Spinal cord stimulation in chronic neuropathic pain: mechanisms of action, new locations, new paradigms

Abstract

1. Introduction Neuropathic pain is a complex, heterogeneous disorder that affects approximately 8% of the total adult human population and comes with significant burden for both the patient and health care system.13 The international association for the study of pain defines neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system” and classifies chronic neuropathic pain as a disease under International Classification of Diseases 11th Revision (ICD-11).89 Despite the development and use of many pharmacological drugs and guidelines for the treatment of chronic neuropathic pain over the years,8 a substantial amount of neuropathic pain patients remain undertreated or untreated, with less than 50% of patients responding to pharmacological treatment.30 The development of novel, last-resort interventional treatment therapies is crucial to also relief pain in these refractory patients. Over the years, spinal cord stimulation (SCS) has proven to be a valuable last-resort treatment option (approximately 50% pain reduction in 50%-70% of patients) for a wide variety of refractory pain disorders, such as painful diabetic peripheral neuropathy (PDPN),22,94 complex regional pain syndrome (CRPS),42,43 and failed back surgery syndrome (FBSS).53,77 The mechanism underlying Tonic SCS (see section 2) is partly understood, and evidence has been provided for a mechanism of action through both spinal (section 2.1) and supraspinal levels (section 2.2). Recently, new physiological targets for stimulation as well as novel SCS paradigms were introduced to bridge the gap between currently achieved pain relief (as obtained with Tonic SCS) and the desired pain relief. Literature on the effect of stimulation at new anatomical locations, such as dorsal root ganglion stimulation (DRGS) (see section 3), and the use of new subsensory SCS paradigms such as high-frequency (HF) SCS (see section 4.2) and Burst SCS (see section 4.3) are discussed. This review ends with concluding remarks and future directions for research. 2. Tonic spinal cord stimulation: mechanisms of action 2.1. Tonic spinal cord stimulation and spinal segmental mechanisms Experimental studies on the effect of SCS have predominantly been performed in rodent models including the partial sciatic nerve ligation model (PSNL) (for review, see Smits et al.97). Electrodes are carefully inserted, either transcutaneous or through laminectomy, in the epidural space on top of the dura mater surrounding the spinal cord. Then, electrical pulses are administered to the dorsal columns of the spinal cord through an implantable pulse generator or an external stimulation device. Tonic SCS settings vary within a range of 30 to 80 Hz, 100 to 500 µs of pulse width, and an amplitude above sensory threshold.71,73,93,97 The concept of Tonic SCS emerged as a direct spin‐off from the gate control theory.65 Based on this gate control theory, it was postulated that antidromic stimulation of the non-nociceptive Aβ fibers in the dorsal columns could close a “spinal gate,” located in the dorsal horn of the spinal cord.92 Meanwhile, orthodromic stimulation of the Aβ fibers in the dorsal columns also caused paresthesias (ie, abnormal tingling sensation) in the area innervated by the stimulated fibers9 (Fig. 1). Nowadays, during implantation of the SCS lead the physician makes sure these paresthesias overlap the painful area.9,76 Closing of the “spinal gate” is mediated by inhibitory interneurons located in the upper laminae of the dorsal horn. In line with the gate control theory, these inhibitory interneurons, when antidromically activated by Tonic SCS, modulate the nociceptive signal through the release of gamma-aminobutyric acid (GABA). Indeed, experimental research has demonstrated that Tonic SCS decreases intracellular GABA immunoreactivity in the dorsal horn of chronic neuropathic rats.39 At the same time, extracellular GABA levels in the spinal dorsal horn increase when applying Tonic SCS in chronic neuropathic rats.18,61,104 Thus, enhanced GABA release in the spinal dorsal horn seems to be a vital aspect of the mechanisms underlying Tonic SCS. The mechanism underlying interference with nociception at the spinal cord level using Tonic SCS was further elucidated by the administration of pharmacological agents. Local intrathecal application of a GABAB receptor antagonist in the dorsal horn transiently abolished the stimulation-induced analgesic effect in neuropathic rats, and rats not receiving adequate reductions in tactile allodynia with Tonic SCS (nonresponders) were turned into responders by administration of the GABAB receptor agonist baclofen.17 The aforementioned preclinical findings were successfully translated to the clinic, where some neuropathic pain patients not responding to Tonic SCS were turned into responders with additional intrathecal administration of low (subeffective) doses of baclofen.59,60,88 Hence, the