A Comparison of Oral Prednisolone Given as Single or Multiple Daily Doses for Active Proctocolitis J. POWELL-TUCK, R. L. BOWN & J. E. LENNARD-JONES St. Mark's Hospital, London, England
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Powell-Tuck, J., Bown, R. L. & Lennard-Jones, J. E. 4 comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis. Scand. J. Gastroent. 1978, 13, 833-837. Forty mg has been shown to be the optimal daily dosage of prednisone for outpatients requiring oral steroids for active proctocolitis. AIthoiigh daily doses of oral steroids are commonly divided, a single dose each morning causa less adrenal suppression and is more convenient to take. A randomized controlled trial has been performed on patients with proctocolitis, in which 23 received 4 0 mg prednisolone each morning as one dose, and 22 received 10 mg four times a day, over two weeks. Physicians unaware of the dosage schedule scored the disease activity and assessed the steroid side-effects when the patient entered the trial, at day 7 and at day 14. Of those taking the divided dose the disease improved in 17 and failed to improve in five. No side-effects were observed in ten patients. ,Of those receiving a once daily regimen, 17 improved and six did not. Nine patients had no side-effects. Further assessment showd no difference between the two groups either in response rate or side-effects produced. When oral steroids are indicated for active proctocolitis, 40 mg prednisolone, as a single dose each morning can be recommended.
Key-words: Activity score; prednisolone; proctocoli tis; single daily dose; steroid sideeffects J. Powell-Tuck, M E MRCP, St Mark's Hospital, City Road, London ECl V 2PS, England
In a trial comparing three dosages of prednisone (20 mg, 40 mg, and 60 mg) given to outpatients with active proctocolitis, 40 mg daily given as four doses of 10 mg was shown to be best, taking into account both the improvement achieved and the side-effects observed (1). Although for active colitis prednisolone is generally administered by divided dose, a single dose each day is more convenient for most patients and is known to produce less adrenal suppression (3). The purpose of this study is to assess whether the once daily regimen with its apparent advantages is as effective therapeutically as the already proven divided dose regimen.
PATIENTS AND METHODS A single-blind controlled trial has been performed on outpatients and inpatients treated at St. Mark's Hospital between June 1975 and December 1977.
The patients included were those who gave their consent, had active rocto to colitis with no proximal limit of the disease visible at sigmoidoscopy,and for whom oral steroid therapy seemed appropriate. In each case the diagnosis was confirmed by the histological assessment of'several rectal biopsies, and the extent of disease was assessed by double-contrast barium enema. Patients were excluded if they were already taking oral steroids or azathioprine. Restricted randoriization allocated the patients to two groups, one given prednisolone 10 mg four times a day and the other prednisolone 40 mg in one dose each morning. Patients already taking Salazopyrin continued this drug in unaltered dose during the study, and the restriction on the randomization ensured that the groups contained similar numbers of such patients, and were of similar size. Each patient was seen at entry to the trial (day 0) and day 7. If, at day 7, there was either cause for
834
J. Powell-Tuck. R . L . Bown & J. E. Lennard-Jones
Table I. The composition of the series Extent *
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
Treatment
No. & Sex
Age mean? S.D.
10 mg 4 x daily
16 M 6F
215.8
40 mg once daily
12 M 11 F
45.9 44. I 14.3
Salazo.
No Salazo.
Extensive
Substantial Proctosigmoiditis
16
6
10
7
5
15
8
I
6
10
~-
‘Extensive-involving at least hepatic flexure and distally. Substantial-involving the transverse or left colon and distally. Proctosigmoiditis-involving the rectosigmoid.
clinical concern or, on the other hand, a very marked improvement, the trial was stopped. All other patients continued with the unchanged treatment until day 14, when they were seen again. The trial then finished and treatment was continued according to individual needs. For their convenience seven patients were seen on the first and 14th days of the study only. Provision was made for the removal from the study of patients in whom steroid sideeffects became troublesome. Clinicians unaware of the treatment group assessed the activity of the colitis and any steroid sideeffects by using special assessment sheets on day 0 and 7 and 14. Table I11 shows the system used for scoring symptoms and signs. Blood was taken at each visit for haemoglobin, white cell count, ESR and serum albumin. The side-effects sought on each occasion were those in Table IV. After the trial was completed results were classified as remission, improved, no change, or worse. ‘Remission’ was defined as a symptom score of zero, ‘improved‘ as a reduction in the total score by two or more points, ’no change’ as a fluctuation of the total score by one point or less, and ’worse’ as an increase of two or more.
