Intravenous Lidocaine for the Management of Chronic Pain: A Narrative Review of Randomized Clinical Trials

Abstract

Background

Chronic pain remains a serious health problem with significant impact on morbidity and well-being. Available treatments have only resulted in relatively modest efficacy. Thus, novel therapeutic treatments with different mechanisms have recently generated empirical interest. Lidocaine is postulated to provide anti-inflammatory and anti-nociceptive effect through its action at the N-methyl-D-aspartate (NMDA) and voltage gated calcium receptors. Emerging research indicates that lidocaine could be a reasonable alternative for treating chronic pain.

Objective

Considering the evidence surrounding lidocaine’s potential as a therapeutic modality for chronic pain, we conducted a narrative review on the evidence of lidocaine’s therapeutic effects in chronic pain.

Methods

A review of the PubMed, and Google scholar databases was undertaken in May 2022 to identify completed studies that investigated the effectiveness of lidocaine in the treatment of chronic pain from database inception to June 2022.

Results

A total of 25 studies were included in the narrative review. Findings on available studies suggest that intravenous infusion of lidocaine is an emerging and promising option that may alleviate pain in some clinical populations. Our narrative synthesis showed that evidence for intravenous lidocaine is currently mixed for a variety of chronic pain syndromes. Findings indicate that evidence for efficacy is limited for: CRPS, and cancer pain. However, there is good evidence supporting the efficacy of intravenous lidocaine as augmentation in chronic post-surgical pain.

Conclusion

Lidocaine may be a promising pharmacologic solution for chronic pain. Future investigation is warranted on elucidating the neurobiological mechanisms of lidocaine in attenuating pain signaling pathways.

Introduction

Chronic pain affects over 1 in 5 adults in the U.S. and contributes significantly to physical, emotional, and financial distress for patients.¹ Opioids are frequently prescribed for chronic pain, though up to 29% of patients misuse them and up to 12% have an opioid addiction.² In 2021 alone, there were 77,697 deaths attributed to opioid overdose.³ In light of this epidemic, the management of chronic pain using non-opioid medications thus remains a topic of interest.

Lidocaine, an amine-amide local anesthetic, has been studied widely as an adjunctive pain medication. First synthesized by Swedish scientists in 1943, lidocaine improved upon older local anesthetics due to its stability and longer duration of action.⁴ While still commonly utilized as a local and topical anesthetic, lidocaine can be administered systemically (i.e. intravenously) to be used as an antiarrhythmic and to blunt the physiologic response to direct laryngoscopy and intubation.⁵

Additionally, researchers have studied lidocaine infusions for improving acute and chronic pain. System use of local anesthetics for the treatment of pain has been reported since at least the 1950s.⁶ Multiple studies suggest that intraoperative infusion of lidocaine reduces post-surgical pain, especially in the early postoperative period.^7–9 Intravenous lidocaine is also effective in treating other sources of acute pain, including renal colic, critical limb ischemia, abdominal pain, and acute headaches.^10–13 Intravenous lidocaine has also proven to be useful in chronic pain, with generally positive results for treating conditions such as post-herpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, and fibromyalgia.^10,14–17

This study aims to present an updated and comprehensive narrative review of randomized controlled trials that evaluate the effectiveness of lidocaine infusions for the management of chronic pain. We limited our selection to only randomized controlled trials in order to assess the highest level of evidence. We will focus on several chronic pain syndromes: neuropathic pain syndromes, fibromyalgia, chronic post-surgical pain, cancer pain, and complex regional pain syndrome.

Drug/Molecule

Lidocaine traces its origins back to research conducted in Stockholm, Sweden, in 1943 where it was discovered to have potent anesthetic effects.¹⁸ By 1948 it was approved by the FDA and its use became widespread. Today, it is primarily used in peri-operative anesthesia, although there is a growing field of study suggesting lidocaine’s effectiveness in alleviating neuropathic pain.¹⁹ While lidocaine’s effects are mainly anti-nociceptive, it also has anti-inflammatory properties that expand its therapeutic utility. It acts via modulation of voltage-gated sodium channels, blocking muscarinic (M1, M3) and N-methyl-D-aspartate (NMDA) receptors under therapeutic concentrations.^19,20 This blockade effectively decreases peripheral nociceptor sensitization in addition to central hyperexcitability. Anti-inflammatory effects are achieved by decreasing circulating inflammatory cytokines.²¹ At higher, toxic concentrations, lidocaine will additionally interfere with toll-like receptors, voltage-gated calcium channels, 5HT-3 receptors, among others.¹⁹

Following administration, lidocaine will be metabolized into mono-ethylglycinexylidide and glycinexylidide by hepatic enzymes and excreted renally.¹⁹ For these reasons, any disease state affecting the liver and/or kidneys can lead to serious lidocaine toxicity. Lidocaine exhibits non-linear pharmacokinetics with a half-life of approximately 100 minutes when infused for <12 hours and 190 minutes when infused for >12 hours.¹⁹ It is not recommended to infuse lidocaine for greater than 24 hours or in patients weighing <40 kg.¹⁹ Effects tend to wear off 2–6 hours following the end of lidocaine infusion.²¹ It should also be noted that lidocaine has a narrow therapeutic window, meaning a slight increase in the plasma concentration of lidocaine at therapeutic levels can cause toxicity.

