Intravenous Lidocaine Infusion for the Management of Early Postoperative Pain: A Comprehensive Review of Controlled Trials

Abstract

Previously used as anti-arrhythmic, intravenous lidocaine infusion is becoming popular for use in management of acute pain. There is still much to be understood about its pharmacokinetics and pharmacodynamics, especially with regard to optimal dosing to avoid side effects. In this article, we selected and reviewed randomized controlled trials to summarize the pharmacokinetics, antinociceptive effects, anti-hyperalgesic effects, anti-inflammatory effects, side effects, and role of intravenous lidocaine in the management of early postoperative pain. The mechanisms of action of lidocaine are still unclear but there are many theories postulated. Optimal dosing of lidocaine is not known but general consensus indicates that a loading dose of 1–2 mg/kg, followed by 1–2 mg/kg/hr continuous infusion during early postoperative pain control while recovering from anesthesia to achieve therapeutic levels of 0.5–5 mcg/kg clearly improves analgesia in the immediate postoperative period. Although lidocaine was initially studied and proven to have clear analgesic effects following laparoscopic and open abdominal surgeries, it has now been shown to be applicable in different clinical settings perioperatively including following spinal, breast, ENT and other surgeries. It is generally safe, with hypotension, headache and vomiting being the more common side effects. Serious adverse effects include cardiovascular block and arrhythmias, neuro-excitability and hypersensitivity, although the frequency of these are not known.

Background

Lidocaine, also known as lignocaine, is an amino-amide local anesthetic (LA) and a class 1b antiarrhythmic agent by the Vaughn Williams classification.¹ It was first synthesized in 1942 and was endorsed for human use in 1948 in Sweden and in 1949 in United States.² The postoperative analgesic effects of perioperative intravenous (IV) lidocaine use was perceived and suggested in 1951.^3,4

Nonopioid analgesics such as IV lidocaine have been increasingly used due to concerns about opioid safety in the postoperative period.⁵ Clinical uses of lidocaine include anesthetic blockade for local and regional anesthesia, as well as use for its antiarrhythmic, antinociceptive, anti-inflammatory and antibacterial properties. It has been used widely in chronic and neuropathic pain management and postoperative analgesia via IV infusion.²

Lidocaine and Chronic Pain Management

The management of chronic pain is particularly challenging. Boas et al. revealed that IV lidocaine reduced central pain which led to a renaissance in the analgesic use of systemic lidocaine in the 1980s.^6,7 There has been an increased use of systemic lidocaine for chronic pain syndromes. Its use for neuropathic pain management became popular because of its ability to inhibit spontaneous ectopic discharges of an injured nerve in animal model as well as the suitability of oral formulations like mexiletine for long-term treatment.⁸ In a systematic literature search of evidence linking lidocaine infusions and chronic postsurgical pain, Bailey et al.⁹ concluded that perioperative lidocaine infusions reduced the presence of procedure-related pain 3 months or longer after surgery. A retrospective review of medical records of 40 patients with intractable neuropathic pain showed a marked decrease in pain levels (p < .001) after lidocaine infusions.¹⁰

Lidocaine and Acute Pain Management

In a systematic review of 13 studies involving 512 patients, Masic et al.¹¹ reported that IV lidocaine had a higher efficacy than morphine for renal colic and critical limb ischemia, as well as a higher efficacy than IV dihydroergotamine for acute migraine. It was found to have similar efficacy to ketorolac for acute radicular pain and decreased efficacy compared to IV chlorpromazine for acute migraine.

With regards to pain on propofol injection, different meta-analyses^12,13 have proved lidocaine efficacious in prevention of pain. Since its first clinical use in 1961, various meta-analyses have established the efficacy of IV lidocaine use. The results of these reviews showed a remarkable reduction of pain and/or opioid requirements during the first 24 hours postoperatively.¹⁴ A Cochrane review¹⁵ of 45 trials suggested that lidocaine reduced postoperative pain at 1–4 hours and 24 hours after surgery but not after 48 hours. In addition, subgroup analysis observed maximal benefit for patients undergoing abdominal surgery, but not for other surgeries.

The goal of this article is to review the effects of lidocaine on early postoperative pain.

Drug Properties

Mechanism of Action of Lidocaine

Lidocaine has various mechanism of actions with which it exerts different clinical effects (Table 1). It acts primarily by blockade of voltage gated sodium channels^16,17 which alters the channel and prevents depolarization. Other mechanisms of action include blockade of potassium current,¹⁷ blockade of presynaptic muscarinic and dopamine receptors,^18,19 reduction in excitability and conduction of unmyelinated C fibers,²⁰ modulation of glutamate and ion channel protein receptor,²¹ inhibition of leukotriene B4²² and other pro-inflammatory cytokines,^23,24 inhibition of histamine release,²⁵ and inhibition of prostaglandin release.^26–29

Table 1. Mechanisms of Action of Intravenous Lidocaine Infusion.

EFFECT		MECHANISM OF ACTION		REFERENCE
Antinociceptive		Blockade of sodium gated channels		16, 17, 30, 47
		Blockade of presynaptic muscarinic and dopamine receptors		18, 19, 31, 32
		Blockade of potassium current		17
		Reduce excitability and conduction of unmyelinated C fibers		20
		Decreased excitability of the spinal dorsal horn		20, 34
		Modulation of NMDA-receptors		21, 35
		Increased in CSF acetylcholine aggravating the descending inhibitor pain pathways		31
		Inhibiting release of endogenous opioids		33
Anti-hyperalgesic		Inhibition of NMDA receptor		21
		Affecting mechanoinsensitive nociceptors		36, 37
Anti-inflammatory		Inhibits leukotriene B4		22
		Inhibiting release of superoxide anion		48, 49
		Blocking of interleukin 1		22–24
		Inhibiting histamine release		25
		Reduction of pro-inflammatory cytokines		38–41
		Inhibiting prostaglandin release		26–29, 45, 46
		Attenuating vascular inflammation		42
		Increase in cell mediated immunity		43, 44

Analgesic and Antihyperalgesic Effect

Although the mechanism of action of IV lidocaine for the prevention of acute pain in the perioperative setting has been established to be via sodium channel blocking effects and inhibition of potassium current,^16,17 additional ancillary mechanisms by which it achieves analgesia remain unclear.⁴ Lauretti et al.³⁰ noted that the ultimate analgesic action of lidocaine is multifactorial, including: increasing concentration of cerebrospinal fluid acetylcholine following IV lidocaine would aggravate the descending pain inhibitor pathway,³¹ possibly binding to muscarinic 18, 32 and dopamine¹⁹ receptors, and by inhibiting the release of endogenous opioids.³³ Additionally, similar to its local anesthetic effect, systemic lidocaine decreased excitability of the spinal dorsal horn and conduction of unmyelinated C fibers.^20,34 Additionally, through the N-methyl-D-aspartate (NMDA) receptors and neurokinin receptors on the spinal cord, systemic lidocaine acts directly or indirectly to reduce postsynaptic depolarization.^21,35 Koppert et al.^36,37 concluded that the hyperalgesic mechanism involved in increasing pain during sustained pinching was particularly sensitive to low concentrations of systemic lidocaine.

