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 ill-defined 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.

KEYWORDS:

• Chronic neuropathic pain management
• ketamine
• hydroxynorketamine
• NMDA receptor antagonist
• pain

Article highlights

• Chronic neuropathic pain (NP) is a debilitating disease caused by a lesion of the somatosensory nervous system and is associated with several diseases or syndromes including trauma (surgical trauma, spinal cord injury, amputation with phantom limb pain), infectious diseases (for example HIV/AIDS, leprosy, shingles), systemic diseases (for example, diabetes mellitus, sarcoidosis, alcoholism) and genetic disorders (for example, erythromelalgia, Fabry’s disease, sodium channelopathy) or cancer.

• Given the fact that the N-methyl-D-aspartate receptor (NMDA) plays a crucial role in the development and chronification of NP, and the fact that the current selection of treatment options still lacks adequate efficacy in the majority of patients, ketamine is considered a viable alternative in refractory neuropathic pain, most importantly in patients with signs of central sensitization and opioid-refractory NP.

• Ketamine is a racemic mixture, containing S- and R-isomers, and has several active metabolites, including (2R,6R)-hydroxynorketamine (HNK). While ketamine has a predominant analgesic effect by blocking the NMDA receptor, (2R,6R)-HNK has antidepressant effects by activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor. Experimental data indicate efficacy of (2R,6R)-HNK for the treatment of NP.

• Relatively new routes of ketamine administration are the inhaled and intranasal routes. Ketamine inhalation allows long-term ketamine treatment outside the conventional hospital setting. An intranasal S-ketamine preparation was recently approved by the FDA to treat treatment-resistant depression.

• While experimental studies often show long-term ketamine analgesic efficacy in NP, proof of a sustained and large effects of ketamine in the treatment of NP from randomized controlled clinical trials is limited. However, it may well be that subpopulations of patients such as those with central sensitization, opioid-induced hyperalgesia, or opioid tolerance may benefit from ketamine treatment.

• Observational studies and case series indicate benefit from ketamine to treat NP with positive patient-related outcome measures. Possibly, NP conditions preclude the detection of ketamine efficacy in often rigid randomized placebo-controlled trials.

• Future ketamine trials should be conducted in patients with specific NP symptoms (central sensitization, opioid-induced hyperalgesia, opioid tolerance) rather than in ill-defined chronic pain populations. Mood-related indices and other patient-related outcome measures related to quality-of-life, daily activity and sleep may better reflect the effect of ketamine on the patient’s overall condition.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.