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Treatment of De Quervain Disease With Triamcinolone Injection With or Without Nimesulide: a Randomized, Double-Blind, Placebo- Controlled Trial

Posted on: Friday, 24 December 2004, 03:01 CST

Background: There is uncertainty as to whether supplemental oral nonsteroidal anti-inflammatory medication improves the effectiveness of steroid injections in the treatment of de Quervain disease. We tested the hypothesis that there are no significant differences in the success rates when this condition is treated with triamcinolone injection with or without supplemental oral nimesulide.

Methods: In a randomized, double-blind trial, 160 patients with de Quervain disease received an injection of 10 mg of triamcinolone acetonide and either 200 mg of oral nimesulide for seven days (eighty patients) or placebo tablets for seven days (eighty patients). An independent, blinded evaluator assessed the primary outcomes (tenderness, pain, and the result on the Finkelstein test) at three weeks after injection. Adverse reactions were assessed, and probabilities of recurrence for both groups were compared. Factors possibly predictive of disease recurrence were also assessed.

Results: The success rate after one injection was 67% in the nimesulide group and 68% in the placebo group. The overall success rates after single or multiple injections with a mean follow-up of 13.6 months were 95% for both groups. No significant differences were noted with respect to the success rates (p = 0.69) or pain scores after treatment (p = 0.11). The most common adverse reactions to triamcinolone injection and nimesulide were pain after injection and dyspepsia, respectively. The symptoms of de Quervain disease recurred in 33% of the patients in the nimesulide group and in 37% of those in the placebo group. The median time of recurrence was at the fifth month in the nimesulide group and at the fourth month in the placebo group. The recurrence of symptoms was significantly (p = 0.01) related to the presence of crepitation (relative risk, 2.13; 95% confidence interval, 1.19 to 3.80).

Conclusions: Supplemental oral administration of the nonsteroidal anti-inflammatory drug nimesulide does not improve the effectiveness of a single injection of triamcinolone acetonide in the treatment of de Quervain disease. Patients with crepitation in the first dorsal compartment during thumb extension or abduction are at increased risk for recurrence of this disease.

Level of Evidence: Therapeutic study, Level I-1b (randomized controlled trial [no significant difference but narrow confidence intervals]).

Stenosing tenosynovitis of the first dorsal compartment of the wrist was originally described by Fritz de Quervain in 1895(1). Many reports have described successful outcomes after nonoperative treatment of de Quervain disease2-11. The rate of a successful result after a single steroid injection has been reported to range from 45% to 81%3-8. In clinical practice, some physicians use nonsteroidal anti-inflammatory drugs with or without splinting as first-line treatment of this condition12. However, there is uncertainty as to whether supplemental oral nonsteroidal anti- inflammatory medications improve the effectiveness of steroid injection in de Quervain disease. Furthermore, few studies have identified the predictive factors for the recurrence of this condition6,8.

Nimesulide (Eurodrug Laboratories, The Hague, The Netherlands) is a nonsteroidal anti-inflammatory drug of the sulfonamide class, which is marketed in European and Asian countries. It is administered orally (usually 200 mg/day) or rectally (400 mg/day) for a variety of inflammatory and pain states. It exerts some actions in addition to inhibiting cyclooxygenase that contribute to its anti-inflammatory effect: it inhibits neutrophil activation and also exhibits antioxidant properties. Nimesulide has been found to be a selective cyclooxygenase-2 inhibitor in human beings at clinically recommended doses13. It is associated with a low prevalence of adverse side effects, especially in the gastrointestinal tract13.

We conducted a randomized, double-blind, placebo-controlled trial to assess the effectiveness and safety of triamcinolone injection and nimesulide compared with triamcinolone injection and placebo in 160 patients with de Quervain disease. We tested the hypothesis that there are no significant differences in the success rates when this condition is treated with triamcinolone injection with or without supplemental oral nimesulide. We also studied the probability of the recurrence of symptoms after triamcinolone injection with or without oral nimesulide and investigated whether factors such as patient age, gender, duration of symptoms, dominant hand involvement, previous steroid injection, and the presence of crepitation were predictive factors for the recurrence of the disease.