Anti-inflammatory Effect

Like its antinociceptive effect, lidocaine’s anti-inflammatory effect is multifactorial and elaborate. In vitro study showed that pretreatment with lidocaine had a dose-dependent inhibitory effect on human polymorphonuclear granulocytes (PMNGs) and mononuclear cells. It also inhibited the release of inflammatory mediators leukotriene B4 (LTB4) and interleukin-1 (IL-1) which may support its anti-inflammatory effect^22–24 and edema prevention. Lidocaine also reduced histamine release from human mast cells and basophils in a dose-dependent manner.²⁵ Perioperative lidocaine infusion reduced inflammatory markers (tumor necrosis factor-alpha, myeloperoxidase activity, chemokine and intracellular adhesion molecule-1 protein expression), resulting in a protective effect in mice from septic peritonitis.³⁸ Other studies^39–41 reported improved postoperative pain following perioperative lidocaine infusion and reduced surgery-induced pro-inflammatory cytokines. In addition, the benefit of lidocaine may include attenuation of vascular inflammation, which would reduce microvascular endothelium injury and inflammatory hyperpermeability.⁴² Systemic lidocaine has been reported to increase natural killer T-cell activity and other cell mediated immunity, thereby reducing septic complications.^43,44 Finally, lidocaine administration has been shown to significantly reduce prostaglandin biosynthesis^28,29 leading to a strong anti-inflammatory effect. This was confirmed by Goel et al.²⁷ in a study that demonstrated reduced prostaglandin from the gastric mucosa and in patient with severe burns^45,46 following parental lidocaine.

Drug Pharmacokinetics

Lidocaine is a weak base and hydrophobic in its neutral form. During its early years of discovery, it was shown to have a rapid onset and a short duration of approximately 20 minutes following IV administration.⁴⁷ IV lidocaine starts distribution from well vascularized organs (heart, brain, lung, kidney) to less vascularized organs (adipose tissue, skin, muscles). Its volume of distribution at steady state is 0.6–4.5 L/kg⁴⁸

About 90% of lidocaine is metabolized in the liver by oxidative dealkylation through cytochrome P450 (mostly CYP3A1 and CYP1A2 subfamilies).⁴⁹ Though lidocaine’s active metabolites (monoethylglycine xylidide and glycine xylidide) have reduced potency, their accumulation due to lidocaine infusion may hinder the metabolism of lidocaine⁵⁰ and possibly lead to intoxication.

Lidocaine and its metabolites are excreted mostly by the kidney with less than 10% excreted unchanged in urine. Total body plasma clearance of lidocaine was reported to be around 10–20 ml/min/kg in healthy volunteers.² The half-life of lidocaine is 1.5 to 2 hours after a bolus dose; however, the half-life of lidocaine can be prolonged with specific populations and infusion durations. During lidocaine infusion in obese patients^14,51 the half-life could be increased by more than 3 hours following 24 hours of administration to 6.9 hours following 48 hours of administration. The rate of metabolism is reduced in patients with chronic liver disease, congestive heart failure, and after myocardial infarction.² Hence, these comorbidities should be taken into consideration, especially during prolonged infusions.

To attain desired clinical effects, plasma levels of between 0.5 and 5 mcg/ml are required.² A therapeutic steady-state concentration can be achieved during IV lidocaine infusion using a two-compartment model described by Hsu et al.⁵² The authors recommended that lidocaine infusions should be dosed by body weight and reduced after 24 hours to avoid toxicity. They also suggested a 2-day infusion protocol of 1 mg/kg loading dose, then 50 mcg/kg per minute infusion for the first hour, then 25 mcg/kg per minute for the second hour, 12 mcg/kg per minute for the succeeding 22 hours and lastly, 10 mcg/kg per minute for the later 24 hours.

Clinical Studies (Perioperative Applications)

Laparoscopic Abdominal Surgeries

Laparoscopic abdominal surgeries have gained popularity due to their minimally invasive nature which forgoes the necessity of large incisions in the abdominal wall. Concomitantly, lidocaine administration in the perioperative period has attracted increased interest for analgesia, especially due to its potential for decreasing opioid administration, hastening recovery from anesthesia, and ultimately decreasing the amount of time patients spend in the post-anesthesia care unit and in any subsequent hospitalization. We identified ten randomized controlled trials investigating the use of lidocaine in laparoscopic abdominal surgery (Table 2A). The types of surgeries investigated in these studies included laparoscopic sterilization,⁵³ cholecystectomy,^54,56,62 renal surgery,⁵⁵ colectomy^57,61 appendectomy⁵⁸ and gastrectomy.^59,60

Table 2A. Characteristics of Selected Studies on Lidocaine Infusion in Laparoscopic Abdominal Surgeries.

First Author, Year

Study Design and Setting

Patient Population

Treatment Group

Lidocaine Infusion Duration and Maximum Dose*

Control Group

Pain Outcomes Assessed

Pain Assessment Time-points

Pain Relief Result

Adverse Effects

Dewinter 201653

Double-blind placebo-controlled randomized trial; ambulatory surgery

79 women undergoing laparoscopic sterilization

IV lidocaine (n = 39)

1.5 mg/kg bolus at induction followed by continuous infusion 1.5 mg/kg/h until 30 minutes in PACU

Equivalent dosing of normal saline (n = 40)

Proportion of patients with NRS greater than 3 30 minutes after PACU arrival Opioid consumption

NRS pain score assessed every 15 minutes for first 2 hours postoperatively and at 24 hours

No difference in NRS > 3 at 30 minutes post-PACU arrival No difference in NRS pain scores No difference in opioid consumption Shorter time to discharge in lidocaine group

Greater severity of nausea and required more PONV rescue medication in lidocaine group

Lauwick 200854

Double-blind randomized controlled trial; ambulatory surgery

50 adult patients undergoing laparoscopic cholecystectomy

IV lidocaine and fentanyl 1.5 mcg/kg at induction (n = 25)

1.5 mg/kg bolus followed by continuous infusion 2 mg/kg/h until end of surgery

Fentanyl bolus 3 mcg/kg at induction (n = 24)

Amount of fentanyl administered postoperatively to maintain VAS < 3 in PACU VAS pain scores Level of inflammatory markers (cortisol, CRP, procalcitonin)

VAS pain scores assessed Every 30 minutes for first 90 minutes after PACU arrival

Decreased amount of postoperative fentanyl requirement in lidocaine group No difference in VAS scores No difference in time to discharge No difference in inflammatory markers

No difference in PONV

Wuethrich 201255

Double-blind placebo-controlled randomized trial; inpatient

64 patients undergoing laparoscopic transperitoneal renal surgery

IV lidocaine (n = 32)

1.5 mg/kg bolus at induction followed by continuous infusion 2 mg/kg/h until end of surgery, then 1.3 mg/kg/h until 24 hours post-operatively

Equivalent dosing of normal saline (n = 32)

NRS pain ratings at rest and during mobilization

NRS pain scores assessed 2 hours and 6 hours post-operatively, then twice-daily during hospital stay

No difference in NRS scores at rest or with mobilization No difference in length of stay Decreased morphine consumption on POD 2 in lidocaine group

No difference in PONV No difference in return of bowel function

Ortiz 201656

Multicenter double-blind placebo-controlled randomized trial; inpatient

43 adult patients undergoing laparoscopic cholecystectomy

IV lidocaine (n = 21)

1.5 mg/kg bolus at induction followed by continuous infusion 3 mg/kg/h until end of surgery

Equivalent dosing of normal saline (n = 22)

VAS pain ratings at rest and during coughing Use of fentanyl PCA

VAS pain scores assessed 1, 2, 4, 12, and 24 hours post-operatively

No difference in VAS pain scores at rest or while coughing No difference in opioid consumption No difference in time to discharge Decreased inflammatory markers (IL-1, IL-6, IL-10, IFN-γ, TNF-α) in lidocaine group

No difference in return of bowel function

Kaba 200757

Double-blind placebo-controlled randomized trial; inpatient

40 patients undergoing laparoscopic colectomy for nonmalignant disease

IV lidocaine (n = 20)