The composition of the groups is compared in Table I. Three patients in each group were suffering a first attack of colitis. The initial severity of the colitis in the two groups can be compared in Fig. 1 and Table 111. RESULTS Table I1 shows the overall results in the two groups. Table I11 shows the mean results for the two groups at day 0, 7 and 14 for each item, scorkd as indicated. Fig. 1 shows the total scores for each patient at the three times of assessment. The results of the haemoglobin, white cell count, ESR and serum albumin were all examined, and no difference or trend between the groups was detected. Table N shows the side-effects observed together with the numbers of each observation made. Hypertension was seen in fewer patients in group B than group A, but this difference did not achieve statistical significance as measured by Fisher’s exact test (p= 0.059). No other statistically significant differences were seen.
DISCUSSION
The administration of steroids in divided doses through the day is a tradition presumably based on Composition of the series the plasma prednisolone half life of about 2+ hours Forty-five patients were studied, 42 outpatients (4). In fact, steroids accumulate in inflamed tissue, and three inpatients. Two patients were excluded and their anti-inflammatory effect persists longer because the data collected were inadequate, apd than might be expected from plasma levels (2). Once three other patients were not included because they daily administration of a steroid drug in the morning were assessed by a clinician aware of the treatment produces less adrenal suppression than the same they were receiving. Exclusion of these patients did dose given divided throughout the day (3). not influence the results. The result of the trial shows no detectable differ-
Oral Prednisolone for Colitis
835
Activity score 16
15 14
X
\
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
13 12 11 10 9 8
7 6
5 4 3 2 1 0
I
0
T
7 Once daily
0
14
7 14 Four times daily
Fig. 1. The activity score at the beginning and end of the study.
Table 11. Outcome of treatment in 45 patients ~~~
Remission *
Improved
No change
Worse
10 mg 4 x daily
5
12
3
2
10
40 mg once daily
3
14
5
1
9
~~
No side-effects __--
~~~
Symptom score z e r e s e e text.
836
J. Powell-Tuck, R . L . Bown & J. E . Lennardilones Table 111. The mean activity score for each attribute in the two treatment groups OM6 FOUR TIMES A D A Y
I
40M6 ONCE A DAY
6ENERAL HEALTH I
Slightly ompawed AcIlrl.S
2
reduced
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
Unable l o work
0.85
3
ABDOMINAL P A I N With bowel aclmons
I
Pvo1onp.d
2
0.18
BBWEl FREQUENCY 1-1
I
,s
2
STBOL CONSISTENCY Semi formed
I
Liquid
2
BLOOD IN STOOL T,.E*
I
More than trace
2
ANOREXIA NAYSEA/VOMITIN6
0
ABOOMINAl TENDERNESS Mild
I
Marked
2
Rebound
3
EYE INFLAMMATION ARTHRAL61A O R A L ULCERATION RELATEB SKIN L E S I O N S
"...
1 mild 1
*.
0,
0.20
0 a03
I >I
2
BODY TEMPERATURE 37 1 - 3 8
1
> 31
2
SI6WOIDOSCOPY NDn Haemorrhagic
0
Friable
I
S p 0 n 1 i n . 0 ~ 1 blmeding
2
0
0 .71
TOTAL
ence between the two methods of administration in ing as a single dose can be recommended for patients the number of patients responding, the quality of the with active proctocolitis needing oral corticosteroid response, the speed at which the response occurs, or treatment. the number of side-effects observed. Because patients generally find a once daily regimen more convenient, and because adrenal suppres- ACKNOWLEDGEMENTS sion is less than with a multiple small dose regimen, The authors acknowledgethe assistance of Dr. N. A. 40 mg of prednisolone given by mouth each morn- Buckell, Dr. W. R. Burnham, Dr. S.R. Gould, Dr.
