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Effect of ibuprofen dosage on patient response in rheumatoid arthritis.

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135
EFFECT OF IBUPROFEN DOSAGE
ON PATIENT RESPONSE IN
RHEUMATOID ARTHRITIS
ROBERT G. GODFREY and SUSAN0 DE LA CRUZ
Ibuprofen (Motrina) is a rapid-acting, nonsteroidal, antiarthritic drug that is a propionic acid
derivative [ (+)-2-(p-isobutylphenyl)-propionic acid].
Since the first clinical studies of this drug, the trend
has been an increase in dosage. Studies by Brooks and
coworkers have shown that in healthy volunteers the
drug is tolerated in dosages up to 1800 mg/day (1)
and 2400 mg/day (unpublished study). Dosages of
1200 mg/day or less have been demonstrated to provide symptomatic relief in rheumatoid arthritis (2-5).
Whether this relief came from analgesia or from an
antiinflammatory effect remained a question.
The purposes of the present study were a) to
compare the tolerance of 1200 mg/day and 2400 mg/
day of ibuprofen over a 4-week treatment period in
patients with rheumatoid arthritis (RA); and b) to
compare effects of these two dosage levels on selected
parameters of disease activity. The study was conducted as a 4-week, double-blind comparative trial
with tolerance and antiarthritic effects assessed at
weekly intervals.
From the University of Kansas Medical Center, Kansas
City, Kansas, and the Kansas City Veterans Administration Hospital, 4801 Linwocd Boulevard, Kansas City, Missouri 64128; and
the Clinical Pharmacology Unit, University of Puerto Rico
School of Medicine, Puerto Rico Medical Center, Rio Piedras,
Puerto Rico.
Presented in part a t the VI Pan-American Congress of
Rheumatic Diseases, Toronto, June 16-21, 1974.
Robert G. Godfrey, M.D.: Chief, Arthritis Section
KCVAH. and Assistant Professor of Medicine, University of
Kansas School of Medicine; Susano de la Cruz, M.D.: Assistant
Professor of Medicine, Department of Medicine, University of
Puerto Rico School of Medicine, Rio Piedras, Puerto Rico.
Address reprint requests to R. G. Godfrey. M.D., Arthritis Section, Kansas City Veterans Administration Hospital,
4801 Linwood Boulevard, Kansas City, Missouri 64128.
Submitted for publication August 12, 1974; accepted
November 18, 1974.
After being informed of the purposes a n d hazards
of the study, a n d signing their consent to participate, 41
patients were entered i n t o the study by the three participating clinics. The patients were selected to have classic or
definite RA according to the American Rheumatism Association ( A M ) criteria a n d exclusions (6). Patients were
not included if they had serious o r interfering illness, if
they were pregnant or likely to become pregnant during
the study, or if they were receiving interfering therapy.
None of the patients h a d been treated with gold, corticosteroids, or antimalarials.
T h e patients were allocated by use of random numbers to either the 1200 mg/day or the 2400 mg/day treatment groups. T h e 20 in the 1200-mg group a n d the 21 i n
I n a 4week double-blind trial in 41 patients
with rheumatoid arthritis, ibuprofen (Motrina) decreased the swollen joint count significantly at a
dosage level of 2400 mg/day, but not at 1200 mg/day.
Ibuprofen probably does have antiinflammatory effects in man, but only at higher dosages; antiarthritic
activity at lower dosages reflects primarily analgesia
and perhaps antipyretic effects. Complaints and
clinical laboratory findings did not differ significantly
between the dosage groups.
Arthritis and Rheumatism, VoL 18, No. 2 (March-April 1975)
MATERIALS AND METHODS
GODFREY AND DE LA CRUZ
136
Table 1. Complaints Related to Ibuprofen Therapy
Complaint
1200 mg/day
2400 mg/day
Definitely
or Probably Possibly
Related
Related
Definitely
or Probably Possibly
Related
Related
Gastrointestinal
Epigastric pain
Nausea
.