1.5 mg/kg bolus at induction followed by continuous infusion 2 mg/kg/h until end of surgery, then 1.33 mg/kg/h until 24 hours post-operatively

Equivalent dosing of normal saline (n = 20)

Self-reported pain scores at rest, during mobilization, and with coughing and self-reported abdominal discomfort Piritramide consumption for 24 hours post-surgery

Self-reported pain assessed 2 hours and 6 hours post-operatively, three times on POD 1, and twice on POD 2

No difference in pain at rest, but decreased pain with mobilization, pain with coughing, and abdominal discomfort in lidocaine group Decreased use of piritramide for 24 hours post-operatively in lidocaine group Shorter time to discharge in lidocaine group

No difference in PONV Increased return of bowel function in lidocaine group

Kim 201158

Double-blind placebo-controlled randomized trial; inpatient

68 patients undergoing laparoscopic appendectomy for unperforated appendicitis

IV (n = 22) or intraperitoneal (IP, n = 25) lidocaine

IV: 1.5 mg/kg bolus at induction, followed by continuous infusion 2 mg/kg/h until end of surgery + intraperitoneal placebo normal saline IP: 3.5 mg/kg intraperitoneal instillation before beginning operation + IV placebo normal saline

Equivalent dosing of normal saline (n = 21)

VAS pain score Use of fentanyl PCA

VAS pain score assessed 2, 4, 8, 12, 24, and 48 hours post-operatively

Decreased VAS pain scores up to 8 hours post-operatively in IV group compared to control and up to 12 hours post-operatively in IP group compared to control No difference in VAS pain scores between IV and IP groups Decreased fentanyl consumption up to 24 hours post-operatively in IV group compared to control and up to 48 hours post-operatively in IP group compared to control Overall decreased fentanyl consumption in IP group compared to IV No difference in length of stay among groups

No significant differences in PONV or recovery of bowel function among groups

Yon 201459

Double-blind placebo-controlled randomized trial; inpatient

36 adult patients undergoing laparoscopic subtotal gastrectomy for early gastric cancer

IV lidocaine (n = 17)

1.5 mg/kg bolus at induction followed by continuous infusion 2 mg/kg/h until end of surgery

Equivalent dosing of normal saline (n = 19)

VAS pain score Use of fentanyl PCA Patient satisfaction scores regarding pain control Measurement of CRP

VAS scores assessed 2, 4, 8, 12, 24, and 48 hours post-operatively

Decreased VAS pain scores up to 24 hours post-operatively in lidocaine group Decreased use of fentanyl PCA up to 24 hours post-operatively and decreased overall fentanyl dose in lidocaine group Higher patient satisfaction score regarding pain control in lidocaine group Decreased CRP on POD 3 in lidocaine group No difference in length of stay between groups

No difference in incidence of PONV, shivering, tinnitus, or recovery of bowel function between groups

Kim 201360

Double-blind placebo-controlled randomized trial; inpatient

34 patients undergoing laparoscopic gastrectomy for early gastric cancer

IV lidocaine (n = 17)

1.5 mg/kg bolus at induction followed by continuous infusion 2 mg/kg/h until end of surgery

Equivalent dosing of normal saline (n = 17)

VAS pain score Use of fentanyl PCA Patient satisfaction scores regarding pain control

VAS scores assessed 2, 4, 8, 12, 24, and 48 hours post-operatively

Decreased VAS pain scores up to 24 hours post-operatively in lidocaine group Decreased use of fentanyl PCA up to 12 hours and overall fentanyl consumption post-operatively in lidocaine group Trend towards increased patient satisfaction (p = 0.53) in lidocaine group No difference in length of stay between groups

Decreased incidence of nausea but not vomiting in lidocaine group No difference in recovery of bowel function between groups

Ahn 201561

Double-blind placebo-controlled randomized trial; inpatient

50 adult patients undergoing laparoscopic colectomy

IV lidocaine (n = 25)

1.5 mg/kg bolus at induction followed by continuous infusion 2 mg/kg/h until end of surgery

Equivalent dosing of normal saline (n = 25)

VAS pain score Use of fentanyl PCA Patient satisfactions scores regarding pain control Measurement of CRP

VAS scores assessed 2, 4, 8, 12, 24, and 48 hours post-operatively

Decreased VAS pain scores up to 24 hours post-operatively in lidocaine group Decreased use of fentanyl PCA up to 12 hours and overall fentanyl consumption post-operatively in lidocaine group Higher patient satisfaction score regarding pain control in lidocaine group Decreased CRP on POD 1 and POD 2 in lidocaine group No difference in length of stay between groups

Decreased incidence of nausea but not vomiting in lidocaine group No difference in recovery of bowel function between groups

Saadawy 201062

Double-blind placebo-controlled randomized trial; inpatient

120 patients undergoing laparoscopic cholecystectomy

IV lidocaine (n = 40)

2 mg/kg bolus at induction followed by continuous infusion 2 mg/kg/h until end of surgery

IV magnesium (n = 40) bolus 50 mg/kg followed by continuous infusion 25 mg/kg/h until end of surgery IV normal saline (n = 40) bolus 25 mg/kg followed by continuous infusion 50 ml/h until end of surgery

VAS pain score evaluating abdominal and shoulder pain at rest and on coughing Use of morphine PCA VAS score evaluating quality of sleep on first post-operative night

VAS pain scores assessed 0, 2, 6, 12, 18, and 24 hours post-operatively

Decreased VAS scores for abdominal pain at rest at 2, 6, and 12 hours post-operatively and with coughing at all time points in lidocaine and magnesium groups compared to placebo Decreased VAS scores for abdominal pain at rest and with coughing at 2, 6, and 12 hours post-operatively in lidocaine group compared to magnesium group Decreased VAS scores for shoulder pain at rest and with coughing at 12, 18, and 24 hours post-operatively in magnesium and lidocaine groups compared to placebo Decreased morphine PCA consumption at 2 and 24 hours post-operatively in lidocaine and magnesium groups compared to placebo Decreased morphine PCA consumption at 2 hours post-operatively in lidocaine group compared to magnesium group Improved VAS score for sleep on first post-operative night for magnesium group compared to lidocaine group and placebo

Decreased time to first flatus in lidocaine group compared to magnesium group and placebo

CRP: C-reactive protein; IV: intravenous; NRS: numeric rating scale; PACU: post-anesthesia care unit; PCA: patient-controlled analgesia; POD: post-operative day; PONV: post-operative nausea and vomiting; VAS: visual analog score

All studies administered a bolus dose of lidocaine at induction; the dose was 1.5 mg/kg for nine of these studies and 2 mg/kg in the tenth.⁶² All studies also continued intravenous infusions of lidocaine during surgery; dosing for the infusions ranged from 1.3 mg/kg/h to 3 mg/kg/h. Three studies^53,55,57 continued lidocaine infusion postoperatively with duration from 30 minutes to 24 hours. Nine studies compared lidocaine to placebo, while one study⁵⁴ compared lidocaine plus fentanyl to lidocaine alone. Two studies included a third experimental arm in addition to intravenous lidocaine and placebo control: one⁵⁸ where patients were dosed with intraperitoneal lidocaine 3.5 mg/kg before the beginning of surgery and one⁶² where patients received a magnesium bolus followed by continuous magnesium infusion.

