Abstract
IntroductionAmitriptyline is prescribed to reduce the intensity of chronic neuropathic pain. There is a paucity of validated in vivo evidence in humans regarding amitriptyline’s mechanism of action. We examined the effect of amitriptyline therapy on cerebrospinal fluid (CSF) neuropeptides and proteome in patients with chronic neuropathic pain to identify potential mechanisms of action of amitriptyline. MethodsPatients with lumbar radicular neuropathic pain were selected for inclusion with clinical and radiological signs and a >50% reduction in pain in response to a selective nerve root block. Baseline (pre-treatment) and 8-week (post-treatment) pain scores with demographics were recorded. CSF samples were taken at baseline (pre-treatment) and 8 weeks after amitriptyline treatment (post-treatment). Proteome analysis was performed using mass spectrometry and secreted cytokines, chemokines and neurotrophins were measured by enzyme-linked immunosorbent assay (ELISA). ResultsA total of 9/16 patients experienced a >30% reduction in pain after treatment with amitriptyline and GO analysis demonstrated that the greatest modulatory effect was on immune system processes. KEGG analysis also identified a reduction in PI3K-Akt and MAPK signalling pathways in responders but not in non-responders. There was also a significant decrease in the chemokine eotaxin-1 (p = 0.02) and a significant increase in the neurotrophin VEGF-A (p = 0.04) in responders. ConclusionThe CSF secretome and proteome was modulated in responders to amitriptyline verifying many pre-clinical and in vitro models. The predominant features were immunomodulation with a reduction in pro-inflammatory pathways of neuronal-glia communications and evidence of a neurotrophic effect.
Highlights
Amitriptyline is prescribed to reduce the intensity of chronic neuropathic pain
Nine patients reported a >30% reduction in pain according to Numerical Pain score (NRS) after 8 weeks of amitriptyline (9/16, 56%)
There was no difference in demographics, opioid use and pre-treatment neuropeptide concentrations within the cerebrospinal fluid (CSF) of the responder group and the non
Summary
Amitriptyline is prescribed to reduce the intensity of chronic neuropathic pain. There is a paucity of validated in vivo evidence in humans regarding amitriptyline’s mechanism of action. The pharmacodynamics of amitriptyline proposed from pre-clinical and in vitro studies are extensive but many have not been validated by in vivo evidence in humans (Couch and Amitriptyline Versus Placebo Study G, 2011; Freysoldt et al, 2009; Guan et al, 2019; Himmerich et al, 2010; Hisaoka et al, 2011; Hisaoka-Nakashima et al, 2016; Hutchinson et al., 2010; Jang et al, 2009; Jeanson et al, 2016; Kajitani et al, 2012; Kim et al, 2019; Kremer et al, 2016; Kremer et al, 2018; Lawson, 2017; Moore et al, 2015; Obuchowicz et al, 2006; Paumier et al, 2015; Rambe et al, 2015; Tai et al, 2006; Valera et al, 2014; van den Driest et al, 2017; Wang et al, 2004; Wolff et al, 2016) For this reason, amitriptyline’s mechanism of action in many off-label applications including neuropathic pain, fibromyalgia, migraine prophylaxis and complex regional pain syndrome (CRPS) have yet to be defined. This suggests that at different concentrations amitriptyline targets different pathways and may have a different mechanism of action for off-label applications including chronic neuropathic pain (CNP)
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