Materials and Methods

Study Population

We conducted a randomized, double-blind, placebo-controlled trial at Srinagarind Hospital, Khon Kaen University. The study was approved by the institute's Ethics Committee, and all patients provided written informed consent before participation. In order to establish the diagnosis of de Quervain disease, the patients were required to have all of the following three physical findings: radial styloid tenderness, pain over the first extensor compartment on resisted thumb abduction or extension, and a positive Finkelstein test. The Finkelstein test was performed by having the patient flex his or her fingers over the involved thumb during passive ulnar deviation of the wrist. Patients were excluded if they had contraindications to the use of nonsteroidal anti-inflammatory drugs, had had a lidocaine or steroid injection, were pregnant or lactating, had inflammatory joint disease of the affected wrist, had a previous wrist injury, had taken nonsteroidal antiinflammatory drugs during the previous two weeks, or had received a steroid injection during the previous two months.

Randomization and Treatment

The patients were randomly allocated, with use of a table of random numbers, into the nimesulide or the placebo group. All patients in both groups received a 1-mL (10-mg) injection of triamcinolone acetonide (Bristol-Myers Squibb, Princeton, New Jersey) and 0.5 mL of 1% lidocaine (Astra Pharma, Mississauga, Ontario, Canada). After the injection, a sealed opaque envelope that contained the allocation to treatment with either 100 mg of oral nimesulide twice daily for seven days (the nimesulide group) or placebo tablets for seven days (the placebo group) was opened. In order to preserve the blinding, the injection was given by a physician other than the evaluators.

The patients were strongly encouraged to avoid gripping, grasping, and lifting heavy objects with the injected wrist over the next three days. All patients were advised to use ice to control the postinjection pain for twenty-four to forty-eight hours. Splinting was not used. All patients were discouraged from receiving other steroid injections, nonsteroidal anti-inflammatory drugs, and analgesic drugs.

Data Collection

At the time of the first visit, demographic data on the patient, including age, gender, the duration of symptoms before treatment, the side affected, dominant hand involvement, new or recurrent disease, previous treatment, crepitation, and pain intensity on performing a Finkelstein test, were recorded. The initial follow-up examination was performed one week after the injection to record the presence of and provide treatment for any adverse reactions. A physical examination was performed three weeks after the injection to evaluate the outcome. A physician who was blinded with respect to the treatment allocation conducted all follow-up examinations.

After completion of the trial, subsequent follow-up examinations were done every six months, or when the symptoms recurred, to evaluate the recurrence rate. We conducted a final follow-up evaluation of 155 patients at an average (and standard deviation) of 13.6 5.5 months (range, six to twenty-four months) after the initial treatment. Patient follow-up included a physical examination, telephone interview, or completion of a written questionnaire.

Outcome Measures

The primary outcome measures that were evaluated were the three physical signs of de Quervain disease: (1) tenderness over the radial styloid, (2) pain reproduced by resisted thumb abduction and extension, and (3) a positive result on the Finkelstein test.

Pain aggravated by the Finkelstein test was recorded at the initial visit on a 100-mm visual analogue scale14, with 0 indicating no pain and 100 indicating extremely intense pain. At three weeks after the injection, patients were asked to compare the pain with the pain before treatment. Their responses were rated on a 200-mm- long visual analogue scale with a 0 at the center that indicated no change in pain. Values to the right represented deterioration or an increase in pain with an end point at 100 mm denoting the worst pain ever. Values to the left indicated improvement or decrease in pain, with an end point at -100 mm indicating no pain15.

The patient's response was graded as a success if all three physical signs were completely resolved and the patient had at least 90% improvement in the pain score. Patients with any one of the three signs and/or <90% improvement in the pain score were graded as a failure.

The following s\econdary outcomes were also assessed: (1) the safety of the drug, i.e., the adverse events reported by the patient or observed by the investigator as recorded in the patient's medical chart; (2) the probability of recurrence; and (3) the possible predictive factors for recurrence of the disease.

Statistical Analysis

Before the beginning of the study, we estimated that a sample size of at least seventy-five patients in each group would give an 80% power (β = 0.2) of detecting a difference of 20% in the proportion of patients with a successful outcome between the two groups at the 5% significance level (α = 0.05) on a two-sided significance test16,17.

