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CHAPTER 96  Spinal Cord Stimulation

Basic Science of Conventional Spinal Cord Stimulation INTRODUCTION The work of several investigative teams in the five decades since Shealy et al. 2 implanted the first “dorsal column stimu­ lation” electrode has helped us identify promising avenues of research, refine experimental techniques, and develop evidence in support of hypotheses that explain aspects of the mecha­ nisms of action of SCS. The challenge in experimental studies is to mimic the human painful condition and deliver stimulation, for example in rats, with parameters that would be clinically relevant in humans. Even in a homogeneous population of lab­ oratory animals, however, the yield of neuropathic pain models is uncertain, and clinical studies must grapple with even greater variability among human subjects and painful pathologies. Furthermore, as already mentioned earlier, the clinical applica­ tion of SCS elicits a discernible tingling, known as paresthesia, which confounds experimental blinding. An additional chal­ lenge is the fact that the universally agreed on measurement of the effectiveness of SCS (reduction in pain) is subjective and depends to an uncomfortable degree on a patient’s ability to remember the intensity of past pain in order to make a valid comparison with current pain. Pain assessment also relies on rather crude measurements, such as verbal rating scales and the Visual Analogue Scale. Thus, patient assessment has to be assisted by measures of medication use, physical activity, well-being, general perception of change, etc. Despite these obstacles, researchers have learned enough to propose distinct mechanisms of action for the therapeutic effects of SCS in the treatment of neuropathic, ischemic, and visceral pain. NEUROPHYSIOLOGY AND NEUROCHEMISTRY SCS affects both spinal and supraspinal circuits 15–21 and thus does not rely solely on antidromic activation of the dorsal columns. 17,22 Some SCS effects actually survive disruption of supraspinal circuits by transection of the dorsal columns, the dorsolateral funiculi, and even the entire spinal cord rostral to a lumbar electrode. 23–25 SCS modulates DH and/or supraspinal neurotransmitters; thus, the beneficial effects of SCS often outlast the period of active stimulation (see following discussion). Most studies indicate that endogenous opioids are not in­ volved in the pain-relieving effects of conventional SCS; for example, the effects of SCS are not reversed by the opioid an­ tagonist naloxone, 26 and the neuropathic pain of SCS patients is usually resistant to opioid therapy. SCS might 27 or might not 28 cause release of spinal opioids. There is some experimental evidence that only stimulation with very low frequencies (e.g., 4 Hz) might involve the release of endogenous opioids. 29 Additionally, in patients with angina, SCS during atrial pac­ ing and at rest has been demonstrated to release the opioid peptide b -endorphin into cardiac circulation, indicating that SCS affects “local myocardial turnover of the opioid peptides leu-enkephalin, b -endorphin, and calcitonin gene-related pep­ tide (CGRP), a powerful vasodilator.” 30 Nerve or nervous system injury can lead to neuropathic pain, which is often radiating, generally described as “burning,” and in some cases involves hyperalgesia (an extreme sensitivity to pain) and allodynia (pain from normally nonpainful stimuli). In contrast, dull, aching nociceptive pain, which is mediated by receptors in skin, muscle, bone, viscera, etc., is responsive to opioids. Because SCS, in most cases, is not thought to cause the release of endogenous opioids, 28 the clinical expectation is that SCS will be more effective as a treatment of neuropathic, ischemic, and visceral pain than of nociceptive pain. The fact

that SCS is effective in treating ischemic pain, which is con­ sidered a form of nociceptive pain, does not necessarily mean that SCS directly affects this type of pain. Instead, SCS seems to exert a beneficial effect on the underlying ischemic condition and pain relief in considered as secondary to that (see following discussion). Among the things rats and humans have in common are that nerve injury alone sometimes causes allodynia (in neuro­ pathic pain cases merely around 20% report allodynia 31 ) and that SCS is not universally therapeutic. Only in single clinical studies have the SCS effects on allodynia been monitored, but in selected material presented by Harke et al., 32 the therapeutic effect on allodynia was similar to that on continuous pain. Investigators also used models of painful neuropathy to ex­ plore the impact of SCS on the pain threshold in rats and found that during and after SCS, the threshold of withdrawal from innocuous mechanical stimuli increases and that SCS affects only the component of the flexor reflex mediated by A fibers (not the late component mediated by C fibers). 33 Thus, current thinking holds that, to a large extent, SCS acts at a segmental spinal level, 34 although additional inhibitory influences might be transmitted by descending serotonergic and noradrenergic pathways. A related study used the partial sciatic nerve ligation model to examine how SCS affects the response to innocuous stimuli in postligation rats with and without allodynia and in controls. Only in the allodynic rats did SCS significantly de­ press abnormal responses and spontaneous discharge of wide dynamic range (WDR) neurons. 35 The same research group introduced acetylcholine (ACH) into the list of transmitters possibly involved in the beneficial effects of SCS after a micro­ dialysis study demonstrated that ACH is released in the DHs of rats whose pain-related symptoms after nerve injury decreased in response to stimulation. 36 These effects seem to be caused by activation of muscarinic M4 and M2 receptors in the DH. 36,37 This finding might lead to new ways to enhance an otherwise inadequate effect of SCS in certain patients. Allodynia occurs when the activation of nerve fibers in the periphery causes hy­ peractivity of WDR neurons in the superficial laminae of cor­ responding DHs. 38 SCS relieves allodynia by suppressing this hyperactivity. 35 Treatment with g -aminobutyric acid (GABA) agonists also has this effect, and SCS induces GABA release in the DH of rats 18 and activates the GABA-B receptor. 39,40 SCS also decreases DH release of the excitatory amino acids glutamate and aspartate in rats. 40 One probable mechanism would be that release of GABA binding to presynaptic GABA-B receptors could inhibit the release of excitatory amino acids (e.g., glutamate). Investigators have also proposed that SCS might relieve pain by blocking conduction of primary afferents at the branch points of dorsal column fibers and collaterals. 6 This explana­ tion is insufficient, however, because the effect of SCS extends beyond the dorsal columns and electrical stimulation does not inhibit every type of pain. 21 Dorsal column activation, how­ ever, is more successful than ventral stimulation, 41 which might exert effects on the spinothalamic tract fibers that transmit nociception. SCS inhibition of the pathologic response (increased firing frequency of WDR neurons, afterdischarge in response to pres­ sure, etc.) of DH neurons in rats exhibiting symptoms of al­ lodynia after peripheral nerve injury continues for more than 10 minutes, 35 consistent with SCS-induced release of DH and ce­ rebral neurotransmitters, and changes the concentration of neu­ rotransmitters and their metabolites in cerebrospinal fluid. 41–44 Through the use of microdialysis and immunohistochemical techniques, investigators have examined the effects of SCS on the cerebral neurotransmitter serotonin. In decerebrate cats, SCS applied with clinical parameters evokes a DH release of serotonin. 42