Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization

Abstract

Intravenous ketamine infusions have been used extensively to treat often-intractable neuropathic pain conditions. Because there are many widely divergent ketamine infusion protocols described in the literature, the variation in these protocols presents a challenge for direct comparison of one protocol with another and in discerning an optimal protocol. Careful examination of the published literature suggests that ketamine infusions can be useful to treat neuropathic pain and that certain characteristics of ketamine infusions may be associated with better clinical outcomes. Increased duration of relief from neuropathic pain is associated with (1) higher total infused doses of ketamine; (2) prolonged infusion durations, although the rate of infusion does not appear to be a factor; and (3) coadministration of adjunct medications such as midazolam and/or clonidine that mitigate some of the unpleasant psychomimetic side effects. However, there are few studies designed to optimize ketamine infusion protocols by defining what an effective infusion protocol entails with regard to a respective neuropathic pain condition. Therefore, despite common clinical practice, the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. The objectives of this topical review are to (1) analyze the available clinical evidence related to ketamine infusion protocols and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. The Oxford Center for Evidence-Based Medicine classification for levels of evidence was used to stratify the grades of clinical recommendation for each infusion variable studied.

Etiology and Pharmacology of Neuropathic Pain

“…Mechanistically, spinal LTP involves presynaptic mechanisms as well as opening of T-type [voltagaegated Ca2 + channels type 3 (Ca v 3)] calcium channels and activation of NMDA receptors (Ikeda et al, 2003(Ikeda et al, , 2006Zhuo, 2016b). These receptors have long been implicated in the etiology of neuropathic pain (Woolf and Thompson, 1991;Kerr et al, 1999;Latremoliere and Woolf, 2009;Salter and Pitcher, 2012;Hildebrand et al, 2016), and this may account for the effectiveness of the NMDA receptor blocker, ketamine, in the management of chronic pain (Hewitt, 2000;Niesters et al, 2014;Maher et al, 2017) and the observation that T-type calcium channel blockers mibefradil and ethosuximide can reverse neuropathic pain in an animal model (Dogrul et al, 2003). Physiological blockade of NMDA channels with Mg 2+ has been shown to be effective in reducing signs of pain in animal models (Brill et al, 2002;Rondon et al, 2010), and there is some evidence that it may play a role in the treatment of human neuropathic pain (Pickering et al, 2011).…”

Comparative Study between Oral Pregabalin versus Intravenous Low Dose Ketamine for Post-Operative Pain Management in Laminectomy

“…Ketamine's analgesic properties in acute pain likely derived from its reversible antagonism of NMDA receptor, although it exerts effects on pi -opioid, muscarinic, monoaminergic receptors, GABA receptors. Ketamine when administrated in sub-anesthetic doses prevents the development of central sensitization, hyperalgesia and opioid resistance [17] .…”

Recommendations for Evaluation and Management of Pain in Patients With Mucopolysaccharidosis in Latin America

“…10,43 A Phase 2, randomized, double-blind, pilot study evaluating safety and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome concluded that patients with relatively good endurance showed a trend of increased exercise capacity and muscle strength and decreased pain. 40 Other interventions for pain management in MPS patients may include infusions of lidocaine 40,44 or ketamine 45 for neuropathic pain and other chronic pain states, radiofrequency ablation, 46,47 particularly for hip pain, and peripheral nerve blocks. 48 Current exploratory options include pamidronate acid 49 and dexmedetomidine.…”