Study design and setting:
The proposed trial is a double-blind, parallel-group, randomized control. This trial is reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. This trial will be conducted in the physical therapy clinic at Golestan Hospital, affiliated with Ahvaz Jundishapur University of Medical Science, Iran. The experimental design of this study is shown in Figs 1 and 2.
Inclusion criteria will be aged range between 18 to 60, history of pain greater than twelve weeks, tingling, numbness, burning or pain in at least 2 of digits 1, 2, or 3, positive Phalen or Tinnel test or Carpal compression test, pain intensity at least a 4/10 on a Visual Analog Scale over the past 24 hours. A neurologist diagnoses carpal tunnel syndrome based on a nerve conduction study. Participants with mild to moderate damage to the median nerve include (mild: sensory nerve conduction velocity in the third digit-wrist segment <44 meters/second(m/s) and distal motor latency ≤4 milliseconds. moderate: sensory nerve conduction velocity in the third digit-wrist segment <44 m/s and distal motor latency >4 ms) (19).
Participants will be excluded if they have any sensory or motor deficit in either the ulnar or radial nerve, history of surgery, or injection in the wrist area. Presence of systemic diseases such as rheumatoid arthritis, fibromyalgia, diabetes mellitus, hyperthyroidism, or hypothyroidism. Also, the presence of conditions that might cause numbness in the hand, including cervical radiculopathy, cervical ribs, plexopathy, polyneuropathy, pregnancy. And history of neck, shoulder, or upper extremity trauma.
Ethical considerations and trial registration
This study was approved by the Ethics Committee of the Jundishapur University of Medical Science, Ahvaz, Iran (Approval number IR.AJUMS.REC.1399.727). This study was also registered at the Iranian Registry of Clinical Trials (registration number: IRCT20201201049565N1) on 15 December 2020. All participants that agree to attend this study will provide written informed consent.
Participants in both group receive a conventional exercise program for two weeks, five times a week. It consist wrist splints(neoprene wrist splint tebosanat 31190), TENS (Novin, model 733x, Iran) to the wrist region for 20 min (20), phonophoresis of betamethasone valerate 0.1% ointment (using ultrasound Novin, model 215P, Iran. 3MHz, 5-cm probe, 1.5 W/cm, pulse 1:4, 10 min/ each session( (21), and wrist joint mobilization (20).
Patients in this group will receive cervical manual therapies. The interventions apply to the neck include manual cervical distraction, lateral glides, and poster- anterior pressure applied to the mid-cervical spine. Besides, patients in this group will be instructed to complete an exercise program for stretching neck muscles (the upper fibers of the trapezius muscle, upper fibers of the scalene muscles, and levator scapulae muscle) (see Appendix for details). All treatments were applied by a skilled and experienced physiotherapist in manual therapy approaches.
Outcomes will be assessed in random order at baseline before treatment and after completion of treatment sessions. Outcomes will be median nerve motor distal latency (mMDL) and median sensory nerve conduction velocity (mSNCV) that measure by a neurologist. Other outcome measures were pain intensity, the Boston Carpal Tunnel Questionnaire, and the DASH questionnaire will assess by the physical therapist that will be blind to the group allocation.
Electrophysiological study of the median nerve:
The neurophysiological studies will be performed using a Tru trace 4 EMG system DEYMED electromyography device. At first, we will prepare the patients' hands by asking them to rest for 10 minutes at room temperature, 22-24 ° C. To record the mSNCV, an antidromic technique is used; Ring electrodes (4 cm apart) placed on the distal metacarpophalangeal and interphalangeal joints of the index finger at a standard distance of 14 cm from the active electrode. It is stimulated with supramaximal stimulation. To record the mMDL, the ground electrode will be placed on the dorsal of the wrist at the distance between the stimulating and active electrodes. After cleaning the skin to reduce resistance, the bipolar surface electrode at a distance of 8 cm is placed on the extensor pollicis brevis muscle so that the active electrode is on the muscle motor endplate and the reference electrode is on the metacarpophalangeal joint. It is stimulated to supramaximal stimulation (30% more than maximal stimulation) (22).
