Mechanism of Action

The introduction of SCS was inspired by Melzack and Wall’s gate control theory in 1965.⁹ This theory proposed that painful “nociceptive” information in the periphery is transmitted to the spinal cord in small-diameter, unmyelinated C-fibers and lightly myelinated A-delta fibers, which end in the superficial laminae of the dorsal horn (i.e., the gate) of the spinal cord. Other sensory information such as touch or vibration is carried in large, myelinated A-beta fibers that pass through this gate. As they do, they give off small branches that terminate in the dorsal horn, where they have an inhibitory effect on the nociceptive conduction. The basic premise of the gate control theory was that stimulation of large, low-threshold fibers would close the gate to the reception of small-fiber information. In the first volume of Pain more than 35 years ago, Lindblom and Meyerson¹⁰ reported that SCS increased vibration thresholds and tactile thresholds but did not change the perception of cutaneous pain induced by pinching in five patients responding to SCS, suggesting that SCS affects A-beta fiber function but not C-fiber function.

The general mechanism of pain relief by SCS still is understood in these gating terms, even if there are several substantial problems with this understanding.⁷ For example, both acute and chronic pain should be suppressed by SCS, but this is not the case. It became obvious that not all types of pain are modulated uniformly; whereas SCS primarily affects neuropathic pain and nonnociceptive pain, activation of large afferent fibers can still signal pain,¹¹ and only chronic pain appears to be affected. Thus the mechanism of action of SCS must involve more than a direct inhibition of pain transmission in the dorsal horn of the spinal cord.

Pain modulation by SCS may involve supraspinal activity via the posterior columns of the spinal cord (i.e., down-modulation involving loops or feedback mechanisms that influence rostral transmission of pain from higher centers to the spinal cord). In humans suffering from several types of neuropathic pain, electrical stimulation of the dorsal columns in the thoracic spinal cord generated antidromic action potentials, activating large myelinated fibers in pure sensory peripheral nerves¹²; and late cellular activation in the dorsal horn after SCS has been also hypothesized, as suggested by an increase in c-Fos immunoreactive cells in the dorsal horn after SCS.¹³ Recent results in an animal model of neuropathic pain showed that the spinal serotonergic system plays a crucial role in the pain-relieving effect of SCS, suggesting an activation of serotonergic descending pathways that may inhibit spinal nociceptive transmission.¹⁴ Moreover, evidences of SCS-induced activation of specific areas of the brain (primary and secondary sensorimotor cortex, cingulate cortex, insula, thalamus, and premotor cortex) have recently been published¹⁵; and regional cerebral blood flow measured by positron emission tomography in patients undergoing SCS therapy for intractable pain was increased in the right thalamus, superior parietal lobule, and left inferior parietal lobule after application of SCS. Thus SCS controls pain cognition by modulating the thalamus and parietal association area, and it also controls the emotional aspects of pain by modulating the prefrontal region.

However, spinal segmental inhibition still seems to be crucial. Animal studies show that second-order afferent nerves and interneurons can be activated by SCS,¹⁶ and a proportion of these may manifest delayed inhibitory activity following brief stimulation.¹⁷ SCS also selectively inhibits abnormal hypersensitivity in dorsal horn neurons¹⁸ and significantly modulates neuronal activity in dorsal column nuclei.¹⁹ It does not directly activate the neurons of the pars gelatinosa, but elicits inhibitory responses of these neurons via A-fibers by reducing excitatory neurotransmitters.²⁰ At the cellular level SCS was shown to stimulate the neurons of the dorsal horn of the spinal cord to release increased amounts of acetylcholine, substance P, serotonin, noradrenaline, glycine, and γ-aminobutyric acid (GABA).^21–23 In a series of acute experiments using microdialysis in the dorsal horn of nerve-lesioned rats, SCS reduces the release of excitatory amino acids (glutamate, aspartate) and at the same time increases the GABA release²⁴; the reduction in excitatory amino acids is prevented by blockade of GABA receptors.²⁵ The state of central hyperexcitability manifested in the development of allodynia after peripheral nerve injury seems to be related to dysfunction of the spinal GABA systems, and it appears that SCS may act by restoring normal GABA levels in the dorsal horn.^25,26 Moreover, rats that were nonresponders to SCS (their mechanical allodynia was not attenuated by SCS) could be converted to responders with intrathecal administration of low doses of baclofen.²⁵ Similar results were obtained in a pilot clinical study in humans in which the SCS effect was enhanced by simultaneous intrathecal administration of low dose baclofen, and the obtained pain relief results appeared to be long lasting.^27,28 Thus experimental and clinical evidences point toward a significant role played by the activation of the GABA system within the spinal cord in the analgesic mechanism of SCS.

