Perioperative Lidocaine Infusions for the Prevention of Chronic Postsurgical Pain

A Systematic Review and Meta-analysis of Efficacy and Safety

Martin Bailey; Tomas Corcoran; Stephan Schug; Andrew Toner

Disclosures

Pain. 2018;159(9):1696-1704. 

In This Article

Abstract and Introduction

Abstract

Chronic postsurgical pain (CPSP) occurs in 12% of surgical populations and is a high priority for perioperative research. Systemic lidocaine may modulate several of the pathophysiological processes linked to CPSP. This systematic review aims to identify and synthesize the evidence linking lidocaine infusions and CPSP. The authors conducted a systematic literature search of the major medical databases from inception until October 2017. Trials that randomized adults without baseline pain to perioperative lidocaine infusion or placebo were included if they reported on CPSP. The primary outcome was the presence of procedure-related pain at 3 months or longer after surgery. The secondary outcomes of pain intensity, adverse safety events, and local anesthetic toxicity were also assessed. Six trials from 4 countries (n = 420) were identified. Chronic postsurgical pain incidence was consistent with existing epidemiological data. Perioperative lidocaine infusions significantly reduced the primary outcome (odds ratio, 0.29; 95% confidence interval, 0.18–0.48), although the difference in intensity of CPSP assessed by the short-form McGill Pain Questionnaire (4 trials) was not statistically significant (weighted mean difference, −1.55; 95% confidence interval, −3.16 to 0.06). Publication and other bias were highly apparent, as were limitations in trial design. Each study included a statement reporting no adverse events attributable to lidocaine, but systematic safety surveillance strategies were absent. Current limited clinical trial data and biological plausibility support lidocaine infusions use to reduce the development of CPSP without full assurances as to its safety. This hypothesis should be addressed in future definitive clinical trials with comprehensive safety assessment and reporting.

Introduction

Chronic postsurgical pain (CPSP) occurs in 12% of mixed surgical populations[7] and affects up to half of patients undergoing high-risk procedures.[12,23] Strategies designed to reduce the human, public health, and financial burden of CPSP are therefore a high priority for perioperative research.[5,10] A range of pharmacological interventions have been investigated in small trials for efficacy in attenuating CPSP, including N-methyl-D-aspartate (NMDA) receptor antagonists, gabapentinoids, corticosteroids, and nonsteroidal anti-inflammatory drugs. However, a Cochrane systematic review and meta-analysis in 2013 reported that, beside techniques of regional anesthesia,[1] the only systemic drug with encouraging albeit limited evidence to support a reduced incidence of CPSP at 6 months was intravenous ketamine.[8] To address the potential of this drug, a large, international, multicenter trial of perioperative ketamine infusions with CPSP as the primary outcome is scheduled to commence in 2018.[35]

In the Cochrane review in 2013, only a single trial reported on systemic lidocaine administration in relation to CPSP. Since then, investigators have increasingly explored this amide local anesthetic agent in surgical patients, as it stands to modulate many of the pathophysiological processes involved in the development of chronic pain. In a similar fashion to ketamine, lidocaine reversibly antagonizes human NMDA receptors expressed in ex vivo models.[14] This effect is significant and apparent at lidocaine concentrations well within the range of plasma concentrations achieved clinically. The NMDA receptor in the spinal dorsal horn plays a critical role in neuroinflammation[20] and hyperalgesia,[34] phenomena that develop in response to repetitive peripheral nociceptive inputs and underpin chronic pain states. Lidocaine has the added benefit of reducing peripheral nociceptive input, principally through blockade of voltage-gated sodium channels, but also through antagonism of other receptor systems that modulate peripheral signal transduction.[43] Furthermore, lidocaine exhibits potent anti-inflammatory effects across in vitro and in vivo models.[16,30] Inflammation is a key driver of increased nociceptive inputs that occur with peripheral sensitization and also acts to maintain central sensitization through spinal neuroinflammation.[20]

In clinical settings, systemic lidocaine has been successfully used for the treatment of acute and established chronic pain. A recent meta-analysis concluded a modest but statistically significant reduction of surgical pain severity in the first 4 postoperative hours measured by the visual analogue scale (0–10 cm); mean difference −0.84 cm, 95% confidence interval (CI) −1.10 to −0.59.[29] Subgroup analyses indicated that this early analgesic effect was only apparent with higher dose (≥2 mg/kg/hours) infusion regimens. An earlier systematic review also identified that 13 of 16 perioperative studies[3] reported a preventive analgesic effect for intravenous lidocaine (defined as analgesia outlasting 5 and a half times the lidocaine plasma half-life[22]), although pain outcomes beyond the inpatient admission were not assessed. Similarly, in patients with chronic pain, therapeutic lidocaine infusions confer effective analgesia at plasma concentrations around 2 to 3 μg/mL, which often outlasts the systemic presence of lidocaine by days and weeks.[4,6,11] Finally, lidocaine infusions at relevant doses (2 mg/kg/hours) reduce experimentally induced hyperalgesia in healthy volunteers.[27,28] In view of this promising multifaceted biological plausibility, we set out to identify and synthesize the evidence linking perioperative lidocaine infusions and CPSP.

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