Current Medical Research and Opinion
Vol. 3, No. 5, 1975
Alclofenac in ankylosing spondylitis
D. Y.Bulgen, M.B., B.S., M.R.C.P., and
B. L. Hazleman, M.B., B.S.,
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
M.R.C.P., Addenbrooke’s Hospital, Cambridge, England
Curr. med. Res. Opin., (1975), 3, 321.
Paper read: 6th June 1975
Summary Eighteen patients with definite ankylosing spondylitis were treated with 3 to 4 g . alclofenac daily for up to 8 months in an open trial against previous therapy. Therapeutic eficacy was greater than or equivalent to previous therapy in I0 of 18patients after 1 month and 8 patients remain on alclofenac. There was a signgcant increase in symptoms, particularly morning stiffness after I month, but they tended to improve with time. Measurement of spinal movements was not found useful. Side-effects were commoner than expected but not serious. Alclofenac may prove a useful alternative drug in the management of ankylosing spondylitis andfurther trials are indicated. Key words :Spondylitis, ankylosing - alclofenac
Introduction In the treatment of ankylosing spondylitis, the objectives are to obtain a reduction in pain and stiffness and also an increase in spinal movement and mobility. Although indomethacin and phenylbutazone have been shown to be equally effective in achieving these end results, side-effects are common and may be hazardous. Pre-pyloric ulceration may occur with indomethacin therapy’ 1 and blood dyscrasias and chromosomal abnormalities are attributed to phenylbutazone.l0 Gastro-intestinal side-effects on either drug may occur in almost 40 % of the patients.5 There seems to be a place, therefore, for an alternative antiinflammatory agent with few side-effects.’ Pain and stiffness are the predominant symptoms in ankylosing spondylitis and the patients themselves have been found to be the best discriminators of the effectiveness or otherwise of a new drug therapy :6 within a few weeks they can give an unequivocal assessment. Alclofenac has been shown to be effective as an anti-inflammatory agent in rheumatoid arthritis.’ There is no information available as to the effect of alclofenac in ankylosing spondylitis and so a preliminary open trial against previous therapy was undertaken. 32 1
Alclofenac in ankylosingspondylitis
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Methods and materials Patients Eighteen out-patients who fulfilIed the New York criteria2 of definite ankylosing spondylitis agreed to enter the trial. There were 17 men and 1 woman, all but 1 in full-time employment, and aged 24 to 63 years. Patients with sacro-iliitis associated toll@ ileitis, psoriasis, Reiter’s disease or BehWs disease were excluded, as were patients with peptic ulcer, renal or hepatic disease or blood dyscrasia. Patients were only included if the disease state was such that improvement could be expected with treatment.
with ulcerative
regional
Assessments Patients were assessed at monthly intervals by one physician and objective measurements were made by a second observer. Patients remained on their present drug therapy for 1 month and were then transferred to 1 g. alclofenac t.d.s. after food. This dosage was increased to 4 g. daily if improvement was not obtained. Disease activity and therapeutic effcacy compared to previous therapy were assessed by both patients and physician. In addition, patients were asked about pain at rest, pain on movement, and morning stiffness. Side-effects were asked for. Clinical measurements The following clinical measurements were made : (i) chest expansion. This was measured at the level of the 4th intercostal space by the method described by Moll and Wright;8 (ii) distance to$oor. The distance from the finger tips to the floor was measured with the patient bent forwards and the knees straight; (iii) occiput to wall. With the patient standing against a wall, the distance between the occiput and the wall was recorded; (iv) anteriorflexion of the lumbar spine. With the patient standing erect, 3 marks were made on the lumbar spine. The first was made at the lumbo-sacraljunction, at the spinal intersection of a line drawn through the dimples of Venus. Marks were placed 10 cm. above and 5 cm. below this mark. The patient bent as far forwards as possible and the new distance between the upper and lower marks noted. The distraction between these marks has been found to correlate closely with anterior flexion of the lumbar spine measured radiologically;’ Cv) thoracicflexion. A further skin mark was made over the 7th cervical vertebra and the distance to the mark 10cm. above the lumbo-sacral junction was measured. The difference in distance between these marks was noted when the patient attempted to arch his back;3 (vi) lateralflexion of lumbar spine. With the patient standing erect, 2 marks were made on the skin of the lateral trunk on the coronal line. One was level with a horizontal line through the xiphisternum and one level with the highest point on the iliac crest. With the patient leaning sideways as far as possible, the increase in distance between these points was measured and (vii) tenderness of the sacro-iliacjoints was noted. ;Q
