AM Sunday, etc). The first six-hour period of treatment was ex-

Table ~}eedN E-l•tdi- o/ C-.la F,..,..,.er in Y - . . Adalu witla Acu~ Rapiratory DiHtue Reeeif1in• Grud/.,._,n or Y elaiele Vehicle Six-Hour Time Intervals

Guaifenesin Six-Hour Time Intervals

Patient Number

Baseline

5

6

7

8

9

10

1

11

9

6

6

8

6

5

5

2

0

14

8

3

5

3

3

1

0

1

2

1

18

6

7

6

4

4

5

2

6

8

6

6

19

7

6

7

5

1

2

2

2

5

2

1

1

22

10

9

8

7

5

4

3

4

4

4

5

3

3

23

8

5

4

3

3

2

2

9

7

7

6

6

7

6

26

11

10

9

9

9

7

5

28

9

7

6

6

4

3

3

27

8

3

4

6

1

1

1

33

5

6

1

1

1

2

3

30

8

7

6

6

6

5

4

35

8

6

5

4

2

1

1

34

8

5

4

1

2

1

0

44

6

4

5

5

5

5

5

36

7

5

5

5

3

2

2

48

3

1

0

0

1

1

1

38

9

7

6

5

4

5

4

49

4

3

1

2

3

2

2

41

5

4

4

2

2

2

2

52

8

5

2

3

2

3

2

45

6

4

4

5

3

2

2

54

5

3

3

3

2

1

1

56

5

3

3

1

2

1

1

55

7

6

3

4

5

3

1

57

7

6

5

5

5

4

4

58

6

4

2

1

4

1

2

60

5

3

3

2

1

1

1

59

4

4

1

2

3

2

1

62

8

8

4

4

6

5

2

61

6

3

5

5

4

3

3

63

6

5

4

3

2

2

2

64

5

4

1

1

3

1

1

66

9

8

6

5

4

3

2

67

2

1

0

1

2

1

1

68

1

0

0

0

0

0

0

Mean

6

5

3

3

3

2

2

Mean

7

5

5

4

3

3

2

Patient Number

Bueline

5

6

7

8

9

10

6

6*

3

3

2

3

1

10

4

7

0

10

2

16

5

4

4

2

17

7

6

6

20

7

7

21

8

25

•Estimated frequency of cough baaed on a scale of 0 to 12

711

AntltuMive Effect of GualfanMin (Kuhn af af)

eluded from analysis to allow for delay in the onset of therapeutic eHect with the "expectorant" being tested. The percentage of change in cough frequency for each of the paired periods was determined for the individual patients and then the median percentage for the paired periods was calculated for the entire study group (Table 3). The number of patients in the two groups (treatment and control) showing a lesser or greater change in cough frequency compared to the median value for the entire group was then determined. In three of five periods, the suppression in cough frequency was greater for the guaifenesin group than was the median value. The diHerences observed in favor of guaifenesin was modest. The diHerence in percent change in median cough frequency between the two groups was not significant for any of the period ( x2 test). Subfective Impression of Changes in Cough and Sputum

The results of the subjective evaluation of cough frequency are shown in Table 4 and Figure lB. The pre-treatment scores were based on evaluations made on Saturday, 6:00 PM. Each successive column in the table corresponds to the same six-hour interval described in Table 2. The evaluations of cough frequency for the individual patients ranged from 0 to 11 for the guaifenesin group and from 0 to 10 for the vehicle group. Mean numerical scores ranged from two to seven for the guaifenesin group and two to six for the control group. Both the pre-treatment and treatment mean numerical scores were consistently higher for the guaifenesin group than the control group. This diHerence gradually diminished during the course of the 36-hour treatment period (Fig lB). The marked diurnal pattern seen with the cough counts obtained by tape recording was not clearly evident from the subjective results (Fig 1B). There was a steady decline in cough frequency for both groups over the 36-hour treatment period except that the control group exhibited a slight dip in cough frequency at 6:00 AM Sunday. It was not possible to compare the two methods during the six-hour intervals within the period between 6:00 PM Friday and 6:00PM Saturday, since subjective data were not available. The efficacy of guaifenesin was evaluated by comparing baseline scores ( 6:00 PM Saturday) with scores of the corresponding treatment ( 6:00 PM Sunday), (Table 5). Of 26 patients with productive cough receiving guaifenesin, 25 ( 96 percent) reported a decrease in sputum thickness compared to 13 (54 percent) of 24 patients receiving the