Lidocaine can be administered intravenously or cutaneous via patches. Typical IV infusions begin with a loading dose of no more than 1.5 mg/kg over 10 minutes, with maintenance of 1.5 mg/kg · hr. Lidocaine patches have recently gained approval from the FDA in concentrations of 1.8% and 5% by prescription for treatment of post-herpetic neuralgia.²² Serious toxicity can occur at plasma concentrations of 9–10 mg/ml.¹⁹ Common adverse effects include drowsiness, light-headedness, peri-oral numbness, tinnitus, nausea, and bradycardia.^19,21 Serious adverse effects suggesting toxicity include muscle twitching, loss of consciousness, convulsions, cardiac arrythmias, coma, and respiratory/cardiac arrest.¹⁹ Toxicity is related to total dose given in addition to the speed and duration of IV infusion.

Neuropathic Pain Syndrome

Neuropathic pain is defined by the International Association for the study of Pain (IASP) as pain secondary to a lesion or disease of the somatosensory nervous system.²³ Clinically, neuropathic pain syndrome manifests as constant or intermittent spontaneous (or evoked) pain of different qualities (burning, shooting, pricking, pins and needles or freezing). Patients also experience non-painful sensations such as dysesthesia or parasthesia.²⁴ At the molecular level, neuropathic pain syndrome is mediated through central and peripheral processes. In the peripheral, axonal injury results in fiber dysregulation such as fiber degeneration and changes to expression of voltage gated sodium channels. In the central nervous system (CNS), central sensitization occurs. Central sensitization is a maladaptive hypersensitivity to nociceptive stimuli. Overall, neuropathic pain can occur due to injury at the level of peripheral nervous system. Pain-generating central processes such as central sensitization propagate the chronic pain state observed clinically.²⁴ For treatment of neuropathic pain, the therapies with the strongest evidence include pregabalin, gabapentin, tricyclic antidepressants, and serotonin-noradrenalin-reuptake inhibitors (duloxetine, venlafaxine).

The evidence for the use of IV lidocaine for the treatment of neuropathic pain syndrome has mixed outcomes. Studies that were able to demonstrate benefits of IV lidocaine showed that the agent is most effective in the immediate post transfusion period. Fewer studies were able to demonstrate long-term advantages of IV lidocaine. The proposed mechanism of lidocaine in the treatment of neuropathic pain is two-folds. Systemic lidocaine is thought to decrease peripheral nociception sensitization and central sensitization through inhibition of the aberrantly expressed sodium channels.²⁵ In addition, IV lidocaine has anti-inflammatory properties, which reduces the release of inflammatory cytokines that mediate central sensitization.²⁶ In 2017, Zhu et al. produced one of the largest analyses of the effect of IV lidocaine on neuropathic pain.²⁷ The study consisted of 26 randomized control trials, which included patients with neuropathic pain secondary to several etiologies (diabetes, cancer, post-amputation and spinal cord trauma). The analysis divided the studies into two groups. One group consisted of studies that investigated the efficacy of IV lidocaine in the post transfusion period. The second group consisted of studies that investigated the use of IV lidocaine for long-term effects. Overall, the review demonstrated that IV lidocaine was more effective than placebo at relieving neuropathic pain in the immediate post-transfusion period (defined as just after infusion to up to 3 days post infusion).²⁷ However, the study was unable to demonstrate the persistent efficacy of lidocaine after repeated weekly infusion for four weeks.²⁷ Lidocaine was associated with more adverse effects, albeit mild in nature, than the placebo. These adverse effects included lightheadedness, peri-oral paresthesia, dry mouth and nausea.²⁷

A recent study noted a modest and transient (approximately up to 2 hours post transfusion) reduction in diabetic neuropathic pain after administration of IV lidocaine.²⁸ In the study, IV lidocaine at a dose of 5 mg/kg was administered and pain metrics were assessed before infusion and every 15 minutes over the course of 120 minutes. The same study attempted to use quantitative sensory testing (QST) to predict treatment response to IV lidocaine in patients with diabetic neuropathy.²⁸ QST measurements were performed using several metrics including Thermal Sensory Analyzer (TSA-II), Heat pain threshold (HPT), cold pain threshold (CPT) and warm detection threshold (WDT). The hypothesis was that patients with thermal and mechanical hypersensitivity phenotypes would be most responsive to IV lidocaine.²⁸ This is because aberrant sodium channel expression plays a particularly important role in the clinical manifestations of thermal and mechanical hypersensitivity. In the study, QST measurements were not predictive of response to treatment.

