Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature

Abstract

Introduction: Chronic neuropathic pain (NP) is an incapacitating illness caused by a lesion of the somatosensory nervous system and is associated with several diseases or syndromes. Since current treatment options lack adequate efficacy in the majority of patients, ketamine is often administered to treat refractory NP. Areas covered: This review gives an overview of new ketamine pharmacokinetic data including data on intranasal and inhaled ketamine. The outcome of seven systematic reviews and meta-analyses, published since 2012, on ketamine efficacy in NP is discussed. The reader will additionally get an understanding of ketamine's complex metabolism with emphasis on the metabolite hydroxynorketamine. Expert opinion: Proof of sustained, large effects of ketamine in the treatment of NP from randomized controlled clinical trials is lacking, although we cannot exclude selective ketamine efficacy in patients with central sensitization, opioid-induced hyperalgesia or opioid tolerance. Interestingly, data from observational trials and case series do suggest the efficacy of ketamine in producing effective pain relief in NP with positive patient-related outcome measures. Additional randomized trials in often illdefined groups of chronic pain patients are not useful and we suggest to conduct future studies in NP patients with central sensitization and/or with opioid refractory severe NP.

The multiple faces of ketamine in anaesthesia and analgesia

“… 29 In addition, the effect of metabolic enzyme variants or sex on pharmacokinetics is still unknown. 30 …”

A review of the clinical applications of ketamine in pediatric oncology

“…While lacking. [44][45][46][47] The analgesic efficacy of ketamine has also been replicated in children of various ages and disease profiles. [48][49][50]…”

“…The excellent analgesic effect of ketamine has been known for almost five decades. While several reports have found it to be remarkably effective for neuropathic pain, including chronic cancer‐related pain, systematic evidence for the same from large‐scale randomized controlled trials (RCTs) is lacking 44–47 . The analgesic efficacy of ketamine has also been replicated in children of various ages and disease profiles 48–50 …”

Stem Cell Therapy for Modulating Neuroinflammation in Neuropathic Pain

“…Following nerve injury, significant amounts of excitatory neurotransmitter glutamate are continuously released in the synaptic junctions of the spinal dorsal horn, activating the glutamate receptor (Glu-R), N -methyl- d -aspartate (NMDA) receptor (NMDAR), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR). Receptors then transmit pain signals to sensory brain regions [ 88 , 89 , 90 ]. Studies in various animal models have confirmed that blocking NMDAR can relieve NP [ 91 ].…”