Chronic pain is a rampant disease affecting large swaths of global populations. The 2016 Global burden of disease study found that pain-related conditions, especially low-back and neck pain, are the leading cause of disability worldwide (1). Defined as intractable pain lasting >3 months, chronic pain is complex and difficult to treat. Neuropathic pain, a subtype of chronic pain, is related somatosensory nerve dysfunction and does not generally respond to opioid medications (2). Spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS) are two neuromodulatory techniques that have been shown to effectively treat neuropathic pain.

SCS is a form of neuromodulation that targets the spinal cord with electrical impulses to treat various pain conditions. It was first clinically utilized in 1967 by Shealy et al. to treat chronic pain induced by metastatic lung cancer (3). Since then, its applications include failed back surgery syndrome (FBSS), angina, critical limb ischemia, neuropathic pain and complex regional pain syndrome (CRPS) (4–8). The mechanism of action of SCS was based on the gate control theory postulated by Melzack and Wall in 1965, which proposed that stimulation of Aβ fibers could attenuate or suppress pain signals traveling through Aδ and C fibers (9). However, new waveform stimulation techniques such as high-frequency stimulation (HFS) and burst stimulation have challenged this understanding, and the precise mechanism is much more nuanced (10–13). SCS usage has grown despite this gap in knowledge (4–6, 14, 15), likely in part because it is cost-effective compared to conventional medical management and primary spine surgery (16–20).

The success in treating other chronic pain disorders has led to SCS's use in treating cancer and chemotherapy-induced pain. Cancer-related pain affects more than 70% of patients and up to 40% of these patients report experiencing neuropathic pain (21). In multiple reports and retrospective reviews, SCS has been demonstrated to effectively treat cancer-related pain (22–27). Preliminary evidence from small case studies note significant improvements in pain relief from neuromodulation in patients with metastatic bone disease (28, 29). It has been also employed to treat chemotherapy-induced neuropathy (CIN) (22, 23). Cata et al. conducted a case study of two patients with CIN refractory to medication, who completed a successful trial of SCS and proceeded to permanent implant. Both patients showed improvement in pain scores, gait, flexibility, touch, sharpness detection, and reduction in medication, and improvements in gait and flexibility (23). Abd-Elsayed et al. similarly reports a case study in which a patient with breast cancer and CIN had excellent pain relief, improvement in daily functioning and sleep, and reduction of pain medication following SCS (22). CIN occurs in up to 40% of patients treated with agents known to have the potential for neurotoxicity and has been shown to significantly increase cancer survivor morbidity and healthcare expenditures (30). Given that pain and motor dysfunction are the most common reasons for discontinuation of chemotherapy prior to course completion—-particularly with the frequently used platinum-containing compounds, vinca alkaloids, and taxols—-SCS efficacy may be particularly significant (Table 1) (31–33). Though these initial results have been promising, large-scale RCTs have not yet been performed for this application. In this review paper, we give a general overview of SCS use, including stimulation types and novel closed-loop systems, as well as DRGS for treatment of neuropathic pain.

When a patient has failed conservative measures and wishes to pursue SCS as a means of treatment, the first step is a 5–7 day trial with temporary leads. If >50% pain relief is achieved with the trial, the patient is considered for permanent implantation (34). In general, SCS devices consist of two parts: electrodes which deliver the electric impulses and an implantable pulse generator (IPG) that serves as the power source and pacemaker. Leads for these devices can either be directly implanted via a small laminectomy to place a paddle, or percutaneously (Figure 1). IPGs may either be rechargeable or non-rechargeable. The physical footprint of the IPG is larger for non-rechargeables, but they have less patient burden and are less expensive. Rechargeable IPGs last two to three times as long as non-rechargeables. Charging IPGs varies based on the amount of energy consumed but in general patients should charge their devices at least once a week for about 1 h by placing a charger over skin at the battery site. This process can become burdensome and sometimes painful. There are two options for intraoperative feedback required during surgery. Intraoperative mapping establishes stimulation frequencies, amplitude, width, and location and requires patient feedback during the operation. Alternatively, intraoperative electromyography can be used on patients under general anesthesia to predict energy requirements and device placement (35). Either immediately or shortly after the procedure is complete, patients will meet with a company-specific device representative to program their devices for everyday use.