These studies were varied on the use of other analgesic operations intraoperatively. Four studies^58–61 explicitly excluded the use of any other analgesic medications. In the other six studies, one⁵⁴ compared fentanyl plus lidocaine to fentanyl alone, although the fentanyl dose in the group that received lidocaine was decreased. Opioids were used during induction in two study groups: one⁵⁷ using sufentanil (0.15 mcg/kg) and one⁶² using fentanyl (2 mcg/kg). In five studies, intra- and postoperative nonopioid analgesia was administered; agents included acetaminophen (15 mg/kg or 1 mg), ketorolac (0.5 mg/kg or 30 mg), and/or metamizole (1 g). All ten studies administered postoperative opioids for pain control and measured the amount of opioids required as a study outcome.

The results of perioperative lidocaine administration on pain control in laparoscopic abdominal surgery were mixed when considering the group of studies as a whole. Four studies^53–56 did not find any statistical improvement in patient self-reported pain on numeric rating scales (NRS) or visual analog scores (VAS) in the lidocaine group, while the remaining six studies^57–62 described lower pain scores with lidocaine administration. In all studies, these effects were most apparent within the first 24 hours post-operatively. In one study,⁵⁷ pain improvement with lidocaine was only seen in pain with coughing and/or mobilization, while pain at rest was not significantly improved. Eight studies found decreased use of postoperative opioids in the lidocaine group, while two^53,56 did not find a significant difference. The extent to which postoperative opioid requirements were decreased varied between studies, ranging from no significant difference to reducing average opioid requirement to zero.⁵⁵ As with patient-reported pain scores, this reduction in opioid use was primarily seen in the first 24 hours after surgery. Three studies which solicited patient satisfaction scores regarding pain control^59–61 all found improved patient satisfaction or a trend towards increased satisfaction in the group treated with lidocaine. Intraperitoneal instillation of lidocaine was found to temporally extend improvement in VAS pain scores and decreased opioid requirements versus placebo but did not demonstrate significant differences from IV lidocaine in either regard.⁵⁸

The role of lidocaine on adjunctive measures of pain control also varied between studies. Three studies^54,56,59 measured serum levels of inflammatory markers in both experimental groups. C-reactive protein elevation in the group receiving lidocaine was seen in only one out of two studies that measured that marker. Serum levels of IL-1, IL-6, IL-10, IFN-γ, and TNF-α were decreased in the one study that included these markers.⁵⁶ Decreased time to discharge was observed in two studies,^53,57 while no significant difference was observed in seven other studies.^{54–56,58–61} Self-reported quality of sleep was not significantly different in patients receiving lidocaine compared to placebo in the one study reporting this metric.⁶²

Side effects of lidocaine were rare. One study observed increased incidence of post-operative nausea and vomiting (PONV) in the lidocaine group,⁵³ although this was not observed in any other study, and nausea was actually reduced in two groups.^60,61 Bowel function returned more rapidly in two studies^57,62 but this observation was not universal among studies. No adverse events related to lidocaine administration were reported.

In summary, lidocaine has demonstrated analgesic effects in patients undergoing laparoscopic abdominal surgery. The studies mentioned above were limited by small sample size and their mostly single-center nature. Patient selection also limits generalizability of these results, as six out of ten studies^53–57,62 limited patient enrollment based on American Society of Anesthesiologists (ASA) status, mostly restricting subjects to ASA I or II status. Although lidocaine’s true effect on patient-reported pain scores and patient length of stay are equivocal between studies, the majority of studies demonstrate a reduced opioid requirement post-operatively, which could be beneficial in reducing levels of sedation, bowel ileus, and respiratory depression associated with these drugs. Combined with lidocaine’s low cost and safety profile, these advantages suggest a role for lidocaine in pain control for these surgeries.

Open Abdominal Surgeries

Although the proportion of abdominal cases being performed laparoscopically continues to rise, open abdominal surgery remains a common procedure in most operating rooms. Compared to the laparoscopic approach, open abdominal surgeries have increased severity of pain, thereby lengthening the time of recovery and ultimately increasing length of hospital stay. However, the abdominal studies investigated in studies on postoperative lidocaine are generally less complicated (Table 2B), including abdominal hysterectomy with or without oophorectomy, elective cholecystectomy, radical retropubic prostatectomy, open prostate adenomectomy, and colorectal surgery.

Table 2B. Characteristics of Selected Studies on Lidocaine Infusion in Laparoscopic Abdominal Surgeries.

First Author, Year

Study Design and setting

Patient Population

Treatment Group

Lidocaine Infusion Duration and Maximum Dose

Control Group

Pain Outcomes Assessed

Pain Assessment Time-points

Pain Relief Result

Adverse Effects

Bryson 201063

Triple-blind randomized placebo controlled trial; Inpatient

90 women ages 30–69 undergoing abdominal hysterectomies with or without oophorectomy

IV lidocaine (n = 44)

1.5 mg/kg prior to induction followed by continuous infusion 3 mg/kg/hr for duration of surgery

Equivalent dosing of normal saline (n = 46)

11-point verbal NRS pain score assessed at rest and with coughing Narcotic consumption

NRS pain score assessed at rest and with coughing in PACU, at 6 hrs, 24 hrs, and 48 hrs post-operatively

NRS pain score and narcotic consumption similar at all time points No differences in length of hospital stay Earlier consumption of oral intake in lidocaine group

Subjective symptoms of lightheadedness, tinnitus, dysguesia reported more in control than treatment group

Cassuto 198564

Double-blind randomized placebo controlled trial; Inpatient

20 adult patients undergoing elective cholecystectomy

IV lidocaine (n = 10)

20 mg/kl 30 mins prior to incision followed by continuous infusion 2 mg/min for 24 hrs post-operatively

Equivalent infusion of normal saline (n = 10)

Linear analogue scale ranging from 0–100 Meperidine requirement

Score assessment every 2 hrs start 1 hr post-operatively

Pain scores significantly reduced in treatment group 1 hr post-op and before meperidine (P < 0.001) Significant reduction for need for meperidine in lidocaine group No difference in systolic BP and pulse between groups

One report of lightheadedness in each group, otherwise no subjective side effects from drug overdose

Maquoi 201665

Double-blind randomized placebo controlled trial; Inpatient

101 males age >18 undergoing radical retropubic prostatectomy and open prostate adenomectomy

IV lidocaine (n = 33) TAP (n = 34)

Lidocaine group given 1.5 mg/kg prior to induction followed by continuous infusion 2 mg/kg/hr for 24 hrs post-operatively TAP block group given 20 ml levobupicavaine + 5 μg/mL of epinephrine

Equivalent infusion of normal saline for both (n = 34)

VAS of 100 mm at rest and upon coughing Total amount of Piritramide administered postoperatively

Score assessment every 6 hrs at rest and upon coughing after surgery Cumulative piritramide consumption after 24 and 48 hrs Number of patients requiring rescue tramadol

Cumulative piritramide consumption after 48 hrs was 28 mg in control group, 21 mg in TAP block group, and 21 mg in lignocaine group (P = 0.15) Cumulative piritramide consumption after 24 hrs was similar in each group (P = 0.07) Both treatments had no effect on VAS for pain at rest (P = 0.37) or coughing (P = 0.37) 13% of pts in placebo group, 15% in TAP block group and 24% in lignocaine group required at least one dose of tramadol Time to first flatus or bowel movement similar in each group 24% in placebo group and 6% in TAP block group, and 18% in lignocaine group received anti-emetic 60% in placebo group, 42% in TAP block group, and 62% in lignocaine group received anti-emetic with bladder spasms

Subjective reports of nausea

Weinberg 201666

Double-blind randomized controlled trial; Inpatient

76 males ages > 18 undergoing radical retrobupic prostatectomy

IV Lidocaine (n = 36)

0.075 ml/kg of Lidocaine given prior to induction followed by continuous infusion 0.075 ml/kg/hr for the duration of the surgery