SCS is effective on mechanical allodynia in animal models of neuropathic pain.²⁹ The antiallodynic effect was observed after 30 minutes of stimulation, with a complete return to preneuropathy levels, and it lasted up to 60 minutes after SCS cessation. However, a differential antiallodynic effect seems to be related to the degree of severity of the allodynia itself. SCS leads to faster and better pain relief in mildly allodynic rats compared to the more severely allodynic ones.³⁰

Finally, SCS yields a marked sympatholytic effect. This effect is considered responsible for the effectiveness of SCS in peripheral ischemia, cardiac ischemia, and at least some cases of complex regional pain syndrome (CRPS) and FBSS.⁷

Spinal Cord Stimulation: An Evidence-Based Therapy?

Patient Selection

Patient selection is the key to having positive outcomes.⁷ As with any procedure that has risk, choosing a patient who wants to get better and has an etiology that has been shown to benefit from SCS is a must. Although not all patients are suitable for treatment with SCS, careful patient selection and implantation after evaluation by a multidisciplinary pain management team can offer safe and effective treatment of refractory neuropathic pain.⁴⁶ The search for objective criteria that predict an optimal result using implantable systems must include psychological criteria in the decision algorithm.³⁶ However, at present there is insufficient empirical evidence that psychological screening before surgery or device implantation helps to improve treatment outcomes, even if the current literature suggests that psychological factors such as somatization, depression, anxiety, and poor coping are important predictors of poor outcome.⁴⁷

One of the unique and inherent benefits of SCS is the ability to perform a trial before permanent implantation.⁴⁸ A 50% pain relief reported by the patient is the minimal yet usually the only efficacy measurement that needs to be met during the trial. Unfortunately, this 50% gold standard is purely subjective and is potentially biased by placebo effects. Therefore the need for valid objective test(s) that, along with the subjective report of pain relief, can help the implanter define a “successful” trial is obvious. In a small prospective pilot study of patients with FBSS or CRPS, Eisenberg and associates⁴⁹ showed that some quantitative sensory measures—vibration threshold and tolerance to electrical stimulation at 5 and 250 Hz—were changed with an SCS trial. These changes were also correlated with the decision regarding the permanent implantation, which was made independently of them.

The delay between the first back surgery and the trial of SCS seems to be a significant prognostic factor. In a study of 235 patients treated over 15 years, the success rate of SCS dropped from 93% in patients who had a 3-year delay between surgery and implantation to 9% for those who had a 12-year delay.⁸ Thus SCS should be considered early in the management of FBSS, before a second operation and before the use of high-dose opioid analgesics.⁵⁰

However, despite a proper patient selection some patients do not benefit adequately from SCS, in spite of the fact that stimulation-induced paresthesia covers the painful area.²⁴ In a recent retrospective analysis of a single-center experience with SCS over the past 22 years, Kumar, Hunter, and Demeria⁵¹ reported an 84% early–SCS trial success in FBSS patients, the success rate dropped to 60% in the long-term follow-up (mean 98 months).⁵¹ Interestingly, authors reported a lower failure rate (16%) in FBSS patients with a clear pain etiology and radicular distribution compared to a higher rate (33%) in FBSS patients who did not experience obvious neuropathic pain but had nonspecific pain in their arms or legs that was not in the distribution of any particular nerve root or roots and was not associated with radicular neurological deficits.

During the patient selection process some commonly accepted contraindications should be taken into consideration.²³ Absolute contraindications are (1) sepsis, coagulopathy, or other conditions associated with an unacceptable surgical risk; (2) previous surgery or trauma that obliterates the spinal canal; (3) localized infection at the implantation site; and (4) spinal bifida. Relative contraindications are (1) physical and/or cognitive/psychological disability, (2) unresolved major psychiatric disorder, (3) unmanaged substance abuse or cognitive disorders, (4) pregnancy, and (5) presence of a cardiac pacemaker or defibrillator.

