DOUBLE-BLIND STUDY OF KETOPROFEN AND PHENYLBUTAZONE IN ANKYLOSING SPONDYLITIS BY J. D. JESSOP
(Orudis) has been shown to be effective and well tolerated in the treatment of both rheumatoid arthritis and osteoarthrosis (Cathcart et ah, 1973; Mills et ah, 1973; Zutshi et ah, 1973; Gyory et al., 1972). This study was undertaken to compare the effect of ketoprofen with phenylbutazone in a short-term clinical trial in patients with ankylosing spondylitis.
KETOPROFEN
MATERIAL AND METHODS Patients Twenty-six patients with ankylosing spondylitis (Bennet and Wood, 1968) currently receiving treatment in the out-patient department were admitted to the trial. Excluded were those with renal, hepatic, or cardiac failure, severe dyspepsia or previous intolerance to phenylbutazone and those with sacro-ileitis associated with ulcerative colitis, regional ileitis, Reiter's disease or psoriasis. There were 6 withdrawals leaving 20 patients, 17 men and 3 women, available for analysis. The clinical features of this group are shown in Table I. TABLE I CLINICAL CHARACTERISTICS OF PATIENTS
Trial drug sequence Group C*
Number of patients 12 (10M+2F) 8 Group Xf (7M+1F) Totals 20 (both groups) (17M+3F)
Duration of disease (years)
Age (years)
Functional dependency!
range
mean
1-5
>5
0
1
2
3
4
20-59
46.0
2
10
2
2
8
0
0
28-54
37.3
1
7
1
2
5
0
0
20-59
40.2
3
17
3
4 13
0
0
* Ketoprofen followed by phenylbutazone. t Phenylbutazone followed by ketoprofen. + Functional dependency: 0 = normal function; 1 = slightly affected—usual duties carried out with minimum of difficulty; 2 = slightly affected—usual duties carried out only with difficulty; 3 = partially dependent; 4 = fully dependent. 37
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SUMMARY A series of 26 patients with ankylosing spondylitis have been included in a double-blind crossover comparison of ketoprofen 200 mg daily and phenylbutazone 300 mg daily, each drug being given for 4 weeks, with paracetamol as a 'rescue drug'. Six patients -withdrew from the study: three on phenylbutazone and one on ketoprofen—two defaulted treatment. Twenty patients (17 males and 3 females) were eligible for assessment. Their ages ranged between 20 and 59 years (mean 40.2 years). Patient characteristics were comparable in both groups. The results of this series indicate no suggestion of statistically significant differences in any of the nine movements measured. The only significant differences, both in favour of phenylbutazone, were in the paracetamol consumption in the second treatment period in the group receiving ketoprofen first (0.01 >P>0.005) and in the patients' preference for phenylbutazone (0.005> P >0.001). Adverse reactions were comparable in both groups.
38
A SYMPOSIUM ON KETOPROFEN
Withdrawals Six patients were withdrawn from the trial—two defaulted follow-up and the remaining four stopped treatment because of side-effects. These six have been excluded from the analysis, but the four who stopped treatment because of side-effects have been included under the adverse reactions section. The drop-outs were equal—three in each group—but all three receiving phenylbutazone stopped the capsules because of sideeffects. Assessments The following assessments were made, as far as possible at the same time of day on each visit, on Day 0 (pre-trial), Day 28 (end of first 4 weeks) and Day 56 (end of second 4 weeks): Subjective. Severity of pain and degree of morning stiffness were each recorded on a 0-4 scale (0=none; 1=slight; 2—moderate; 3=severe; 4—very severe) and the duration of morning stiffness was recorded to the nearest £ hour. A global assessment of the current clinical state was recorded on a 0-4 scale (0=very good; l = g o o d ; 2=fair; 3=poor; 4=very poor). Patients' drug preference was recorded at the end of the study when patients were asked to state their preference for either the first 4 weeks or second 4 weeks of treatment and give their reasons. Adverse reactions