Equivalent infusion of saline (n = 38)

VAS at rest and with coughing Opioid consumption

VAS every 4 hours post-operatively then every 4 hrs for 20 hrs then every 61–12 hrs the next 24 hrs Morphine consumption for 24 hrs postoperatively

Reduction in post-operative hospital stay in lidocaine group (P = 0.017) Reduction in pain at rest during first 24 postoperative hrs in lidocaine group (P = 0.001) Reduction in 24 hr morphine consumption in lidocaine group (P = 0.021) No differences in other outcomes

Subjective perioral numbness

Grady 201267

Double-blind randomized placebo controlled trial; Inpatient

60 women ages 18–65 undergoing elective open abdominal hysterectomy for fibroids disease or uterine myomectomy

IV Lidocaine (n = 31) IV Ketamine (n = 30) IV lidocaine + letamine

1.5 mg/kg lidocaine bolus followed by continuous lidocaine infusion 0.2 mg/kg/hr for first 2 hrs then 0.12 mg/kg/hr for 24 hrs postoperatively IV ketamine bolus 0.35 mg/kg followed by continuous ketamine infusion of 0.2 mg/kg/hr the first 2 hrs then 0.12 mg/kg/h for 24 hrs postoperatively

Unspecified placebo: with lidocaine (n = 31) with ketamine (n = 32) with another dose of placebo (n = 63)

6 MWD VRS (0–10) Opioid consumption postoperatively Nausea and vomiting

6 MWD on second postoperative morning VRS upon arrival to PACU, 24 hrs post op and 48 hrs post op Nausea and vomiting between given time intervals

No interaction between primary outcome of 6-MWD (P = 0.96) No difference found for either intervention in mean postoperative pain severity, opioid consumption, fatigue, or postoperative nausea/vomiting

Mild toxicity and excessive sleepiness in the lidocaine + ketamine group

Herroeder 200768

Double-blind randomized placebo controlled trial; Inpatient

60 adult patients undergoing colorectal surgery

IV lidocaine (n = 31)

1.5 mg/kg bolus prior to induction followed by continuous infusion 2 mg/min until 4 hrs postoperatively

Equivalent infusion of normal saline (n = 29)

VAS at rest and with coughing Opioid consumption

VAS at 2 and 4 hrs postoperatively and 12 hrs until time of discharge Daily opioid demand by PCA

No significant differences at rest or with coughing between groups No significant difference in demand for piritramide postoperatively

Gastrointestinal atonia, wound healing disturbances, skin wound irritation

Staikou 201469

Double-blind randomized placebo controlled trial; Inpatient

60 adult patients undergoing open colonic surgery

IV lidocaine (n = 20) Lumbar epidural lidocaine analgesia (n = 20)

1.5 mg/kg bolus of IV lidocaine followed by continuous 2 mg/kg/hr intraoperatively 1.5 mg/kg bolus lidocaine in epidural followed by continuous 2 mg/kg/hr epidural infusion

Equivalent infusion of normal saline (n = 20)

Numerical pain rating scale (0–10) at rest and with coughing Opioid consumption

Score assessment at 1,2,4,12, and 48 hrs postoperatively 48 hr opioid consumption

IV lidocaine group significantly lower pain scores at rest and cough at 1,2, and 4 hrs postoperatively compared to other two groups (P =< 0.005) No significant difference in 48 hr analgesic requirements between any groups (P => 0.05)

None reported

Yardeni 200939

Double-blind randomized placebo controlled trial; Inpatient

65 women ages 45–70 undergoing transabdominal hysterectomy

IV lidocaine + PCEA (n = 32)

2 mg/kg bolus prior to induction followed by continuous infusion 1.5 mg/kg/hr for the duration of the surgery

Equivalent infusion of saline + PCEA (n = 33)

Visual analogue scale (10 cm) at rest and with coughing

Pain assessment at 4,8,12,24,48, and 72 hrs post operatively

Patients in Lidocaine + PCEA group experienced less intense pain at 4 and 8 hrs No difference in scores between 12–72 hrs No significant differences in volume of PCEA between groups at time intervals

None reported

IV: intravenous; MWD: minute walk distance; NRS: numeric rating scale; PCEA: patient-controlled epidural analgesia; TAP: transversus abdominis plane block; VAS: visual analog scale; VRS: verbal response score.

All eight studies explored the role of IV lidocaine continuous infusion, typically following a bolus. These infusions occurred for the duration of the surgery and were typically stopped at the end of surgery. Therapeutic concentrations of lidocaine are typically around 5.5 mg/L with ranges of 8–12 mg/L and beyond resulting in toxic levels in plasma. The dosages of lidocaine infusion across the studies ranged between 0.075 mg/kg/h to 3 mg/kg/h for the surgical duration and often, 24 hours postoperatively.

In addition to IV lidocaine, some studies explored the conjunctional effects of other analgesics intraoperatively. Grady had several treatment groups comparing the effects of IV ketamine to IV lidocaine alone and in addition to one another.⁶⁷ For that particular study, the dose of ketamine was a bolus followed by continuous ketamine infusion of 0.2 mg/kg/h the first 2 hours then 0.12 mg/kg/h for 24 hours postoperatively. Unfortunately no significant differences were found in those treatment groups and instead resulted in mild toxicity. No other studies explored the use of additional analgesics intraoperatively.

The overall outcome of effectiveness of pain control with lidocaine infusion varied by study. Three studies of patients undergoing open cholecystectomy, retropubic prostatectomy, open abdominal hysterectomy, and open colonic surgery demonstrated improved postoperative pain control with lidocaine.^39,64,66,69 The other studies did not report any significant changes.^{39,63,65,67,68} In general, the data appears to be inconclusive at fully supporting lidocaine infusion intraoperatively as a superior form of pain control for open abdominal surgeries.

Spine Surgeries

Back pain is one of the most common patient complaints; the incidence of those receiving spinal surgery for desired pain relief has been increasing to more than half a million per year.⁷⁰ Table 2C summarizes the studies investigated include patients undergoing lumbar discectomy or multilevel complex spinal surgery. Overall, these surgeries have an increased risk of more pain postoperatively than from initial pain levels. Postoperative pain remains a significant indication for postoperative hospitalization in these patients, thus underlining the need for effective analgesic strategies.

Table 2C. Characteristics of Selected Studies on Lidocaine Infusion in Open Abdominal Surgeries.

First Author, Year

Study Design and setting

Patient Population

Treatment Group

Lidocaine Infusion Duration and Maximum Dose

Control Group

Pain Outcomes Assessed

Pain Assessment Time-points

Pain Relief Result

Adverse Effects

Farag 201370

Triple-blind randomized placebo controlled trial; Inpatient

113 adult patients undergoing complex spinal surgery

IV lidocaine (n = 56)

2 mg/kg/h continuous infusion with max. dose of 200 mg/hr at induction until discharge from PACU

Equivalent volume of normal saline (n = 56)

VRS (0–10) Opioid consumption

Pain assessment in 30 min intervals while in PACU and every 4–6 hrs after until discharge Opioid consumption for 48 hrs postoperatively Postoperative nausea and vomiting the first 24 hrs

Pts in treatment group significantly noninferior to the placebo group on both pain and opioids (P =< 0.001 and P =< 0.011) Noninferiority tests for placebo group relative to lidocaine group were not significant (P = 0.12 and P = 0.54) Superiority results revealed significant results for pain with lidocaine (P =< 0.001) but not for opioids (P = 0.12)

None reported

Kim 201471

Double-blind randomized placebo controlled trial; Inpatient

51 adult patients undergoing lumbar micro discectomy

IV lidocaine (n = 25)

1.5 mg/kg bolus followed by continuous infusion 2 mg/kg/hr for the duration of the surgery

Equivalent volume of normal saline (n = 26)

VAS (0–100 mm) Opioid consumption with PCA pump Pain control satisfaction scores

Pain assessment 2,4,8, 12, and 48 hrs postoperatively Frequency that pts pushed the button Fentanyl consumption at 2,4,8,12,48 hrs postoperatively Satisfaction scores regarding pain control 48 hr postoperatively Postoperative nausea and vomiting

VAS significantly higher in placebo group up to 24 hrs postoperatively Fentanyl consumption significantly higher in placebo group until 12 hrs Higher fentanyl consumption from PCA and rescue analgesia up to 24 hrs postoperatively Treatment group required overall less analgesia (P =< 0.001) Satisfaction score higher in treatment group (P = 0.05) Nausea and vomiting less frequent in treatment group, but not statistically significant Length of hospital stay significantly shorter in treatment group (P = 0.039)

None reported

IV: intravenous; PACU: post-anesthesia care unit; PCA: patient-controlled analgesia; VAS: visual analog scale; VRS: visual response score.