presynaptic GABAB-mediated inhibition of the communication between nociceptive afferents and the second-order neurons in the spinal dorsal horn is important in the mechanism underlying Tonic SCS. Nevertheless, also postsynaptic GABAergic modulation through GABAA receptors in conjunction with K+/Cl− cotransporter 2 (KCC2) expression is involved in neuropathic pain15 and in the mechanism underlying Tonic SCS.17,39,40Figure 1.: The spinal nociceptive network and mechanisms of action of SCS of the dorsal columns and DRGS. The spinal cord dorsal horn contains 2 types of second-order projection neurons: the nociceptive-specific (NS) projection neurons located in lamina I and the wide-dynamic range (WDR) projection neurons located in the deeper laminae. These projection neurons receive input from nociceptive afferents, but also from thickly myelinated, touch-affiliated, Aβ fiber afferents. Spinal cord stimulation (electrode placed on top of the dorsal columns) is believed to depolarize the touch-affiliated Aβ fibers, and this can occur in both the antidromic and orthodromic directions. Antidromically, SCS can activate GABAergic inhibitory interneurons located in the dorsal horn. Consequently, these inhibitory interneurons release GABA, which, after binding to its GABA receptor (either to GABAB or GABAA presynaptically or postsynaptically), inhibits the incoming signals from nociceptors and thereby closes the “spinal gate.” In addition, SCS can also interfere with further processing of the nociceptive signal through the spinothalamic tract, thereby modulating supraspinal brain centers such as the thalamus, somatosensory cortex, cingulate cortex, and insula. Orthodromically, SCS can also depolarize Aβ fibers in the cranial direction, thereby further modulating supraspinal centers like the cuneate nucleus or gracile nucleus. After supraspinal integration of the signal, a descending feedback loop of both serotonergic and noradrenergic projections to the dorsal spinal horn further modulates and controls the “spinal gate.” Dorsal root ganglion stimulation (electrode placed on top of the DRG) might engage mechanisms dependent on stimulation of non-nociceptive Aβ fibers (as occurs in SCS) as well as stimulation of nociceptive C fibers in the DRG. Recent studies suggest that DRGS may induce a conduction block through the C-type T-junction located in the DRG itself. This T-junction can act as a low-pass filter for action potentials (nociceptive signals) travelling from the periphery to the spinal cord. SCS, spinal cord stimulation; DRGS, dorsal root ganglion stimulation; GABA, gamma-aminobutyric acid.A decreased GABA release as noted in animal models of neuropathic pain results in further enhanced and uncontrolled glutamate release of the nociceptive afferents, which in turn activates and opens the N-methyl-D-aspartate (NMDA) receptor due to removal of the Mg2+ block. Enhanced Ca2+ influx through the NMDA receptor then leads to central sensitization, which is a process fundamental to neuropathic pain.119 From this, it was suggested that interference with the process of central sensitization through antagonism of the NMDA receptor might attenuate chronic neuropathic pain, a process that may also be involved in the antidromic mechanism underlying Tonic SCS. Indeed, a combined treatment of Tonic SCS and the intrathecal application of a subeffective dose of ketamine (a NMDA antagonist replacing the Mg2+ block) has been shown to convert SCS nonresponders into responders in a rat model of chronic neuropathic pain.109 It needs to be stressed that these experimental findings have not yet been implemented and/or confirmed in clinical studies. Importantly, intrathecal administration of ketamine was shown to result in severe histological abnormalities, including central chromatolysis, nerve cell shrinkage, neuronophagia, microglial upregulation, and gliosis in a patient suffering from chronic intractable neuropathic pain.116 Although it is very well possible that subeffective doses of ketamine can in fact be safely used in a clinical setting, more research is needed as to determine safe intrathecal administration dosages. The main goal of Tonic SCS in the treatment of (experimental) chronic neuropathic pain is to stimulate the thickly myelinated Aβ fibers in the dorsal columns. It can, however, not be excluded that also incoming dorsal root fibers, including C and Aδ fibers, are directly stimulated through the relatively large-sized experimental electrodes as used in rodent studies.97 This possible involvement of dorsal root fibers and the dorsal root as the site of action is further substantiated by where not stimulation of the dorsal but also stimulation of the dorsal root dorsal horn in Although Tonic SCS and its spinal mechanisms are partly studies that more and cell types are Tonic SCS of in the dorsal horn and this is by of receptor the intrathecal application of a receptor was to block of in The receptor is located on microglial which that the and in the a in the of