Oral drug of choice in carpal tunnel syndrome

The symptoms of carpal tunnel syndrome (CTS) are paresthesia or pain in the wrist, hand, and fingers, often occurring during sleep. On awakening, the patient usually gets relief by shaking or rubbing the hands. The best way to confirm the diagnosis of CTS is to perform a median nerve conduction study(NCS) across the transverse carpal ligament. Characteristic abnormalities are focal reduction of conduction velocity (CV) in the distal motor and sensory fibers with or without reduced amplitudes of the compound action potentials.

The clinical manifestation^1-3 and electrodiagnostic criteria of CTS^4-6 have been well documented in the literature. However, conservative therapy for mild to moderate CTS varies. Established therapies such as splinting and steroid injection into the carpal tunnel are frequently effective, although recurrences are common.^7-9 In addition, oral medications are used in patients with CTS.^1,2,10-12 In a survey of American hand surgeons, oral steroids, diuretics, and nonsteroidal anti-inflammatory drugs (NDSAIDs) were used most frequently.¹¹ However, the relative effectiveness of commonly used oral medications such as NSAIDs, diuretics, or oral steroids is unknown. Therefore, we conducted a study comparing the effectiveness of NSAIDs, diuretics, and oral steroids in the treatment of CTS.

Methods. Patients. Patients enrolled in this study and clinical symptoms and signs of CTS confirmed by standard electrodiagnosis, with no abnormalities in the radial and ulnar nerves. Motor and sensory NCSs were performed using standard techniques of supramaximal percutaneous stimulation and surface electrode recording. The median, ulnar, and radial nerves were sampled. Compound muscle action potentials (CMAP) and sensory nerve action potentials (SNAP), amplitudes, and CV were measured using the methods described by Delisa et al.¹³ The electromyographic (Viking IV; Nicolet, WI) recordings of motor CV were made with the filter band pass at 2 Hz to 10 kHz, a sweep speed of 2 ms/cm, and the amplifier gain adjusted for full viewing of the CMAP. For measurement of SNAP, the instrument settings were these: filters, 20 Hz to 10 kHz; sweep, 2 ms/cm; and gain, 10 to 20 µV/cm.

The electrophysiologic criteria for the diagnosis of CTS specified either distal motor latency greater than 4.7 ms or mixed nerve wrist-palm conduction time greater than 2.0 ms at a distance of 8 cm.¹⁴ Exclusion criteria were as follows:

1. CTS patients with either fibrillation potentials of reinnervation by needle electromyographic (EMG) examination in abductor pollicis brevis (APB) muscle (a criterion aimed at including only mild to moderate patients). In our study, mild CTS referred to patients with decreased CV over the palm-wrist segment, with normal median SNAP amplitude and CMAP amplitude of APB muscle. Moderate CTS described patients with either decreased median SNAP amplitude or decreased CMAP amplitude of APB muscle.

2. Clinical or electrophysiologic evidence of accompanying conditions that could mimic CTS or interfere with its evaluation, such as cervical radiculopathy, proximal median neuropathy, or significant polyneuropathy.

3. Evidence of obvious underlying causes of CTS such as hypothyroidism, diabetes mellitus, arthritis of the wrist, pregnancy, vibratory machine use, or obesity.

4. Cognitive impairment interfering with the subject's ability to follow instructions and relate symptoms.

5. Recent peptic ulcer or history of steroid or NSAID intolerance.

Study design and treatment. The study protocol was approved by the institutional review board of our hospital. If patients fulfilled the criteria and gave consent, they were enrolled in this study. At first visit, we assessed standardized medical and neurologic history, biochemical and endocrine screenings (i.e., fasting blood sugar, renal function, rheumatoid factor, thyroid stimulating hormone [TSH], T3 and T4), detailed physical and neurologic examinations (PE and NE), NCS, and needle EMG. Baseline assessments included the symptomatic questionnaire described by Herskovitz et al.,¹² which rated symptoms from 0 (no symptoms) to 10(severe) in each of five categories: pain, numbness, paresthesia, weakness/clumsiness, and nocturnal awakening. The total of the scores of the five categories was the global symptom score (GSS). Each patient was directly questioned, and each score was based on the patient's subjective answers. Therefore, the maximum score was 50 (most severe symptoms), and the minimum score 0 (absence of symptoms).

