Introduction and Background

As we now know, intravenous (IV) lidocaine is used widely, predominately in the perioperative setting in gastrointestinal surgeries and as an outpatient chronic pain intervention. However, despite widespread use, numerous clinical investigations, and integration into practice guidelines,¹ there exists much hesitation and concern over its use, which may be due to its off-label indication, shifting levels of evidence, and the potential risk of adverse events. This article aims to briefly discuss the existing literature evaluating the benefits of IV lidocaine on acute postoperative pain and as a preventative agent for chronic post-surgical pain (CPSP) and consider the terrain of shifting evidence and propose strategies that could improve safer use and adoption. Lastly, we discuss current and future large trials likely to have an impact on the use of IV lidocaine.

IV lidocaine infusions are a promising analgesic intervention in the perioperative setting.

The discovery of lidocaine occurred somewhat serendipitously in the 1940s because of work being conducted by Swedish chemists, Nils Löfgren and Bengt Lundqvist.² Early investigations into its intravenous use began in the 1950s with case reports suggesting an impressive effect on improving postoperative pain³ and the depth of anesthesia.⁴ However, formal investigations were limited and did not occur until decades later.

Beyond the pharmacodynamic effect of sodium channel blockade, existing studies support its actions on N-methyl-D-aspartate (NMDA) receptors, potassium and calcium channels, as a glycine inhibitor, and as possessing anti-inflammatory properties.⁵ However, not being a typical analgesic (such as an NSAIDs for example), we cannot associate an exact mechanism(s) to a clinically measurable and consistent effect. Further, these additional sites are typically found along pain pathways in the central nervous system (CNS) or in the dorsal root ganglion and may explain why systemic IV lidocaine has analgesic benefits through peripheral and central sites of action.

Improved Acute Pain and Recovery After Surgery

Several studies and meta-analyses have now been published on the merits of perioperative IV lidocaine across a range of surgical groups on acute pain and improved recovery after surgery. A 2018 Cochrane review of randomized controlled trials (RCT) evaluating IV lidocaine compared to placebo/no treatment in patients undergoing elective or urgent surgeries under general anesthesia [68 trials (4,525 randomized patients)] indicated statistical significance of IV lidocaine in reducing pain at 1-4 hours and at 24 hours after surgery. Since standardized mean differences (SMD) were used, the exact reduction in pain scores is difficult to establish; however, a decrease in overall opioid consumption (mean difference -4.52 mg of morphine equivalence, 95% CI -6.25 to -2.79) was observed. These are important findings as the effectiveness of an analgesic intervention should be held in consideration with both pain scores and opioid consumption. Pain intensity scores are directly influenced by the amount of analgesics consumed, and patients enrolled in clinical trials are ethically entitled to standard clinical practices, which often include self-administration of opioid medications (i.e., patient-controlled analgesia). As a result, pain scores and opioid consumption are co-dependent outcomes, and some investigators have gone as far as advocating for an integrated score.^6,7 With this perspective in mind, the findings of the Cochrane review, where both pain scores (1-4 hours and 24 hours) and opioid consumption were reduced, convey a compelling story for IV lidocaine.^6,7 Further, many of their secondary and objective outcomes were improved by IV lidocaine infusion, including reduced risk of ileus, time to first defecation/bowel movement, and postoperative nausea.

In contrast, there is much less data regarding IV lidocaine initiated or continued after surgery. The majority of the RCTs included in the Cochrane review stopped the lidocaine infusion at the end of surgery. Several institutions to our knowledge within the U.S. and Canada currently utilize postoperative IV lidocaine infusions on hospital wards, and while formal clinical trials are needed, data from these centers aid in developing our understanding of this intervention. A large retrospective analysis of 544 patients has been published where patients received IV lidocaine perioperatively (either started during surgery or as a rescue analgesic after surgery) as part of routine clinical care. IV lidocaine was administered for an average of 68 hours (2.8 days) perioperatively,⁸ and 56% of patients receiving postoperative infusions (dose ranging from 0.5-2 mg/kg/hr) met their definition of clinically important difference (CID) of ≥ 2 point difference in pain intensity or ≥ 30% reduction in pain intensity. The authors also found that when IV lidocaine was used as a rescue analgesic (initiation only after surgery), it was associated with a CID of 70%. For patients with chronic pain, a CID of 54% was found.^9,10