Technical Issues

Briefly, SCS is applied through a subcutaneous electrical generator that delivers pulses by means of electrodes placed in the epidural space adjacent to a targeted spinal cord area presumed to be causing the pain. Definitive electrodes can be placed percutaneously or through a surgical procedure (most of the time, a laminectomy). Although electrodes placed via laminectomy in the thoracic region appear to be associated with significantly better long-term effectiveness,⁵² no definitive evidence has been published so far. However, a percutaneous trial is always required before proceeding to the full implant of the system.^48,53,54

Trial of Spinal Cord Stimulation

The patient is positioned in a comfortable prone position on a fluoroscopy table. A pillow underneath the abdomen may correct lordosis curve and open posterior interlaminar space, which can facilitate electrode insertion. The choice of level of electrode insertion is guided by several factors. A fundamental consideration is that several centimeters of the lead have to lie in the epidural space to ensure maximal stability of the electrode and minimize unwanted migration. To ensure this, insertion must take place at least two spine segments below the desired target.

The epidural space is accessed using median or paramedian approach and angling steeply up from below. It is recommended that the loss of resistance technique be used to access the epidural space since contrast may obscure lead placement and saline flush can decrease the consistency of paresthesias. Some physicians now believe that a single lead is sufficient, and the lead is manipulated up under fluoroscopic guidance to the target level. If dual leads are desired, most are placed parallel but can be staggered according the final electrical field elicited with the different configuration provided with the position of the electrodes. Manipulation of the leads up the epidural space can be a tricky and subtle technique. Several stylets are available with different tip configurations that aid in the placement of the lead to its desired location. Once satisfied with lead positioning (check for the position in the posterior epidural space), the next step is assessing paresthesia coverage.

Ultimately the patient must determine if the paresthesia that occurs in his or her back and/or legs is better than the back and/or leg pain that drove him or her to attempt the trial. During the trial period the patient should be encouraged to log activities, activity durations, and medications and possibly measure pain levels on a VAS equivalent. Pain treatment with SCS therapy is considered effective when a patient experiences a clinically significant (50% or greater) reduction in pain. When this occurs, the patient is then recommended for permanent SCS placement.

Full Implant of Spinal Cord Stimulation

If a two-electrode implant technique is chosen, usually two needles are inserted either on one side of the midline at two different levels or on both sides of midline. The first technique is preferred to perform leads anchoring through a single paramedian incision. The needles are inserted, and the leads are placed under fluoroscopy guidance using techniques similar to those described in the trial procedures.

The skin incision, starting at the stab wound around the needle shaft and extending 5 cm caudally, should be deep enough to expose either the supraspinous ligament or the fascia of the paravertebral muscles.

Several anchors to secure the lead to the ligament or fascia are marketed by different companies. A silicone anchor with percutaneous leads improved average time to mechanical failure compared to a rigid plastic anchor; moreover, supporting the lead with the tip of the anchor as it entered the lumbodorsal fascia improved average time to failure (fracture) by 60-fold compared to the nonsupported condition.⁵⁵ Finally, bonding the lead to the silicone anchor with silicone adhesive was shown to be the only method that reliably prevented slippage of the lead through the anchor during cyclical loading.⁵⁵

The positions of the leads are then documented again by fluoroscopy, and they are tunneled subcutaneously from the midline incision to the exit side where the pulse generator is going to be implanted. The skin incision is then irrigated (with or without antibiotic solution) and closed in layers using absorbable sutures for the subcutaneous tissue and nylon sutures for the skin (e.g., Vicryl sutures to close the subcutaneous tissue and 3.0 nylon sutures to close the skin).

No consensus exists regarding the best site for implanting the pulse generator (buttock, lower abdomen, subclavicular area) or the need of interposing an extension with safety loops between the lead and the implantable pulse generator (IPG) to release tension generated by patient’s movements (especially bending). However, it seems that placement of the IPG in the buttock region may produce up to a fivefold increase in tensile loading compared with placement in the abdomen or midaxillary line, and that the configuration that places the least amount of mechanical strain on the anchor is a coil lead with strain relief loops.⁵⁵

The totally IPG contains a lithium battery, and activation and control occurs through an external transcutaneous telemetry device (for the physician) or through a small portable controller (daily carried by the patient). Life span of the battery varies with usage and with the parameters used (i.e., voltage, rate, and pulse width). Most patients can expect the battery to last, under average usage, between 2.5 to 4.5 years.