After the baseline assessment, patients were randomized to the following treatment arms: 1) 4 weeks of placebo; 2) 4 weeks of diuretic treatment with trichlormethiazide, 2 mg daily; 3) 4 weeks of NSAID-SR with tenoxicam-SR, 20 mg daily; and 4) 2 weeks of prednisolone at a dose of 20 mg daily, followed by another 2-week dosage of 10 mg daily. We used white pills of a similar size and shape in each group. The randomization list was developed and kept by an individual not involved in the care or evaluation of the patients or in data analysis. Neither the patients nor the physicians were aware of the treatment allocation. Access to the treatment was restricted. Furthermore, to ensure consistency, the evaluating physician was the same each time for each patient. Follow-up assessments, identical to the baseline procedure, were performed at the second and fourth weeks, and included PE, NE, and the same biochemical and endocrine examinations as well as the standardized symptom questionnaire used in the screening visit. Adverse side effects such as nausea, epigastric pain, tarry stool, leg edema, or cushingoid appearance were recorded. No changes of vocation or additional treatments (including splint, local injection, or surgery) were allowed during the study.

Statistical analysis. For statistical analysis, the differences in GSS at baseline and after medication were tested by one-way ANOVA. When a statistical difference occurred on one-way ANOVA, it was then applied in Scheffe's test to determine which medication was statistically different from the placebo (p < 0.05 was considered significant). In addition to comparing outcome among groups, we compared 2-week and 4-week treatment points within each group if treatment was effective.

Results. Demographic characteristics. A total of 91 patients consented to participate in this study. Of these, 18 were excluded for the following reasons: 1) seven patients (two in the placebo, two in the diuretic, one in the NSAID-SR, and two in the steroid) had undergone surgery before completing this study; 2) five patients (two in the placebo, two in the NSAID-SR, and one in the steroid) refused to continue participation; and 3) six subjects (three in the placebo, two in the diuretic, and one in the NSAID-SR) could not be reached and were lost to follow-up. Because 13 patients did not complete 2-week treatment and five patients (two in the placebo, one in the diuretic, one in the NSAID-SR, and one in the steroid) did not complete the 4-week treatment, they were excluded from this study and data analysis.

In all, 73 patients finished this study. There were no major adverse effects from the medications. Nausea and epigastric pain occurred in each group as shown in table 1. The results of biochemical and endocrine examinations were similar to those of the pretreatment status. The 73 patients who completed this study were randomized to 16 patients in the placebo group, 16 in the diuretic group, 18 in the NSAID-SR, and 23 in the oral steroid group. There was no significant difference in age, gender, or severity of electrodiagnostic measurements including CMAP amplitudes of APB muscle, distal motor latencies, and palmwrist CV of median nerves. The results are summarized in table 1. The mean of baseline GSS was not significantly different among these four groups, as shown in table 2.

Two-week treatment response. Further significant reduction the steroid group had a significantly greater reduction in mean GSS than the placebo, NSAID-SR, and diuretic groups (F_3,69 = 7.37, p = 0.0002) (see table 2, figure).

Four-week treatment response. Further significant reduction in the mean GSS occurred only in the steroid treatment group (F_3,69 = 13.6, p = 0.00001) as compared with the placebo group. There was no significant difference between the NSAID-SR and diuretic groups and the placebo group (see table 2^,figure). In the steroid group, there was a significant reduction of mean GSS at the 4-week treatment (F = 107, p = 0.0001).