Laboratory measurements The erythrocyte sedimentation rate (E.S.R.) was measured at every visit. Since alclofenac is well established, full haematological and biochemical screening was not undertaken. 322
D. Y. Bulgen and B. L. Hazleman
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Results Subjective assessments (i) Comparison with previous therapy. The response to alclofenac was assessed after 1-month’s treatment and compared with previous therapy, (Table I). Five of the 18 patients were better on alclofenac, 5 considered alclofenac as effective as their previous drug therapy, and 5 developed side-effects sufficient to cause them to stop the drug by 2 months. Of the patients able to tolerate alclofenac, 10 of 13 considered alclofenac better than or equivalent to their previous therapy after 1 month. Table I. Assessment of response to alclofenaccompared to previous therapy: 18 patients
No. patients on alclofenac
Previous therapy
Much better ~
~~
Indomethacin Phenylbutazone Other drugs
~
Better
Same
Worse
1
3 1 1
7 I
~
2
2
(ii) Assessment of symptoms. Symptoms were graded as severe, moderate, mild or no symptoms,(Table 11). After 1month onalclofenac, the symptoms were unchanged in 9 of 18 patients, worse in 7 ( ~ ~ 0 . 0and 2 ) improved ~ in 2 patients. After 3-months on alclofenac, 3 of 9 patients had fewer symptoms, 4hadmoresymptoms,and2 were unchanged. These results are not statisticallysignificant. Table U. Assessment of symptoms after 1-month’s (18 patients) and 3-months’ (9 patients) treatment with alclofenac Treatment period
None
Mild
Moderate
2 3
9
I
5
6
5 3 2
4
Severe
AN patients
Baseline After I month
Patients completing 3-months’ treatment Baseline 1 After 1 month 2 After 3 months 2
4
3 2
3
(iii) Pain at rest andpain on movement. These parameters were recorded as absent, occasionally or constantly present, (Table 111). The control of pain at rest and on movement was not altered in 13 of 18 patients after 1 month on alclofenac. Pain at rest was improved in 2 patients, but increased in 3 patients. Pain on movement was lessened in 1 patient and was increased in 4 patients. In patients completing 3-months’ treatment with alclofenac, pain control was maintained. Increasing the dose of alclofenac to 4 g. daily in 7 patients resulted in improved pain control in 2 patients. There was no statistically significant alteration in pain control in our patients after 1 month on alclofenac. 323
Alclofenac in ankylosing spondylitis
Table III. Assessment of pain at rest and pain on movement after 1-months' (18 patients) and 3-months' (9 patients) treatment with alclofenac
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Treatment period
Pain on movement
Pain at rest
AN patients Baseline After 1 month
Absent
Occasional Constant
I 8
8 6
Patients compreting 3-months' treutment Baseline 3 5 After 1 month 4 4 After 3 months 4 3
Absent
Occasional Constant
3 4
4 4
13 12
1 1 2
3 3 3
6 6 6
1 2
Objective assessments Measurements of spinal flexion and chest expansion were made by an independent observer and may be considered as objective assessments. However, they do depend on the effort which the patient exerts, which is a reflection of his interest and enthusiasm, as well as the disease activity. (i) Distance to thefloor and occiput to wall. There was no significant alteration in the distance to the floor or of the occiput to the wall in patients on alclofenac for 1 month or 3 months, (Figures 1 and 2). Figure 1. Changes in the distance from floor at 1 month for each patient: 15 patients
Figure 2. Changes in the distance of occiput to wall at 1 month for each patient: 15 patients
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D. Y, Bulgen and B. L. Hazleman
Figure 3. Changes in chest expansion at 1 month (13 patients) and at 3 months (9 patients) for each patient mi\. ‘i-
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Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Alclofenac in ankylosing spondylitis
(ii) Spinalflexion. Spinal measurements were taken after 1 month of the 13 patients who tolerated alclofenac. Eleven of 13 patients had the same or improved anterior flexion of the lumbar spine, 5 patients had the same or better thoracic flexion, and 5 and 10 had the same or better left or right lateral flexion respectively. The amounts by which the measurements changed were small, the maximum being 5 cm. The method of measurement proved relatively crude and difficult to reproduce. Chest expansion tended to improve on alclofenac but did not reach statistical significance owing to the small size of the sample. This improvement, however, was maintained at 3 months and after, (Figure 3). (iii) Morning stifness. Morning stiffness was recorded in minutes, (Figure 4). It varied from day to day and so an approximation to the nearest quarter of an hour was made. Alclofenac was found to cause a significant increase in morning stiffness (p
Vol. 3, No. 5, 1975
Alclofenac in ankylosing spondylitis
D. Y.Bulgen, M.B., B.S., M.R.C.P., and
B. L. Hazleman, M.B., B.S.,
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
M.R.C.P., Addenbrooke’s Hospital, Cambridge, England
Curr. med. Res. Opin., (1975), 3, 321.