Electrical Issues

Understanding the somatotopy of the spinal cord is paramount in understanding the technical aspects of implantation. It is generally agreed that SCS relieves pain only if it induces paresthesias in the area of the patient’s pain, although scientific proof is lacking. To this end, correlation of the somatotopy and the level of the spinal cord is necessary. Barolat and associates⁵⁶ have published extensively about the mapping of the human spinal structures. A database was created to suggest areas of sensory response to dorsal SCS: the lead contact typically is several levels above the desired area for concordant paresthesia. Moreover, the low threshold of the dorsal root sensory fibers makes it imperative that the lead position is sufficiently midline to avoid recruitment of the root. However, despite an optimally placed electrode, differences in paresthesia coverage between subjects should be expected because of the large interpatient variability of the intraspinal geometry.⁵⁷

It is clear that stimulation on the dorsal aspect of the epidural space creates complex electrical fields that affect a large number of structures.⁵⁴ Electrical stimulation depends on the conductivity of the intraspinal elements in relation to the lead position.¹¹ If a neuron is made more electrically positive or depolarized, it will produce an action potential. Thus the neuron is activated or caused to propagate an action potential. An external electrode that can produce this effect must be negatively charged or a cathode. These effects are called cathodal effects. When the neuron is hyperpolarized or its membrane made more negatively charged, its ability to propagate an action potential is reduced, or its threshold for propagation is raised. A positively charged external electrode or anode produces this anodal effect. Thus the active electrode for stimulation is the cathode, and the anode or positive electrode may shield neuronal structures from the effects of stimulation.

The relative positions of cathodes and anodes and their distance from the spinal cord were demonstrated to be major determinants of axonal activation and paresthesia.¹¹ As the distance between the cathode and anode increases, the influence of the anode diminishes. At larger distances the field about the cathode becomes a sphere, with little influence produced by the anode. Closer contact produces the greatest influence on the anode, significantly shaping the field by pulling it toward the positive contact.⁵⁸ Thus dorsal columns of the spinal cord are most efficiently stimulated with closely spaced longitudinal bipolar (+ −) or tripolar (+ − +) configurations placed on the physiological spinal cord midline because the main current component of the stimulation field corresponds with the orientation of these fibers.^59,60

The deepest penetration of the cord without creation of a larger electrical field is produced by a technique termed guarding.¹¹ A tripole, in which there is an anode, is placed in close proximity to each side of the cathode. This prevents the cathodal field from expanding beyond the anode on either side. Thus the anode represents the ultimate boundary for the cathodal field. When a guarded cathode is placed in a longitudinal fashion, as in classic SCS, it produces a field with greater penetration of the spinal cord. On the other hand, a guarded cathode used to stimulate in a transverse fashion (using three parallel leads) has the effect of shielding the nerve root and allowing use of greater amplitude to produce better penetration of the cord, contributing to maximum dorsal column stimulation with minimal dorsal root stimulation and providing analgesia to the lower back.⁶⁰ Left and right anodes can be set at different voltages, and changes in their voltage ratio (“balance”) can steer the electric field from one side of the dorsal columns to the other, thus changing the body area covered with paresthesia.⁶¹ Results from a pilot clinical study showed that the best “steering” score was obtained when the central cathode was >3 mm dorsal to the spinal cord and centered <2 mm from the midline, whereas the electrical field “steering” was impossible when, because of the transverse geometry of the spinal canal, the electrode–spinal cord distance was small compared with the anode-cathode distance (≈3 mm).⁶¹

According to 22 years of experience of a single teaching center in treating patients with a predominance of axial pain combined with either unilateral or bilateral leg pain, staggered, parallel, multicontact electrodes seem to be more efficacious than parallel, nonstaggered configurations.⁵¹ At present it is difficult to be clear about the electrophysiological explanation for the higher success rate achieved with staggered configuration. A possible explanation is that, by staggering the electrodes, the contact separation distance is reduced, providing more extensive paresthesia coverage.

However, when the paresthesia area can be covered with several configurations, it is beneficial for the patient to program a configuration with one cathode and either no or multiple anodes to decrease energy consumption and increase battery lifetime.⁶²

Although how and where the SCS stimulus is applied determines what structures are activated or inactivated,¹¹ no evidence has been published about the best lead configuration for SCS, and little is known about the effects of frequency and pulse width on SCS efficacy. SCS at 4 and 60 Hz seems to be more effective in reducing hyperalgesia than higher frequencies (100 and 250 Hz).⁶³

Failures

Most of the failures are hardware related. Electrode displacement in either the axial or transverse planes was the most frequently encountered complication in SCS,⁵¹

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