Abdominal distress
Flatulence or feeling
of fullness
Diarrhea or frequent
bowel movements
Central nervous
system
Drowsiness
Insomnia
Nervousness
Fatigue
Dizziness
Skin
Eruption
Pruritus
Other
Myalgia
Excessive thirst
Genitourinary
infection
3
0
2
4
0
1
0
1
0
0
0
0
0
1
0
0
0
0
2
1
0
1
0
0
1
0
0
0
4
1
0
2
0
0
1
0
3
0
0
0
1
0
0
0
2
1
1
0
1
1
0
2
0
1
0
1
0
0
0
1
0
0
0
1
the 2400-mg group did not differ significantly in distribution according to sex, race, ARA classification, number of
symptoms at the start of the study, or duration of arthritis.
The 2400-mg group did tend to be somewhat heavier and
younger and to have had an earlier onset of RA. T h e
mean age in the 1200-mg group was 57.1 years and in the
2400-mg group 46.5 years; the mean age at onset had been
47.3 years and 34.4 years, respectively.
Several patients in both groups had other diseases,
including hypertension in 2 in each group, cardiovascular
disease in 1 in each group, and iron deficiency anemia in
1 in the 1200-mg group. One patient was dropped from
the 1200-mg group because of acute onset of congestive
heart failure, which was not considered drug-related, and
one was dropped from the 2400-mg group when he was
discovered to be using interfering therapy.
The ibuprofen dosage regimen was two tablets four
times daily for 4 weeks. The 150-mg or 300-mg ibuprofen
tablets were identical in appearance and blind-labeled.
Patients were asked to refrain from taking any form of
salicylate, and blood salicylate checks at weeks 2 and 4
indicated generally good compliance. Of 77 assays for salicylate, only three showed values of more than 5 mg/100
ml. When supplemental analgesia could not be avoided,
patients used occasional 65-mg propoxyphene capsules and
recorded the number of capsules taken.
RESULTS
Tolerance of ibuprofen therapy was evaluated
by nondirective questioning about complaints at each
weekly visit, and by repeated laboratory determinations. Table 1 shows the incidence of complaints that
were judged by the physician to be possibly, probably,
or definitely related to treatment. Most complaints
were mild. T h e only severe symptoms were nervousness and dizziness in one patient in the 1200-mg
group, who withdrew from the study because of these
symptoms.
Clinical laboratory determinations included
screening studies for liver and renal function, blood
cell and platelet counts, urinalyses, and tests for occult
blood in stools. Complete studies were done at weeks
0 and 4, and partial studies at week 2. Stools were
tested for blood weekly. Neither individual observations nor statistical analyses showed significant differences between the treatment groups, and there was no
evidence suggesting substantial toxicity from either
dosage of ibuprofen. Some patients in both groups
changed categories from normal to low, or from low
to normal hematocrit. Generally there was a greater
tendency to go from normal to low rather than low
to normal. Overall, 10 patients changed categories by
decreasing from normal to low, whereas only 5 increased from low to normal.
Albuminuria and glucosuria appeared in 1 patient in each group during the study. Microscopic
hematuria was present at week 4 in 2 of 21 patients
with initially negative values; on the other hand, 6 of
13 with initially positive microscopic hematuria had
negative values at week 4.
Stool guaiac determinations were infrequently
positive throughout the study and were similar in f r e
quency in the two treatment groups. N o guaiac values
were greater than 2+.
Weekly evaluations for efficacy included assessment by standard methods of painful joint count;
swollen joint count; duration of morning stiffness;
time after arising until onset of fatigue; Westergren
erythrocyte sedimentation rate (ESR); grip strength;
and timed 50-foot walk. I n addition, each week during
treatment the patient and the physician compared the
overall disease status with that at the beginning of
the study, rating the condition as much worse, worse,
same, better, or much better. Statistical analyses i n
cluded the chi square test and analysis of variance
or of covariance.
Table 2 shows the mean number of swollen
joints, which decreased significantly by week 4 only
in the 2400-mg group. Direct joint counts were used
137
EFFECT OF IBUPROFEN DOSAGE IN RA
Table 2. Mean Number Swollen Joints Before and During Zbuprofen Therapy
1200 mg/day
Mean,
Mean,
Patients Week 0 Followup
2400 mg/day
No. of
No.of
Followup
1
2
3
4
19
20
17
12.3
12.1
18
12.6
12.6
11.6
11.5
11.8
12.1
P*
Patients
0.14
0.33
21
0.61
20
0.72
20
21
Mean,
Mean,
Week 0 Followup
10.3
10.3
10.9
10.9
9.1
8.5
8.3
8.1
P*
0.23
0.19
0.12
0.05
"Paired t test.
without a weighted index. Although the mean number of painful joints showed a gradual diminution
during the study in both groups, the mean decrease
was not statistically significant in either group.