Paper read: 6th June 1975
Summary Eighteen patients with definite ankylosing spondylitis were treated with 3 to 4 g . alclofenac daily for up to 8 months in an open trial against previous therapy. Therapeutic eficacy was greater than or equivalent to previous therapy in I0 of 18patients after 1 month and 8 patients remain on alclofenac. There was a signgcant increase in symptoms, particularly morning stiffness after I month, but they tended to improve with time. Measurement of spinal movements was not found useful. Side-effects were commoner than expected but not serious. Alclofenac may prove a useful alternative drug in the management of ankylosing spondylitis andfurther trials are indicated. Key words :Spondylitis, ankylosing - alclofenac
Introduction In the treatment of ankylosing spondylitis, the objectives are to obtain a reduction in pain and stiffness and also an increase in spinal movement and mobility. Although indomethacin and phenylbutazone have been shown to be equally effective in achieving these end results, side-effects are common and may be hazardous. Pre-pyloric ulceration may occur with indomethacin therapy’ 1 and blood dyscrasias and chromosomal abnormalities are attributed to phenylbutazone.l0 Gastro-intestinal side-effects on either drug may occur in almost 40 % of the patients.5 There seems to be a place, therefore, for an alternative antiinflammatory agent with few side-effects.’ Pain and stiffness are the predominant symptoms in ankylosing spondylitis and the patients themselves have been found to be the best discriminators of the effectiveness or otherwise of a new drug therapy :6 within a few weeks they can give an unequivocal assessment. Alclofenac has been shown to be effective as an anti-inflammatory agent in rheumatoid arthritis.’ There is no information available as to the effect of alclofenac in ankylosing spondylitis and so a preliminary open trial against previous therapy was undertaken. 32 1
Alclofenac in ankylosingspondylitis
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Methods and materials Patients Eighteen out-patients who fulfilIed the New York criteria2 of definite ankylosing spondylitis agreed to enter the trial. There were 17 men and 1 woman, all but 1 in full-time employment, and aged 24 to 63 years. Patients with sacro-iliitis associated toll@ ileitis, psoriasis, Reiter’s disease or BehWs disease were excluded, as were patients with peptic ulcer, renal or hepatic disease or blood dyscrasia. Patients were only included if the disease state was such that improvement could be expected with treatment.
with ulcerative
regional
Assessments Patients were assessed at monthly intervals by one physician and objective measurements were made by a second observer. Patients remained on their present drug therapy for 1 month and were then transferred to 1 g. alclofenac t.d.s. after food. This dosage was increased to 4 g. daily if improvement was not obtained. Disease activity and therapeutic effcacy compared to previous therapy were assessed by both patients and physician. In addition, patients were asked about pain at rest, pain on movement, and morning stiffness. Side-effects were asked for. Clinical measurements The following clinical measurements were made : (i) chest expansion. This was measured at the level of the 4th intercostal space by the method described by Moll and Wright;8 (ii) distance to$oor. The distance from the finger tips to the floor was measured with the patient bent forwards and the knees straight; (iii) occiput to wall. With the patient standing against a wall, the distance between the occiput and the wall was recorded; (iv) anteriorflexion of the lumbar spine. With the patient standing erect, 3 marks were made on the lumbar spine. The first was made at the lumbo-sacraljunction, at the spinal intersection of a line drawn through the dimples of Venus. Marks were placed 10 cm. above and 5 cm. below this mark. The patient bent as far forwards as possible and the new distance between the upper and lower marks noted. The distraction between these marks has been found to correlate closely with anterior flexion of the lumbar spine measured radiologically;’ Cv) thoracicflexion. A further skin mark was made over the 7th cervical vertebra and the distance to the mark 10cm. above the lumbo-sacral junction was measured. The difference in distance between these marks was noted when the patient attempted to arch his back;3 (vi) lateralflexion of lumbar spine. With the patient standing erect, 2 marks were made on the skin of the lateral trunk on the coronal line. One was level with a horizontal line through the xiphisternum and one level with the highest point on the iliac crest. With the patient leaning sideways as far as possible, the increase in distance between these points was measured and (vii) tenderness of the sacro-iliacjoints was noted. ;Q
Laboratory measurements The erythrocyte sedimentation rate (E.S.R.) was measured at every visit. Since alclofenac is well established, full haematological and biochemical screening was not undertaken. 322
D. Y. Bulgen and B. L. Hazleman