TABLE I Baseline Characteristics of the Patients

Descriptive statistics (means, standard deviations, and frequencies) were performed on all variables. The null hypothesis of no difference between the two study groups was tested. Categorical outcomes were compared with both the z test of proportions and a 95% confidence interval for the difference between proportions. Continuous outcomes were compared with the Student t test. The Kaplan-Meier method was used to analyze the risk of recurrence between the groups within twenty-four months after the injections18. The log-rank test was used to determine whether there was a significant difference between the groups. The Cox proportional- hazards model was used to adjust for possibly confounding covariates such as patient age, gender, duration of symptoms, dominant hand involvement, previous steroid injection, and the presence of crepitation by means of a backward stepwise elimination procedure. We calculated the relative risks and 95% confidence intervals associated with the recurrence of symptoms. The alpha level for all analyses was set at 0.05. Endpoint data were analyzed according to the intention-to-treat principle. Statistical analyses were performed with use of SPSS software (version 11.5; SPSS, Chicago, Illinois) and Stata software (version 7.0; Stata, College Station, Texas).

Results

Baseline Characteristics

Between April 2001 and March 2003, 168 consecutive patients were diagnosed as having de Quervain disease. Eight of those patients were excluded for the following reasons: refusal of consent (five patients), rheumatoid arthritis of the affected wrist (two patients), and previous wrist injury (one patient). Thus, a total of 160 patients (165 wrists) were included in the trial, with eighty patients (eighty-three wrists) randomized to the nimesulide group and eighty patients (eighty-two wrists), to the placebo group (Fig. 1). All patients completed the three-week trial. In the nimesulide group, seventy-seven patients (96%) were followed for at least six months; fifty-six (70%), for twelve months; thirty-three (41%), for eighteen months; and fifteen (19%), for twenty-four months. In the placebo group, seventy-eight patients (98%) were followed for at least six months; fifty-five (69%), for twelve months; thirty (38%), for eighteen months; and twelve (15%), for twenty-four months.

Fig. 1

Profile of the randomized control trial.

TABLE II Outcomes After Treatment

Table I shows the demographic and baseline characteristics of the participants. Both groups were similar with respect to age, gender, duration of symptoms, dominant hand involvement, classification of the disease (new or recurrent), previous steroid injection, the presence of crepitation, and pretreatment pain scores on the visual analogue scale.

Primary Outcome

Success Rate

The overall results are shown in Table II. The success rates, assessed at three weeks after the first injection (the primary outcome), were 67% in the treatment group and 68% in the placebo group. The overall success rates at the final follow-up examination after a single injection or multiple (two, three, or four) injections were 95% in both groups. No significant differences between the two groups were found with respect to the success rates or the pain scores on the visual analogue scale after treatment.

Secondary Outcomes

Adverse Reactions

The overall prevalences of adverse reactions are shown in Table III. No significant differences were detected between the two groups with respect to adverse reaction rates for either drug. There were no serious adverse effects of either triamcinolone or nimesulide. The most common adverse reaction to the triamcinolone injection was pain after the injection. Infection and tendon rupture did not occur in our patients, even in the forty-three who had multiple injections, with an average follow-up period of 15.3 6.2 months after the initial treatment. The most common adverse reaction to nimesulide was dyspepsia.

Probability of Recurrence

The results of a Kaplan-Meier survivorship analysis presenting the proportion of patients who had no recurrence at each time-point are shown in Figures 2-A and 2-B. Twenty-four patients (twenty- seven wrists) in the nimesulide group and twenty-eight patients (thirty wrists) in the placebo group had recurrence of the disease at the final follow-up evaluation. The results of the log-rank test (chi-square = 0.39, p = 0.53) showed no significant association between the recurrence of disease and the type of treatment. The median time of recurrence was five months in the nimesulide group and four months in the placebo group.

TABLE III Adverse Events

Prediction of Recurrence

Bivariate analysis from the Cox regression model revealed that recurrence of symptoms was significantly related to the presence of crepitation (relative risk, 2.10; 95% confidence interval, 1.21 to 3.67) at the time of presentation. After adjustment for the covariates of age, gender, duration of symptoms, dominant hand involvement, and previous injection in the Cox proportional hazards model, the relative risk of recurrence when crepitation was present was 2.13 (95% confidence interval, 1.19 to 3.80). Other factors were not shown to be predictive for the recurrence of disease (Table IV).

