Current Medical Research and Opinion Vol. 1, No. 4, 1973

Evaluation of the effect and duration of triamcinolone

Mastair C. Kennedy, M.B., Ch.B., M.R.C.P., D.Obst.R.C.0.G.. Peter Lee, M.B., M.R.A.C.P., John Webb, M.B., M.R.A.C.P., and Shridhar Deodhar, M.D.

acetonide in the treatment of rheumatoid arthritis

The Centre for Rlieuniatic Diseases, and the University Department of Medicine, Royal Infirmary, Glasgow, Scotland

Received: 22nd December 1972 Curr. med. Res. Opin., (1973), 1,212.

Summary The effect of 80 tng. triarncinalone acetonide giveti by inrraniuscular injectiort was mdiedin 12patients with active rheumatoid arthritis. The patients were followed for 4 weeks, with weekly assessments of joint pain and tenderness, digital joint circuiii- ference, hand grip, and radioactive pertechnetate (99mTc) knee joint uptakes. Atiother 12 patients with active rheumatoid arthritis received an injection of saline and acted NS controls.

The results showed that triarncinalone aceronide acrecl on average .for 3 weelib. Subjective clinical parameters showed greater improvement than objective nieasure- rnents, such as 9gmTc knee joint uptakes.

Key words: Arthritis, rheumatoid - triamcinalone acetonide - radioisotope scanning

Triamcinolone acetonide ('Kenalog't) is the 16: 17 acetonide of 9afluro - 16rr.hydroxyprednisolone, (Fig. I ) . The drug has been designed for depot intra- muscular administration and the advantage in producing sustained dosage control has been emphasized by a number of workers.'-3 The extended duration of thera- peutic effect removes the necessity of daily intramuscular injections and the duration of activity has been claimed to vary from 20 to 30 days.2 Figure 1. Formula of triamcinalone acetonide

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Alastair C. Kennedy, Peter Lee, John Webb and Shridhar Deodhar

Clinical trials in rheumatoid arthritis have suggested a diminution of cortico- steroid side-effects when compared to oral corticosteroid therapy,’ and that less of the drug is required to achieve the same therapeutic effect.2 However, the numbers studied in many of these reports are small and in most of the trials only subjective clinical indices were employed.

To date, there is to our knowledge no adequate study comparing the duration and effect of a standard dose of triamcinolone acetonide in patients with rheumatoid arthritis compared with a placebo injection.

In this paper we attempt such an evaluation of this drug.

Materials and methods Twenty-four patients with ‘definite’ or ‘classical’ rheumatoid arthritis, as defined by the diagnostic criteria of the American Rheumatism Association,4 took part in the study. Each patient had a positive test for rheumatoid factor and articular erosions were present on X-ray examination of the joints, (Stage 111 Steinbrocker classi- ficat ions).

The patients were divided into two groups, Table I summarises the clinical and laboratory data. It can be seen that the two groups were comparable.

Table I. Clinical and laboratory data in the two groups studied (mean f S.E.M.)

Clinical groups Triamcinolone acetonide Saline

Total number Mean age (years) Sex : Male Female Mean duration of rheumatoid arthritis bears) Sheep cell agglutination test* (mean) Serum albumin @./I00 ml.) Serum globulin (g./lOO ml.) Functional class

12 50.2 f 3.9

2 (16.6%) 10 (83.4%)

6 f 0.8

319.7 & 106.7 3.1 f 0.1 4 f 0.2 2.1 f 0.2

12 49.9 f 3.8

2 (16.6%) 10 (83.4%)

6.1 f 0.8

227.8 f 82.6 3.1 f 0.2 3.8 f 0.2 2.2 f 0.2

*Mean of reciprocal of titre6.

The patients were alternatively allocated to receive 80 mg. triamcinolone acetonide or placebo (saline), by intramuscular injection, neither patient nor physician being aware of the nature of the injection. Clinical assessment was made at the start of the study and weekly thereafter, for a period of 4 weeks. The patients’ subjective impression of pain was recorded as a scale of 0 to 4, (O=no pain; 1 =slight; 2 =moderate; 3 =severe; 4=very severe), and a pain index which included all joints was also recorded.’ An articular index of joint tenderness was estimated as described by Ritchie et a1.8

Grip strength was estimated in each hand as the mean of three attempts at gripping a rolled sphygmomanometer cuff with the pressure at a basal level of 30 ~ n m H g . ~

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Evaluation of the effect and duration of triamcinolone acetonide in the treatment of rheumatoid arthritis -

The circumference of the proximal interphalangeal joints of the fingers and the interphalangeal joints of the thumbs were measured on each hand using the plastic- spring apparatus supplied by Geigy Ltd.’o

In addition, radio-active technetium studies were performed at the commence- ment of the study and weekly throughout the 4 week period of the trial.

