Placebo Versus Active Spinal Cord Stimulation for Refractory Pain Randomized Controlled Trial: the PAcStim RCT

1. Background and Rationale 1.1 Clinical burden and limitation of current care Neuropathic pain (NP) is a severe form of chronic pain caused by lesions or diseases affecting the somatosensory nervous system. It is characterized by burning, shooting pain and allodynia.) The global population prevalence of NP is about 6-10%. The Canadian prevalence of neuropathic pain is 1.9% to 3.4%, meaning that approximately 302,000 to 537,000 Ontarians suffer from NP. This high prevalence is concerning because NP is associated with substantial decreases in quality of life, high rates of comorbidity with sleep problems, depression, and anxiety, and high economic costs to the individual and the society. Current pharmacological treatments for NP, including anticonvulsants, antidepressants and opioids, have a low success rate (25%) and most patients experience adverse effects3 leaving many patients without effective treatment. Non-pharmacological and interventional treatments provide additional approaches to managing NP, including spinal cord stimulation, peripheral nerve stimulation, dorsal root ganglion stimulation, intrathecal drug delivery systems, sympathetic nerve blocks, radiofrequency ablation, epidural steroid injections, and chemical neurolysis, but many patients remain refractory to available NP therapies.

1.2 Mechanism of action of spinal cord stimulation (SCS) Spinal cord stimulation (SCS) modulates pain signaling via electrical stimulation of dorsal column fibres, interfering with transmission of nociceptive signals to the brain. Neuromodulation approaches such as SCS are often effective for treating chronic refractory NP syndromes but long-term benefits are limited in some patients. There is evidence to support benefits of SCS in diabetic NP and its superiority over repeat surgery for patients with history of failed previous back surgery syndrome (FBSS) and the cost-benefits of SCS also support its use.

1.3 Paresthesia-based vs paresthesia-free spinal cord stimulation Modern SCS uses epidural leads positioned over the dorsal columns, programmed to either paresthesia-based (PB-SCS) typically below 80 Hz, or paresthesia-free (PF-SCS) modes (500-10,000 Hz high-frequency.

Paresthesia-based SCS (PB-SCS), with stimulating frequencies lower than 80 Hz, has been extensively used to treat NP in the limbs with or without axial pain with mean reduction in pain intensity of 60%.8 However, PB-SCS suffers from limitations including up to 40% of patients reporting attenuation of benefit at one year after implant and 10% to 15% experiencing painful or uncomfortable paresthesias.9 The recent increase in availability and use of paresthesia-free SCS (PF-SCS) modes that use high stimulating frequencies (500-10,000 Hz) are potentially more efficacious tools to treat NP. PF-SCS has a number of advantages over PB-SCS. PF-SCS stimulates analgesic pathways within the nervous system without stimulating fibers responsible for paresthesias (i.e., without tingling), making it more tolerable for patients. PF-SCS is likely more effective than PB-SCS, which simply masks pain signals with paresthesia. In the pivotal SENZA-RCT, HF10 demonstrated superior responder rates versus traditional low-frequency SCS at 3 months (back pain: 84.5% vs 43.8%; leg pain: 83.1% vs 55.5%) and maintained superiority through 12-24 months, with no paresthesias reported in HF10 recipients.

Quality-of-life analyses from the SENZA program show greater improvements (Oxygen Desaturation Index (ODI), sleep quality, global functioning, clinician impression of change) with HF10 than with conventional SCS at 12 months. Finally, because PF-SCS is imperceptible, it is less susceptible to habituation and may have more durable effects.