The dosage of lidocaine infusion for each study was fairly consistent. Farag explored a continuous infusion of 2 mg/kg/h with a maximum dose of 200 mg/hr at induction.⁷⁰ This infusion continued from the time of induction until discharge from the postanesthesia care unit (PACU). Kim’s study involving patients also undergoing spinal surgery, specifically lumbar microdiscectomy, and investigated a continuous infusion rate of 2 mg/kg/h that lasted for the duration of the surgery with a 1.5 mg/kg bolus prior to the start of the infusion.⁷¹

In the two studies presented, IV lidocaine treatment during surgery appears to reduce inflammation and postoperative pain. On patients undergoing unspecified, complex multidisc surgery, patients in the treatment group were significantly “not worse” than those in the placebo group in regard to pain and opioid consumption. Noninferiority tests for placebo group relative to lidocaine group, however, were not significant. Superiority results revealed significant results for pain with lidocaine in the treatment group, but not for opioid consumption. In regard to patients undergoing lumbar microdiscectomy, the pain score assessment was significantly higher in the placebo group up to 24 hours postoperatively with overall satisfaction score being higher in treatment group.⁷¹ Total fentanyl consumption was significantly higher in placebo group than that in the treatment group up until 12 hours and at 24 hours postoperatively. This included consumption from PCA and rescue analgesia. The length of hospital stay was significantly shorter in the treatment group. Incidence of nausea and vomiting was not different between groups. The results of each study show that continuous IV infusion of lidocaine during spinal surgeries, in general, appears to be beneficial for patient recovery.

Breast Surgeries

Breast cancer surgery is associated with a high incidence of persistent postsurgical pain (PPSP). Two selected studies (Table 2D) assessed the effect of intraoperative IV lidocaine infusion on the quality of postoperative recovery and pain experienced after breast cancer surgery.^72,73

Table 2D. Characteristics of Selected Breast Cancer Surgery Studies on Lidocaine Infusion on Breast Surgeries.

First Author, Year

Study Design and Setting

Patient Population

Treatment Group

Lidocaine Infusion Duration and Maximum Dose*

Control Group

Pain Outcomes Assessed

Pain Assessment Time-points

Pain Relief Result

Adverse Effects

Terkawi 201472

Double-blind placebo-controlled trial; Inpatient

71 subjects undergoing breast cancer surgery

IV lidocaine bolus at induction, then infusion stopped 2 hours after arrival in PACU (n = 37); intraoperative and postoperative morphine

1.5 mg/kg bolus at induction, then continuous infusion at 2 mg/kg/h

Normal saline + intraoperative and postoperative morphine (n = 34)

Postoperative pain scores (0–10), PONV, and fatigue

Pain assessed every 15 minutes after arrival in PACU – 2, 24, 48 hours after surgery

No significant difference in intraoperative or postoperative morphine consumption between the groups; overall pain scores either at rest or activity, PONV, fatigue, or duration of postoperative hospital stay were not statistically different

No significant adverse effects reported

Grigoras 201273

Double-blind placebo-controlled trial; Inpatient

36 subjects undergoing breast cancer surgery

IV lidocaine bolus at induction, followed by infusion stopped 1 hour after the end of surgery; intraoperative and postoperative morphine (n = 17)

1.5 mg/kg bolus at induction, then continuous infusion at 1.5 mg/kg/h

Normal saline + intraoperative and postoperative morphine (n = 19)

Postoperative pain scores (McGill Pain Questionnaire) and analgesic consumption; later assessment for PPSP and secondary hyperalgesia

Baseline 2, 4, 24 hours, and then daily for 1 week postoperatively 3 months postoperatively for PPSP and secondary hyperalgesia

2 patients in the lidocaine group and 9 patients in the control group reported PPSP at 3 months follow-up (p = 0.031); greater pain intensity VAS in the control group (p = 0.025); secondary hyperalgesia was significantly less in the lidocaine group (p = 0.002); no difference in analgesic consumption during the early postoperative period

No significant adverse effects reported

IV: intravenous; PACU: post-operative care unit; PONV: post-operative nausea and vomiting; PPSP: persistent post-surgical pain, *Maximum dose was calculated based on a 70 kg patient.

These two studies utilized similar dosing strategies for intraoperative lidocaine infusion. Patients in both studies received a bolus of IV lidocaine 1.5 mg/kg at the induction of general anesthesia. Terkawi, et al. followed the initial bolus with a continuous lidocaine infusion of 2 mg/kg/h that was stopped 2 hours after the end of surgery.⁷² Grigoras, et al. followed the initial bolus with a continuous lidocaine infusion of 1.5 mg/kg/h that was stopped 1 hour after the end of surgery.⁷³

Terkawi, et al. limited intraoperative analgesia to fentanyl IV (5 μg/kg maximum). The intraoperative analgesia used by Grigoras, et al. consisted of IV paracetamol 1 g, IV diclofenac 75 mg, and IV morphine sulphate as needed. Terkawi, et al. found no statistically significant difference in intraoperative or postoperative morphine consumption between the lidocaine treatment and control groups.⁷² Pain scores either at rest or activity, fatigue, and duration of postoperative hospital stay were not statistically significant between the groups. While Terkawi, et al. did not find a significant level of effect of IV lidocaine on opioid consumption, pain score, PONV, or fatigue during breast cancer surgery, Grigoras, et al. did find positive effects from lidocaine treatment. Fewer patients in the lidocaine treatment group reported PPSP at 3 months follow-up. Greater pain intensity was reported in the control and secondary hyperalgesia was significantly reduced in the lidocaine group at 3 months follow-up.⁷³ Similarly to Terkawi et al. Grigoras et al. did not find a significant difference in terms of analgesic consumption during the early postoperative period. Across both studies, no significant adverse effects were reported.

ENT Surgeries

Intraoperative IV lidocaine infusions have also been studied in ENT surgeries to assess potential reductions in pain experienced during the postoperative period. Of the selected studies (Table 2E), one assessed the potential benefits of IV lidocaine during elective tonsillectomy procedures,⁷⁴ while others studied its used in thyroidectomy⁷⁵ and in functional endoscopic sinus surgery (FESS)⁷⁶.

Table 2E. Characteristics of Selected ENT Surgery Studies on Lidocaine Infusion.

