Drug-enhanced spinal cord stimulation for neuropathic pain : studies on neurochemical mechanisms and clinical applications

Spinal cord stimulation (SCS) is an effective surgical treatment for neuropathic pain refractory to pharmacological therapy. For many patients suffering from this type of chronic pain, SCS is in fact the ultimate treatment option. However, 30 to 40 percent of well selected patients fail to obtain useful pain relief with SCS, and in some patients an initial good analgesic effect diminishes over time. Therefore, the need to improve the efficacy of SCS in these patients, prompted us to perform experimental research in order to advance the comprehension of the underlying mechanisms of SCS and further, to apply this knowledge clinically in order to develop new therapeutic strategies.

When SCS is applied to the dorsal columns, multiple neuronal networks may be activated and several neurotransmitters are released in the spinal dorsal horn. This neuronal response to SCS may be regarded as equivalent to in situ drug delivery to the spinal cord in physiological amounts.

The present thesis provides evidence that the analgesic effect of SCS partially relies on the activation of the cholinergic system because stimulation applied in rats with nerve injury produces a release of acetylcholine (ACh) in the dorsal horn. This effect occurred only in rats that in preceding experiments have been found to respond to SCS. It was also demonstrated that the SCS effect on signs of neuropathy was mediated via the activation of muscarinic, particularly M4, receptors. Intrathecal clonidine, a partial α2 receptor agonist, has proven to be an effective drug for both neuropathic and nociceptive pain. It is known that its analgesic action is in part related to an augmented spinal release of ACh, binding mainly to M4 receptors. In this thesis it was demonstrated that in nerve injured rats, concurrent administration of clonidine and SCS may potentiate the suppressive effect of SCS on mechanical hypersensitivity.

In a previous experimental study, it was shown that the administration of subeffective doses of a GABAB receptor agonist, baclofen, may enhance the effect of SCS. It is now demonstrated that also two anticonvulsants, gabapentin and pregabalin, in low and by themselves ineffective doses, may potentiate the suppressive effect of SCS on signs of neuropathy in rats. On the basis of these experimental studies, a double-blind, placebo-controlled clinical trial was performed, demonstrating that clonidine and baclofen in low intrathecal doses may enhance the analgesic effect of SCS in neuropathic pain, improving also quality of life. A long-term follow-up of a group of patients with combined SCS and baclofen treatment revealed that they still enjoyed good pain relief.

The present studies contribute to the understanding of the mode of action of SCS and it provides a new therapeutic option to enhance the pain relieving effect of SCS by concomitant administration of low doses of intrathecal drugs for patients who obtain insufficient analgesia by SCS alone. This thesis also represents an attempt to translate knowledge from experiments performed in animals to clinical application.

List of scientific papers

I. Schechtmann G, Song Z, Ultenius C, Meyerson BA, Linderoth B (2008). Cholinergic mechanisms involved in the pain relieving effect of spinal cord stimulation in a model of neuropathy. Pain. 139(1): 136-45.
https://pubmed.ncbi.nlm.nih.gov/18472215

II. Schechtmann G, Wallin J, Meyerson BA, Linderoth B (2004). Intrathecal clonidine potentiates suppression of tactile hypersensitivity by spinal cord stimulation in a model of neuropathy. Anesth Analg. 99(1): 135-9.
https://pubmed.ncbi.nlm.nih.gov/15281519

III. Wallin J, Cui JG, Yakhnitsa V, Schechtmann G, Meyerson BA, Linderoth B (2002). Gabapentin and pregabalin suppress tactile allodynia and potentiate spinal cord stimulation in a model of neuropathy. Eur J Pain. 6(4): 261-72.
https://pubmed.ncbi.nlm.nih.gov/12161092

IV. Lind G, Schechtmann G, Winter J, Meyerson BA, Linderoth B (2008). Baclofen-enhanced spinal cord stimulation and intrathecal baclofen alone for neuropathic pain: Long-term outcome of a pilot study. Eur J Pain. 12(1): 132-6.
https://pubmed.ncbi.nlm.nih.gov/17475522

V. Schechtmann G, Lind G, Winter J, Meyerson BA, Linderoth B (2009). Intrathecal clonidine and baclofen enhance the pain relieving effect of spinal cord stimulation: a comparative placebo-controlled randomized trial. [Submitted]