A slight modification of the procedure described by Dick and his colleagues’ 1.12

was used. Approximately 200 pCi of 9 9 m T ~ (as sodium pertechnetate) was standardised by counting for 2 mins. at 30 cm., using a thallium activated sodium iodide scintillation crystal and photomultiplier. The pulses were fed through a pulse-height analyser (EKCO M5050) and digital rate meter (EKCO M5183A) and read out from the latter. Thereafter, the dose was injected intravenously into an antecubital vein, great care being taken to ensure no extravasation of the dose occurred at the time of injection. At 15 minutes after injection, counting was performed over both knees (always ensuring that each knee was measured in the same order on each occasion). Each count lasted for 2 minutes. The scintillation counter was positioned 2.5 cm. above the joint being examined.

In the knee, alignment of the counter was made with the midpoint of the upper pole of the patella. Counts over the joints were expressed as a percentage of the administered dose.

The results are shown in Figures 2 to 7, where it can be seen that significant differences between the group of patients receiving triamcinolone acetonide and that receiving saline occurs only during weeks one, two and three. The subjective clinical indices, i.e. the patients’ assessment of their pain, the pain index and the articular index of joint tenderness all showed highly significant improvement in the patients who received triamcinolone acetonide.

Finger joint circumference showed very little significant improvement in the patients receiving theactive drug at one, two or three weeks. Grip strength, however, showed a highly significant improvement in the left hand although only significant improvement in the right over all three weeks.

9 9 m T ~ uptakes of the right and left knee joints showed a significant fall during all three weeks in the group receiving the active drug.

Discussion This study was designed to answer the question of the duration and the magnitude of the effect of an intramuscular injection of triamcinolone acetonide. The patients studied were selected on the basis of continuing and severe pain, despite regular administration of standard non-steriodal anti-inflammatory analgesics. The patients continued to take this medication during the four-week period of study, but at an unchanged dose.

From the results of the study, it is apparent that clinical benefit can be expected for up to 3 weeks after 80 mg. of triamcinolone acetonide is administered in a single intramuscular dose. This corresponds to the results of Zucker,2 who observed the average duration of improvement to be 20 days with a maximum improvement of 69 days.

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Alastair C. Kennedy, Peter Lee, John Webb and Shridhar Deodhar

Figure 2. Patient assessment of overall pain (mean & S.E.M.) for 4 weeks after administration of triamcinolone acetonide and saline. Highly s i g n i i t dilierences are present a t weeks 1,2 and 3.

Note: In this graph and in Figs. 3 to 7, the left-hand result in each pair represents the mean -+ S.E.M. for the group receiving triamcinolone acetonide and the right-hand result is the mean and S.E.M. for the group receiving saline placebo.

Figure 3. Pain Index (mean f S.E.M.) for 4 weeks after administration of triamcinolone acetonide and saline. Highly significant differences are present a t weeks 1,2 and 3.

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pc 0.001 pe 0.001 p c 0.001

1 2 3 4Time-Weeks OL

Figure 4. Articular Index (mean acetonide and saline. Highly significant ditrerences are present at weeks 1,2 and 3.

S.E.M.) for 4 weeks after administration of triamcinolone

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Evaluation of the effect and duration of triamcinolone acetonide in the treatment of rheumatoid arthritis

Figure 5. Joint Circumference (mean & S.E.M.) for 4 weeks after administration of triamchlone acetonide and saline. Significant differences are present in the left hand at weeks 1 and 2.

Figure 6. Grip Strength (mean i S.E.M.) for 4 weeks after administration of triamcinolone acetonide and saline. Highly significant ditrerences are present in the left hand at weeks 1,2 and 3. In the right hand, a highly significant difference is present at week 1 and significant differences at weeks 2 and 3.

