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CHAPTER 96  Spinal Cord Stimulation

CONVENTIONAL SPINAL CORD STIMULATION MECHANISMS IN ISCHEMIC PAIN

SCS lead

SCS is thought to induce vasodilatation and improve micro­ perfusion in patients with ischemic pain, which is sharp, ach­ ing, heavy, and tiring 103 and a signal of local ischemia. Thus, SCS has a beneficial effect on the cause, not merely the symp­ toms, of ischemic pain. This might explain why ischemic pain is one of the few types of nociceptive pain known to respond to SCS and why the mechanisms seem to be fundamentally dis­ tinct from those that provide relief of neuropathic pain. 28,42,104 PERIPHERAL VASCULAR DISEASE To investigate the mechanism of SCS in the treatment of pe­ ripheral vascular disease (PVD), better renamed “peripheral arterial occlusive disease” (PAOD) (especially because if the vascular problem affects the venous side, standard SCS pro­ duces little or no effect), investigators developed a new ani­ mal model that involves applying mechanical pressure to an artery in the groin of rats. 105 Using this model, SCS delivered with clinically relevant stimulation parameters recovered nor­ mal microcirculation in 100% of treated rats versus 28% of controls. In addition, administering SCS preemptively reduced the amplitude of the invoked spasm and significantly shortened the time to recovery of microcirculation. In skin flaps with se­ verely compromised arterial blood supply, application of SCS could significantly increase the flap survival as judged 1 week after the provocation. If a CGRP receptor antagonist was given before the SCS treatment, the survival rate decreased consider­ ably, implicating this vasodilatory compound in the effect. 106 SCS also suppresses efferent sympathetic activity (maintained by nicotinic ganglionic receptors and a 1 -adrenoreceptors) 104 and might activate antidromic mechanisms at intensities far below the MT, 107–111 thus causing peripheral vasodilation by stimulating release of CGRP 106–108 from the terminals of sen­ sory fibers that contain transient receptor potential vanilloid-1 (TRPV1) receptors 112,113 and the release of nitric oxide from en­ dothelial cells. 113 The balance between these two mechanisms seems to de­ pend on the activity level of the sympathetic nervous system, the intensity of SCS, and individual patient factors (genetic dif­ ferences, diet, etc.). 111 In fact, antidromic activation dominated at low autonomic baseline activity, whereas the sympatholytic effects of SCS were clear with high baseline activity. 111,114 Later studies have indi­ cated that even small-diameter fibers are involved at SCS in­ tensities much below the MT 112,113 and have pointed toward additional mechanisms. The observation that SCS has a powerfully beneficial ef­ fect on vasospastic conditions, such as Raynaud’s syndrome, is consistent with theories that the cause of this syndrome is a combination of heightened sensitivity or increased density of a -adrenergic receptors 115 and CGRP-system dysfunction. 116 A stimulation-induced “normalization” of function in each sys­ tem could underlie the efficacy of SCS in treating this condition. Up to the present, most animal studies have utilized SCS frequencies that are routinely applied in the clinic (i.e., 40 to 80 Hz), but in a more recent study, higher SCS frequencies up to 500 Hz were tried at intensities 30% to 90% of MT. 89 This study showed that although the MTs for SCS at all frequencies were similar, SCS at 500 Hz induced a significantly larger blood flow elevation in the hind paw than did SCS at 50 Hz. The ef­ fects of these frequencies and intensities seem to depend on ac­ tivation of TRPV1-containing fibers and the release of CGRP. Thus, further trials with new stimulation parameters should be undertaken to increase benefits of SCS. A review of the mechanisms involved in SCS-induced vaso­ dilation is included in a report by Wu et al. 117 and by Foreman and Linderoth. 118

Dorsal roots

CGRP NO

A

A

DC

c

Artery

1 Adrenorec.

nicotinic

Sympathetic Efferent Fibers

The mechanisms and neurotransmitters known or hypoth­ esized to be involved in the effects of SCS in ischemic pain are depicted in Figure 96.4. SPINAL CORD STIMULATION FOR ANGINA PECTORIS AND CARDIAC DISEASE Investigators studying the mechanism of action of SCS in pa­ tients with otherwise refractory angina agree that SCS reduces ischemia 119 but disagree about how this occurs. Positron emis­ sion tomography has indicated that SCS causes a redistribution of coronary blood flow in patients with refractory angina 120,121 (even though other experimental studies have failed to demon­ strate this effect). 122 On the other hand, the decrease in the de­ pression extending from the end of the S wave to the beginning of the T wave (ST-segment depression) that appears on electro­ cardiograms (ECGs) during SCS treatment and the observed SCS-induced reversal of lactate production to extraction might indicate an accompanying decrease in cardiac myocyte oxygen demand. 123 The SCS-induced protective changes that increase myocar­ dial resistance to critical ischemia 124 are manifest by the im­ proved tolerance of patients to a deliberately paced increase in heart rate 119 and by increased time-to-angina in exercise tests. 119,123 This effect might signal an SCS-induced inhibition of the excitatory effect of ischemia on the intrinsic cardiac nervous system (such an excitatory effect might lead to dysrhythmia and increased ischemia). 124–126 The possibility that SCS modu­ lates cardiac neurons is supported by the finding that transcuta­ neous electrical nerve stimulation increases blood flow in intact human hearts but not in transplanted, denervated hearts. 127 There is no proper animal model of angina pectoris mimick­ ing the syndrome in humans. The animal studies discussed in the following text are instead focused onto various deleterious effects of experimentally induced chronic and/or acute coro­ nary ischemia. Because SCS reduces total body, but not cardiac-specific, norepinephrine spillover during pacing to moderate angina, 128 part of the anti-ischemic effect of SCS might owe its potency to an overall reduction in sympathetic activity. An experimental study using induced cardiac infarcts in a rabbit model, how­ ever, indicates that the decrease in infarct size with SCS therapy FIGURE 96.4  Schematic illustration of mechanisms and neurotransmit- ters possibly involved in effects of spinal cord stimulation (SCS) in ischemic pain. SCS probably indirectly exerts inhibition onto medullary neurons, thus perpetuating sympathetic efferent vasoconstriction via nicotinic gan- glionic receptors, mainly a 1 ( a 1 Adrenorec. 5 adrenoreceptors) peripheral receptors. In parallel, SCS activates an antidromic loop inducing peripheral release of calcitonin gene-related peptide (CGRP), probably also involving small-diameter fibers. An inhibition of nociceptive transmission has also been indicated in experimental studies but is clinically unlikely. c, small diameter unmyelinated “c-fibers”; DC, dorsal columns; NO, nitric oxide.