Ketamine Infusions for Chronic Pain

A Systematic Review and Meta-analysis of Randomized Controlled Trials

Vwaire Orhurhu, MD, MPH; Mariam Salisu Orhurhu, MD, MPH; Anuj Bhatia, MD, FRCPC; Steven P. Cohen, MD

Disclosures

Anesth Analg. 2019;129(1):241-254. 

In This Article

Abstract and Introduction

Abstract

Background: IV ketamine is widely used to treat patients with chronic pain, yet the long-term impact remains uncertain. We synthesized evidence from randomized control trials to investigate the effectiveness of IV ketamine infusions for pain relief in chronic conditions and to determine whether any pain classifications or treatment regimens are associated with greater benefit.

Methods: We searched Medline, Embase, and Google Scholar, as well as the clinicaltrials.gov website from inception through December 16, 2017 for randomized control trials comparing IV ketamine to placebo infusions for chronic pain that reported outcomes for ≥48 hours after the intervention. Three authors independently screened the studies, pooled the data, and appraised risk of bias. Random-effects model was used to calculate weighted mean differences for pain scores and secondary outcomes. Our primary outcome was the lowest recorded pain score ≥48 hours after cessation of treatment. Secondary outcomes included responder rate and adverse effects.

Results: Among 696 studies assessed for eligibility, 7 met inclusion criteria. All studies except one were at high risk of bias. These studies randomly assigned 211 patients with neuropathic (n = 2), mixed (n = 2), and nonneuropathic (nociplastic or nociceptive) (n = 3) pain. Three studies reported significant analgesic benefit favoring ketamine, with the meta-analysis revealing a small effect up to 2 weeks after the infusion (mean difference in pain scores, −1.83 points on a 0–10 numerical rating scale; 95% CI, −2.35 to −1.31 points; P < .0001). In the 3 studies that reported responder rates, the proportion with a positive outcome was greater in the ketamine than in the placebo group (51.3% vs 19.4%; relative risk, 2.43; 95% CI, 1.10–5.40; P = .029; I 2 = 0.0%). No differences were noted based on pain classification or condition. Compared to low-dose ketamine studies and investigations that evaluated non–complex regional pain syndrome conditions, a small but nonsignificant greater reduction in pain scores was found among studies that either utilized high-dose ketamine therapy (P = .213) or enrolled complex regional pain syndrome patients (P = .079).

Conclusions: Evidence suggests that IV ketamine provides significant short-term analgesic benefit in patients with refractory chronic pain, with some evidence of a dose–response relationship. Larger, multicenter studies with longer follow-ups are needed to better select patients and determine the optimal treatment protocol.

Introduction

Ketamine is classified by the Food and Drug Administration as an anesthetic induction agent in doses ranging from 1 to 4.5 mg·kg−1.[1] Consequently, there is an absence of regulatory guidance on subanesthetic dosing regimens for chronic pain and depression. Yet, in the past decade, the use of ketamine for these conditions has skyrocketed. "Ketamine clinics" have sprouted up worldwide with little oversight on myriad issues such as indications, contraindications, and safety such that its unbridled use has been compared to the "Wild West."[2]

The progression of analgesic drug development typically follows a pattern whereby animal studies precede human experimental studies, which eventually lead to clinical trials establishing efficacy and safety in disease-based populations. Human studies designed to seek a new indication or that involve increased risk may be subject to Investigational New Drug application requirements, which can be cumbersome for individual investigators. Because ketamine is available as a generic formulation and has been in clinical use since 1970, the typical model has been upended.

Although several reviews have been published on ketamine for chronic pain, these are flawed or do not address pertinent questions, as outlined in consensus guidelines based on a collaborative effort of 3 pain societies.[3] For example, the meta-analysis by Michelet et al[4] for non–cancer pain considered routes of administration other than IV, which negatively skewed the results. The decision to include other routes of administration is questionable because the mechanism(s) of action may be different and the question payers, patients, regulators, and clinicians are struggling with is whether IV administration is effective.[3] Unlike other routes of administration with poor bioavailability that use administration of ketamine "as needed," IV infusions block N-methyl-D-aspartate (NMDA) receptors in the central nervous system (CNS), a target intricately involved in neuroplasticity. In addition, because they are utilized in a controlled setting as a long-term treatment (ie, not for pain exacerbations), they are less likely to negatively impact patients on a day-to-day basis (eg, ability to operate a motor vehicle). Although ketamine acts via a multitude of different receptors that may contribute to analgesia, parenteral administration, particularly via continuous infusion, is postulated to work primarily by reversing central sensitization (ie, reducing the hyperexcitability of the CNS and amplification of noxious and non-noxious stimuli).

The recently published guidelines for the use of IV ketamine to relieve chronic pain[3] provide a framework for this systematic review but are based on subjective evaluation of the available evidence, and do not estimate an effect size, or examine relevant subgroup comparisons (eg, neuropathic versus mixed versus nociceptive versus nociplastic pain, high-dose versus low-dose infusion regimens). Still other systematic reviews have focused on the use of ketamine in specific contexts, such as in the emergency department or as a tool to preventive chronic postsurgical pain.[5,6] These lacunae in knowledge formed the underpinnings for our rationale to include only studies evaluating IV administration with intermediate-term follow-up. In this study, we examined pain scores and complication profiles of chronic pain patients who received either IV ketamine or "placebo." The objectives of our systematic review and meta-analysis of clinical trials evaluating the analgesic effects of ketamine for chronic pain were as follows: (1) to quantify the magnitude of analgesic effect of ketamine infusions, and to determine response rate; (2) to quantify the rate and types of adverse effects; and (3) to identify which pain conditions and patients are most likely to respond to treatment with ketamine and whether there is a dose–response relationship.

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