Design & Setting
The study was registered wile recruiting patients on the Iranian Registry of Clinical Trials (IRCT) website http://www.irct.ir/, a WHO primary register setup, with registration number of IRCT20130523013442N29 on 13/09/2019. We conducted a randomized controlled trial with two 1:1 parallel arms from January 2019 to November 2020. The study was conducted in two outpatient physical medicine and rehabilitation clinics at Modaress and Shohadaye Tajrish hospitals. Both are teaching hospitals of Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran, with a high patient volume.
The study was conducted in accordance with the Declaration of Helsinki. Ethics approval was obtained from the institutional research ethics committee of Shahid Beheshti University of Medical Sciences under reference number IR.SBMU.MSP.REC.1397.397. All participants signed their written informed consent. The trial investigator explained the objectives, benefits, and potential side effects of the trial to eligible patients. Patients were informed that they were free to withdraw from the study at any time before surgery.
We invited males or females aged >18 years with signs/symptoms of CTS to undergo an electrodiagnostic study. According to the electrodiagnostic criteria (16), patients with mild to moderate CTS, with pain intensity of ≥4, were considered eligible. Exclusion criteria were: severe CTS requiring surgical intervention, polyneuropathy, cervical radiculopathy, thoracic outlet syndrome (TOS), local triamcinolone injections into the carpal tunnel or night splint in the past 6 months, carpal tunnel release surgery (CTR), allergic reactions to triamcinolone and NSAIDs, malignancy, skin infections at the injection site, and pregnancy.
Initially, patients with signs/symptoms of CTS were invited for a screening appointment. During the interview at the first visit, the study phases and reasons for participation were explained to all potential participants. When a patient declined to participate, another was selected and invited in the same manner until the required sample was recruited. At the screening visit, medical history and physical examination were obtained. Electrodiagnostic studies were then requested. Patients were asked about their medication history and dietary supplement use; their responses were recorded on case report forms that conformed to principles of good clinical practice. We reviewed the records, and patients were then presented to a consensus committee of the authors, who confirmed their eligibility and invited them to participate in the study. Participants who gave written informed consent were assigned to one of the study groups.
Interventions & Preparations
At the beginning of the study, participants were given both verbal and written information by a specialist in physical medicine and rehabilitation about the injections and their benefits and possible side effects. In both groups, the procedure involved an injection. In the ketorolac group, patients received 1 mL of 30 mg/mL ketorolac (Exir Company, Iran) and 0.5 ml lidocaine (2%, Caspian Company, Iran). In contrast, in the second group, the local injection was 1 mL of 40 mg/mL triamcinolone acetonide (Hexal Company AG, Germany) and 0.5 mL lidocaine.
Patients in both groups received a local injection via proximal access by a single experienced physical medicine and rehabilitation specialist under ultrasound (US) guidance. Participants were placed in the supine position. The skin over the injection site of the affected wrist was thoroughly prepared with povidone-iodine 10%. Under US guidance, the injection was performed with a 23-gage needle approximately 1.5 inches long. After identifying the palmaris longus tendon, the needle was inserted on the volar side of the wrist at an angle of 30-40º on the medial side of this tendon 1-2 cm proximal to the distal wrist crease. Figure 1 shows the injection technique under US guidance. All patients were prescribed a static wrist splint for 6 weeks at night (prefabricated CTS orthoses with a static volar splint to position the wrist in a 0-5º extension). In both groups, patients were sent home with written instructions. They were instructed to maintain relative rest for 24 hours. It was recommended that a cold compress be applied for 10 minutes three times daily. Patients were allowed to take acetaminophen 500 mg (without codeine) every 4-8 hours if the pain was not under control. Patients were not allowed to take other pain-relieving medications such as NSAIDs, supplements, or vitamins for one week after the injection. It was generally recommended that they continue to do low to moderate physical activity and gradually increase it at their own pace.
The primary outcome of this study was the Boston Carpal Tunnel Questionnaire (BCTQ). The secondary outcomes were the visual analog scale (VAS), electrodiagnostic findings, patient satisfaction, and any complications of the injection.