Another study demonstrated that intraoperative administration of IV lidocaine prevented the development of neuropathic elements of chronic postsurgical pain six months after gynecological surgery.²⁹ This result signifies that IV lidocaine might have a protective role against development of post-surgical neuropathic pain.

Moulin et al. demonstrated that administration of IV lidocaine did not provide long-term (defined as 4 weeks post infusion) benefits in the treatment of chronic peripheral neuropathic pain.³⁰ Furthermore, the study did not illustrate improvement in quality of life factors such as mood and physical functioning in the IV lidocaine group.³⁰ In addition, the study did not observe any immediate post-transfusion benefits in the IV lidocaine group.³⁰ Short-term effects were assessed by collecting pain scores six hours after IV lidocaine infusion.³⁰ Similarly, another randomized trial demonstrated that IV lidocaine at doses of 1 mg/kg or 5 mg/kg were equivalent to placebo in the reduction of neuropathic pain associated with failed back surgery syndrome (FBSS).³¹ Of note, the study revealed that the 5 mg/kg dose of lidocaine produced decreased pain scores for sharp, dull and deep pain. These pain items are similar to clinical descriptors of neuropathic pain; this suggests that higher doses of IV lidocaine might be effective at alleviating neuropathic pain associated with FBSS.

Lastly, a study that investigated the effects of IV lidocaine in post herpetic neuralgia (PHN) demonstrated that there was no difference in pain reduction between the IV lidocaine group with concentrations of 5 mg/kg and the placebo group.³² Interestingly, the study did note a reduction in total analgesia consumption and improved emotional and health status.³² In the study, emotional health was assessed using anxiety and depression diagnostic questionnaires. Results from Liu et al. demonstrates that perhaps IV lidocaine promises to play a role as an adjuvant agent in the multimodal pain management of neuropathic pain and might mitigate opioid consumption.

The mixed success in the aforementioned studies signify that IV lidocaine might have some clinical utility in the alleviating neuropathic pain immediately after transfusion and perhaps can play a preventative role. In some instances, intraoperative administration might prevent development of neuropathic pain.²⁹ The prophylaxis use of IV lidocaine for neuropathic pain associated with chronic postsurgical pain is discussed later in this analysis. Further research is needed to understand how these findings can be meaningfully translated to clinical practice.

Chronic Postsurgical Pain (CPSP)

Pain after surgery is expected and by most accounts should resolved within 1–3 months postoperatively.^33,34 When surgical pain persists three months after surgery, it is known as chronic postsurgical pain (CPSP). Chronic postsurgical pain is defined as pain that persists at the incision site or related areas of surgery for one month longer that it takes for most tissues to heal.³⁵ Using this definition, the onset of CPSP is usually defined as three months postoperatively. In addition, the pain in CPSP cannot be due to infection, malignancy or pre-existing conditions.³⁵ The incidence of CPSP is about 10%, although some studies have noted incidence rates as high as 40%.^35,36

Clinically, CPSP is an aching pain that has many neuropathic features. As such, patients often report hyperalgesia, dysesthesia and allodynia. In the acute postoperative period, patients describe familiar incision site pain. When the surgical pain evolves to CPSP, patient report a complex, multifaceted pain syndrome that becomes difficult to characterize and predict its onset.³⁷

At the macroscopic level, CPSP is due in part to iatrogenic nerve injury or nerve injury secondary to disease process (for which surgery was indicated).³⁵ At the molecular level, most of the cellular changes that facilitates the transition from acute to chronic pain occurs at the level of the dorsal horn of the spinal cord (SCDH) and is secondary to central sensitization.³⁵ In response to tissue damage and general nociceptive stimuli, glutamate is released. Glutamate then acts at specific receptors to facilitate the intracellular entrance of calcium. The influx of calcium results in toxic neuronal changes which manifest clinically as chronic persistence of postsurgical pain.³⁵

There is a paucity of evidence-based therapies for the treatment of CPSP. Some studies have focused on prevention of CPSP by addressing modifiable risk factors such as BMI or preoperative pain. Other studies have attempted to prevent CPSP by optimizing perioperative pain with agents such as non-steroidal anti-inflammatory drugs, NMDA-receptor antagonists, and antiepileptic and antidepressant drugs, however results have not been promising.³⁸

Given the elusive nature of the management of CPSP, many pharmacological interventions have been proposed; IV lidocaine is one such agent. As mentioned earlier in this analysis, there is evidence that IV lidocaine might have some utility in the management of neuropathic pain. As CPSP has neuropathic pain components, there has been great interest in the use of IV lidocaine for prevention and management of CPSP.