Oral Prednisolone for Colitis
837
Table IV. Steroid side-effects seen in patients receiving either prednisolone 10 mg fcur times a day or 40 mg once daily over two weeks ~
S /E
seen
~~
~~~~~~
No. observations
S/E seen
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
4 0 mg once daily
increased appetite euphoria or severe depression dyspepsia mooning hirsutism acne striae oral candidiasis oedema hypertension * glycosuria hypokalaemiat
5 1
3 3 0 1 0 0 2 0 0 2
19 18 18 19 18 18 18 18 18 18 8 15
No. observations 10 mg 4 x daily
2 0 3 4 0 2 0 0 2 4 0 2
19 19 19 19 19 19 19 19 19 19 7 9
* > l o mm rise in diastolic compared with day 0. t
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
Powell-Tuck, J., Bown, R. L. & Lennard-Jones, J. E. 4 comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis. Scand. J. Gastroent. 1978, 13, 833-837. Forty mg has been shown to be the optimal daily dosage of prednisone for outpatients requiring oral steroids for active proctocolitis. AIthoiigh daily doses of oral steroids are commonly divided, a single dose each morning causa less adrenal suppression and is more convenient to take. A randomized controlled trial has been performed on patients with proctocolitis, in which 23 received 4 0 mg prednisolone each morning as one dose, and 22 received 10 mg four times a day, over two weeks. Physicians unaware of the dosage schedule scored the disease activity and assessed the steroid side-effects when the patient entered the trial, at day 7 and at day 14. Of those taking the divided dose the disease improved in 17 and failed to improve in five. No side-effects were observed in ten patients. ,Of those receiving a once daily regimen, 17 improved and six did not. Nine patients had no side-effects. Further assessment showd no difference between the two groups either in response rate or side-effects produced. When oral steroids are indicated for active proctocolitis, 40 mg prednisolone, as a single dose each morning can be recommended.
Key-words: Activity score; prednisolone; proctocoli tis; single daily dose; steroid sideeffects J. Powell-Tuck, M E MRCP, St Mark's Hospital, City Road, London ECl V 2PS, England
In a trial comparing three dosages of prednisone (20 mg, 40 mg, and 60 mg) given to outpatients with active proctocolitis, 40 mg daily given as four doses of 10 mg was shown to be best, taking into account both the improvement achieved and the side-effects observed (1). Although for active colitis prednisolone is generally administered by divided dose, a single dose each day is more convenient for most patients and is known to produce less adrenal suppression (3). The purpose of this study is to assess whether the once daily regimen with its apparent advantages is as effective therapeutically as the already proven divided dose regimen.
PATIENTS AND METHODS A single-blind controlled trial has been performed on outpatients and inpatients treated at St. Mark's Hospital between June 1975 and December 1977.
The patients included were those who gave their consent, had active rocto to colitis with no proximal limit of the disease visible at sigmoidoscopy,and for whom oral steroid therapy seemed appropriate. In each case the diagnosis was confirmed by the histological assessment of'several rectal biopsies, and the extent of disease was assessed by double-contrast barium enema. Patients were excluded if they were already taking oral steroids or azathioprine. Restricted randoriization allocated the patients to two groups, one given prednisolone 10 mg four times a day and the other prednisolone 40 mg in one dose each morning. Patients already taking Salazopyrin continued this drug in unaltered dose during the study, and the restriction on the randomization ensured that the groups contained similar numbers of such patients, and were of similar size. Each patient was seen at entry to the trial (day 0) and day 7. If, at day 7, there was either cause for
834
J. Powell-Tuck. R . L . Bown & J. E. Lennard-Jones
Table I. The composition of the series Extent *
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
Treatment
No. & Sex
Age mean? S.D.
10 mg 4 x daily
16 M 6F
215.8
40 mg once daily
12 M 11 F
45.9 44. I 14.3
Salazo.
No Salazo.
Extensive
Substantial Proctosigmoiditis
16
6
10
7
5
15
8
I
6
10
~-
‘Extensive-involving at least hepatic flexure and distally. Substantial-involving the transverse or left colon and distally. Proctosigmoiditis-involving the rectosigmoid.
clinical concern or, on the other hand, a very marked improvement, the trial was stopped. All other patients continued with the unchanged treatment until day 14, when they were seen again. The trial then finished and treatment was continued according to individual needs. For their convenience seven patients were seen on the first and 14th days of the study only. Provision was made for the removal from the study of patients in whom steroid sideeffects became troublesome. Clinicians unaware of the treatment group assessed the activity of the colitis and any steroid sideeffects by using special assessment sheets on day 0 and 7 and 14. Table I11 shows the system used for scoring symptoms and signs. Blood was taken at each visit for haemoglobin, white cell count, ESR and serum albumin. The side-effects sought on each occasion were those in Table IV. After the trial was completed results were classified as remission, improved, no change, or worse. ‘Remission’ was defined as a symptom score of zero, ‘improved‘ as a reduction in the total score by two or more points, ’no change’ as a fluctuation of the total score by one point or less, and ’worse’ as an increase of two or more.