First Author, Year

Study Design and Setting

Patient Population

Treatment Group

Lidocaine Infusion Duration and Maximum Dose*

Control Group

Pain Outcomes Assessed

Pain Assessment Time-points

Pain Relief Result

Adverse Effects

Striebel 199274

Double-blind, placebo-controlled randomized trial

40 patients undergoing elective tonsillectomy

IV lidocaine (n = 20)

1.5 mg/kg bolus at induction, then continuous infusion of 2 mg/kg/h for 6 hours followed by 05 mg/kg/h for 18 hours

Equivalent dose of normal saline (n = 20)

VAS Total post-operative opioid requirement at 24 hours post-operatively

VAS at 1, 2, 4, 6, and 24 hours postoperatively

No significant difference in pain scores at any time point post-operatively No difference in opioid use between groups

None reported

Choi 201775

Double-blind placebo-controlled randomized trial

90 patients undergoing robotic thyroidectomy

IV lidocaine (n = 41)

2 mg/kg bolus at induction, then continuous infusion at 3 mg/kg/h

Equivalent dose of normal saline (n = 43)

QoR-40 preoperatively and 24 hours post-operatively VNRS CPSP evaluation with McGill Pain questionnaire Sensory disturbances

VNRS at 10min, 20min, 24h, and 48h post-operatively CPSP evaluated 3 months post-operatively Sensory disturbances evaluated 3 months post-operatively

No significant difference in QoR-40 and pain scores between groups Increased prevalence of CPSP in control group 3 months post-operatively Improved sensory function 3 months post-operatively in lidocaine group

None reported

Omar 201376

Double-blind placebo-controlled randomized trial

48 patients undergoing functional endoscopic sinus surgery

IV lidocaine (n = 24)

1.5 mg/kg bolus at induction, then continuous infusion at 0.15 ml/kg/h

Equivalent dose of normal saline (n = 24)

VAS pain scores Post-operative opioid requirement

VAS evaluated at 15, 30, and 60 minutes post-operatively

Improved VAS scores in lidocaine group at 15, 30, and 60 minutes post-operatively Increased intraoperative opioid requirement in control group No significant difference in postoperative opioid use

None reported

CPSP: chronic post-surgical pain; IV: intravenous; QoR-40: quality of recovery-40 questionnaire; VAS: visual analog scale; VNRS: verbal numeeric rating scale, *Maximum dose was calculated based on a 70 kg patient.

Similar dosing strategies were used among the three studies. Striebel, et al. and Omar both utilized an induction bolus dose of IV lidocaine 1.5 mg/kg, while Choi, et al. used an induction bolus dose of 2 mg/kg.^74–76 Striebel, et al. utilized a continuous maintenance dose of 2 mg/kg/h over 6 hours, followed by 0.5 mg/kg/h for another 18 hours.⁷⁴ Choi, et al. followed the initial bolus with a continuous IV lidocaine infusion of 3 mg/kg/h, and Omar followed the bolus dose with a continuous infusion of 1.5 mg/kg/h.^75,76

Standard anesthesia was utilized in each of the studies; however, Omar included 1–1.5 μg/kg fentanyl at anesthesia induction.⁷⁶ Striebel, et al. reported no differences in VAS pain scores between the lidocaine treatment and control groups during the first 24 hours after surgery. Additionally, there were no differences between groups in postoperative analgesic use.⁷⁴ Choi, et al. found no differences in the acute pain profiles between lidocaine treatment and control groups in the first 48 postoperatively. Chronic postsurgical pain (CPSP) was reduced in the lidocaine treatment group three months after surgery, and tactile sensory scores at three months were higher in the lidocaine treatment group.⁷⁵ While Choi, et al. demonstrated reduced chronic pain and no effect on acute postoperative pain with lidocaine treatment, Omar found that acute postoperative VAS pain scores were significantly lower with intraoperative lidocaine treatment compared to controls.^75,76 Omar also found that intraoperative fentanyl doses were reduced with intraoperative lidocaine treatment.⁷⁶ Across all studies, no significant adverse effects were reported.

Other Surgeries

Intraoperative IV lidocaine has been further assessed for its potential benefits in a variety of other operations (Table 2F). Kang, et al. studied the use of intraoperative IV lidocaine in inguinal herniorrhaphy procedures, which are frequently associated with persistent post-operative discomfort and distress for patients.⁷⁷ In this study, Bassini repair techniques were used with reconstruction of the inguinal floor. This procedure is associated with more intense post-operative pain than tension-free repair, making aggressive post-operative analgesia more imperative. McKay, et al. assessed intraoperative IV lidocaine in a heterogenous population of patients undergoing ambulatory surgery.⁷⁸ Slovack, et al.⁷⁹ examined lidocaine use in video-assisted thoracoscopic surgery (VATS), while Insler, et al.⁸⁰ further studied the impact of intraoperative IV lidocaine in patients undergoing coronary artery bypass surgery (CABG).

Table 2F. Characteristics of Other Selected Surgery Studies on Lidocaine Infusion.

First Author, Year

Study Design and Setting

Patient Population

Treatment Group

Lidocaine Infusion Duration and Maximum Dose*

Control Group

Pain Outcomes Assessed

Pain Assessment Time-points

Pain Relief Result

Adverse Effects

Kang 201177

Double-blind placebo-controlled trial; Inpatient

64 subjects undergoing inguinal herniorrhaphy

IV lidocaine bolus at induction, then continuous lidocaine infusion (n = 32)

1.5 mg/kg bolus at induction, then continuous IV lidocaine infusion of 2 mg/kg/h

Normal saline (n = 32)

Visual analogue scale (VAS) pain scores, fentanyl consumption and frequency that analgesia was administered from a patient-controlled analgesia device

– Baseline – VAS pain scores recorded at 2, 4, 8, 12, 24, and 48 hours after surgery – Frequency of bolus release from patient-controlled fentanyl assessed for 0–2, 2–4, 4–8, 8–12, 12–24, 24–48 hours post-surgery

VAS pain scores were significantly lower in the lidocaine group than in controls until 12 hours post-surgery (p = 0.05); fentanyl consumption and the frequency of patient-controlled analgesia button pushes were significantly lower in the lidocaine group until up to 12 hours post-surgery (p < 0.05); total fentanyl consumption (patient-controlled + rescue administration) was significantly lower in the lidocaine group (p < 0.05)

No significant adverse effects reported; frequency of nausea was significantly lower in the lidocaine treatment group (p = 0.021)

McKay 200978

Double-blind placebo-controlled trial; Outpatient

56 subjects undergoing ambulatory surgery

IV lidocaine bolus at induction, then continuous lidocaine infusion continued until 1 hour after arrival in the PACU (n = 29)

1.5 mg/kg bolus at induction, then continuous IV lidocaine infusion of 2 mg/kg/h

Initial 1.5 mg/kg IV lidocaine bolus at induction, then continuous IV normal saline (n = 27)

Pain assessed by VAS and treated with either fentanyl was or morphine when pain was more than 3 on a VAS of 0–10; patients recorded analgesic use and level of pain for the first 24 hours after discharge

– Pain at rest by VAS every 15 minutes – Self-reported analgesic use 24 hours after discharge

Intraoperative opioid use (MEQ) in the lidocaine group reduced by 30% (p = 0.017), with 50% reductions in use in the PACU (p = 0.015) and 40% reductions during the total study period (p = 0.002); use of analgesics during the first 24 hours after discharge was no significantly different between the groups; in the PACU, lidocaine group patients reported less pain at rest (p = 0.043) but there were no differences in pain scores at 24 hours after surgery

No significant adverse effects reported; one patient reported dizziness and visual disturbance at the end of the infusion

Slovack 201579

Double-blind placebo-controlled trial; Inpatient

36 subjects undergoing video-assisted thoracoscopic surgery (VATS)

IV lidocaine bolus at induction, then continuous lidocaine infusion (n = 19)