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Results Subjective assessments (i) Comparison with previous therapy. The response to alclofenac was assessed after 1-month’s treatment and compared with previous therapy, (Table I). Five of the 18 patients were better on alclofenac, 5 considered alclofenac as effective as their previous drug therapy, and 5 developed side-effects sufficient to cause them to stop the drug by 2 months. Of the patients able to tolerate alclofenac, 10 of 13 considered alclofenac better than or equivalent to their previous therapy after 1 month. Table I. Assessment of response to alclofenaccompared to previous therapy: 18 patients
No. patients on alclofenac
Previous therapy
Much better ~
~~
Indomethacin Phenylbutazone Other drugs
~
Better
Same
Worse
1
3 1 1
7 I
~
2
2
(ii) Assessment of symptoms. Symptoms were graded as severe, moderate, mild or no symptoms,(Table 11). After 1month onalclofenac, the symptoms were unchanged in 9 of 18 patients, worse in 7 ( ~ ~ 0 . 0and 2 ) improved ~ in 2 patients. After 3-months on alclofenac, 3 of 9 patients had fewer symptoms, 4hadmoresymptoms,and2 were unchanged. These results are not statisticallysignificant. Table U. Assessment of symptoms after 1-month’s (18 patients) and 3-months’ (9 patients) treatment with alclofenac Treatment period
None
Mild
Moderate
2 3
9
I
5
6
5 3 2
4
Severe
AN patients
Baseline After I month
Patients completing 3-months’ treatment Baseline 1 After 1 month 2 After 3 months 2
4
3 2
3
(iii) Pain at rest andpain on movement. These parameters were recorded as absent, occasionally or constantly present, (Table 111). The control of pain at rest and on movement was not altered in 13 of 18 patients after 1 month on alclofenac. Pain at rest was improved in 2 patients, but increased in 3 patients. Pain on movement was lessened in 1 patient and was increased in 4 patients. In patients completing 3-months’ treatment with alclofenac, pain control was maintained. Increasing the dose of alclofenac to 4 g. daily in 7 patients resulted in improved pain control in 2 patients. There was no statistically significant alteration in pain control in our patients after 1 month on alclofenac. 323
Alclofenac in ankylosing spondylitis
Table III. Assessment of pain at rest and pain on movement after 1-months' (18 patients) and 3-months' (9 patients) treatment with alclofenac
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Treatment period
Pain on movement
Pain at rest
AN patients Baseline After 1 month
Absent
Occasional Constant
I 8
8 6
Patients compreting 3-months' treutment Baseline 3 5 After 1 month 4 4 After 3 months 4 3
Absent
Occasional Constant
3 4
4 4
13 12
1 1 2
3 3 3
6 6 6
1 2
Objective assessments Measurements of spinal flexion and chest expansion were made by an independent observer and may be considered as objective assessments. However, they do depend on the effort which the patient exerts, which is a reflection of his interest and enthusiasm, as well as the disease activity. (i) Distance to thefloor and occiput to wall. There was no significant alteration in the distance to the floor or of the occiput to the wall in patients on alclofenac for 1 month or 3 months, (Figures 1 and 2). Figure 1. Changes in the distance from floor at 1 month for each patient: 15 patients
Figure 2. Changes in the distance of occiput to wall at 1 month for each patient: 15 patients
CIll\.
4 I
7hS-
5-
4-
4-
3-
3-
7 -
I-
2-
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0-
I-
0-
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45-
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324
1-
2-
23-
-
(0 -
0-
p
N,S.
9 unchanged
D. Y, Bulgen and B. L. Hazleman
Figure 3. Changes in chest expansion at 1 month (13 patients) and at 3 months (9 patients) for each patient mi\. ‘i-
3 motllhc
I iiiontli
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
7-
:I
2-
iiicrcilse
I-
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0-
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I-
,.
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N.S.
325
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 11/05/14 For personal use only.
Alclofenac in ankylosing spondylitis
(ii) Spinalflexion. Spinal measurements were taken after 1 month of the 13 patients who tolerated alclofenac. Eleven of 13 patients had the same or improved anterior flexion of the lumbar spine, 5 patients had the same or better thoracic flexion, and 5 and 10 had the same or better left or right lateral flexion respectively. The amounts by which the measurements changed were small, the maximum being 5 cm. The method of measurement proved relatively crude and difficult to reproduce. Chest expansion tended to improve on alclofenac but did not reach statistical significance owing to the small size of the sample. This improvement, however, was maintained at 3 months and after, (Figure 3). (iii) Morning stifness. Morning stiffness was recorded in minutes, (Figure 4). It varied from day to day and so an approximation to the nearest quarter of an hour was made. Alclofenac was found to cause a significant increase in morning stiffness (p