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-1 p e 0 . y p ~ o 4 o l p<o.w =i 1 2 3 4 Time-Weeks

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Alastair C. Kennedy, Peter Lee, John Webb and Shridhar Deodhar

Figure 7. Technetium Uptake (mean f S.E.M.) for 4 weeks after administration of triamcinolone acetonide and saline. Significant dserences are present at weeks 1,2 and 3.

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It is of interest that, in the present study, the subjective clinical parameters showed greater change with triamcinolone acetonide than the more objective parameters such as the isotope uptake in the knee joints. This confirms previous observations by ourselves’ 3 in clinical trials of non-steroidal antirheumatic drugs.

This study gives no information as to the therapeutic potential of triamcinolone acetonide given by intramuscular injection over a prolonged period of time. It has been claimed that intramuscular triamcinolone acetonide results in fewer side- effects than oral triamcinolone therapy. We do not consider, however, that this has been adequately proven and clearly what is now required is a comparison of side- effects from triamcinolone acetonide given intramuscularly with the standard oral corticosteroid drugs, prednisolone or prednisone, in an adequate number of patients.

Acknowledgements We are grateful to Dr. D. Chahers of E. R. Squibb and Sons Limited for kindly supplying the triamcinolone acetonide and saline injections. The study was supported by financial grants from the Arthritis and Rheumatism Council for Research. One of our group (A.C.K.) is in receipt of a Medical Research Council Research Fellowship.

References 1 . Hartnung, E. F., (1958). Triamcinolone acetonide in the treatment of rheumatoid arthritis. J. Amer. med. Ass., 161,973. 2. Zucker, J., (1961). Treatment of rheumatoid arthritis by intramuscular triamcinolone acetonide and triamcinolone diacetate. Ann. rheum. Dis., 20,274.

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Evaluation of the effect and duration of triamcinolone acetonide in the treatment of rheumatoid arthritis

3. Katoun, G., and Gil, J. L., (1964). Clinical trials with triamcinolone acetonide in the treatment of patients with rheumatoid arthritis. Preliminary report. A.I.R. Arch. Interanier. Rheuni. (Rio cte J . ) 7,93. 4. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A., (1959). Diagnostic criteria for rheumatoid arthritis: 1958 Revision. Ann. rhermi. Dis., 18, 49. 5 . Steinbrocker, 0.. Traeger, C. H., and Batterman, R. C., (1949). Therapeutic criteria in rheu- matoid arthritis. J . .4mer. vied. Ass., 140, 659. 6 . Heller, G., Jacobson, A. S., Koloday, M. H., and Kammerer, W. H., (1954). The haemag- glutination test for rheumatoid arthritis. J . Imrnunol., 72,66. 7. Jasani, M. K., Downie, W. W., Samuels, B. M., and Buchanan, W. W., (1968). Clinical study of analgesic and anti-inflammatory activity. Ann. rheum. Dis., 27,457. 8. Ritchie, D. M., Boyle, J. A., McInnes, J. M., Jasani, M. K., Dalakos, T. G., Grierson, P., and Buchanan, W. W., (1968). Clinical studies with an articular index for the assessment of joint tcnderness in patients with rheumatoid arthritis. Quart. J. Men., 37, 393. 9. Lee, P., Jasani, M. K., Dick, W. C., and Buchanan, W. W. Evaluation of a functional index in rheumatoid arthritis. Scancl. J . Rheum. In press. 10. Webb, J., Downie, W. W., Dick, W. C., and Lee, P. Evaluation of digital joint circumference measurements in rheumatoid arthritis. Scand. J. Rlreum. In press. I I . Dick, W. C., Neufeld, R. R., Prentice, A. G., Woodburn, A., Whaley, K., Nuki, G., and Buchanan, W. W., (1970). Measurement of joint inflammation - a radioisotope method. Ann. theimr. Dis., 29, 135. I ? . Dick, W. C., Deodhar, S. D., Provan,C. J., Nuki, G.,and Buchanan, W. W.,(1971). Isotope btudies in normal and diseased joints; wmTc uptake related to clinical assessment and to synovial perfusion measured by the I33Xe clearance technique. Clin. Sci., 40, 327. 13. Dick, W. C., Nuki, G., Whaley, K., Deodhar, S., and Buchanan, W. W., (1970). Some aspects in the quantitation of inflammation in joints of patients suffering from rheumatoid arthritis. Rheruriatol. Phys. Med., (Suppl.), p.40.

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