While the Gate Control Theory is thought to play a vital role, the specific mechanisms by which neuromodulatory techniques treat pain are not entirely understood. There are, however, several molecular-level changes that have been identified as playing a role. First, most techniques leverage neuroplasticity, with repeated exposure to neuromodulatory stimuli leading to functional and structural changes, including alterations in nerve synapses (ie, changes in activity and the number of ion channels). This leads to a number of downstream effects that can modulate the perception of pain in the CNS, including altered nerve excitability, neuronal activity, and neurotransmitter release. ^, Next, some studies suggest that neuromodulation affects GABA activity within the CNS, in particular, more centrally acting techniques promote GABA release by activating inhibitory interneurons in the spinal dorsal horn. It is theorized that with a higher level of release, the effects of GABA are enhanced, leading to heightened descending modulation of ascending nociceptive C and Aδ fiber signals and repressing the sensation of pain at a central level. ^, Finally, a few studies have suggested that these techniques involve the activation of opioid and cannabinoid systems, modulating nociception by decreasing the activity of thalamic sensory neurons, increasing the activity of periaqueductal gray neurons, and inducing spinal anti-inflammatory effects.

Overall, there are mixed findings on the efficacy of TENS as a pain modality. For example, one pooled systemic review (n = 192) on 3 studies evaluating the use of TENS for acute low back pain reported discrepancy in findings across studies, while one study reported that a 30 minute TENS session while in-route to the hospital reduced pain by (Δ28.0 mm, 95% confidence interval [CI] −32.7–−23.3, P <.05) compared to treatment with placebo, the other studies reported no difference to placebo treatment. Supporting this finding, another study that evaluated previous Cochrane reviews on the effectiveness of TENS compared to sham for pain relief was similarly unable to conclude that TENS was beneficial for pain control. In comparison to these, one large systemic review on 15 studies (n = 724) that utilized TENS compared to sham in adults with chronic neuropathic pain reported that there was a post-intervention difference in pain level (Δ1.58, 95% CI–2.08–−1.09, P <.05), suggesting some potential utility of TENS as a pain modality. Of note, one commonly cited limitation that may explain the different findings between studies is the discrepancy in the schedule in which TENS was applied. Despite the mixed literature, many clinical practice guidelines support the use of TENS as an adjunct modality because of its benign side effect profile and limited cost.

Studies on TMS have also produced inconsistent outcomes for providing analgesia. ^, For instance, current literature involving TMS in patients with migraine and central neuropathic pain has primarily reported benefit for pain control. One systematic review of 5 studies that examined TMS in patients with migraine (n = 313) found that single pulse TMS was effective in the acute window for improving pain in patients with migraine with aura (OR = 2.87; 95% CI 1.17–7.03; P =.02) compared to sham. In addition, a systematic review of 22 studies reviewing patients with migraine also concluded decreased headache frequency, duration, and intensity in treatment groups involving TMS compared to sham or medical management alone. Similar findings have been reported in other studies as well. ^, For central neuropathic pain (ie, central pain secondary to stroke or other CNS disorder), several clinical studies have been published demonstrating the effectiveness of TMS as an adjunct to first-line treatment. ^,,,

Studies on tDCS indicate potential benefits for treating neuropathic pain and headaches; however, overall findings have been more mixed compared to those for TMS. ^, For example, a systematic review of 8 studies investigating tDCS for pain of various origins found variable—but generally positive—evidence supporting its superiority over sham treatment, particularly for neuropathic pain related to spinal cord injury, stroke, and radiculopathy. In comparison, a systemic review of 9 randomized control trials (RCT; n = 411) that examined use of tDCS for chronic low back pain also reported anecdotal improvement in pain with regimens involving tDCS compared to sham, but these differences were non-significant (standard mean difference [SMD] = 0.38; 95% CI = − 0.26–1.02; P =.25), (SMD = 0.14; 95% CI = − 0.21–0.50; P =.43). In patients with chronic headache, numerous studies have also noted the superiority of tDCS over sham in improving headache duration and frequency; however, a minority of studies have reported statistical significance in these differences. Several reasons for this have been postulated, including varying power in study protocols, varying treatment schedules, including ramp-on and ramp-off durations, and number of sessions.