were recorded in response to the question: 'Has the treatment upset you in any way during the past four weeks? If so, in what way?' Objective. The following clinical measurements were made in cm: (1) occiput-towall distance, (2) tragus-to-wall distance (straight, turning to right, turning to left) (3) finger-to-floor distance (from tip of middle finger to the floor), (4) intermalleolar distance (two measurements, the first when pain appeared and the second at the greatest displacement tolerated), (5) chest expansion (6) lumbar-spine forward flexion. Laboratory measurements. Haemoglobin (Hb), white-cell count (WBC) and differential count, platelet count and erythrocyte sedimentation rate (ESR) were measured at each visit. RESULTS Twenty patients completed the trial, 12 in the group who received ketoprofen for the first 4 weeks (Group C) and eight who received phenylbutazone first (Group X). Data on these 20 patients were analysed as follows and the figures set out in Tables II (subjective assessment) and III (objective assessment):
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
Treatment allocation Immediately prior to the start of the study all antirheumatic therapy was stopped. A double-blind cross-over technique was used and patients received either phenylbutazone 300 mg/day (2x37.5 mg capsules four times daily) or ketoprofen 200 mg/day (2 x25 mg capsules four times daily). The patients were randomly allocated the trial drug contained in identical capsules and each treatment period lasted 4 weeks. Capsules were swallowed with food and only paracetamol tablets 500 mg from a measured supply could be taken as a 'rescue' analgesic. Physiotherapy was allowed provided it had been started at least 4 weeks prior to the start of the study and was allowed to continue unchanged throughout the trial period which lasted a total of 8 weeks.
39
J. D. JESSOP TABLE II SUBJECTIVE ASSESSMENTS
;Frequency distribution of rating
Parameter
Group C*
Group Xt
DayO
Severity of pain
4 3 2 1 0
3 3 6 0 0
0 1 8 3 0
0 0 3 4 5
0 2 3 3 0
0 1 2 1 4
3 2 0 1 2
Severity of morning stiffness
4 3 2 1 0
2 2 7 1 0
0 1 9 2 0
0 1 2 5 4
0 0 8 0 0
0 0 2 2 4
0 2 2 2 2
Duration of morning stiffness (0-13: i hourly)
13 12 8 6 4 3 2 1 0
5 0 2 1 2 0 2 0 0
1 0 2 0 2 1 5 1 0
1 1 1 1 1 0 3 0 4
2 0 1 0 3 0 0 2 0
1 0 2 0 1 0 0 0 4
2 0 0 0 2 0 0 2 2
Global assessment of clinical state
4 3 2 1 0
0 2 8 2 0
0 0 8
0 1 2 4 5
0 2 4 2 0
0 1 2 2 3
0 2 2 1 3
Patients' drug preference
Day 28 1Day 56
4 0
Group C* ketoprofen phenylbutazone 2
10
Day C) Day 28 1Day 56
Group Xf phenylbu- ketoprofen tazone 7
1
* Ketoprofen followed by phenylbutazone. t Phenylbutazone followed by ketoprofen.
(a) Subjective assessments As these ratings are based purely on the patients' subjective opinions and are not absolute measured figures, it was considered that the size of the patient sample in each group was too small to submit the figures to statistical analysis. However, the frequency distribution of ratings in each group, for each assessment day, has been calculated and is shown in Table II. The frequency distribution shows that there is a trend towards less pain and stiffness after 4 weeks' treatment, regardless of which drug was given first, and, after 8 weeks, this trend is further increased in the group receiving phenylbutazone for the last 4 weeks. The same pattern is followed for the patients' over-all assessment of their current clinical state.
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
Rating
Total C X Total C X Total
C X
X Total
C
c X Total
12 6 18 12 7 19
9 7 16
12 8 20 12 8 20
2.0 2.4
4.2 4.5
1.8 1.8 8.3 18.9
29.8 11.6
4.4 4.7
91.3 103.5
91.2 103.5
22.0 26.2
12.8 14.3
13.4 15.2
18.9 19.9
Day 56 7.9 9.0
1.9 2.4
3.9 5.2
85.9 105.0
25.0 22.6
26.3 27.3
85.2 102.0
13.4 13.7
14.3 15.4
85.3 105.0
13.8 14.9
14.6 15.5
85.2 102.0
19.6 20.1
20.0 20.0
Day 28 8.3 8.6
Mean value (cm)
N.S. N.S N.S N.S N.S N.S
N.S. N.S. N.S. N.S. N.S. Significant N.S.