A meta-analysis of randomized controlled trials demonstrated that perioperative IV lidocaine infusion reduced the incidence of CPSP between 3–6 months after noncardiac surgery.³⁹ In the studies, IV lidocaine was administered around induction of anesthesia and the infusion was stopped at wound closure, 2 hours after arrival in the recovery area or latest 24 hours after surgery.³⁹ Likewise, Ibrahim et al. demonstrated that perioperative administration of IV lidocaine provided patients with both short and long-term benefits.⁴⁰ Patients in the study reported lower pain scores in the first 48 hours post-surgery, at time of hospital discharge and at three months post operation.⁴⁰ In the study, IV lidocaine was administered at a dosage of 2.0 mg/kg before induction of anesthesia, then at a rate of 3 mg/kg until the end of surgery. The study also illustrated that perioperative administration of IV lidocaine resulted in decreased hospital length of state and morphine consumption in the first 24 hours postoperatively.⁴⁰

Several studies have investigated the prevention of CPSP by adequately managing acute postoperative pain with perioperative administration of IV lidocaine. One study found that IV lidocaine might reduce postsurgical pain during early time points (defined as 1–4 hours) and intermediate time points (~24 hours).⁴¹ There was no evidence of utility of IV lidocaine at late time points (48 hours post operation). In the study, IV lidocaine was most effective at reducing postoperative pain during early times points in patients undergoing laparoscopic or open abdominal surgeries.⁴¹ This same study demonstrated that perioperative administration of IV lidocaine reduced length of hospital stay, postoperative nausea, intraoperative and postoperative opioid consumption. In a similar study, Rekatsina et al. demonstrated that perioperative administration of IV lidocaine was associated with reduction in opioid consumption and was protective against the development of CPSP.⁴² The study however was unable to demonstrate a concomitant decrease in pain scores in patients who received IV lidocaine.⁴² Interestingly, in a different analysis, Rekatsina et al. noted that pain scores 48 hours postoperatively correlated with pain scores at 3, 6 and 12 months after surgery.²⁹ Higher pain scores in the first 48 hours were correlated with higher pain scores at 3,6 and 12 months after surgery. This finding underscores the importance of adequately controlling acute surgical pain and haltering the transition to CPSP.

On the contrary, in a pooled analysis of randomized controlled trials, Chang et al. was unable to demonstrate the efficacy of perioperative IV lidocaine for the management of acute postsurgical pain. Although, the study suggested that perhaps IV lidocaine might play a role in attenuating the risk of developing CPSP.⁴³

A study that analyzed postoperative pain in patients undergoing radical gastrointestinal tumor surgery showed that perioperative administration of IV lidocaine provided positive effects on pain management and postoperative recovery/comfort.⁴⁴ Furthermore, the study followed subjects for 3 months to assess for development of CPSP. The study was able to demonstrate that IV lidocaine reduces the incidence of CPSP in patients who had underwent gastrointestinal tumor surgery.⁴⁴

The variations in the use of IV lidocaine for the management and prevention of CPSP underscore the complex nature of the transition from acute to chronic pain. The studies signify that while the evidence is of weak to moderate strength, IV lidocaine might play a role in the management of acute postsurgical pain. By aiding in the management of acute surgical pain, IV lidocaine promises to reduce the incidence of CPSP by eliminating an important risk factor (poorly managed acute postsurgical pain). IV lidocaine also appears to be most effective for certain surgical procedures including spinal fusion, open and laparoscopic abdominal surgeries and gastrointestinal tumor surgery.^29,40 The mechanism of pain in these surgeries seem to be secondary to systemic and local inflammation, in addition to release of cytokines that mediate peripheral and central sensitization.⁴⁰ Furthermore, it appears that IV lidocaine can be used in Enhanced Recovery after Surgery (ERAS) protocols, as it reduces opioid consumption and restores functionality after surgery.⁴² Further research is needed to identify the time points and surgeries for which IV lidocaine is most effective.

