Chronic neuropathic pain affects 8.2% of adults, extrapolated to roughly 18 million people every year in the United States. Patients who have pain that cannot be controlled with pharmacologic management or less invasive techniques can be considered for deep brain stimulation or motor cortex stimulation. These techniques are not currently approved by the Food and Drug Administration for chronic pain and are, thus, considered off-label use of medical devices for this patient population. Conclusive effectiveness studies are still needed to demonstrate the best targets as well as the reliability of the results with these approaches.
Key points
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Motor cortex stimulation (MCS) and deep brain stimulation (DBS) have been used for the treatment of refractory pain with good early results.
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MCS and DBS are used off label for pain applications because conclusive effectiveness studies are still needed to prove therapeutic value.
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New targets are being evaluated with new clinical trials that will explore pain with regard to the afferent component.
Introduction
Chronic neuropathic pain affects 8.2% of adults, extrapolated to roughly 18 million people every year in the United States. Patients who have pain that cannot be controlled with pharmacologic management or less invasive techniques can be considered for deep brain stimulation (DBS) or motor cortex stimulation (MCS). These techniques are not currently approved by the American Food and Drug Administration for chronic pain and are, thus, considered off-label use of medical devices for this patient population. Conclusive effectiveness studies are still needed to demonstrate the best targets as well as the reliability of the results with these approaches.
Introduction
Chronic neuropathic pain affects 8.2% of adults, extrapolated to roughly 18 million people every year in the United States. Patients who have pain that cannot be controlled with pharmacologic management or less invasive techniques can be considered for deep brain stimulation (DBS) or motor cortex stimulation (MCS). These techniques are not currently approved by the American Food and Drug Administration for chronic pain and are, thus, considered off-label use of medical devices for this patient population. Conclusive effectiveness studies are still needed to demonstrate the best targets as well as the reliability of the results with these approaches.
MCS
In the early 1990s, stimulation of feline and rodent cortex via epidural leads was found to modulate thalamic hyperactivity in a model of deafferentation. This concept, when applied to patients with chronic central or peripheral deafferentation pain, demonstrated initial success. However, subsequent studies have exhibited mixed clinical outcomes of MCS. MCS has been explored as an option to treat trigeminal neuralgia, poststroke central pain, spinal cord injury pain, and other pain disorders. In a review of 22 chronic pain studies, Lima and Fregni found that epidural MCS showed a significant effect in chronic pain and recommended further clinical trials to elucidate the role of MCS. It is important to note that, as for all meta-analysis, the conclusions are limited by the level of evidence of the literature included. Because there is no large, randomized placebo-controlled trial to date, the meta-analysis included mostly uncontrolled case series with various technical approaches. A recent randomized, double-blind, placebo-controlled, crossover trial examined the efficacy of MCS in a small number of patients with a variety of peripheral neuropathies. Although MCS efficacy was considered good or satisfactory in 60% of the patients during the open phase, no significant differences in pain ratings were detected between the ON and OFF stimulation groups when adjusting for multiple comparisons. The mixed clinical outcomes of MCS indicate that the therapy would benefit from a multicenter, prospective, randomized controlled trial with systematic patient selection, surgical technique, programing methodology, and follow-up. In the meantime, it is likely that MCS will continue to be used sporadically for selected patients in need of alternatives for refractory pain. MCS has risks that are typical of most craniotomies, including infection, hemorrhage, and neurologic deficits but is considered to be, overall, safe. MCS has been associated with seizures during stimulator programing and active stimulation; however, seizures and epilepsy do not seem to be a long-term complication.
Pain pathways
Pain transmission and its pathways are complex. It is thought that activity in two pathways, the lateral pain system and the medial pain system, can be modulated with DBS. The lateral pain system consists of spinothalamic tracts, which connect to the ventral posterior lateral (VPL), ventral posterior medial (VPM), and ventral posterior inferior nuclei of the thalamus, which then project to the primary and secondary somatosensory cortices. This pathway, thought to be involved in central pain, is seen in the Dejerine-Roussy syndrome (or thalamic pain syndrome) whereby damage to the thalamus or afferent and efferent fiber bundles can cause chronic pain with or without allodynia and hyperalgesia. The medial pain system consists of spinothalamic projections to the medial thalamic nuclei, limbic cortices, anterior cingulate cortex, and reticular formation and has been found to modulate emotional and affective perception with painful stimuli. The periaqueductal gray (PAG) is part of a pain inhibitory pathway in which dopamine and serotonin signaling are linked with pain suppression and analgesia whereas norepinephrine facilitates pain transmission.
DBS targets
DBS for modulation of refractory pain goes back to studies beginning in the 1950s, with targets including the septal region, central medial, and parafascicular thalamic nuclei. The most frequently reported targets are the sensory nucleus of the thalamus (ventral caudal or VPL/VPM) and the PAG and periventricular gray matter (PVG) ( Fig. 1 A). New targets under exploration include the mesial thalamic nuclei and the area of the ventral anterior limb of the internal capsule (VC) and ventral striatum (VS) (see Fig. 1 B).
