The Use of N-acetylcysteine Supplementation in Addition to Night Splinting for Treatment of Mild to Moderate Carpal Tunnel Syndrome: A Randomized, Double-blind, Placebo-controlled Trial

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.