Evidence for the Use of Lidocaine Infusion for Fibromyalgia

Fibromyalgia is a chronic neurosensory syndrome characterized by diffuse musculocutaneous pain and tenderness. Fibromyalgia syndrome (FMS) often presents with a constellation of symptoms including fatigue, sleep disruptions, morning stiffness, and joint pains. FMS can cause psychiatric manifestations such as cognitive impairment, forgetfulness, depression, and anxiety.⁴⁵ The etiology of fibromyalgia is unknown, and the pathogenesis is not well understood. It is believed that genetic predispositions, environmental factors, and psychiatric triggers may play a role in the development of the syndrome. ACR diagnostic criteria for FMS includes the following: Widespread Pain Index(WPI) score ≥ 7, Somatic Symptom(SS) score ≥ 5, symptoms lasting for a minimum of three months without trauma or any other identifiable cause.⁴⁶ Treatment of fibromyalgia is focused on managing pain and psychiatric symptoms. Low dose TCAs (amitriptyline), SSRIs, and anticonvulsants (pregabalin) are often used as first line medications. Patients who do not respond to mono therapy may be treated with a combination of these medications in addition to cognitive behavioral therapy, physical therapy, and lifestyle modifications.

Randomized controlled trails have been done to assess the use of intravenous lidocaine infusions for pain management in FMS patients. These studies have yielded mixed result. Posner et al. conducted a prospective randomized pilot study to assess whether IV lidocaine infusions could improve symptoms in fibromyalgia patients who were already receiving standard conventional therapies.⁴⁷ The study consisted of 21 female patients mostly around 20 to 40 years of age who had been receiving various conventional therapies for about 1 year prior to the trial. These therapies included a regimen of amitriptyline, ketoprofen, alprazolam, naproxen, and/or topical capsaicin. At the beginning of the trial, 11 participants were randomly selected to receive once weekly 240 mg of IV lidocaine infusions for 4 weeks in addition to their respective conventional therapies. The remaining 10 participants, randomly assigned to the control group, did not receive IV lidocaine and were maintained on their conventional therapies. Visual analog scale for pain (VAS) and patient global improvement self-assessments were used to measure patient outcomes. At the end of the 4-week treatment period, patients who were treated with lidocaine therapy had a significantly greater improvement in VAS for pain than participants in the control group [P = 0.01]. The study concluded that periodic lidocaine infusions may provide clinical benefits for FMS patients already receiving standard therapies. Furthermore, a randomized placebo-controlled study would be necessary to elucidate the value of these benefits as well as the possible demographic of patients that would benefit the most from the treatment. Lastly, the pilot study suggested that oral mexiletine, a lidocaine analog efficacious in treating neuropathic pain, should be considered for use in future FMS trials.

6 years after Posner’s pilot study, McCleane et al. conducted a randomized double-blind cross over study to investigate possible analgesic effects of IV lidocaine infusions in FMS patients.⁴⁸ The study consisted of 75 male and female patients with a mean age of 45 who met the ACR diagnostic guidelines for FMS. Daily VAS score recordings and weekly patient reported analgesic pill consumption were used to measure patient outcomes. Results showed that after 5 weeks analgesic consumption of patients did not change after receiving lidocaine and placebo infusions. However, there was a statistically significant decrease in mean pain VAS score reported after the first 4 weeks of lidocaine treatment(p < 0.01). The study concluded that the administration of 960 mg IV lidocaine over a 24hr period produced analgesia in some patients with fibromyalgia, however more research should be done to determine the ideal dosage and duration of IV lidocaine treatment.

In 2009 Schafranski et al. conducted an open trial to assess the effect of IV lidocaine in pain and quality of life of FMS patients.⁴⁹ The trial consisted of 23 Brazilian patients with FMS. Patients were given 5 consecutive infusions of 2% IV lidocaine diluted with 500 mL of 0.9 % saline. Doses were increased daily in 1 mg/kg increments during the first 4 days. The dosage reached 5 mg/kg on day 4 and was maintained as the daily dose for rest of the trial (26 days). Fibromyalgia impact questionnaire (FIQ) score, a health Assessment Questionnaire (HAQ), and VAS were used to measure patient outcomes. Patient responses were documented before treatment, after the fifth lidocaine infusion, and after 30 days of treatment. There was a significant improvement in patient symptoms after the fifth infusion and after 30 days of treatment based on FIQ score, HAQ, and VAS (P = 0.04, 0.16, 0.05 respectively). The study concluded that IV lidocaine infusions were safe and effective in managing pain in FMS.