by SCS, and the mechanism underlying Tonic SCS to control of Tonic spinal cord stimulation and mechanisms supraspinal cell are to modulate the incoming nociceptive signals at the spinal level through descending fiber such as the and the nucleus but also the are activated by Tonic SCS and in turn modulate the spinal nociceptive signal (Fig. 1). The descending projections release a variety of including which an inhibitory effect on the receptor on the incoming nociceptive and this neuropathic research on the spinal receptors that to the of Tonic SCS in chronic neuropathic rats was and with use of intrathecal application of and for the it was shown that the of the receptor seems to through spinal GABAergic evidence for a of mechanisms underlying Tonic SCS was by et demonstrated that Tonic SCS of the dorsal allodynia and in an experimental model of chronic neuropathic pain, after dorsal these From this, it was suggested that the inhibition in of allodynia and can be to the of centers through projections of the dorsal Tonic SCS can also modulate in brain at and levels has been shown in a rodent model of chronic neuropathic Tonic SCS processing has also been shown by clinical studies using such as and in et These during Tonic SCS may direct from dorsal stimulation or inhibition of nociceptive signals from the or may complex on somatosensory and clinical on the supraspinal of Tonic SCS has demonstrated modulation of brain with the spinothalamic The is for the of pain such as the and of the painful This from the dorsal through the thalamus, to such as the somatosensory study performed in patients receiving Tonic SCS demonstrated that this of stimulation of the dorsal columns signals in somatosensory the cortex, and the a more study with Tonic SCS as treatment for of the and its to the and cingulate cortex, and the In over the years, on Tonic SCS has provided evidence for a mechanism of action through both spinal and supraspinal Tonic spinal cord stimulation and of experimental studies It be noted that preclinical studies on on a to supraspinal of Although the peripheral nerve as used in experimental animal studies result in chronic pain, the use of is more to of nociception of This may the of experimental findings to the Recently, an was which and of pain in the use of Tonic SCS was shown to also the of the pain in chronic neuropathic This that Tonic SCS, in to spinal also supraspinal brain a further substantiated by of brain including the cingulate These findings that be when the analgesic of SCS in chronic neuropathic pain this is not to increase the of experimental findings to the but also to the underlying mechanisms of In addition, also between and may direct of findings to the These the models used with heterogeneous clinical the use of of in for stimulation the of the in to the dorsal columns in in dorsal and the of the that between the SCS lead and dorsal it is important to carefully these when to preclinical findings to the Tonic spinal cord stimulation: which dorsal fibers are Although both spinal and supraspinal are involved in Tonic SCS, it has been demonstrated that Tonic SCS results in reductions of allodynia in the rat when administered at the level where the sciatic nerve fibers the spinal dorsal horn as to application at more levels The of the dorsal in the rat spinal cord makes the Aβ fibers within the columns at fibers but then to at more levels dorsal Aβ fibers were also to be from the dorsal and and on the of dorsal fibers that are stimulated by Tonic SCS that this is not to of the located afferents the of the SCS to depolarize dorsal fibers decreases to the of the from the the findings on pain relief of Tonic SCS in a model of chronic neuropathic are in line with the aforementioned anatomical and physiological it is that Tonic SCS through a site of action (Fig. 1). In the of dorsal it be stressed that these fiber not myelinated Aβ fibers but also of fibers in the and that is of the of the dorsal columns in and as the of these fibers is not understood, it is important to where these fibers Although the fibers may to including or fibers descending from in the nucleus or dorsal root that a significant of the fibers in the gracile to the nucleus in the brain and also that a significant of these fibers on pharmacological it is suggested at at a of these fibers might be nociceptive and involved in This then may a more on the mechanism underlying Tonic SCS not non-nociceptive Aβ fibers but also nociceptive C fibers are In this it is that a for the of dorsal horn spinal cord neurons that receive peripheral input and to the brain was This may for further of not nociceptive-specific in the dorsal horn but also possible projections in the dorsal Tonic spinal cord stimulation: Despite however, to the of Tonic SCS. 50% to of patients with or pain reductions of the pain reduction is to approximately 50% to Tonic SCS is to and stimulate such as the or the of the leads on top of the dorsal columns makes this to due to in between stimulation lead and