Efficacy of Diclofenac in Osteoarthritis

Experience in the United States

JOHN R. WARD, M.D. Salt Lake Cify, Utah

The role of diclofenac sodium in patients with symptomatic osteoar- thritis of the hip or knee has been evaluated in five prospective, randomized, double-blind, controlled trials with placebo, aspirin, and naproxen conducted in the United States. The objectives were to evaluate efficacy, tolerability, and safety. In these trials, diclo- fenac, 100 or 150 mg daily, was more effective than aspirin, 2.4 or 3.6 g daily, and as effective as naproxen, 500 mg daily. In individual trials, there were no statistically significant differences in the inci- dence of adverse effects between treatment groups. For all trials combined, the dropout rate due to adverse effects was similar for each treatment group. The dropout rate because of an unsatisfac- tory response was lowest for patients treated with diclofenac.

Treatment of osteoarthritis with nonsteroidal anti-inflammatory drugs is generally accepted as useful in relieving symptoms and improving func- tion. A number of nonsteroidal anti-inflammatory drugs are available for the treatment of osteoarthritis, and many clinicians prefer these drugs to salicylates or simple analgesics [l]. Efficacy is presumably related to their anti-inflammatory action in addition to their analgesic effect, although there is no convincing data in patients that these treatments either retard or accelerate the basic process of cartilage degeneration.

It would be useful to have comparisons with all alternative drugs used in osteoarthritis, but cost and time limit the feasibility of such studies. In the United States, diclofenac sodium has been evaluated in patients with symptomatic osteoarthritis of the hip or knee in five randomized, double- blind, controlled trials with placebo, aspirin, and naproxen, as well as in two open-label, long-term trials. The objectives were to evaluate efficacy, tolerability, and safety.

PATIENTS AND METHODS

Patients. Patients with symptomatic osteoarthritis of the hip or knee were enrolled in a study if they satisfied the following criteria: diagnosis of osteoar- thritis; symptomatic disease of at least three months’ duration; aged 40 to 75 years; in functional class II or Ill according to the American Rheumatism As- sociation’s classification [2]; flare in symptoms with placebo treatment; and absence of contraindications. Patients were excluded if they had arthritis other than osteoarthritis or another rheumatic disease; active gastrointestinal disease such as peptic ulcer, gastritis, or inflammatory bowel disease; liver disease; renal disease; hematologic disease; other significant concomitant illness; or a hypersensitivity to aspirin or nonsteroidal anti-inflammatory drugs. Additional exclusion criteria were concomitant use of analgesic drugs, nonsteroidal anti-inflammatory drugs, or cotticosteroid therapy; intra-articular injection of corticosteroids four to 12 weeks before enrollment into the study; and previous noncompliance with other treatments. Potential candidates for

From the Department of Internal Medicine, Division of Rheumatology, University of Utah School of Medicine, Salt Lake City, Utah. Requests for re- prints should be addressed to Dr. John R. Ward, School of Medicine, Medical Center, 50 North Med- ical Drive, Salt Lake Cii, Utah 84132.

April 28, 1986 The Amedcan Journal of Medlclna Volume 80 (suppl 4B) 53

TABLE I Design of Double-blind Trials of Diclofenac in Patients with Osteoarthritis

Trial

Hip Hip

Knee Knee

Hip, knee

Diclofenac Comparative Duration Dosage Treatment (weeks)

50 mg t.i.d. Placebo 6 50 rni b.i.d. or Aspirin, 2.4 or 12

t.i.d. 3.6 g/day 50 mg Cd. Placebo 6 50 mg b.i.d. or Aspirin, 2.4 or 12

t.i.d. 3.6 g/day 75 mg b.i.d. Naproxen, 10

250 mg b.i.d. Placebo

t.i.d = three times daily; b.i.d. = two times daily.