The composition of the groups is compared in Table I. Three patients in each group were suffering a first attack of colitis. The initial severity of the colitis in the two groups can be compared in Fig. 1 and Table 111. RESULTS Table I1 shows the overall results in the two groups. Table I11 shows the mean results for the two groups at day 0, 7 and 14 for each item, scorkd as indicated. Fig. 1 shows the total scores for each patient at the three times of assessment. The results of the haemoglobin, white cell count, ESR and serum albumin were all examined, and no difference or trend between the groups was detected. Table N shows the side-effects observed together with the numbers of each observation made. Hypertension was seen in fewer patients in group B than group A, but this difference did not achieve statistical significance as measured by Fisher’s exact test (p= 0.059). No other statistically significant differences were seen.
DISCUSSION
The administration of steroids in divided doses through the day is a tradition presumably based on Composition of the series the plasma prednisolone half life of about 2+ hours Forty-five patients were studied, 42 outpatients (4). In fact, steroids accumulate in inflamed tissue, and three inpatients. Two patients were excluded and their anti-inflammatory effect persists longer because the data collected were inadequate, apd than might be expected from plasma levels (2). Once three other patients were not included because they daily administration of a steroid drug in the morning were assessed by a clinician aware of the treatment produces less adrenal suppression than the same they were receiving. Exclusion of these patients did dose given divided throughout the day (3). not influence the results. The result of the trial shows no detectable differ-
Oral Prednisolone for Colitis
835
Activity score 16
15 14
X
\
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
13 12 11 10 9 8
7 6
5 4 3 2 1 0
I
0
T
7 Once daily
0
14
7 14 Four times daily
Fig. 1. The activity score at the beginning and end of the study.
Table 11. Outcome of treatment in 45 patients ~~~
Remission *
Improved
No change
Worse
10 mg 4 x daily
5
12
3
2
10
40 mg once daily
3
14
5
1
9
~~
No side-effects __--
~~~
Symptom score z e r e s e e text.
836
J. Powell-Tuck, R . L . Bown & J. E . Lennardilones Table 111. The mean activity score for each attribute in the two treatment groups OM6 FOUR TIMES A D A Y
I
40M6 ONCE A DAY
6ENERAL HEALTH I
Slightly ompawed AcIlrl.S
2
reduced
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
Unable l o work
0.85
3
ABDOMINAL P A I N With bowel aclmons
I
Pvo1onp.d
2
0.18
BBWEl FREQUENCY 1-1
I
,s
2
STBOL CONSISTENCY Semi formed
I
Liquid
2
BLOOD IN STOOL T,.E*
I
More than trace
2
ANOREXIA NAYSEA/VOMITIN6
0
ABOOMINAl TENDERNESS Mild
I
Marked
2
Rebound
3
EYE INFLAMMATION ARTHRAL61A O R A L ULCERATION RELATEB SKIN L E S I O N S
"...
1 mild 1
*.
0,
0.20
0 a03
I >I
2
BODY TEMPERATURE 37 1 - 3 8
1
> 31
2
SI6WOIDOSCOPY NDn Haemorrhagic
0
Friable
I
S p 0 n 1 i n . 0 ~ 1 blmeding
2
0
0 .71
TOTAL
ence between the two methods of administration in ing as a single dose can be recommended for patients the number of patients responding, the quality of the with active proctocolitis needing oral corticosteroid response, the speed at which the response occurs, or treatment. the number of side-effects observed. Because patients generally find a once daily regimen more convenient, and because adrenal suppres- ACKNOWLEDGEMENTS sion is less than with a multiple small dose regimen, The authors acknowledgethe assistance of Dr. N. A. 40 mg of prednisolone given by mouth each morn- Buckell, Dr. W. R. Burnham, Dr. S.R. Gould, Dr.
Oral Prednisolone for Colitis
837
Table IV. Steroid side-effects seen in patients receiving either prednisolone 10 mg fcur times a day or 40 mg once daily over two weeks ~
S /E
seen
~~
~~~~~~
No. observations
S/E seen
Scand J Gastroenterol Downloaded from informahealthcare.com by Nanyang Technological University on 11/06/14 For personal use only.
4 0 mg once daily
increased appetite euphoria or severe depression dyspepsia mooning hirsutism acne striae oral candidiasis oedema hypertension * glycosuria hypokalaemiat
5 1
3 3 0 1 0 0 2 0 0 2
19 18 18 19 18 18 18 18 18 18 8 15
No. observations 10 mg 4 x daily
2 0 3 4 0 2 0 0 2 4 0 2
19 19 19 19 19 19 19 19 19 19 7 9
* > l o mm rise in diastolic compared with day 0. t