stimulation to paresthesias and/or with Tonic SCS, is significant to the such as the the electrical the spinal cord dorsal It is important to that in the of SCS may result in these These be as to either the use of new for stimulation (see section and/or the use of new SCS paradigms (see section stimulation the dorsal root ganglion DRGS, the leads are in the epidural space on top of the dura mater surrounding the spinal cord but are then through the to the lead over the DRG of the DRGS in DRGS has been successfully implemented for a wide variety of neuropathic pain disorders, but not low back I and and clinical on DRGS has been to This study DRGS to be and to Tonic SCS for chronic intractable pain of the to I and In addition, patients receiving DRGS were to have less as to patients with Tonic SCS at and the amount and of paresthesias were to be less with DRGS over Tonic SCS, and DRGS was to be more in to in as to Tonic some DRGS patients achieved it was that DRGS the spinal mechanisms dependent on stimulation of non-nociceptive Aβ fibers and GABA release in the dorsal horn of the spinal cord as occurs in Tonic SCS of the dorsal columns. Although a study suggested that DRGS may nociception by mechanisms in the dorsal horn through of myelinated study that the effect of DRGS is not to be dependent on GABA release in the spinal dorsal horn at the experimental studies suggest DRGS of neurons with predominantly nociceptive fibers of the of DRG the DRG is to act as an or low-pass filter to electrical from the peripheral to the spinal cord in to electrical stimulation (Fig. a study by et an GABAergic communication network between sensory the DRG. These that sensory neurons in the DRG for GABA and release and are of GABA From this, it was that this GABAergic in the DRG may act as a in to the aforementioned gate control and that DRGS might its analgesic action by this This conduction block at the site of the DRG is with the that DRGS signals of brain that are to be of the pain including the and and that were by stimulation in Although the of DRGS be confirmed and in additional including pain experimental studies are also needed to the underlying mechanisms of DRGS, including the of a gate in the DRG itself. The use of new spinal cord stimulation high-frequency spinal cord stimulation and Burst spinal cord stimulation Introduction to novel physiological targets for novel SCS paradigms were introduced to bridge the gap between currently achieved and desired pain relief. SCS and Burst SCS, were introduced to to the of SCS treatment for chronic neuropathic SCS and Burst SCS are at stimulation sensory which the patient not paresthesias during This has for the SCS was introduced in the to clinical spinal cord stimulation in neuropathic pain SCS is at a above Hz, with a pulse at approximately 30 µs and an amplitude of to the underlying mechanism of SCS Although Tonic SCS and its pain inhibition is by the SCS is sensory and not activate or the conduction of the dorsal Aβ Experimental research has shown that the dorsal are activated with use of Tonic SCS, with SCS, the neurons in the gracile nucleus not a reduction of peripheral stimulation in a chronic neuropathic pain mechanism for SCS and its effect was by et suggested that the electrical to the spinal cord may a and of in the spinal dorsal horn and dorsal root Hence, SCS in fact the communication between the nociceptive C fibers, which in the dorsal horn laminae and the nociceptive neurons (Fig. 1). the of a electrical in the dorsal the the underlying mechanism of SCS also which could a where pulses on to and a that might occur and where action potentials are by the the for SCS has not yet been and clinical evidence that SCS can significant pain Burst spinal cord stimulation in neuropathic pain The Burst was introduced in by et This Burst of administered at and 500 with a pulse of and in The of the is during the after the in a which it from SCS and Tonic SCS, in which pulse is after in a This Burst was it in the central nervous Indeed, neurons for of nociception from peripheral and the have been to in Although possible overlap between the Burst (as and used by et and the in the central nervous it is important to that Burst have not yet been in to the space has not been effect of have not been many can be pulse width, of but also the of research is needed to as well as to the physiological by Burst SCS paradigms are in preclinical and in the SCS, the Burst has been to pain relief paresthesias in that stimulation is not dorsal Aβ stimulation at low amplitude may be with to and with to the of are to dorsal horn fibers, the pulse and/or are This could in additional dorsal horn mechanisms that are not activated with Tonic SCS. the between Tonic SCS and Burst SCS is believed to be located the at supraspinal evidence that Burst SCS not through the to be involved in and of but also the which is to brain involved in and of pain, such as the the and the In addition, it was that Burst SCS pain including amount of patients