TABLE II Number of Patients Evaluated per Treatment Group in Double-Blind Trials

Diclofenac Aspirin Napmxen Placebo

Efficacy Hip Hip Knee Knee Hip, knee Total

Safety Hip Hip Knee Knee Hip, knee Total

15 71 56

152 90

384

24 78 73

188 94

457

64

144

208

78

187

265

a5

a5

92 92

14

37

80 131

22

72

92 186

joint replacement were also not permitted to enter the stud- ies. Evaluation of Efficacy. Efficacy was evaluated on the basis of 11 variables measured in studies of osteoarthritis of the hip, and nine variables measured in trials of osteoarthritis of the knee. In this review, six assessments were considered as the principal efficacy variables, including investigators’ assessment of disease severity and patients’ assessment of disease severity, each rated on a scale of 0 (no symptoms) to 10 (most severe symptoms); joint pain on active motion, rated by patients on a scale of 0 (no pain) to 10 (most severe); 50-foot walking time; range of motion (range of painless pas- sive flexion); and pain on palpation, rated by patients on a scale of 0 (no pain) to 4 (most severe). Other assessments were night pain, weight-bearing pain, range of passive inter- nal rotation (for patients with osteoarthritis of the hip only), range of passive external rotation (for patients with osteoar- thritis of the hip), knee circumference (for patients with osteo- arthritis of the knee only), and intermaileolar distance (for pa- tients with osteoarthritis of the hip). In all studies, global eval- uations of efficacy were also made by the investigators and patients at the final visit; these were rated on a scale of 1 (marked improvement) to 5 (deterioration).

SYMPOSIUM ON DICLOFENAC SODIUM AND INFLAMMATORY DISEASE-WARD

Study Design. The treatment schema of the five double- blind studies is shown in Table I. During the washout period of two to 14 days, patients were observed for flare of symp- toms, a requirement for entry into double-blind treatment. Ef- ficacy measurements and evaluations of tolerability and safety were recorded at various intervals, depending on the particular protocol. Efficacy analyses were made at one week after treatment and then at time points of two or more weeks to adjust for the gradual increase in discontinuation during the trial and the different rates of discontinuation between treat- ment groups. Statistical Evaluations. Treatment group comparability for demographic characteristics was tested using two-sample t tests, Chi-square tests, and exact probability tests. Baseline comparability of each treatment group for the principal effi- cacy assessments was examined using two-sample t tests. For all of the principal efficacy variables, within-treatment comparison of changes from baseline was made by paired t tests or the Wilcoxon signed-rank test; between-treatment comparisons were made with two-way analysis of covari- ante. This test was also used in the analysis of the study effect and the drug-by-study interaction. Drug-by-study inter- action measures the consistency of drug differences over study centers. interaction is present if there is a lack of con- sistency. in addition to the primary analysis of the investigator assessment of disease severity for efficacy-evaluable pa- tients, an additional analysis was performed for ail patients treated.

Differences between treatment groups with regard to safety variables were analyzed by either Chi-square tests or exact probability tests.

Statistical significance was declared if p ~0.05.

RESULTS

Efficacy: bauble-Blind Studies. A total of 1,000 pa- tients were treated in the double-blind phases of the trials. Of these, approximately 70 percent were women, 90 per- cent were over 50 years of age, and approximately 80 percent were in the American Rheumatism Association’s functional class ii. The mean duration of disease ranged from seven to 11 years. Table Ii shows the number of patients included in the evaluations of efficacy and safety. In each trial, the patients eligible for the efficacy analysis were comparable between treatment groups on baseline characteristics.

Diclofenac versus placebo (hip): in a six-week trial comparing diciofenac with placebo in patients with osteo- arthritis of the hip, diciofenac was administered at a dos- age of 150 mg daily. Diciofenac was statistically superior to placebo in terms of both investigators’ and patients’ assessments of disease severity and in measurements of joint pain on motion or palpation at one week of treatment and at exit from the study (Table Ill). The increase in joint flexion also was statistically superior with diciofenac at one week.