Another study, conducted in 2010 by Vlainich et al. evaluated the use of amitriptyline and IV lidocaine in FMS in comparison to amitriptyline use alone.⁵⁰ The randomized double-blind study consisted of 30 female patients with FMS. All participants received 12.5 mg of amitriptyline during the first week of the trial and thereafter were maintained on 25 mg of amitriptyline for the remainder of the trial (4 weeks). 15 patients were randomly selected for the intervention group and received 240 mg IV lidocaine in 125 mL of saline once a week for 4 weeks in addition to amitriptyline. The remaining 15 patients were assigned to the placebo group and received 125 ml 0.9% saline once a week for 4 weeks in addition to amitriptyline. Pain intensity and clinical manifestation (sleep disorders, fatigue, paresthesia, number of tender points) were recorded at the beginning and end of the study. The study concluded that 240 mg IV lidocaine once a week in addition to 25 mg of amitriptyline daily did not significantly improve pain or clinical manifestation in FMS patients in comparison to the use 25 mg of amitriptyline alone. A continuation of this study the following year also showed that there was no significant difference in plasma concentrations of serotonin, norepinephrine, and domaine in FMS patients receiving IV lidocaine and amitriptyline compared to patients who only received amitriptyline.⁵¹

Lastly, a very similar study was conducted by Giraldes et al. in 2016.⁵² The randomized double-blind study was conducted on 42 male and female FMS patients and lasted for 8 weeks. Like the previous two studies, this study compared the difference in pain intensity and clinical manifestation of FMS patients receiving amitriptyline and lidocaine therapy vs amitriptyline alone. However, this study also evaluated plasma IL-1, IL-6, and IL-8 levels of all patients. The results of the study suggested there was no significant differences in clinical manifestations or plasma cytokine levels between the two groups. Notably however, the pain intensity in the lidocaine group was significantly decreased in comparison to the placebo group (P = 0.01) during week 2 of the study, suggesting that lidocaine may have provided additional analgesic effects to the amitriptyline therapy.

Current treatment regiments for FMS are not always adequate in managing the chronic and sometimes debilitating pain experienced by patients. 4 out of the 6 studies discussed above suggest that IV lidocaine infusions, especially when used adjunctively with standard therapies, may provide analgesic benefits to FMS patients. Additional clinical trials should be conducted to ascertain the duration of symptom relief as well as the ideal lidocaine dosage and intervals needed to provide long term sustainable pain management in FMS patients.

Cancer Pain

In one randomized double blinded controlled cross-over study, Sjogren et al. examined the impact of lidocaine versus placebo on pain relief in ten patients (aged 44 to 68 years) with metastatic bone pain.⁵³ All ten patients were treated with intravenous lidocaine in a dosage of 5 mg/kg body weight infused over a period of 30 minutes or the same volume of isotonic saline. The reported primary outcome measure was visual analog scale (VAS) on a scale of 0–100 mm which was measured immediately before, during and up to 1 week after the infusion. Only five patients experienced more than 10 mm pain relief one hour after the infusion of lidocaine while two experienced more than 10 mm pain relief 1 hour after placebo (saline) infusion. There was no statistically significant difference in the change in mean pain score during the week before and after (p = 0.3438) the infusion. Also, four out of the ten participants experienced transient adverse events after lidocaine infusion, including drowsiness, nausea, circumoral paresthesia, euphoria, and confusion. The authors noted that although intravenous lidocaine may provide transient pain relief in the immediate period after infusion, their findings do not support any benefit of intravenous lidocaine over placebo for long term pain relief in patients with chronic pain due to bone metastases.⁵³ In another randomized doble blind controlled cross over study, Bruera et al. evaluated the effect of intravenous lidocaine on the neuropathic pain of eleven advanced cancer patients.⁵⁴ All eleven patients had pain due to direct tumor invasion of surrounding nerve plexus. Patients were randomized to receive either lidocaine, 5 mg/kg administered as an intravenous infusion over 30 min, or a placebo infusion. The outcome measure was visual analog scale (VAS) on a scale of 0–100 mm which was measured at 10, 20, 30, 40, 60, 90, and 120 min after the infusion. If patients did not experience significant pain relief, they were crossed over to the other treatment arm. Ten patients were crossed over to the opposite treatment 48 hr after the first period because no significant improvement occurred following the first infusion. There was no significant statistical difference between lidocaine and placebo infusion on reducing pain intensity and no differences in adverse effects reported. The authors highlight that intravenous lidocaine does not appear to have a significant analgesic effect on neuropathic cancer pain. A similar observation was reported in the study by Ellemann et al.⁵⁵ They conducted a randomized double-blind cross over trial on ten cancer patients with cutaneous allodynia to compare the analgesic effects of intravenous lidocaine (5 mg/kg body weight) with placebo (0.9% NaCl). Study findings demonstrated that neither lidocaine nor placebo significantly reduced pain intensity or additional analgesics requirements during the study period. The authors conclude that intravenous infusion of lidocaine cannot be recommended as routine pain treatment in cancer patients with cutaneous allodynia. More recently, a study was conducted in 2009 to compare the effectiveness of 4 mg/kg intravenous lidocaine with placebo (saline) for the management of opioid refractory cancer pain in fifty patients.⁵⁶ Infusions were administered double-blind and there were 14 days between the two infusions. Primary endpoints were magnitude of pain relief and the durability of response measured using a Numeric Analog Scale (NAS) (scale from 0 to 10, with 0 being no pain and 10 being worst imaginable pain) was done immediately before starting each infusion, immediately after completion of each infusion, and two hours after completion of the infusion. Pain intensity was also self-reported daily for the next 14 days after the infusions and a record of the frequency of rescue medications needed were also documented. Their results show that pain relief was significantly better (P < 0.001) and more patients reported a decrease in analgesic requirements (P = 0.0012) after lidocaine infusion than after placebo. The average duration of the analgesic effect after the single infusion was about 9 days and was significantly longer than that for placebo (P < 0.01). The most common side effects that were observed during infusion and in the peri-infusion period were perioral numbness, sedation, light-headedness, tinnitus, and headache. However, all side effects were self-limited and did not require any intervention except termination of lidocaine infusion in one patient. Study authors demonstrate that a single IV infusion of lidocaine was significantly superior to placebo in inducing pain relief than placebo infusion in opioid-refractory patients with cancer pain.⁵⁶

Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is defined as a regional pain disorder characterized by spontaneous swelling, vasomotor instability, patchy bone demineralization, and skin changes often occurring after trauma or surgery. Symptoms do not follow a dermatomal distribution or specific nerve territory, and the syndrome displays variable progression over time.⁵⁷ Currently, two subtypes of CRPS are recognized. Type 1 CRPS occurs in patients without evidence of peripheral nerve injury and represents about 90 percent of clinical presentations. Type 2 CRPS occurs in cases in which peripheral neve injury is present.^57,58 The pathogenesis of CRPS is currently unknown but thought to involve both the peripheral and central nervous system via mechanisms such as neurogenic inflammation and abnormal changes in pain perception.⁵⁹ The Budapest consensus criteria is used for the clinical diagnosis of CRPS and is as follows.^57,60

• Continuing pain that is disproportionate to any inciting event

• One symptom in three of the following four categories:

  • Sensory: Hyperesthesia and/or allodynia

  • Vasomotor: Temperature asymmetry and/or skin color changes and/or skin color asymmetry

  • Sudomotor/edema: Edema and/or sweating changes and/or sweating asymmetry

  • Motor/trophic: Decreased range of motion and/or motor dysfunction

• One sign at the time of evaluation in two of following four categories:

  • Sensory: hyperalgesia (to pinprick) and/or allodynia (to light touch)

  • Vasomotor: temperature asymmetry (>1°C) and/or skin color changes and/or asymmetry

  • Sudomotor/edema: Edema and/or sweating changes and/or sweating asymmetry

  • Motor/trophic: Decreased range of motion and/or motor dysfunction

• No other diagnosis that better explains signs and symptoms

Treatment for CRPS follows a multidisciplinary approach and involves a combination of first line medications such as NSAIDs, low dose TCAs (amitriptyline), anticonvulsants (gabapentin, pregabalin), and lidocaine, alongside physical and occupational therapy to restore function of the affected limb and decrease pain and disability. Patients with CRPS have also been known to benefit from psychosocial and behavioral therapy.

The use of IV lidocaine to treat CRPS has shown mixed results among reducing painful response to stimuli. In 2000, Wallace et al. conducted a randomized, double-blind placebo-controlled study in 16 subjects with CRPS 1 and 2 with substantial allodynia.⁶¹ Each patient received an IV infusion of lidocaine and diphenhydramine separated by 1 week. Diphenhydramine was selected as the control given it has similar side effects to lidocaine but does not affect pain thresholds. Infusions of IV lidocaine were delivered using a computer-controlled infusion pump that targeted stair-step increases in plasma levels of lidocaine of 1,2, and 3 μg/ml. Spontaneous and evoked pain scores alongside neurosensory testing (i.e., thermal and tactile thresholds, area of allodynia to punctate, stroking and thermal stimuli) within the painful area were measured at baseline and at each plasma level. The study showed no significant effect on the cool, warm, or cold pain thresholds at any lidocaine plasma level. A significant elevation of pain threshold for hot stimuli was observed at the highest plasma level. Furthermore, IV lidocaine resulted in significant improvement of pain in response to cool stimuli versus mechanical pain at the 3 μg/ml plasma level. A lesser effect was observed on spontaneous pain induced by stroking stimuli and no effect was seen on pain induced by punctate stimuli. With regards to side effects, lidocaine significantly produced more lightheadedness than diphenhydramine while sedation and dry mouth were similar in both groups. No other adverse effects were noted.