to as well as in as by the and to a than Tonic SCS or Burst SCS in more in of and back pain than on the significant between Burst and Tonic SCS were in of These findings are further substantiated by the fact that Burst and Tonic SCS brain of the as well as descending pain inhibitory these suggest that both Burst SCS and Tonic SCS are of modulating the but Burst SCS to this by also modulating the of the may the of the pain further the mechanism underlying Burst SCS and pain experimental studies are experimental studies on the effect of Tonic SCS were performed in sciatic nerve models including the model (see section it is important to use models to and the administration of both and receptor the effect of both Tonic SCS but also Burst SCS in a rat model of chronic neuropathic pain, it is that Burst SCS, like Tonic SCS, is mediated through spinal GABAergic Burst SCS is suggested to modulate at a supraspinal levels in a as to Tonic it is that the GABAergic mechanisms underlying these stimulation at at a spinal the with the use of in the the of Burst SCS were and with Tonic SCS in a rat model of chronic neuropathic (see also section 2.2). the Burst SCS from Tonic SCS and from this, it was that Burst SCS more than Tonic SCS, supraspinal for the processing of of These findings were further substantiated with of Burst SCS in chronic neuropathic involvement and of brain including the as well as the and to be involved in and of The and studies on Burst SCS and Tonic SCS in pain relief in a neuropathic animal model suggest that the mechanism underlying Burst SCS from that of some overlap in underlying mechanism GABA release in dorsal spinal The fact that Burst SCS has been shown to result in a and analgesic effect in a chronic neuropathic pain model as to Tonic might some additional the underlying the Burst SCS activates including the and (Fig. it is possible that Burst SCS modulates descending serotonergic and noradrenergic The may the and effect in experimental studies. Although not substantiated by clinical on a of Burst SCS In addition, results from a that Burst SCS a that on the of is as as Burst SCS, a after Burst The or of such a supraspinal loop might more as to the antidromic spinal mechanism to be in Tonic SCS (see section and 1). of a supraspinal loop signal at levels in the brain including brain but also involved in the descending of the loop such as the and nucleus as well as signal and over the or pain the mechanism underlying Burst SCS from Tonic SCS is further by experimental studies on the effect of pulse amplitude and the of in a neuropathic rat Burst SCS and are by a where Burst SCS is at an amplitude of 50% of as to of and of At the same time, the between pulse amplitude and effect with Tonic SCS is Hence, the Burst SCS amplitude 50% of was with Tonic SCS at the of for and the was for Burst SCS than for Tonic SCS at From this, it is suggested with Burst SCS, a complex, between of and pain relief future and research Spinal cord stimulation and in Tonic SCS have been shown to a safe and last-resort for patients with refractory pain with and Nevertheless, (see section the main is that with Tonic SCS, 50% to of patients with refractory neuropathic pain pain reductions of and the pain reduction is to approximately 50% to Then, is also a of that occurs over and these research in the of SCS and neuropathic pain introduced new stimulation like DRGS and new subsensory SCS paradigms such as SCS and Burst SCS. This for the neuropathic pain patient at the same time, the for and treatment the mechanisms of action are understood, and as the in of pain relief with use of these new and new SCS paradigms is not that achieved with Tonic SCS, further research is This then be on an between experimental animal studies and clinical In this the research and research in line with by the international association for the study of pain to be are the segmental and supraspinal involved in The use of cell types further of these The involvement and of is needed and further stimulation paradigms (ie, in and/or and/or pulse the spinal and supraspinal and is the of the total and not SCS (see section 4.2) and Burst SCS (see section but also stimulation paradigms such as and have shown both experimental studies and studies are needed to and these and the use of SCS of action potentials is to the between and which may then have direct for SCS and pain research and be on and of pain and clinical of of and of involvement of supraspinal as to SCS paradigms and stimulation (DRGS) and effect on pain relief are It is of to the of the dorsal and the of fibers (see section Tonic SCS has been shown to processing and and the fact that new SCS paradigms like Burst SCS may activate the and with that brain involved in the and of pain makes this also for treatment of such as and These also to are to be to of or brain SCS for Burst SCS, may a future option for modulating and not chronic neuropathic pain but also its of The have of to

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