Diclofenac versus aspirin (hip): Diclofenac at a dos- age of 100 or 150 mg daily was compared with aspirin

54 April 29, 1996 The Amerlcen Journal of Medicine Volume 99 (suppl 48)

SYMPOSIUM ON DICLOFENAC SODIUM AND INFLAMMATORY DISEASE-WARD

TABLE III Probability Levels for Between-Treatment Differences with Diclofenac: Osteoarthritis of Hip

Diclolenac versus Placebo Diclofenac versus Aspirin

Variable 1 week l-6 weeks 1 week 2-4 weeks 6-12 weeks

Principal Investigators’ assessmel Patients’ assessment Joint pain on motion Joint pain on palpation Joint flexion Fifty-foot walking time

Secondary Night pain Weight-bearing pain Internal rotation External rotation lntermalleolar distance

nt 0.002 0.003 0.014 0.005 0.026 0.016 0.001 0.020 0.011 NS

NS NS

NS *

NS NS NS NS

0.047 NS 0.015 NS 0.046 NS 0.01 NS

0.036 NS NS

NS NS NS

0.026 NS

NS NS

0.025 0.045

NS

NS NS NS NS NS

0.001 0.007

NS 0.026

NS

0.004 0.003

NS NS

0.021

At all points of statistical significance, diclofenac was better than comparative agents. NS = Not statistically significant for p 50.05. l = Statistically significant (p ~0.05) drug-by-study interaction.

given at 2.4 or 3.6 g daily in a 12-week trial of patients Gth osteoarthritis of the hip. Statistically significant differences favoring diclofenac were found for one of the six principal efficacy variables at one week of treatment and for four principal variables at two to four weeks of treatment (Table Ill). Improvement in the investigators’ assessment of dis- ease severity, flexion, walking time, pain on palpation, and internal and external rotations favored diclofenac at each visit analyzed. Only relief of night pain was consistently better in patients treated with aspirin. Of the patients eval- uated, 70 percent of those treated with diclofenac re- ceived 150 mg per day whereas 69 percent of those treated with aspirin received 3.6 g per day.

Diclofenac versus placebo (knee): Diclofenac given

at 150 mg per day was compared with placebo in a six- week trial involving patients with osteoarthritis of the knee. There were statistically significant differences favoring diclofenac for three of the six principal efficacy assess- ments at one week of treatment and for three principal variables at later time points (Table IV). Treatment differ- ences for all variables favored diclofenac, regardless of statistical significance.

Diclofenac versus aspirin (knee): In the comparison between diclofenac and aspirin, patients with osteoarthri- tis of the knee received either 100 or 150 mg daily of diclo- fenac, or 2.4 or 3.6 g of aspirin. The duration of the study was 12 weeks. After one week of treatment, there were statistically significant differences favoring diclofenac for

TABLE IV Probability Levels for Between-Treatment Differences with Diclofenac: Osteoarthritis of Knee

Variable

Diclolenac versus Placebo Dlclofenac versus Aspirin

1 week 2-3 weeks 4-6 weeks 1 week 2-4 weeks 6-12 weeks

Principal investigators’ assessment Patients’ assessment Joint pain on motion Joint pain on palpation Joint flexion Fifty-foot walking time

Secondary Night pain Weight-bearing pain Knee circumference

0.001 0.001 0.001

NS NS NS

0.013 l

0.020 NS NS

l

NS 0.001 NS 0.001

0.050 0.001 0.008 0.016

NS 0.028 NS 0.028

t

0.004 NS NS NS

0.005 NS NS

0.002 NS

0.033

0.003 0.001 NS

NS NS

l

0.040 0.004

l

0.001 NS 0.001 0.008

NS NS

At all points of statistical significance, diclofenac was better than comparative agents. NS = Not statistically significant for p 10.05. l = Statistically significant (p 50.05) drug-by-study interaction.