Possible Effect on Reducing Chronic Post-Surgical Pain and Cancer Recurrence

Chronic post-surgical pain (CPSP) is a devastating complication of surgery that occurs in 3-10% of all surgeries.^11,12 A recent systematic review evaluating perioperative pharmacotherapies on preventing CPSP found in a subgroup analysis that IV lidocaine infusions reduced the prevalence of any pain at 6-months after breast surgery when administered ≤ 24 hours.¹³ This is in keeping with a prior systematic review on RCTs in breast cancer surgery, demonstrating a large effect size on CPSP reduction in this patient population (relative risk [RR] 0.33, 95% CI 0.14 to 0.78). There are limited investigations to definitively establish perioperative IV lidocaine as a preventative agent for CPSP, but large ongoing RCTs are underway that seek to identify this effect (discussed below).

Emerging evidence also suggests that the type of perioperative anesthesia, including the use of LA, might affect cancer recurrence.^14–19 Lidocaine, in particular, has specific effects on cancer cells in preventing tumor progression and cancer recurrence in pre-clinical studies.^20–22 In clinical studies, IV lidocaine infusion during cancer surgery affects hematological markers of inflammation, angiogenesis, and immune function,²³ and in one retrospective study (n=2,239), IV lidocaine during pancreatic cancer surgery was associated with longer overall survival (hazard ratio [HR] 0.62, 95% CI 0.29 to 0.78), but not longer disease-free survival (HR=0.91, 95% CI 0.82 to 1.61).²⁴ While IV lidocaine is believed to impact cancer progression and recurrence, evidence from large clinical trials has been inconclusive.

Barriers Limiting the Wider Use of IV Lidocaine

Off-label Use: Concerns exist among clinicians about the off-label use of IV lidocaine with possible medical-legal repercussions.²⁵ While such considerations are reasonable, they should not unilaterally supersede thoughtful and informed clinical decision-making and judgement. In anesthesia practice, we routinely administer off-label medications daily, such as epidural fentanyl (off-label route) and dexamethasone for preventing postoperative nausea and vomiting (off-label indication). Clearly, restricting medication use to only on-label medications would have drastic impacts on routine anesthesia care. Furthermore, regulatory bodies recognize that off-label use is essential to medical care and in fact, rely on physicians to make balanced clinical judgements when utilizing an off-label medication.^26,27

Delayed Emergence: Another reason often used to justify not using IV lidocaine intraoperatively is the belief that it delays emergence from anesthesia. To date, there is no formal level 1 evidence to support this observation.

Population: Uncertainties exist among providers on the appropriate patient population that would most benefit from an IV lidocaine infusion. The aforementioned Cochrane review found no difference in outcomes across surgical subgroups (open abdominal, laparoscopic abdominal, other surgery). Despite this, clinical scenarios that would benefit most from an IV lidocaine infusion may include those with inadequate epidural coverage; laparoscopic surgery that has been converted to open; trauma patients; those sensitive to opioid-related side-effects (e.g., those with ileus, obese patients); those with chronic pain history; and those undergoing opioid-sparing surgeries.²⁸

Dosing Regimen: The doses used in the literature vary substantially with bolus doses ranging from 1 to 3 mg/kg (1.5 mg/kg most common dose) and infusion dosages ranging from 1 to 5 mg/kg/hr (with 2 mg/kg/hr being the most common). It is important to note that this review that included > 4,000 patients did not find any increased adverse events, even at higher doses. The review also found no differences in outcomes between infusion above or below 2mg/kg/hr. Further, while the literature generally recommends dosing using ideal body weight, there is limited data to support this. Pharmacokinetic studies have suggested that lidocaine infusions should be based on total body weight, and most of the trials included in the Cochrane review used total body weight with no signal towards toxicity.^9,29 Nonetheless, in certain populations, it is reasonable to consider dose reductions, such as those who are obese, elderly, have renal and hepatic impairments, and experience cardiac failure.³⁰

