8-A860A-2018-Books-00091Rathmell5e_Ch096-NO CROP-ROUND1

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PART FIVE  METHODS FOR SYMPTOMATIC CONTROL

It was recently demonstrated in neurophysiologic studies with microelectrode recordings from different brainstem re­ gions that both the “serotonergic cells” and the OFF-cells in the rostroventromedial medulla (RVM) are selectively acti­ vated by lumbar SCS in neuropathic rats, and this happens only in animals responding to the stimulation in previous behavioral studies. 45 In SCS-responding animals, the tissue concentration of 5 hydroxytryptamine (5-HT) is increased in lumbar DHs following stimulation. 46 The behavioral effects of the 5-HT release in the DHs seem to be mediated by 5-HT2A, 5-HT3, and the 5-HT4 receptors. 47,48 Similarly, a massive activation of neurons induced by SCS occurs in the locus coeruleus, another brainstem center, where many noradrenergic cell bodies are gathered. In contrast to the RVM where 5-HT release could be observed at the spinal level, there was no sign of direct projection of noradrenergic neu­ rons activated by SCS to the DHs (as demonstrated by several methods 49 ). Based on the finding that spinal extracellular GABA levels are lower in allodynic rats than in controls but increase in allo­ dynic rats that respond to SCS, 50 investigators have attempted to potentiate the therapeutic effect of SCS in nonresponding rats with concurrent intrathecal administration of normally sub­ therapeutic levels of GABA or the GABA-B agonist baclofen. 39 This strategy caused a marked increase in the rats’ threshold for paw withdrawal from innocuous mechanical stimulation. Intrathecal administration of the selective a 1 -adenosine recep­ tor agonist R-phenyl isopropyl adenosine produced similar re­ sults. 40 Administration of subtherapeutic doses of these agents as adjunct therapy with SCS causes nonresponding rats to re­ spond to SCS. 51 In the first clinical study based on this response, however, the addition of intrathecal baclofen and/or adenosine in small doses was effective, but the latter potentiated SCS in only 2 of 5 patients. 52 This result caused investigators to try instead other drugs administered orally in man for neuropathic pain. In rodents, the drugs were given intrathecally and intravenously instead: gabapentin and pregabalin in per se ineffective doses in non-SCS-responding rats with partial sciatic nerve lesion. In these rats, the drugs together with SCS reduced tactile allodynia in a dose-dependent manner and enhanced suppression of hyperex­ citability of WDR neurons. 53 Accordingly, investigators conducted a pilot study that of­ fered intrathecal baclofen (and, in a few cases, intrathecal ad­ enosine) to 48 patients who did not successfully respond to technically adequate SCS. 54 Although 20 patients achieved sat­ isfactory pain relief with baclofen plus SCS or baclofen alone, only 11 continued treatment: 7 with a combination SCS sys­ tem and intrathecal baclofen pump and 4 with only a baclofen pump. At mean 67 months postimplant, 2 SCS/intrathecal pa­ tients had their pumps removed and the remaining 9 in the group (5 SCS/intrathecal, 4 intrathecal) reported continued pain relief. The baclofen dose was increased 160% from base­ line, but 5 patients reduced their use of other analgesics. A similar dose-dependent effect occurred in rodents with intrathecal administration of an otherwise subtherapeutic dose of clonidine, which partially exerts its effects via release of ACH in the DH. 36,55 A small randomized, double-blind prospective clinical study reportedly indicated that clonidine could be equally useful as low-dose baclofen to enhance the effect of SCS. 56 We have yet to identify all of the neurotransmitters and neuromodulators affected by SCS, let alone to decipher their doubtless complicated interactions. 40,42,57 The mechanisms and neurotransmitters known or hypothesized (so far) to be in­ volved in the effects of conventional SCS in neuropathic pain are illustrated in Figure 96.2.

5-HT; NE

SCS

DLF

Dorsal roots

STT

DC

A

GABA

A

WDR

Ach

c

X

Skin (or organ)

Basic Science of New Spinal Cord Stimulation Waveforms HIGH-FREQUENCY SPINAL CORD STIMULATION In principle, high-frequency (HF) sinusoidal stimulation ap­ plied to a nerve or an axon provides a local conduction block (e.g., Kilgore and Bhadra 58,59 ). In contrast to HF current appli­ cation to a peripheral nerve, HF SCS applied to the dorsal spi­ nal cord of lightly anesthetized rats with the pulse width (PW) and the low amplitudes used clinically induced no block of transmission in the dorsal columns (DCs) nor any activation. 60 Clinical HF SCS is applied via bipolar stimulation at a pulse repetition rate of 10 kHz and a short PW of about 30 micro­ seconds at an amplitude that is below perceptual threshold (see Fig. 96.1). The “working hypotheses” for HF SCS so far have been (1) a transmission block or (2) activation of some pathways in the spinal cord. However, a recent computer simulation study 61 has demonstrated that both these hypotheses require high stimulation amplitudes that are at the upper end or outside of the ranges used clinically in HF SCS. A third hypothesis was based on observations from studies of the auditory system in cats and on some few patients with cochlear implants. HF stimulation seemed to be able to induce a desynchronization of neural signals from groups of neurons firing in synchrony. This interesting hypothesis has, to the best of our knowledge, never been studied in nociception (review Linderoth and Foreman 62 ). Furthermore, a study by Song et al, 60 has shown that trans­ mission in the DCs is not affected because there is neither fiber recruitment nor block with HF SCS. Another recent study 63 where recordings from rats with nerve injury were performed with tungsten electrodes on single DC fibers provided data sup­ porting the view that no blockade of the DCs is obtained with HF SCS at clinically relevant amplitudes. It seems that there is a therapeutic effect of HF SCS, but so far, it has not been found superior to that of traditional SCS in our FIGURE 96.2  Schematic illustration of mechanisms and neurotransmitters possibly involved in the effects of spinal cord stimulation (SCS) in neuro- pathic pain. SCS activation of dorsal column collaterals secondarily induces release of g -aminobutyric acid (GABA) from dorsal horn (DH) interneurons, activating mainly GABA-B receptors and decreasing the release of excit- atory amino acids from hyperexcited second-order DH wide dynamic range (WDR) neurons. SCS also causes cholinergic neurons to activate M4 and M2 muscarinic type receptors (Ach). Several other transmitters, adenosine, and hitherto unknown substances are also likely involved. Furthermore, the orthodromic SCS-induced activity in the dorsal columns might—via neuro- nal circuitry in the brainstem (or even more rostrally)—induce descending inhibition via serotonergic (5-HT) and noradrenergic (NE) pathways in the dorsolateral funiculus (DLF), which might contribute to inhibitory influences in the DHs. c, c fibers accompanying A d and A b fibers; DC, dorsal columns; STT, spinothalamic tract; X, unknown transmitters probably modulated by spinal stimulation.