Table 5--Sub/ec:tiH EtiCIIacdion o/ SrrnP'O.,.. ..4uoef...ntA c,_.h and S,.,_m: CompariMna o/ Buell- Y..._ (6:00PM Stmarfl4r) .nlla Corre.pondin• Tr-lment Pmod (6:00PM S•rul"T)

Group

No

p Fisher Exact Improved Test No % (2-tailed)

0.5

30

94

Guaifenesin 33 Vehicle 32

33

100 91

0.2

29

Cough discomfort

Guaifenesin 32 Vehi<'le 32

29 29

91 91

>0.6

Chest discomfort

Guaifenesin 31 Vehicle 29

28

90 72

0.1

Sputum quantity• Guaifenesin 26 24 Vehicle

23 15

88

0.07

Sputum thickness• Guaifenesin 26 24 Vehicle

25 13

96 54

0.001

Cough severity

33

100

Guaifenesin 33 32 Vehicle

Cough frequency

21

62.5

• Analysis done only on patients with productive cough

vehicle (p=O.OOl, Fisher exact test) . Twenty-three of 26 ( 88 percent) patients receiving guaifenesin also reported reduction in sputum quantity compared to 15 of 24 (62.5 percent) receiving the vehicle (p=0.07, Fisher exact test). Differences in the occurrence of other symptoms between the two groups were not observed. DISCUSSION

The current study failed to show an antitussive action of guaifenesin in young adults with acute respiratory illness by objective measurement. Few previous studies have been devoted to the evaluation of guaifenesin as a cough suppressant. Recently, Packman and London;' in a study of cough induced by citric acid in healthy volunteers, reported the guaifenesin was no more active as an antitussive than a syrup vehicle. However, guaifenesin did enhance the antitussive activity of a dextromethorphan-phenylpropanolamine combination. It is possible that the syrup vehicle itseH had sufficient antitussive properties to mask any antitussive activity guaifenesin might have. In the present study, the vehicle control also may have contained sufficient concentrations of alcohol and sugars to have local cough suppressant activity. In the subjective evaluation of efficacy, guaifenesin was associated with a perceived decrease in sputum quantity and a reduction in sputum thickness. These two actions of guaifenesin have been repeatedly observed in unpublished studies in which CHEST I 82 I 8 I DECEMBER, 11182

717

information was obtained by questionnaire.' Although these subjective effects of guaifenesin appear to be real, objective evidence of guaifenesin's effect on sputum viscosity in patients with colds has not been reported In this study, the pattern of cough frequency in natural colds was recorded over a 60-hour period A marked diurnal variation was observed with maximum cough frequency occurring between noon and 6:00 PM and minimum cough frequency between midnight and 6:00 AM. In contrast, when cough frequency was determined by responses to a questionnaire, the diurnal variation was not apparent. Thus, it appears that patients with colds do not assess variability in cough frequency with a very high degree of accuracy. This observation is in accord with the finding of Sevelius and Colmore8 that the measurement of cough frequency obtained from a questionnaire given to patients with chronic lung disease correlated poorly with cough counts obtained from a tape recording.

ACKNOWLEDGMENT: Supported by A. H. Robins Company, Richmond~ Virginia. We wish to eJ:Press our appreciation to DonaJd L. Kaiser, Ph.D. for his assistance with the analysis of the data.

REFERENCES 1 Federal Register, Thursday, September 9, 1976 (part II entitled, Over-the-Counter Drugs Establishment of a Monograph for OTC Cold, Cough, Allergy, Bronchodilator, and Anti-asthmatic Products 2 Eddy NB, Friebel H, Hahn K-J, Halbeck H. Codeine and its alternates for pain and cough relief. The antitussive action of codeine-mechanism, methodology and evaluation. Bull Wid Hlth 0rg 1969; 40:425-54 3 Loudon RG, Roman WE. Cough-monitoring equipment. Med Res Eng} 1967; 6:25-27 4 Packman EW, London SJ. The utility of artificially induced cough as a clinical model for evaluating antitussive drug combinations. Part 1: Liquid and solid formulations of systemic drugs. Current Therap Res 1977; 21:855-66 5 Files of AH Robins Company. 6 Sevelius H, Colmore JP. Objective assessment of antitussive agents in patients with chronic cough. J New Drugs 1966; 6:216-23 ·

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718

Antltvaalve Effect of Gualfe-ln (Kuhn et a/}