Discussion

The results of treatment of de Quervain disease with nonsteroidal anti-inflammatory drugs have been previously reported7,9,12. In clinical practice, oral nonsteroidal antiinflammatory drugs are sometimes added after steroid injection. We could not find a report on the results of treatment of de Quervain disease with steroid injection combined with an oral nonsteroidal anti-inflammatory drug in the literature. As far as we know, this study is the first randomized, placebo-controlled trial of the effectiveness of the addition of a nonsteroidal anti-inflammatory drug to the treatment of de Quervain disease with steroid injection.

We found no advantage with the addition of nimesulide to the steroid injection in the present study, despite the large number of patients. Clarke et al.19 reported that the histopathology of de Quervain disease is not characterized by inflammation but by thickening of the tendon sheath and by the accumulation of mucopolysaccharides. These findings may explain why nimesulide provided no additional value when combined with the steroid injection.

Figs. 2-A and 2-B The Kaplan-Meier curves for the study groups demonstrate a decrease in the probability of no recurrence as the time after injection increases. The point estimates and their respective 95% confidence intervals at each period of time are presented. The results of the log-rank test (chi square = 0.39, p = 0.53) showed no significant association between the recurrence of disease and the type of treatment. Fig. 2-A The patients at risk in the nimesulide group.

Fig. 2-B

The patients at risk in the placebo group.

TABLE IV Relative Risk (Hazard Ratio) of Recurrence from the Cox Proportional Hazard Model

In the present study, the most common adverse event was pain after the injection. Subcutaneous tissue atrophy or depigmentation are more likely if large or repeated doses of a long-acting steroid are given20, but we rarely observed this morbidity in our Asian patients.

One of the serious adverse reactions of steroid injection in general is tendon rupture. It has been recommended that multiple injections be avoided to prevent this complication21. We found that, among the forty-three patients (fifty-seven wrists) who had multiple injections, none had a tendon rupture. This low rate is similar to that in another report7 and implies that multiple injections may be safe when direct injection into the tendon substance is avoided.

The secondary objective of our study was to assess the probability of recurrence and the possible predictive factors for recurrence of de Quervain disease after injection. To our knowledge, this is the first randomized clinical trial that reports the recurrence rate in terms of the probability of recurrence. Several factors have consistently been associated with the development of de Quervain tenovaginitis: female gender, perimenopausal age, variation in the anatomy of the first extensor compartment, acute trauma, work or repetitive trauma, and rheumatic disorders. However, these factors might not be related to the recurrence of the disease. Witt et al.6 reported that age, hand dominance, and the duration of symptoms before treatment did not affect the outcome, but the results were not adjusted for other confounding factors. Crepitation in de Quervain disease is the feeling or sensation of triggering when the affected thumb is moved, especially in abduction or extension. It is usually found in patients who present with swelling and thickening of the first extensor compartment sheath. This study demonstrated that crepitation in the first extensor compartment was the only factor studied that might be predictive of the recurrence of disease. This may be the case as crepitation implies extensive stenosis of the first dorsal compartment or nodule formation in the tendons.

The median time to recurrence in this study was five months in the nimesulide group and four months in the placebo group. This time was shorter than that i\n a previous report. One possible reason for the earlier recurrence in our patients was the type and the amount of steroid used. For instance, methylprednisolone had greater efficacy and a more sustained clinical effect than did triamcinolone, as was used in this study.

Our study did not investigate whether concurrent medical conditions had an effect on the outcomes. Weiss et al.8 observed that a trend toward failure was noted in patients with diabetes. We did not classify the work status of our patients, and we also excluded patients who had rheumatic disorders. The results of treatment in these particular conditions need further investigation.

In conclusion, steroid injection alone was safe and effective in the treatment of de Quervain disease, but the oral administration of nimesulide did not provide any additional benefit beyond that of the injection. Crepitation in the first extensor compartment during thumb extension or abduction was found to be a predictive factor for recurrence of the disease.