0.36 0.44 0.42 0.44 0.49 0.40 0.27 0.40 0.28 0.48 0.28 0.48 0.25 0.49 0.45 0.34 0.0034 0.13
Significance
P value 0.33 0.44
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* Group C = ketoprofen 200 mg/day for thefirst4 weeks phenylbutazone 300 mg/day for the second 4 weeks. Group X = phenylbutazone 300 mg/day for thefirst4 weeks ketoprofen 200 mg/day for the second 4 weeks.
Lumbar spine fonvard flexion Paracetamol consumption
Chest expansion
greatest displacement tolerated
Intermalleolar distance: when pain first appears
Finger to floor
turning to left
turning to right
12 8 20 12 8 20 12 8 20 12 8 20
Day 0 00
C X Total C X Total C X Total C X Total
Group* C X Total 00 OO
Tragus to wall straight
Parameter Occiput to wall
No of Observations 12 8 20
TABLE III: OBJECTIVE MEASUREMENTS
O
J. D. JESSOP
41
In response to a standard question regarding the patient's preference for one or other treatment periods, it was found that 17 preferred phenylbutazone and three preferred ketoprofen (two in the group who received ketoprofen first). This is highly significant in favour of phenylbutazone (0.005>P>0.001). The usual basis for patient preference was reduction of pain and stiffness.
Side-effects Nine patients had no untoward symptoms throughout the 8-week trial period. Eleven patients reported symptoms at various times throughout the study: three of these reported dyspepsia in both drug-treatment periods. Also three patients stopped treatment after 1 week while taking phenylbutazone and one while on ketoprofen. The reported sysmptoms are shown in Table IV. TABLE IV REPORTED SIDE-EFFECTS
Symptoms Dyspepsia Epigastric pain/vomiting Nausea Constipation Giddiness and chest pains Giddiness/abdominal pain Giddiness/sweating Frequency /urgency of micturition Impotence Dry mouth and mouth ulcers
Ketoprofen
Phenylbutazone
6
3
1 1
1 (withdrawn)
1 (withdrawn) 1
1 (withdrawn) 1
1 1 1
Laboratory investigations Hb, WBC, ESR, and platelets showed no changes throughout the study. CONCLUSIONS The results of this series of patients studied indicated no suggestion of statistically significant differences in any of the nine movements measured. The only significant differences were in the paracetamol consumption in the second treatment period in the group receiving ketoprofen first (0.01 >P>0.005) and in the patients' drug preference (0.005>P>0.001). Both favoured phenylbutazone. Owing to the small numbers involved, the subjective assessment of pain, morning stiffness and current clinical state have not been submitted to statistical analysis. However, the frequency distribution of ratings in each group showed a trend in favour of phenylbutazone.
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
(b) Objective measurements Analysis of variance, on all the movements measured in those cases studied so far, indicated no suggestion of statistically significant differences. Paracetamol consumption declined significantly in the second treatment period in the group given ketoprofen first (0.01 >P>0.005). This favoured phenylbutazone. No other differences could be shown to attain statistical significance.