April 26,1986 The American Journal ol Medicine Volume 80 (suppl4B) 55

SYMPOSIUM ON DICLOFENAC SODIUM AND INFLAMMATORY DISEASE-WARD

TABLE V Incidence of Adverse Effects by Treatment Group

Trial Treatment Number Treated Dosage

Incidence (percent)

Hip

Hip

Knee

Knee

Hip, knee

Diclofenac 24 Placebo 22 Diclofenac 78 Aspirin 78 Diclofenac 188 Aspirin 187 Diclofenac 73 Placebo 72 Diclofenac 94 Naproxen 92 Placebo 92

150 mg 38 - 32

100 or 150 mg 24 2.4 or 3.6 g 39 100 or 150 mg 30 2.4 or 3.6 g 36

150 mg 27 - 15

150 mg 37 500 mg 26

- 22

m Diclofenac

Placebo

0 Aspirin

Unsatisfactory Treatment Response

Adverse Effects

rrgure 1. rreatment-relatea reasons tar arscontmuafion ot therapy among patients with osteoarthritis (double-blind studies). Reprinted. with permission from Semin Arthritis Rheum 1985; 15: 106-110.

all six of the principal efficacy assessments (Table IV). Significant differences favoring diclofenac were main- tained for three of these variables at later time points. In most treatment comparisons of other variables, the trend favored diclofenac but did not reach statistical signifi- cance. Of the patients evaluated, 69 percent in the diclo- fenac group received 150 mg per day, and 72 percent of aspirin-treated patients received 3.6 g per day.

Diclofenac versus naproxen versus placebo (hip, knee): Diclofenac, 150 mg daily, was compared with naproxen, 500 mg daily, and placebo in a lo-week study of patients with osteoarthritis of the hip or knee. Both ac- tive treatments were superior to placebo, showing results similar to those previously described in the placebo com-

parisons. Naproxen and diclofenac produced comparable improvement from baseline in the efficacy variables for patients with osteoarthritis of the knee. Diclofenac was superior (p ~0.05) to naproxen in three variables (pain on palpation, night pain, and weight-bearing pain) at one week or at three to five weeks of treatment. Diclofenac and naproxen produced equivalent improvement in pa- tients with osteoarthritis of the hip; there were no signifi- cant differences between treatments.

For all double-blind trials, the results of the additional analysis done for all patients treated were consistent with those obtained in the primary analysis of the investigator assessment of disease severity in efficacy-evaluable pa- tients. Safety: Double-Blind Studies. There were no statisti- cally significant differences between treatments in individ- ual trials in the incidences of adverse effects (Table V).

A major concern with the use of any of the nonsteroidal anti-inflammatory drugs is their potential to cause gastro- intestinal toxicity. In these clinical trials, the most fre- quently reported adverse effect for any treatment group involved the digestive system. Gastrointestinal adverse effects occurred in 20 percent of all diclofenac-treated patients and in 21, 16, and 10 percent of all patients treated with aspirin, naproxen, and placebo, respectively. More than 40 percent of the gastrointestinal adverse ef- fects reported were mild in severity. Efficacy and Safety: Long-Term Studies. Diclofenac was administered in an open-label manner at dosages of 50 mg two or three times a day to 562 eligible patients from double-blind trials. The total duration of the study was 46 weeks.

Efficacy evaluations for 555 patients indicated that im- provement in disease symptoms was maintained in at least 70 percent of the patients.

The incidence of adverse effects with diclofenac was similar to that in double-blind trials. Thirty-nine of 156 (25 percent) patients in one long-term trial and 130 of 406 (32 percent) patients in another trial reported adverse effects. Gastrointestinal symptoms occurred most often. Discontinuation of Treatment. Discontinuations be- cause of unsatisfactory therapeutic response and adverse effects provide additional measurements of drug efficacy and safety, respectively. The data shown in Figure 1 are pooled for all double-blind trials.