References

1. De Quervain F. Uber eine Form von chronischer Tendovaginitis. CorrespBlattSchweizer Artze. 1895;25:389-94.

2. Finkelstein H. Stenosing tendovaginitis at the radial styloid process. J Bone Joint Surg Am. 1930;12:509-40.

3. Christie BG. Local hydrocortisone in de Quervain's disease. Br Med J. 1955; 4929:15013.

4. McKenzie JM. Conservative treatment of de Quervain's disease. Br Med J. 1972;4:659-60.

5. Harvey FJ, Hary PM, Horsely MW. De Quervain's disease: surgical or nonsurgical treatment. J Hand Surg [Am]. 1990;15:83-7.

6. Witt J, Pess G, Gelberman RH. Treatment of de Quervain tenosynovitis. A prospective study of the results of injection of steroids and immobilization in a splint. J Bone Joint Surg Am. 1991;73:219-22.

7. Anderson BC, Manthey R, Brouns MC. Treatment of De Quervain's tenosynovitis with corticosteroids. A prospective study of the response to local injection. Arthritis Rheum. 1991;34:793-8.

8. Weiss AP, Akelman E, Tabatabal M. Treatment of de Quervain's disease. J Hand Surg [Am]. 1994;19:595-8.

9. Lane LB, Boretz RS, Stuchin SA. Treatment of de Quervain's disease: role of conservative management. J Hand Surg [Br]. 2001;26:258-60.

10. Avci S, Yilmaz C, Sayli U. Comparison of nonsurgical treatment measures for de Quervain's disease of pregnancy and lactation. J Hand Surg [Am]. 2002;27:322-4.

11. Zingas C, Failla JM, Van Holsbeeck M. Injection accuracy and clinical relief of de Quervain's tendinitis. J Hand Surg [Am]. 1998;23:89-96.

12. Capasso G, Testa V, Maffulli N, Turco G, Piluso G. Surgical release of de Quervain's stenosing tenosynovitis postpartum: can it wait? Int Orthop. 2002;26:23-5.

13. Davis R, Brogden RN. Nimesulide. An update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1994;48:431-54. Erratum in: Drugs. 1994;48:793.

14. Huskisson EC. Measurement of pain. Lancet. 1974;2:1127-31.

15. Torstensen TA, Ljunggren AE, Meen HA, Odland E, Mowinckel P, Geijerstam S. Efficiency and costs of medical exercise therapy, conventional physiotherapy, and self-exercise in patients with chronic low back pain. A pragmatic, randomized, single-blinded, controlled trial with 1-year follow-up. Spine. 1998;23:2616-24.

16. Campbell MJ, Machin D. Medical statistics: a commonsense approach. 2nd ed. New York: Wiley; 1993. p 156.

17. Pocock SJ. Clinical trials: a practical approach. New York: Wiley; 1983. p 125.

18. Kaplan EL, Meler P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-81.

19. Clarke MT, Lyall HA, Grant JW, Matthewson MH. The histopathology of de Quervain's disease. J Hand Surg [Br]. 1998;23:732-4.

20. Binder Al. Corticosteroid injection therapy. In: Maddison PJ, Isenberg DA. Woo P, Glass DN, editors. Oxford textbook of rheumatology. Volume 2. 2nd ed. Oxford: Oxford University Press; 1998. p 1757-72.

21. Sampson SP, Wisch D, Badalamente MA. Complications of conservative and surgical treatment of de Quervain's disease and trigger fingers. Hand Clin. 1994;10:73-82.

BY KITTI JIRARATTANAPHOCHAI, MD, SUKIT SAENGNIPANTHKUL, MD, KITIWAN VIPULAKORN, MD, SURUT JIANMONGKOL, MD, PIYAWAN CHATUPARISUTE, MD, AND SURACHAI JUNG, MD

Investigation performed at the Srinagarind Hospital, Khon Kaen, Thailand

Kitti Jirarattanaphochai, MD

Sukit Saengnipanthkul, MD

Kitiwan Vipulakorn, MD

Surut Jianmongkol, MD

Piyawan Chatuparisute, MD

Surachai Jung, MD

Department of Orthopaedics, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. E-mail address for K. Jirarattanaphochai: kitjir@kku.ac.th

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the Faculty of Medicine, Khon Kaen University. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Copyright Journal of Bone and Joint Surgery, Inc. Dec 2004

Source: Journal of Bone and Joint Surgery; American volume

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