42
A SYMPOSIUM ON KETOPROFEN
ACKNOWLEDGMENTS
I wish to thank Dr. Michael Jeffries of May & Baker Ltd. for statistical analysis and May & Baker Ltd. for the drugs and record cards used in this trial. REFERENCES
P. H. and WOOD, P. H. N. (1968) "Population Studies of the Rheumatic Diseases". Proc. 3rd Int. Symp. July 1968, New York. Int. Cong. Ser. No. 148, p. 456. Amsterdam: Exerpta Medica. BRESNIHAN, F. P., GRAHAME, R. and BURRY, H. C. (1974) "Ketoprofen in the Management of Osteoarthrosis of the Hip: Comparison with Phenylbutazone". Rheumatol. Rehabil. 13, 125-31. CATHCART, B. J., VINCE, J. D., GORDON, A. J., BELL, M. A. and CHALMERS, I. M. (1973) "Studies on 2-(3-Benzoylphenyl)proprionic Acid (Orudis): A Double-blind Cross-over Trial in Patients with Rheumatoid Arthritis and an Assessment of its Influence on Hepatic Drugmetabolizing Enzymes". Ann. Rheum. Dis. 32,62. GYORY, A. N., BLOCH, M., BURRY, H. C. and GRAHAME, R. (1972) "Orudis in Management of Rheumatoid Arthritis and Osteoarthrosis of the Hip: Comparison with Indomethacin". Br. Med. J. 4, 398. MILLS, S. B., BLOCH, M. and BRUCKNER, F. E. (1973) "Double-blind Cross-over Study of Ketoprofen and Ibuprofen in Management of Rheumatoid Arthritis". Br. Med. J. 4, 82. ZUTSHI, D. W., MARR, S., BLOCH, M. and MASON, R. M. (1973) "Double-blind Cross-over Study of Orudis and Placebo in Fifty Patients with Rheumatoid Arthritis". Rheumatol. Rehabil 12, 62-7. BENNETT,
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
The incidence of adverse reactions was comparable with both drugs, but appeared to be rather more severe with phenylbutazone, despite the fact that patients with previous phenylbutazone intolerance had been excluded. Three patients stopped treatment after 1 week on phenylbutazone and only one whilst on ketoprofen. In this study ketoprofen was used at a higher dose of 200 mg daily and for a longer period than in some of the previous trials (Cathcart et al., 1973; Gyory et al., 1972; Mills et al., 1973) although Bresnihan et al. (1974) also used 200 mg daily but only for two weeks, and these factors probably contributed to the problems of dyspepsia and gastrointestinal side-effects. The results of this short-term trial have demonstrated that phenylbutazone 300 mg daily is a more effective anti-inflammatory drug than ketoprofen 200 mg daily for treatment of patients with ankylosing spondylitis and furthermore adverse reactions remain a problem with both drugs.
(Orudis) has been shown to be effective and well tolerated in the treatment of both rheumatoid arthritis and osteoarthrosis (Cathcart et ah, 1973; Mills et ah, 1973; Zutshi et ah, 1973; Gyory et al., 1972). This study was undertaken to compare the effect of ketoprofen with phenylbutazone in a short-term clinical trial in patients with ankylosing spondylitis.
KETOPROFEN
MATERIAL AND METHODS Patients Twenty-six patients with ankylosing spondylitis (Bennet and Wood, 1968) currently receiving treatment in the out-patient department were admitted to the trial. Excluded were those with renal, hepatic, or cardiac failure, severe dyspepsia or previous intolerance to phenylbutazone and those with sacro-ileitis associated with ulcerative colitis, regional ileitis, Reiter's disease or psoriasis. There were 6 withdrawals leaving 20 patients, 17 men and 3 women, available for analysis. The clinical features of this group are shown in Table I. TABLE I CLINICAL CHARACTERISTICS OF PATIENTS
Trial drug sequence Group C*
Number of patients 12 (10M+2F) 8 Group Xf (7M+1F) Totals 20 (both groups) (17M+3F)
Duration of disease (years)
Age (years)
Functional dependency!
range
mean
1-5
>5
0
1
2
3
4
20-59
46.0
2
10
2
2
8
0
0
28-54
37.3
1
7
1
2
5
0
0
20-59
40.2
3
17
3
4 13
0
0
* Ketoprofen followed by phenylbutazone. t Phenylbutazone followed by ketoprofen. + Functional dependency: 0 = normal function; 1 = slightly affected—usual duties carried out with minimum of difficulty; 2 = slightly affected—usual duties carried out only with difficulty; 3 = partially dependent; 4 = fully dependent. 37
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
SUMMARY A series of 26 patients with ankylosing spondylitis have been included in a double-blind crossover comparison of ketoprofen 200 mg daily and phenylbutazone 300 mg daily, each drug being given for 4 weeks, with paracetamol as a 'rescue drug'. Six patients -withdrew from the study: three on phenylbutazone and one on ketoprofen—two defaulted treatment. Twenty patients (17 males and 3 females) were eligible for assessment. Their ages ranged between 20 and 59 years (mean 40.2 years). Patient characteristics were comparable in both groups. The results of this series indicate no suggestion of statistically significant differences in any of the nine movements measured. The only significant differences, both in favour of phenylbutazone, were in the paracetamol consumption in the second treatment period in the group receiving ketoprofen first (0.01 >P>0.005) and in the patients' preference for phenylbutazone (0.005> P >0.001). Adverse reactions were comparable in both groups.