Sensory Nucleus of the Thalamus (VPL, VPM)
In the early 1970s, Mazars and colleagues chronically implanted electrodes to stimulate the sensory thalamic relay nuclei based on prior work in the 1960s in which they stimulated the ventral posterolateral thalamic relay nucleus. Hosobuchi and colleagues chronically implanted electrodes in the sensory thalamus and were able to alleviate refractory facial pain in 4 of 5 patients for up to 2 years of follow-up. Turnbull and colleagues studied 18 cases of sensory thalamic implantation, and they found 72% of successful pain relief over a 10-month average follow-up. In a retrospective evaluation of 76 patients implanted with chronic stimulators in the thalamic somatosensory area for deafferentation pain, 44 patients reported substantial pain relief for longer than 2 years. Levy and colleagues reviewed a series of 84 patients with deafferentation pain implanted in either the VPL (extremity deafferentation) or the VPM (facial deafferentation); they found that 61% had initial success (patients using stimulator regularly with pain relief), but only 30% had long-term success after at least 2 years. Patients with peripheral neuropathy had greater long-term success (50%) compared with central anesthesia dolorosa (18%) or pain associated with spinal cord injury (0%), demonstrating great variability of outcomes depending on the location of the precipitating injury. Ten years later, Kumar and colleagues published a study in which they prospectively evaluated 20 patients who had a negative response to a morphine-naloxone test and were diagnosed with deafferentation pain and implanted with externalized DBS leads targeting the sensory thalamus, 3 of which had dual-implanted PVG and sensory thalamus electrodes. Twelve patients underwent chronic implantation, and 6 patients reported long-term relief at an average of 3.8 years. In a prospective, double-blind, placebo-controlled trial, Marchand and colleagues evaluated the effect of sensory thalamic stimulation in 6 patients who had been implanted for at least 2 years. These patients reported a significant reduction in daily pain with DBS, but a strong placebo component was noted. Hamani and colleagues demonstrated much less favorable results after implantation of 21 patients whereby only 5 patients (4 patients with DBS in the sensory thalamus and one patient with DBS in both the sensory thalamus and the PAG/PVG) experienced at least 1 year of pain relief.
PAG and PVG Matter
Reynolds described an application of focal stimulation to the PAG in rats that induced electroanesthesia via chronic monopolar stainless steel electrodes. The anesthetic effect was so profound that investigators were able to perform laparotomies under the analgesia provided by DBS. This study helped serve as the groundwork to translate the concept of central gray matter stimulation to the human as seen in work by Richardson and Akil. These studies initiated with a group of 5 patients who received a short period of acute stimulation before thalamic ablation. Monopolar stainless steel electrodes were stereotactically implanted into the PAG/PVG, transversing through other locations, which were tested. The 5 patients had diverse conditions, including phantom limb leg pain, abdominal cancer pain, brachial plexus pain, thalamic stroke pain, and intention tremor without pain. During stimulation, numerous side effects were seen, including nystagmus and dizziness. The best relief was seen around the nucleus parafascicularis in the medial thalamus with the least amount of side effects. Based on these findings, the group then decided to test the effects of DBS at a site medial to the parafascicularis nucleus in the PVG, with externalized leads for 1 to 2 weeks. Eight patients with various pain syndromes, including cervical and lumbar back pain, brachial plexus pain, and cancer pain, were included. Six of the eight patients obtained significant pain relief with their implant. The investigators then expanded their case series to include 30 patients, 27 of whom were chronically implanted. Of those implanted, 66% reported significant long-term relief with stimulation. In agreement with these results, Hosobuchi reported successful pain relief in 50 out of 65 patients (77%) with PAG stimulation for pain of peripheral origin. However, the investigator also noted a buildup of tolerance to DBS that was often accompanied by a tolerance to opiate analgesics. DBS analgesic efficacy was usually restored by intermittent stimulation breaks as well as concurrent use of l -tryptophan. Young and colleagues reported a 57% success rate in the stimulation of 26 patients over a 20-month mean follow-up period with implantation of PVG or PAG region alone with excellent pain relief. Levy and colleagues reported more modest results, with only a 32% rate of long-term relief in 57 patients at 7 years of follow-up, indicating that the long-term outcome was much less successful than initially anticipated in patients with nociceptive pain with PVG and VPL leads. Kumar and colleagues implanted 49 patients with PVG electrodes who had positive responses to the morphine-naloxone test and were diagnosed with nociceptive pain. The study found that 71% of those who received a permanent implant after an externalized trial reported adequate pain relief at a mean follow-up of 7.1 years. Additional studies have suggested a benefit from targeting the PAG/PVG regions, but similar limitations of previous studies apply. Recently, the group at Oxford led by Tipu Aziz has reported on the combined targeting of sensory thalamic nucleus and PVG in series of patients with central or peripheral pain syndromes. Unlike prior studies, this group has tried PVG DBS in patients with pain of neuropathic characteristics, showing that the potential analgesic effects of this target are not limited to those with pain of nociceptive characteristics.
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