Pain assessment was done using the visual analog scale. The person is asked to determine the average amount of pain that they felt in the previous week on line 100 mm long. The left end of this line (score zero) indicates the absence of pain and the right end (score 100) indicates the most severe pain imaginable (23).
Boston Carpal Tunnel questionnaire:
The Persian version of Boston Carpal Tunnel Questionnaire will be filled by every patient. This questionnaire consists of two parts: symptom severity scale (SSS) and the functional status scale (FSS). SSS section has 11 questions about the severity and frequency of symptoms and FSS contains 8 questions about usual hand-related tasks. Each item has 5 options and each option has a score from 1 to 5, with a score of 1 indicating the absence of symptoms and 5 indicating the presence of the most severe symptoms. To calculate the severity of symptoms and functional status, the average score in each section is calculated. Higher means show worse functional status and greater symptom severity. The Persian version of Boston scale is a valid and reliable tool for Iranian patients (24).
This questionnaire contains 30 questions about the symptoms and function of the upper limb. Each question has 5 options, the range of which from 1 means no difficulty and symptoms to 5 means the inability to perform the activity and the most severe symptoms. The final score is the sum of the scores in terms of 100, the increase of which is a sign of more involvement (score 100 means severe disability) and the decrease is a sign of less involvement (score 0 means no disability) of the upper limb. In addition to 30 questions, there are two series of questions with 4 items that are optional to answer:1. sport/music component 2. work component. The validity and reliability of DASH has been evaluated in Iran, and the results showed that this questionnaire has high validity and reliability among the Iranian population (25).
The sample size was determined based on the primary outcome measure (changes in the Numeric Rating Pain Scale) in the study by Wolny 2019. Assuming a type, I error of 0.05, power of 80%, 21 patients require for each group. Considering attrition of 10%, we will include at least 24 patients for each group in this study. The length of the trial may need to be extended for achieving adequate participant enrolment to reach target sample size.
Assignment of interventions: allocation
Individuals who met the inclusion criteria will randomly be allocated to Group A (conventional physiotherapy) or Group B (a combination of conventional physiotherapy treatments with cervical manual therapy) using a computerized random allocation sequence with different block sizes. An independent statistician with no clinical involvement in the trial prepare it. The allocation will be concealed in an opaque, sealed envelope.
All eligible patients will guide to the baseline assessment. First, demographic characterizes of each patient are collected, then a research assistant opens the envelopes to reveal group allocation before starting the intervention for that patient. After that, each patient will be directed for treatment in the control group or experimental group. Outcomes measure pre and post intervention.
Participants and the outcome assessor will be unaware of assigning individuals to groups. The physiotherapist that will deliver the intervention, not be blinded to group allocation.
Data collection and management:
Data will be entered by one of research team members. They recheck by a different research member, Database available only for investigators. Personal information all patients protect during and after the trail. One independent professors (physical therapist) is responsible for reviewing of informed consents, the interests and safety of the trial subjects and monitoring the progress of the study. Any deviation from the protocol and adverse effect will reported to the Medical Ethics Committee of Ahvaz Jundishapur University of Medical Sciences.
Data will be analyzed using SPSS version 23.0. The normal distribution the data are determine by the Shapiro-Wilk test. Student’s t-test will be used for comparison of baseline clinical characteristics of the two groups. One-way between-group analysis of covariance (ANCOVA) and Paired t-test or Wilcoxon rank-sum test will be conducted to examine within and between group difference per and post intervention. Scores on the baseline (mMDL, mSNCV, pain, DASH and BOSTON score) are as the covariate that adjust in this analysis. Effect size will be calculated using Cohen’s d coefficient for effectiveness of two interventions. An intention-to-treat analysis will be conducted in this trail to handle non-adherence subjects.
Plans for communicating important protocol amendments to relevant parties:
Agreement for protocol modifications and amendments will be taken for from the ethical committees at the Ahvaz Jundishapur University of Medical Sciences and reported to it. All changes will be entered in the study registration
The results of this study will be disseminated at international physical therapy congress. A full study report will be submitted for publication in a physical therapy journal.