38
A SYMPOSIUM ON KETOPROFEN
Withdrawals Six patients were withdrawn from the trial—two defaulted follow-up and the remaining four stopped treatment because of side-effects. These six have been excluded from the analysis, but the four who stopped treatment because of side-effects have been included under the adverse reactions section. The drop-outs were equal—three in each group—but all three receiving phenylbutazone stopped the capsules because of sideeffects. Assessments The following assessments were made, as far as possible at the same time of day on each visit, on Day 0 (pre-trial), Day 28 (end of first 4 weeks) and Day 56 (end of second 4 weeks): Subjective. Severity of pain and degree of morning stiffness were each recorded on a 0-4 scale (0=none; 1=slight; 2—moderate; 3=severe; 4—very severe) and the duration of morning stiffness was recorded to the nearest £ hour. A global assessment of the current clinical state was recorded on a 0-4 scale (0=very good; l = g o o d ; 2=fair; 3=poor; 4=very poor). Patients' drug preference was recorded at the end of the study when patients were asked to state their preference for either the first 4 weeks or second 4 weeks of treatment and give their reasons. Adverse reactions were recorded in response to the question: 'Has the treatment upset you in any way during the past four weeks? If so, in what way?' Objective. The following clinical measurements were made in cm: (1) occiput-towall distance, (2) tragus-to-wall distance (straight, turning to right, turning to left) (3) finger-to-floor distance (from tip of middle finger to the floor), (4) intermalleolar distance (two measurements, the first when pain appeared and the second at the greatest displacement tolerated), (5) chest expansion (6) lumbar-spine forward flexion. Laboratory measurements. Haemoglobin (Hb), white-cell count (WBC) and differential count, platelet count and erythrocyte sedimentation rate (ESR) were measured at each visit. RESULTS Twenty patients completed the trial, 12 in the group who received ketoprofen for the first 4 weeks (Group C) and eight who received phenylbutazone first (Group X). Data on these 20 patients were analysed as follows and the figures set out in Tables II (subjective assessment) and III (objective assessment):
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
Treatment allocation Immediately prior to the start of the study all antirheumatic therapy was stopped. A double-blind cross-over technique was used and patients received either phenylbutazone 300 mg/day (2x37.5 mg capsules four times daily) or ketoprofen 200 mg/day (2 x25 mg capsules four times daily). The patients were randomly allocated the trial drug contained in identical capsules and each treatment period lasted 4 weeks. Capsules were swallowed with food and only paracetamol tablets 500 mg from a measured supply could be taken as a 'rescue' analgesic. Physiotherapy was allowed provided it had been started at least 4 weeks prior to the start of the study and was allowed to continue unchanged throughout the trial period which lasted a total of 8 weeks.