1.5 mg/kg bolus at induction, then continuous IV lidocaine infusion of 3 mg/min for patients weighing > 70 kg or 2 mg/min for patients weighing < 70 kg

Normal saline (n = 17)

Pain scores; postoperative opioid requirements

– Postoperative morphine use and pains scores measured at 8, 16, 24, and 48 hours

No statistically significant difference in intraoperative fentanyl or morphine use in recovery; postoperative morphine requirements and pain scores were low in both groups and not significantly different at any time

No significant adverse effects reported

Insler 199580

Double-blind placebo-controlled; Inpatient

100 subjects undergoing coronary artery bypass grafting (CABG)

Lidocaine IV infusion at induction; fentanyl/midazolam infusion discontinued at ICU admission; lidocaine continued until ICU discharge (n = 36)

1.5 mg/kg bolus at induction, serum levels measured to maintain below threshold of 10 ug/mL

Normal saline IV infusion at induction; fentanyl/midazolam infusion discontinued at ICU admission; normal saline continued until ICU discharge (n = 34)

Postoperative pain assessment using VAS; postoperative supplemental fentanyl consumption

– VAS measured at 4, 8, 16, and 24 hours postoperatively and on postoperative days 2 and 4

No statistically significant difference in VAS between the groups from 4 hours to 4 days postoperatively; no statistically significant difference detected in postoperative dosages of fentanyl between the groups

No significant adverse effects reported

ICU: intensive care unit; IV: intravenous; MEQ: morphine equivalents; VAS: visual analog score

*Maximum dose was calculated based on a 70kg patient.

Similar dosing strategies were used across studies, with all four utilizing a bolus of 1.5 mg/kg IV lidocaine at induction. Both Kang, et al. and McKay, et al. followed the induction bolus with continuous IV lidocaine infusion of 2 mg/kg/h.^77,78 Slovack, et al. used a continuous infusion of 3 mg/min for patients weighing >70 kg and 2 mg/min for patients weighing <70 kg⁷⁹.

Standard anesthesia was used across all four studies. Kang, et al. did not include any additional IV opioids intraoperatively.⁷⁷ McKay, et al. included anesthetic management during surgery that was standardized for opioid use (fentanyl as required and morphine up to 0.15 mg/kg).⁷⁸ Insler, et al. utilized intraoperative IV fentanyl for pain management dosed at 15 μg/kg/h.⁸⁰

Results varied across studies. According to Kang, et al. VAS pain scores were reported as being significantly lower with lidocaine treatment up until 12 hours post-surgery.⁷⁷ The authors reported reduced patient-controlled postoperative fentanyl use and reduced overall fentanyl consumption in the lidocaine treatment group, also up to 12 hours following surgery. McKay, et al. demonstrated similar results, with patients receiving lidocaine treatment having significantly reduced opioid use in both the intraoperative and postoperative periods. Overall, lidocaine treatment was associated with a 40% reduction in opioid use during the study period. However, the use of analgesics did not differ between the lidocaine treatment group and controls in the first 24 hours after discharge. Lidocaine patients reported less pain at rest in the PACU (p = 0.043), but there were no differences in pain scores 24 hours after surgery.⁷⁸ Unlike McKay, et al. and Kang, et al. Slovack, et al. and Insler, et al. did not report any statistically significant differences in postoperative pain scores or postoperative opioid use between lidocaine treatment and control groups.^79,80 Across all studies, no significant adverse effects were reported.

Safety Profile

Lidocaine toxicity correlated directly with its blood concentration and is most probably to occur when the plasma concentration reaches 5 μg/ml.⁸¹ Body weight is routinely used to determine the lidocaine dose with recommendation at 1–2 mg/kg loading dose and 1–2 mg/kg/h for continuous infusion equivalent to the plasma concentration of 2 μg/ml.³¹ Precautions should be taken to adjust the dose of lidocaine in specific patient population.

The most reported side effects (Table 3) with use of lidocaine includes hypotension, confusion, dizziness, tremor, headache, constipation, nausea and vomiting, and irritation symptoms (erythema, edema).⁸² When the plasma concentration is greater than 5–8 μg/ml, perioral paresthesia, slurred speech, diplopia, tinnitus, metallic taste, light headedness, muscular spasm and seizures have been noted.¹⁴ Severe intoxication leads to atrioventricular heart blocks, arrythmia and death. The manifestation of neurological symptoms corresponds to a plasma concentration of 15 μg/ml⁸³ while for cardiotoxicity it corresponds to a level greater than 21 μg/ml.²

Table 3. Side effects of lidocaine.

Dizziness or lightheadedness

Confusion

Tremor

Perioral paresthesia

Dysgeusia

Nausea and vomiting

Skin irritation (erythema, edema)

Constipation

Headache

Tinnitus

Hypotension

Muscular spam

Diplopia

Seizure

Arrythmia

Cardiovascular block

Cardiovascular depression

Central nervous system depression

Respiratory depression

Cardiac arrest

Death

Anaphylaxis

When the regularly recommended protocols of administration are utilized, research of available data showed no increased risk of adverse effects when IV lidocaine is compared to placebo.⁴

A double-blind placebo-controlled randomized trial of 79 women undergoing laparoscopic sterilization reported greater severity of nausea and need for PONV rescue medication in the lidocaine group.⁵³ However, other laparoscopic studies^58,61 reported decreased incidence of nausea and no difference in incidence of PONV.^{54,55,57–59} Regarding bowel function, early return of gastrointestinal motility was reported following abdominal surgeries^57,62,68 in lidocaine group while others^{55,56,58,59,61} reported no difference in return of bowel function between the groups. No significant adverse was reported following spine surgeries^70,71 and other surgeries.^63,77–80

Some subjective neuropsychological symptoms reported includes lightheadedness,^64,66 tinnitus,⁶⁴ dysgeusia,⁶⁴ perioral numbness,⁶⁷ excessive sleepiness,⁸⁴ visual disturbances, and dizziness.⁷⁹ Skin wound irritation and healing disturbances was reported in one study.⁶⁸ Anaphylaxis is rare and when immediate hypersensitivity reactions occur, they are considered as pseudo-allergic or non-immune mediated.⁸⁵

To minimize side effects from lidocaine infusion, a progressive reduction to about 50% in the rate of infusion every 6 hours for prolonged surgery is recommended. Additionally, infusion could be terminated at the end of PACU stay as no advantage of continuing beyond 60 minutes after surgery was reported by recent review.⁸⁶ It is not recommended to combine lidocaine with beta-blockers, clonidine, cimetidine phenytoin and ciprofloxacin as these drugs could alter its pharmacokinetics. Furthermore, combination with antiarrhythmics of the same class or a different class is contraindicated. Amiodarone reduces lidocaine clearance. Due to combined local anesthetics toxicity, it is not recommended to co-administer infusion lidocaine with another LAs either by infiltration or regional anesthesia.

Conclusion

Lidocaine, an amide local anesthetic, has its primary mode of action by blockade of sodium gated voltage channels. However, the eventual antinociceptive action of infusion lidocaine reveals its multifactorial facets of action. It has been recently used for the management of post-operative analgesia and surgical recovery. Bearing all evidence including a recent meta-analysis⁸⁷ showing evidence of effect of IV lidocaine on reduction of early postoperative pain (1–4 hours) when compared to placebo, especially in abdominal surgery, we would recommend its use with caution on dosing. Furthermore, some advantageous effects were shown in terms of gastro-intestinal motility, length of hospital stays, post-operative nausea and opioid consumption. Therefore, intravenous infusion lidocaine may be added to postoperative pain management protocols to improve recovery.