Safety: Intuitively, there appear to be two clinical scenarios with distinct risk categories in using IV lidocaine: (1) intraoperative administration with the constant supervision of an attending anesthesiologist and (2) administration outside the operating room with intermittent monitoring as would occur on the hospital ward. The former scenario would likely be associated with a high degree of safety as we, anesthesiologists, are vigilant in the recognition and treatment of lidocaine toxicity. As such, the benefit to risk ratio of intraoperative IV lidocaine is weighted heavily in favor of its use in the appropriate patient. Postoperative administration may entail a different risk category, and given that toxicity occurs with increasing plasma levels, safety could be improved if plasma lidocaine levels are serially measured and used to titrate the infusion. This is standard practice at the Stanford University Hospital (verified by primary author's training at Stanford) where patients who are placed on postoperative IV lidocaine infusions automatically get ordered to have serial plasma lidocaine levels read every 8 hours. Dose adjustments are based on plasma levels to target between 2 and 5 mcg/mL. This protocol has been used for years with an extraordinarily high safety profile.

Ongoing Large Trials and Future Directions

The current knowledge base of IV lidocaine suggests an important analgesic effect after surgery with a high safety profile; however, the literature lacks large high-quality multicentre RCTs to confirm these findings in addition to limited definitive data on additional effects on chronic post-surgical pain and cancer recurrence.

Fortunately, there are several large international multicentre RCTs that aim to address these and other unanswered questions on the perioperative use of IV lidocaine. The currently underway VAPOR-C Trial (NCT04316013) looks to understand the effect of IV lidocaine on cancer recurrence in an international sample of 5,736 patients undergoing colorectal and lung cancer surgery. Additionally, the LOLIPOP RCT (NCT05072314) is a large Australian-led multicentre RCT of 4,300 patients, which aims to evaluate the effect of lidocaine infusions commenced during surgery and extending up to 24 hours postoperatively (through subcutaneous infusions) on the incidence of moderate or severe CPSP at 1-year after elective breast cancer surgery. Similarly, our group is undertaking a large RCT known as the PLAN Trial (NCT04874038). PLAN is a large international multicentre RCT looking to evaluate intraoperative IV lidocaine in 1,150 patients undergoing breast cancer surgery to determine the effect on reducing the development of persistent pain. We aim to follow up with patients at 3 and 12 months after surgery. Collectively, these three trials will enroll more than 11,000 patients in a controlled setting receiving either IV lidocaine or placebo with active surveillance to identify important efficacy and safety endpoints in primary and secondary analyses. Further, updated meta-analyses with these trials could lead to additional clinically relevant information on optimal dosing parameters, patient populations, and duration of use.

Conclusion

Overall, IV lidocaine infusions are a promising analgesic intervention in the perioperative setting. Analgesic adjuncts that are associated with benefit with limited risks are worth considering and adopting into clinical practice. The current evidence base supports the use of IV lidocaine in appropriate patients and surgical cases as an analgesic adjunct, and we eagerly await exciting new data on this old intervention from these large ongoing clinical trials.

James S. Khan, MD, MSc, is an assistant professor in the department of anesthesiology and pain medicine at Mount Sinai Hospital, University of Toronto, in Toronto, Canada.

Ajit S. Rai, MD, is an anesthesiologist in the department of anesthesiology and pain medicine at the University of Ottawa in Ottawa, Canada.

---

Harsha Shanthanna, MD, PhD, is an associate professor in the department of anesthesia at St. Joseph’s Hospital, McMaster University in Ontario, Canada.