Patient and physician assessments, grip strength,
and duration of morning stiffness all tended to improve during treatment, but differences between
groups did not reach statistical significance for any
of these efficacy endpoints.
DISCUSSION
Neither the incidence of complaints nor the results of clinical laboratory determinations differed
significantly between the 1200 mg/day and 2400 mg/
day dosage groups in this 4-week study.
Clinical evaluative endpoints of arthritis activity generally failed to discriminate between the dosage
levels despite trends seeming to favor the higher
dosage level. Only the swollen joint count showed a
significant decrease in the 2400-mg group which was
not seen in the 1200-mg group. Because swollen joints
probably reflect primarily inflammation, the difference
between the two groups may indicate a n antiinflammatory effect of ibuprofen at higher dosage levels as
distinct from analgesic and antipyretic activities at
lower dosages, similar to the effects seen with aspirin
(7).
Although most of the early studies of ibuprofen in rheumatoid arthritis, including those reviewed
by Huskisson et a1 (2), indicated antiarthritic activity
for this drug even at dosages of 600 or 900 mg/day,
there has been a question as to whether the relief reported by the patients represented antiinflammatory
activity. I n their first study in 6 patients with RA,
Dick and coworkers (8) did not find a significant alteration in ssmTcknee joint uptake when ibuprofen
was given in a dosage of 1200 mg/day. I n a subsequent larger study under strictly controlled conditions
using ambulatory inpatients with RA, there was an
unequivocal drug effect, with OamTcuptake falling
significantly in both knees in patients receiving 1200
mg/day (3). Brooks and coworkers (1) found that 1800
mg/day of ibuprofen protected against skin inflammation induced by topical tetrahydrofurfuryl nicotinate
in healthy men, whereas ibuprofen dosages of 1200
or 1500 mg/day failed to do so.
We conclude that ibuprofen does have clinically significant antiinflammatory activity in man, but
only in dosages in the upper end of the range of 9002400 mg/day currently recommended in the United
States. Antiarthritic activity of the drug at lower d o s
ages probably reflects primarily analgesia, and perhaps
antipyretic effects, rather than suppression of inflammation.
REFERENCES
1. Brooks CD, Schlagel CA, Sekhar NC, et al: Tolerance
and pharmacology of ibuprofen. Curr Ther Res 15:180190. 1973
2. Huskisson EC, Hart FD, Shenfield GM, et al: Ibuprofen: a review. Practitioner 207:639-643, 1971
3. Deodhar SD, Dick WC, Hodgkinson R, et al: Measurement of clinical response to anti-inflammatory drug
therapy in rheumatoid arthritis. Q J Med 42:387-401,
1973
4. Regalado RG, Fowler PD: Butacote and Brufen in the
treatment of rheumatic diseases. A multi-centre study of
effectiveness and tolerability. J Intern Med Res 2:115124, 1974
5. Pavelka K, Susta A, Vojtisek 0, et al: Double-blind comparison of ibuprofen and phenylbutazone in the shortterm treatment of rheumatoid arthritis. Rheumatology
and Rehabilitation 12:68-73, 1973
6. Ropes MW, Bennett GA, Cobb S, et al: 1958 Revision
of diagnostic criteria for rheumatoid arthritis. Bull
Rheum Dis 9:175-176, 1958
7. Mills JA: Nonsteroidal anti-inflammatory drugs. N Engl
J Med 290:781-784, 1974
8. Dick WC, Nuki G, Whaley K, et al: Some aspects in
the quantitation of inflammation in joints of patients
suffering from rheumatoid arthritis. Symposium on Ibuprofen. Supplement to Rheumatol Phys Med. London,
Bailliere, Tindall & Cassell, 1970, pp 40-47
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