Introduction: Carpal tunnel syndrome (CTS) is the most prevalent and widely studied
peripheral nerve entrapment syndrome, with estimates between 10-20% of the general
population having clinical symptoms of CTS at least once in their lifetime. Classically,
it presents with symptoms of nocturnal numbness and tingling in the distribution of the
median nerve, often progressing to more constant parasthesias, weakness, and pain in the
hand and/or wrist, and eventually thenar muscle atrophy. There is a robust and
continuously growing body of research available on the clinical presentation, diagnosis,
and management of CTS. Conservative, non-operative management strategies, including night
splinting and corticosteroid injections, have shown significant clinical benefit in
improving the severity of CTS symptoms and preventing the need for carpal tunnel release
(CTR) surgery. However, many patients with mild-moderate CTS will still go on to have CTR
due to failure of conservative measures or lack of long-term efficacy. N-acetylcysteine
(NAC) is a safe and extremely well tolerated compound which acts as a powerful
antioxidant and has been utilized in the treatment of many conditions including, but not
limited to acetaminophen toxicity, various psychiatric disorders, Alzheimer's disease,
and polycystic ovarian syndrome. Of note, some studies using animal models have shown NAC
to be effective in reducing oxidative stress and potentially expediting the recovery of
peripheral nerve injuries. This warrants consideration of the potential of NAC to impact
peripheral nerve recovery in the non-operative treatment of mild to moderate carpal
tunnel syndrome. Given the safety of NAC, and promising hypotheses to suggest
neuroprotective and neuronal growth promoting effects on peripheral nerves, The
investigators propose the following project to examine whether supplementation with oral
NAC in addition to standard night splinting significantly improves functional outcomes
for mild to moderate CTS when compared to splinting alone.
Methods: This study will be a randomized, double-blind, parallel-group,
placebo-controlled human clinical trial. Participants for this study will be recruited by
staff, residents, and research assistants on a voluntary basis from both the outpatient
Plastic Surgery clinic, Plastic Surgery clinic waiting list, and the Neurology clinic at
the Queen Elizabeth II Health Sciences Center, Halifax Infirmary, in Nova Scotia, Canada.
These will include patients both waiting for consultation with a hand surgeon for
consideration of carpal tunnel release and patients who have already been assessed by a
hand surgeon but have yet to undergo a trial of night splinting.
For the purposes of this study, a diagnosis of mild to moderate CTS will be primarily
determined by clinical history of any intermittent or persistent numbness in the
distribution of the median nerve and/or pain in the hand or wrist. Clinical exam findings
consistent with a diagnosis of CTS will be determined by a CTS-6 score of 12 or higher,
indicating at least an 80% chance of a diagnosis of CTS.
After identification of eligible participants, they will be informed of the nature of the
study and the proposed intervention and consented both verbally and in writing to
participate in the study by a research assistant. They will undergo permutated block
randomization to either the placebo controlled or experimental group in a 1:1 ratio. The
participants and physicians/assessors will be masked to participant group allocation.
Baseline variables will be collected from each participant including age, gender, smoking
status, previous diagnoses of carpal tunnel syndrome, which side is affected or bilateral
disease, which side will undergo splinting as determined by severity, previous treatments
for carpal tunnel syndrome on both the study and non-study limb (if bilateral disease),
clinical and electrodiagnostic severity of CTS, duration of symptoms, nature of onset,
any current pain medications for both CTS symptoms and non-CTS related pain, employment
status, and comorbidities.
Pre-treatment Evaluation: Once the participants have given informed consent and been
randomized, they will be asked to complete a baseline Boston Carpal Tunnel Questionnaire
(BCTQ). All patients will receive a prescription for a wrist splint and 8 weeks supply of
either NAC tablets or a placebo.
Post-treatment Evaluation: Follow-up will take place at eight weeks by the surgeon to
whom the patient was referred for consideration of carpal tunnel release. Participants
will be asked to complete another BCTQ to be compared to their baseline score. At this
time, patients can decide if they wish to proceed with carpal tunnel release surgery or
defer surgical treatment.
For patients that do not decide to proceed with carpal tunnel release surgery, a
secondary outcome measure will include a follow up at 6 months, at which time The
investigators will collect patient reported outcomes including conversion to surgery,
continued use of conservative treatment modalities including night splinting or other
treatment modalities, and patient-reported outcomes in the way of a final BCTQ if surgery
was not pursued.
Outcome Measures: The primary outcome measure in this study will be the overall score for
symptom severity and hand function limitations as determined by the BCTQ at eight weeks
post initiation of night splinting therapy. A secondary outcome will be ratio of
conversion to surgery versus continuation of conservative treatment or no treatment at
all.
Data Analysis: For baseline demographic variables, The investigators will use descriptive
statistics (means with standard deviations for continuous variables or frequency with
percentages for categorical variables) and assess between group similarities. T-test and
chi-square tests, where appropriate, will be used to determine significant differences in
baseline demographics. The primary between group analysis will be done with multiple
linear regression with adjustments made for age at randomization, gender, symptom
duration, and baseline BCTQ score, with an aim to identify significant differences in
improvements in the BCTQ score between the treatment and control group at eight weeks and
six months, where applicable. The investigators will also examine for significance in the
ratio of conversion to surgery at eight weeks and six months. Significance will be set as
a p-value <0.05.
Sample Size: Based on the INSTINCTS trial by Chesterson and colleagues, this study will
require 240 total participants (120 per group). The investigators will aim to detect a
15% or greater improvement in the BCTQ from assumed baseline value of 2.9 (scale 1-5, SD
1.0). This would mean a 0.9 point (30%) reduction in the NAC plus splinting group and a
0.45 point (15%) reduction in the placebo plus splinting group, with a pooled SD of 1.0
and mean difference of 0.45. Power will be set at 90%, two-tailed significance at 5%, and
a 15% loss to follow up will be anticipated. Recruitment of 120 participants for both the
placebo-controlled and NAC groups will primarily be from the practice of a single hand
surgeon (DT) and the practices of several local neurologists. The primary hand surgeon
(DT) has completed a preliminary audit of his practice and has determined that in the
last year, he completed 200 CTRs in the minor procedure clinic.
Strengths and Limitations: This study will have a robust sample size, minimal potential
for participant loss, and strong clinical applications in the way of a minimally invasive
adjunct to night splinting as a conservative treatment for mild to moderate carpal tunnel
syndrome. This study is limited in that the primary outcome measure is relatively
subjective, despite the fact that the BCTQ is a validated tool that has been applied
clinically in reputable trials. Additionally, despite controlling for between group
variability in baseline function, severity of disease prior to treatment can certainly
impact the degree of response to conservative measures and may confound results.
Ethical Considerations: Given that the participants in this study will have already
decided to pursue investigations and treatment for their carpal tunnel syndrome prior to
being informed of and consented for our trial, there is a negligible ethical conflict of
exposing a patient to tests and treatments that they would not have otherwise had.
Eligible participants will be given the standard information regarding the risks and
benefits of both pursuing and delaying carpal tunnel release surgery and will not be
delayed or denied surgery should they choose not to participate in the trial. It is,
however, acknowledged that there is a remote possibility of placing patients at risk by
administering a medication. NAC has been found to be a safe, non-toxic substance with
little-to-no reported short or long-term side effects. Participants will be given as much
information about the possible intervention as is needed and will be offered the right to
withdraw from the study at any point in time without any repercussion to their medical
care.