Boston Carpal Tunnel Questionnaire (BCTQ)
The BCTQ is a patient-reported questionnaire commonly used in patients with CTS. It includes two subscales, the Boston Questionnaire Symptom Severity Scale (BQ-SS) [11 items with a five-point rating scale ("none" or "never" to "very severe" or "continuous")] and the Boston Questionnaire Functional Status Scale (BQ-FS) [8 items with a five-point scale corresponding to the difficulty of the required daily task ("no difficulty" to "cannot perform")]. The sum of the scores is reported for each subscale because a higher score indicates greater disability (17). Several authors have evaluated the validity and reliability of the Persian version of the BCTQ in recent years (18,19).
Visual Analog Scale (VAS)
The VAS assesses pain and ranges from 0 (no pain) to 10 (severe pain). Participants were asked to indicate the maximum pain they had felt in the past 2 days on the VAS ruler.
The electrodiagnostic evaluation was performed with a Natus Synergy Ultrapro S100 device. The compound motor action potential (CMAP) and sensory nerve action potential (SNAP) of the median nerve were recorded using the techniques described by Dumitru and Amato . Peak distal sensory latency (DSL), onset distal motor latency (DML), and baseline-to-peak SNAP and peak-to-peak CMAP amplitudes were reported for each subject. Any adverse effect of the interventions was registered.
Based on Stevens' modified criteria , diagnosed CTS patients were classified as mild, moderate, or severe: mild CTS was defined as prolonged median DSL, moderate as prolonged DSL and DML, and severe as prolonged DSL and DML, with either an absent SNAP or a low-amplitude or absent thenar CMAP.
Patient Satisfaction with and Complications of the Injection
All patients were rated for complications such as stiffness, heaviness, pain, and their treatment satisfaction on a 5-point Likert scale: 1) very dissatisfied, 2) dissatisfied, 3) neutral, 4) satisfied, and 5) very satisfied.
In this study, the participants were assessed twice: before the intervention and 3 months after the injection. The instruments used were the BSTQ, VAS questionnaire, and electrodiagnostic evaluation.
In one study, Gurcay et al. compared the efficacy of local injection of 6 mg betamethasone in CTS with oral intake of 15 mg/day meloxicam for 3 weeks (20). They divided 32 participants into two groups: 18 patients in the steroid group and 14 in the NSAID group. They measured the functional status scale (FSS) 3 months after the intervention. Their results showed that the two groups were similar in FSS at the baseline. However, after 3 months, there was no significant difference between the oral NSAID group and the local steroid injection group in the mean FSS; P > 0.05. However, using the graphical data with the online Web plot digitizer (21) showed that the improvement percentage was 31.5% in the steroid group and 23.8% in the NSAID group. Given this difference, we needed 22 participants in each group to detect a significant discrepancy in the BCTQ for disability between our two groups at 3 months, a power of 80%, and a two-tailed P value of 0.05 as statistically significant. We added three additional participants to each group to ensure that the study would be sufficiently powered even if 10% of the participants were lost. Thus, a total of 50 participants were assigned to the study groups.
Randomization & Blinding
We used the block randomization method to randomly assign participants to two groups with the same size of 25 participants (50 patients in total). Random numbers were generated in an independent statistical room. The assignment sequence was concealed from all investigators and participants with sequentially numbered sealed envelopes containing cards with the allocation group. Opening of the envelopes, preparation of the injection solutions, and injection were performed by a nurse and an experienced physician who were not involved in the intervention or assessments. Because ketorolac is a clear solution and triamcinolone is a milky suspension, the filled syringes were wrapped with tape to ensure blindness so that the contents of the syringe could not be seen by the patient. Blinded investigators performed all follow-up examinations.
The collected data were stored in the profile of each patient and analyzed using SPSS 24. The Shapiro-Wilk test was used to assess data distribution. Mean and standard deviation were used for quantitative variables, and relative frequency was used for qualitative variables. The t-test was used to compare normally distributed variables, and the Mann-Whitney U test was used when the distribution was not normal. Qualitative data were analyzed using the chi-square test. The level of significance was set at less than 0.05 in this study.