Discussion. Any condition that reduces the cross-sectional area of the carpal tunnel or increases the volume of its contents will compress the median nerve against the flexor retinaculum and result in distal motor and sensory dysfunction. Therefore, any medication that reduces the swelling of structures within the carpal tunnel may be effective in the treatment of CTS. Diuretics,^1,2,11 NSAIDs,^1,2,11 and steroids^11,12 are commonly used to reduce the volume of the swollen tissue, resulting in the improvement of symptoms and signs of CTS.

A survey of American hand surgeons who regularly treat CTS showed that they frequently used oral medications for nonoperative therapy in which oral steroids, diuretics, and NSAIDs were the drugs prescribed most often.¹¹ Our study showed that a significant reduction in the mean GSS occurs exclusively in the steroid group after 4 weeks of therapy, whereas the mean GSS in the diuretic- and NSAID-SR-treated groups remains unchanged. Therefore, we recommend that when oral medications are used to treat idiopathic CTS, a short-term, low-dose oral steroid is the best choice.

Therapies commonly used in CTS have remained essentially the same for years: 1) immobilization of the hand with a splint in the neutral position,^1-3,15 2) injection of steroids just proximal to the carpal tunnel,^1-3,7-9 and 3) decompression of the median nerve by release of the transverse ligament.^1-3 Although decompression offers the most effective management for CTS, conservative nonoperative therapies are effective in the management of mild to moderate CTS. Although simple, safe, and effective, these therapies, however, are frequently short lived. Furthermore, many CTS patients complain that splinting will hinder their work or daily activities.

Local steroid injections into the carpal tunnel may result in initial relief, but relapses are frequent, and mechanical or chemical nerve injury can occur.¹⁶ In our study, once-daily dosing of oral steroids was administered to ensure compliance. Moreover, we used a short-term, low-dose regimen to avert any possible side effects. Thus, oral steroids may be an additional alternative nonoperative therapy besides splinting and steroid injections.

Many studies have used subjective and objective scoring data in the evaluation of treatment efficacy. The GSS, first described by Herskovitz et al.,¹² was used as the subjective evidence to assess symptomatic improvement in CTS patients. We also used this method to evaluate our patients. In addition, quantitative sensory tests (QST), NE, and NCS were commonly used as the objective scoring system. It is well known that a time lag occurs between electrodiagnostic and clinical improvement. Several studies show that significant improvement in objective scores does not reflect improvement in symptomatic scores during a short period of follow-up.^12,17,18 Therefore, we did not perform repeat NCS. Although it might be argued that our patients on steroids registered subjective improvement for psychological reasons, we did not observe this clinically. Furthermore, to make this less likely, our design was a prospective, randomized, double-blind, placebo-controlled study.

A questionnaire survey of American hand surgeons showed variations in the length of nonoperative treatment. It usually lasted an average of 6 weeks before surgical release.¹¹ Our report and others show that a significant improvement usually begins within 2 weeks, most often in 5 to 7 days.^2,11,12 We also considered the short- and long-term side effects of the investigative drugs. Therefore, we chose treatment of 4 weeks duration.

Although we conclude that a short-term, low-dose oral steroid is an effective oral medication for symptomatic relief in CTS, some questions remain unanswered:

1. Is a 2-week or a 4-week treatment better? In our study, the results showed that the effects of 4-week treatment were better. However, the numbers of patients were too small to make a reliable conclusion.

2. Is steroid therapy effective for long-term symptom relief of CTS?

3. Do symptoms recur once steroids are discontinued. and is further steroid therapy effective in patients experiencing a recurrence?

4. Do long-term side effects also occur in low-dose short-term steroids?

5. How do oral low-dose, short-term steroids compare with established conservative therapies such as splinting and local injection of steroids?

To answer these questions, further studies are now in progress.

Acknowledgment

We thank Vinay Chaudhry, MD, for critical review and helpful comments.