The incidence of discontinuation because of an unsatis- factory therapeutic response was lower for diclofenac than for any comparative treatment. The rate of with- drawal for adverse effects was highest for the aspirin group (25 of 265, 9 percent), and approximately equal for the diclofenac (27 of 457,6 percent), naproxen (5 of 92,5 percent), and placebo (9 of 186, 5 percent) groups. Ap- proximately 4 percent of the patients in each active treat- ment group withdrew from the trial because of gastroin- testinal adverse effects.

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SYMPOSIUM ON DICLOFENAC SODIUM AND INFLAMMATORY DISEASE-WARD

The rates of discontinuation for these reasons were similar in the long-term trials. Among 562 patients treated, diclofenac was discontinued in 71 (13 percent) patients because of an unsatisfactory response and in 40 (7 per- cent) patients because of adverse effects.

COMMENTS

In comparative trials, it is important to use “equivalent” doses of the drugs being evaluated, thereby avoiding spu- rious conclusions of superior efficacy if one drug used at therapeutic doses is compared with another given at sub- optimal levels. In these trials, diclofenac given at a daily dosage of 100 or 150 mg was clinically more effective than aspirin, given at 2.4 or 3.6 g per day. In most coinpar- isons of efficacy variables, the effects of diclofenac on dis- ease symptoms were superior; differences were often sta- tistically significant, particularly in those for patients with osteoarthritis of the knee. Diclofenac at a dosage of 75 mg twice a day was as effective as naproxen given at 250 mg twice a day. For many variables, the level of improvement was the same with each drug. Across all trials, patients receiving diclofenac had the lowest incidence of an unsat- isfactory therapeutic response.

In considering treatment for painful conditions such as osteoarthritis of the hip or knee, the onset of relief is of considerable interest to physicians as well as to patients. In this regard, significant improvement in pain and stiff- ness was noted with diclofenac at the first scheduled ob- servation point one week after drug treatment was started. The anti-inflammatory effects of diclofenac after one week were consistently superior to those of aspirin, especially in patients with osteoarthritis of the knee.

Equally desirable is a drug that can be taken on a long- term basis with minimal diminution in potency. This char- acteristic was demonstrated for diclofenac in two 46-week

studies in which at least 70 percent of patients treated daily with 100 or 150 mg of the drug had sustained relief of disease symptoms.

In addition to efficacy, clinicians are appropriately con- cerned about the tolerability and safety of any new drug. The double-blind, controlled clinical trial provides relative data addressing this problem. In comparisons of safety, the “equivalency” of dosages is again important. In the current studies, the tolerability of diclofenac, 100 to 150 mg per day, was superior to that of aspirin, 2.4 or 3.6 g per day, and comparable to that of naproxen, 500 mg per day. The tolerability of diclofenac was essen- tially the same in long-term trials as it was in short-term trials. This point is notable since some patients in the long-term trials had received diclofenac for up to 12 weeks in double-blind trials, thus making the total duration of treatment approximately one year.

Diclofenac has been marketed abroad since 1973 for the treatment of various rheumatic and nonrheumatic con- ditions. Such long-term and worldwide use of diclofenac, as well as ongoing evaluation of its adverse reaction pro- file as compared with other nonsteroidal anti-inflammatory drugs, has established its role as an effective, well-toler- ated, and safe nonsteroidal anti-inflammatory drug. Re- sults of the current trials provide further evidence that di- clofenac, at doses of 100 or 150 mg given in two or three daily doses, is a safe drug that provides effective relief of acute and chronic symptoms in patients with osteoarthritis of the hip or knee.

REFERENCES

1. Huskisson EC, Doyle DV, Lanham JG: Drug treatment of osteoar- thritis. Clin Rheum Dis 1985; 11: 421-431.

2. Steinbrocker 0, Traeger CH, Batterman RC: Therapeutic criteria in rheumatoid arthritis. JAMA 1949; 140: 659-662.

April 28, 1986 The American Journal of Medicine Volume 50 (suppl 48) 57