39
J. D. JESSOP TABLE II SUBJECTIVE ASSESSMENTS
;Frequency distribution of rating
Parameter
Group C*
Group Xt
DayO
Severity of pain
4 3 2 1 0
3 3 6 0 0
0 1 8 3 0
0 0 3 4 5
0 2 3 3 0
0 1 2 1 4
3 2 0 1 2
Severity of morning stiffness
4 3 2 1 0
2 2 7 1 0
0 1 9 2 0
0 1 2 5 4
0 0 8 0 0
0 0 2 2 4
0 2 2 2 2
Duration of morning stiffness (0-13: i hourly)
13 12 8 6 4 3 2 1 0
5 0 2 1 2 0 2 0 0
1 0 2 0 2 1 5 1 0
1 1 1 1 1 0 3 0 4
2 0 1 0 3 0 0 2 0
1 0 2 0 1 0 0 0 4
2 0 0 0 2 0 0 2 2
Global assessment of clinical state
4 3 2 1 0
0 2 8 2 0
0 0 8
0 1 2 4 5
0 2 4 2 0
0 1 2 2 3
0 2 2 1 3
Patients' drug preference
Day 28 1Day 56
4 0
Group C* ketoprofen phenylbutazone 2
10
Day C) Day 28 1Day 56
Group Xf phenylbu- ketoprofen tazone 7
1
* Ketoprofen followed by phenylbutazone. t Phenylbutazone followed by ketoprofen.
(a) Subjective assessments As these ratings are based purely on the patients' subjective opinions and are not absolute measured figures, it was considered that the size of the patient sample in each group was too small to submit the figures to statistical analysis. However, the frequency distribution of ratings in each group, for each assessment day, has been calculated and is shown in Table II. The frequency distribution shows that there is a trend towards less pain and stiffness after 4 weeks' treatment, regardless of which drug was given first, and, after 8 weeks, this trend is further increased in the group receiving phenylbutazone for the last 4 weeks. The same pattern is followed for the patients' over-all assessment of their current clinical state.
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
Rating
Total C X Total C X Total
C X
X Total
C
c X Total
12 6 18 12 7 19
9 7 16
12 8 20 12 8 20
2.0 2.4
4.2 4.5
1.8 1.8 8.3 18.9
29.8 11.6
4.4 4.7
91.3 103.5
91.2 103.5
22.0 26.2
12.8 14.3
13.4 15.2
18.9 19.9
Day 56 7.9 9.0
1.9 2.4
3.9 5.2
85.9 105.0
25.0 22.6
26.3 27.3
85.2 102.0
13.4 13.7
14.3 15.4
85.3 105.0
13.8 14.9
14.6 15.5
85.2 102.0
19.6 20.1
20.0 20.0
Day 28 8.3 8.6
Mean value (cm)
N.S. N.S N.S N.S N.S N.S
N.S. N.S. N.S. N.S. N.S. Significant N.S.
0.36 0.44 0.42 0.44 0.49 0.40 0.27 0.40 0.28 0.48 0.28 0.48 0.25 0.49 0.45 0.34 0.0034 0.13
Significance
P value 0.33 0.44
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* Group C = ketoprofen 200 mg/day for thefirst4 weeks phenylbutazone 300 mg/day for the second 4 weeks. Group X = phenylbutazone 300 mg/day for thefirst4 weeks ketoprofen 200 mg/day for the second 4 weeks.
Lumbar spine fonvard flexion Paracetamol consumption
Chest expansion
greatest displacement tolerated
Intermalleolar distance: when pain first appears
Finger to floor
turning to left
turning to right
12 8 20 12 8 20 12 8 20 12 8 20
Day 0 00
C X Total C X Total C X Total C X Total
Group* C X Total 00 OO
Tragus to wall straight
Parameter Occiput to wall
No of Observations 12 8 20
TABLE III: OBJECTIVE MEASUREMENTS
O
J. D. JESSOP
41
In response to a standard question regarding the patient's preference for one or other treatment periods, it was found that 17 preferred phenylbutazone and three preferred ketoprofen (two in the group who received ketoprofen first). This is highly significant in favour of phenylbutazone (0.005>P>0.001). The usual basis for patient preference was reduction of pain and stiffness.