DRGS is a similar method of neuromodulation to SCS with one important difference: the target of the leads. Instead of placing leads to stimulate the dorsal columns (50), percutaneous leads target the dorsal root ganglion (DRG) where sensory neuronal bodies are housed. This theoretically allows for precise targeting of specific pathological neurons that may be firing aberrantly and causing pain. This mode of neuromodulation has been particularly effective for neuropathic pain conditions including postsurgical pain, CRPS, and phantom limb pain (PLP) (65–67). Case reports and retrospective studies have also demonstrated efficacy treating refractory pelvic pain and postherniorrhaphy pain (68–70). The ACCURATE trial conducted by Deer et al. is a prospective RCT that demonstrated evidence that DRGS achieved higher responder rates as compared to SCS for CRPS and lower limb causalgias (65). This study also supported previous findings of more precise paresthesia coverage achievable with DRGS as compared to SCS, particularly in the ever-challenging regions to target like the foot and lower back (65, 71, 72). However, pain relief was also achieved without paresthesia coverage in the ACCURATE trial, and subsequent retrospective studies recommend that DRGS should aim just below the sensory threshold (73, 74). Additionally, the absence of a significant epidural space limits variation with position (65, 72). The most commonly cited concerns with DRGS are related to the operator, as it is a relatively new procedure that is more technically demanding compared to SCS (66). Other concerns lie in the ability to easily remove the leads. A review of complications following DRG surgery cited lead removal as a common complication (75). Additionally, a case study on 4 patients undergoing DRG for various indications noted lead fracture in all four cases, where 3 of the 4 have undergone previous surgeries (76). Regardless, DRGS is an area of active study.

Research examining DRGS for a variety of pain indications, including cancer-related pain is underway. Studies examining vincristine-induced neuropathy in animal models have demonstrated increased pain tolerance with stimulation of the DRG with ultrasound waves (77, 78). An investigation by Koetsier et al. in animal models with DPN demonstrated that DRGS' effects are not related to GABA release from inhibitory neurons in the dorsal horn (79). This suggests that the mechanism by which DRGS alleviates neuropathic pain is distinct from SCS. While confirmatory studies in larger animal and human subjects are still in the pipeline, DRGS may therefore be a particularly fruitful treatment of cancer-related pain in the future.

Other surgical procedures for cancer pain involve interruptions of pain pathways by lesioning nerves, nerve roots, ganglion, etc. These procedures include spinal cordotomy, midline myelotomy, and thalamotomy. Spinal cordotomy is the most common and it eliminates pain sensations from the opposite side of the body (80). Lesion procedures provide immediate pain relief and are useful for patients suffering with malignant pain. However, there are limitations. Cordotomy is irreversible, may result in unpleasant side effects like numbness and weakness and bilateral cases may result in breathing difficulties (80). Most important is that the relief lasts between 3 and 12 months so for non-malignant pain, this may not be adequate. Risk and benefit profile for myelotomy is similar. Brain ablation results tend to last longer but which patients may benefit is often difficult to predict (80).

Chronic pain not only takes a physical and emotional toll on the patient but it also poses a great financial burden for those suffering from it. The cost of chronic pain to society is up to $USD 635 billion due to patients' excessive utilization of healthcare resources (81). In general, chronic pain patients were found to visit the emergency department more frequently than patients without pain (82–84). More so, the treatment of chronic pain is complex and often results in patients being passed from practice to practice, accumulating bills with little to no relief. Neuromodulation has become an effective alternative treatment for patients refractory to conservative medical management (85). Neuromodulation provides sustainable pain relief for many and subsequently reduces healthcare utilization and unnecessary costs. Kumar et al. demonstrated the incremental cost-effectiveness ratio for SCS ranged from CAN$ 9,293–11,216 (16). The study also showed that SCS provided positive incremental net monetary benefits compared to conventional medical management and the probability of SCS being more cost-effective ranged from 75 to 87% based on pathology (FBSS, CRPS) (16).

Neuropathic pain exacts a significant toll on patients, providers, and health care systems alike. SCS represents a cost-effective and effective treatment for a variety of neuropathic pain indications. Tonic, burst, and HFS have all shown benefit in treating various chronic pain phenotypes, including cancer-related pain and chemotherapy induced neuropathy. Closed-loop SCS systems should be evaluated with cautious optimism as potential future treatments, particularly in patients who have difficulty achieving consistent therapeutic stimulation levels. Finally, the newer DRGS is emerging as an additional therapy for those wishing to more precisely target dysfunctional neurons to mitigate pain. As research continues and neuromodulatory techniques, so too will the pain relief and disability endured by chronic pain patients.

JP designed the manuscript, provided clinical expertise, and edited the manuscript. BS drafted the manuscript with help from JB and OK. All authors approved the final manuscript.

JP was a consultant for Boston Scientific, Nevro, Jazz Pharmaceuticals and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, Jazz Pharmaceuticals, GE Global Research, NIH 2R01CA166379-06, and NIH U44NS115111. She was the medical advisor for Aim Medical Robotics and Karuna and has stock equity. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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