Research on PNS has demonstrated utility in providing analgesia across various pain states. ^, Perhaps the strongest evidence for PNS lies in chronic musculoskeletal pain. For example, a small case series of 9 patients suffering from chronic low back pain who underwent PNS placement and were followed for 1 year postop reported significantly lower pain intensity (defined as ≥50% reduction on Brief Pain Inventory Short Form; BPI) in 67% (n = 6) subjects at follow-up (average 80% reduction among responders; P <.05). At another follow-up 1 year later, the same 6 patients continued with clinically significant reductions in pain (average 63% reduction in pain intensity) and disability (32 point reduction in disability) despite lead removal. In another study involving 9 patients with chronic axial back pain, implantation and use of PNS targeting the medial branch of a lumbar dorsal ramus resulted in significant reductions in both average and worst pain intensity scores on the BPI at 30 days post-implantation, with these improvements persisting at the 4 month follow-up. Similar smaller studies focusing on pain in peripheral joints (ie, knee ^, and the shoulder ^, ) have found similar positive effects of PNS. Furthermore, PNS has shown promising results as a treatment for various neuropathic pain states, including craniofacial neuralgias, CRPS, and neuropathic pain secondary to local nerve injury. ^,

Like with non-implanted cranial stimulators, research on DBS has focused on chronic headache pain. Results have generally suggested positive effects, with many studies noting non-significant findings, which underline the need for high-powered studies in this area. For example, one crossover RCT studied 11 patients with refractory cluster headache randomized to either hypothalamic DBS or sham. The participants underwent active and sham treatment in 1 month periods before crossover and were followed up for symptom relief for 1 year posttreatment. At follow-up, 55% (n = 6) of patients had a significant response to DBS, half of these patients were headache free, while the other half noted a greater than 50% reduction in headache frequency. These findings were anecdotal and did not demonstrate a statistically significant advantage of DBS over sham; however, other smaller studies have reported similar promising, though non-significant, results in chronic headache. More recently, studies have also suggested promise for DBS in the treatment of central neuropathic pain. ^,,

Most MCS studies have focused on neuropathic pain, but similar to DBS, the evidence remains conflicting. For example, one systematic review of 12 studies (n = 198) in patients with variable central (ie, post-stroke pain) or peripheral (ie, CRPS, trigeminal neuralgia, etc.) neuropathic pain noted improvement in a minority of patients, for example, there was improved pain in 35.2% of those with post-stroke pain, 46.5% of those with trigeminal neuralgia, and 34.1% of those with phantom pain. However, other studies have noted less significant pain relief after MCS, for example, a case series of 14 patients who underwent MCS for neuropathic pain of different types noted 5 patients benefited from a transient analgesic effect and only 2 who maintained greater than 50% pain relief through follow-up. The authors concluded that MCS was not effective in producing an acceptable long-term benefit. Overall, the field is in need of more robust, higher powered studies with a standardized approach to better understand the level of analgesic effect possible through the device, as well as identifying which patients best respond to the treatment.

Among implantable devices, SCS is the most extensively studied, with numerous publications evaluating its effects on pain relief and quality of life. Given its widespread use and evidence base, patient selection is particularly important for SCS, with pre-surgical psychological screening and a trial procedure recommended to optimize outcomes and improve success rates. ^,,, The literature generally supports the use of SCS for improving symptoms in specific pain conditions, including CRPS, failed back syndrome, and chronic neuropathic pain. Illustrating the potential utility of SCS in these conditions, one RCT evaluated the effect of SCS as an adjunct to conventional medical management on pain levels in 100 patients with neuropathic pain secondary to failed back syndrome. This study reported significantly improved leg pain ( P <.0001), quality of life ( P ≤.01), and functional capacity ( P ≤.01) at 24 month follow-up, concluding long-term benefit of SCS as an adjunct to conventional management. Another systematic review found similar findings, noting level 1 evidence supporting SCS as a treatment of various pain states, including chronic axial low back pain, lumbar radiculopathy, neuropathic pain, and CRPS. In a separate review, SCS demonstrated long-term pain reduction and functional improvement in patients with chronic pain of various states who underwent SCS. Further, studies by North and Kumar showed significant pain relief for subjects with pain secondary to failed back syndrome who underwent SCS, compared to lumbar re-operation or conventional medical management alone. While still under investigation, studies have also begun to evaluate how different forms of SCS compared to one another—for example, some studies have reported burst SCS to be superior to traditional tonic SCS for pain relief and quality of life. ^,

Finally, although the literature on DRGS is comparatively limited, studies have reported similarly positive findings for its use in isolated neuropathic conditions, such as CRPS and phantom limb pain. More recent RCT studies have suggested superiority of DRGS to SCS for pain control in focal CRPS, while promising but lower quality evidence has been demonstrated for DRGS in failed back syndrome. ^, Given that DRGS is a newer technology, further research on its safety profile and indications is warranted, particularly in identifying areas where it may be superior or inferior to SCS, given their overlap.