Side-effects Nine patients had no untoward symptoms throughout the 8-week trial period. Eleven patients reported symptoms at various times throughout the study: three of these reported dyspepsia in both drug-treatment periods. Also three patients stopped treatment after 1 week while taking phenylbutazone and one while on ketoprofen. The reported sysmptoms are shown in Table IV. TABLE IV REPORTED SIDE-EFFECTS
Symptoms Dyspepsia Epigastric pain/vomiting Nausea Constipation Giddiness and chest pains Giddiness/abdominal pain Giddiness/sweating Frequency /urgency of micturition Impotence Dry mouth and mouth ulcers
Ketoprofen
Phenylbutazone
6
3
1 1
1 (withdrawn)
1 (withdrawn) 1
1 (withdrawn) 1
1 1 1
Laboratory investigations Hb, WBC, ESR, and platelets showed no changes throughout the study. CONCLUSIONS The results of this series of patients studied indicated no suggestion of statistically significant differences in any of the nine movements measured. The only significant differences were in the paracetamol consumption in the second treatment period in the group receiving ketoprofen first (0.01 >P>0.005) and in the patients' drug preference (0.005>P>0.001). Both favoured phenylbutazone. Owing to the small numbers involved, the subjective assessment of pain, morning stiffness and current clinical state have not been submitted to statistical analysis. However, the frequency distribution of ratings in each group showed a trend in favour of phenylbutazone.
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
(b) Objective measurements Analysis of variance, on all the movements measured in those cases studied so far, indicated no suggestion of statistically significant differences. Paracetamol consumption declined significantly in the second treatment period in the group given ketoprofen first (0.01 >P>0.005). This favoured phenylbutazone. No other differences could be shown to attain statistical significance.
42
A SYMPOSIUM ON KETOPROFEN
ACKNOWLEDGMENTS
I wish to thank Dr. Michael Jeffries of May & Baker Ltd. for statistical analysis and May & Baker Ltd. for the drugs and record cards used in this trial. REFERENCES
P. H. and WOOD, P. H. N. (1968) "Population Studies of the Rheumatic Diseases". Proc. 3rd Int. Symp. July 1968, New York. Int. Cong. Ser. No. 148, p. 456. Amsterdam: Exerpta Medica. BRESNIHAN, F. P., GRAHAME, R. and BURRY, H. C. (1974) "Ketoprofen in the Management of Osteoarthrosis of the Hip: Comparison with Phenylbutazone". Rheumatol. Rehabil. 13, 125-31. CATHCART, B. J., VINCE, J. D., GORDON, A. J., BELL, M. A. and CHALMERS, I. M. (1973) "Studies on 2-(3-Benzoylphenyl)proprionic Acid (Orudis): A Double-blind Cross-over Trial in Patients with Rheumatoid Arthritis and an Assessment of its Influence on Hepatic Drugmetabolizing Enzymes". Ann. Rheum. Dis. 32,62. GYORY, A. N., BLOCH, M., BURRY, H. C. and GRAHAME, R. (1972) "Orudis in Management of Rheumatoid Arthritis and Osteoarthrosis of the Hip: Comparison with Indomethacin". Br. Med. J. 4, 398. MILLS, S. B., BLOCH, M. and BRUCKNER, F. E. (1973) "Double-blind Cross-over Study of Ketoprofen and Ibuprofen in Management of Rheumatoid Arthritis". Br. Med. J. 4, 82. ZUTSHI, D. W., MARR, S., BLOCH, M. and MASON, R. M. (1973) "Double-blind Cross-over Study of Orudis and Placebo in Fifty Patients with Rheumatoid Arthritis". Rheumatol. Rehabil 12, 62-7. BENNETT,
Downloaded from http://rheumatology.oxfordjournals.org/ at Cornell University Library on July 13, 2015
The incidence of adverse reactions was comparable with both drugs, but appeared to be rather more severe with phenylbutazone, despite the fact that patients with previous phenylbutazone intolerance had been excluded. Three patients stopped treatment after 1 week on phenylbutazone and only one whilst on ketoprofen. In this study ketoprofen was used at a higher dose of 200 mg daily and for a longer period than in some of the previous trials (Cathcart et al., 1973; Gyory et al., 1972; Mills et al., 1973) although Bresnihan et al. (1974) also used 200 mg daily but only for two weeks, and these factors probably contributed to the problems of dyspepsia and gastrointestinal side-effects. The results of this short-term trial have demonstrated that phenylbutazone 300 mg daily is a more effective anti-inflammatory drug than ketoprofen 200 mg daily for treatment of patients with ankylosing spondylitis and furthermore adverse reactions remain a problem with both drugs.
