Analgesic Effect of Bumetanide on Neuropathic Pain in Patients with Spinal Cord Injury

Abstract

Objectives: The current study evaluated the analgesic effects of bumetanide as an adjunctive treatment in the management of neuropathic pain following spinal cord injury. The peripheral expression of Na-K-Cl-cotransporter-1 1 and K-Cl-cotransporter-2 (KCC2)2 genes in polymorphonuclear lymphocytes (PMLs) assessed as a possible biomarker indicating central mechanisms underlying the observed response. Methods: Through an open-label, single arm, pilot trial of bumetanide (2mg/day), as add-on treatment conducted in 14 SCI patients for 19 weeks. This study consisted of 3 phases: pre-treatment (1month), titration (3 weeks), and active treatment (4 months). Ultimately, 9 patients completed the study. The primary outcome variables were the endpoint pain score using the numeric rating scale (NRS), and also the short-form McGill Pain Questionnaire. Secondary endpoints included the Short-Form Health Survey that assesses the quality of life. Blood samples were collected and used for determining the expression of NKCC1 and KCC2 genes in transcription and translation levels. Results: Bumetanide treatment significantly decreased average pain intensity according to the NRS and the short form of the McGill Pain Questionnaire scores. Baseline expression of KCC2 protein was low between groups and increased significantly following treatment (P<0.05). In the current study, pain improvement accompanied by the greater mean change from the baseline (improvement) for the overall quality of life. Conclusions: These data highlighted the analgesic effect of bumetanide on neuropathic pain and indicated the probable role of upregulation of KCC2 protein and involvement of GABAergic disinhibition in producing neuropathic pain.

Spinal Cord Injury Provoked Neuropathic Pain and Spasticity, and Their GABAergic Connection

“…Factors like microglial activation and raised BDNF significantly contribute to KCC2 downregulation post-SCI [ 22 ]. Recently, in an open label trial, it significantly reduced the pain intensity in SCI patients by enhancing KCC2, confirming its significance in GABAergic disinhibition mediated NP induction ( Table 2 ) [ 55 ].…”

“…22 Recently, in an open label trial, it significantly reduced the pain intensity in SCI patients by enhancing KCC2, confirming its significance in GABAergic disinhibition mediated NP induction (Table 2). 55 Some studies have emphasized the effect of NKCC1 inhibition in reducing the depolarizing GABAA currents; however, its wide distribution in kidney and respiratory system showing undesirable side effects limit its use. 54 NKCC1 antagonist bumetanide, positively aided in reducing the injury initiated CNP by inhibiting the upregulated transporter.…”

“…But, some patients reported adverse effects like diuresis, difficulty in evacuation and incontinence. 55 Considering this and low levels of KCC2 (chloride extruder protein) in NP, promoting intracellular chloride efflux by enhancing KCC2 cotransporter or decreasing its downregulation is a promising therapeutic approach for reducing NP. A KCC2 agonist, CLP290, was found to be effective in attenuating peripheral nerve injury pain in rats.…”

“…NKCC1 antagonist bumetanide, positively aided in reducing the injury initiated CNP by inhibiting the upregulated transporter. But, some patients reported adverse effects like diuresis, difficulty in evacuation and incontinence [ 55 ]. Considering this and low levels of KCC2 (chloride extruder protein) in NP, promoting intracellular chloride efflux by enhancing KCC2 cotransporter or decreasing its downregulation is a promising therapeutic approach for reducing NP.…”

Editorial: Methods and application in integrative and regenerative pharmacology: 2021

“…Chloride homeostasis is controlled by two co-transporters, NKCC1 and K + -Clco-transporter (KCC2), which are essential for chloride homeostasis. NKCC1 has been found to be disrupted in SCI (Nasirinezhad et al, 2021). The axonal pathways that control sensory and motor functions are affected in SCI, leading to neuronal impairments (O'Shea et al, 2017).…”