In 2006, Tremont-Lukats et al. conducted another double-blind, placebo controlled parallel study in 31 patients with pre-existing neuropathic pain using IV lidocaine but using a more sustained IV infusion.⁶² Patients were randomized to one of four treatment arms (saline placebo, or lidocaine at 1, 3, and 5 mg/kg/hr). The study solution was infused over 6 hours followed by observation for 4 hours. Pain was rated using a 0-to-100 mm visual analog scale (VAS). The primary endpoint was relief of spontaneous pain intensity and the individual differences between baseline and posttreatment VAS scores calculated as absolute pain intensity difference (PID). Overall, there was a significant difference in median PID% between the group treated with lidocaine 5 mg/kg/hr (−34.6) and placebo group (−11.96, P = 0.012). Effects began 4 hrs about the onset of treatment and lasted until the end of the study. No pain relief was observed at lower infusion rates of lidocaine. No serious adverse side effects were noted among the groups in the study.

A more recent study in 2020 analyzed the therapeutic effects of lidocaine injections in conjunction with oral citalopram in patients suffering from CRPS.⁶³ 150 patients affected by CRPS at the upper extremity were enrolled in the study between January 2010 and December 2014 and randomly assigned into three groups: group one was treated with regional nerve blocks of affected nerve territories using 5 cc of lidocaine without epinephrine and concurrent citalopram oral drops (7 drops (14 mg/0.35 mL) of citalopram for 3 days, then 10 drops (20 mg/0.5 mL) for 3 days and finally 15 drops (30 mg/0.75 mL) for 1 year), group two was treated with lidocaine nerve blocks and concurrent oral placebo therapy, and group three was treated with placebo for injections and oral therapy. Patients were followed-up at scheduled intervals (1, 6, and 12 months). Severity of CRPS was assessed using the Impairment Level Sum Score (ISS) at baseline and at regular intervals after treatment commenced. It was shown that combined treatment proved to be more effective (ISS 47.6 to 12.6) than local anesthetic alone (ISS 47.5 to 21.5) and to placebo (ISS 47.2 to 29.9). No adverse side-effects were observed in any groups throughout the study. The study demonstrates that intravenous lidocaine with oral citalopram may be an effective management strategy in patients with CRPS.

Table 1. Evidence for IV Lidocaine for Chronic Post Surgical Pain.

Author and Study year		Study design		Pathology		Intervention Group; dose, frequency of IV Lidocaine administration		Control group/Placebo		Any adjunctive Pain treatment?		Primary outcome (s) eg pain relief, pain scores		Duration of effects eg short term vs long term pain relief in hours/days/weeks		Secondary outcome eg QOL, biomarkers, functional ability, need for additional pain meds, additional opioid requirement, analgesic consumption/diminution, mood etc		Adverse effect
Bailey et al. 2018		Systematic review of randomized control trial		Chronic postsurgical pain (CPSP)		Varied based on study		Varied based on study		NA		Presence of procedure-related pain at 3 months or longer after surgery		Varied based on study		Pain intensity, adverse safety events, and local anesthetic toxicity were also assessed		None
Chang et al. 2017		Meta-analysis of randomized controlled trials		Chronic postsurgical pain (CPSP) after mastectomy		Varied based on stuy		Varied based on study		NA		Pain scores and analgesic consumption		Varied based on study		NA		Not documented
Dail et al. 2020		Randomized, double-blind trial		Chronic postsurgical pain (CPSP) after gastrointestinal tumor surgery		1.5 mg/kgIV lidocaine at 1.5 mg·kg from induction to to the surgical suture		sodium chloride 0.9%		2 μg/kg sufentanil + 4 mg tropisetron (total 100 mL)		Pain assessment at 2, 4, 7, 14, 30, and 90 days after surgery		Lower NRS scores in lidocaine group at 2, 4, 7, 14, 30, and 90 days postoperatively		Postoperative recovery, including the return of flatus, the bowl movement, the hospitalization days		Drowsiness and dry mouth
Ibrahim et al. 2018		Prospective randomized, double-blinded		Postsurgical pain after spinal fusion		IV lidocaine 2.0 mg/kg before induction of anesthesia, then IV lidocaine IV 3.0 mg until the end of surgery.		sodium chloride 0.9%		Ketorolac, tylenol and fentanyl perioperatively		postoperative Visual Analog Score (VAS) for 3 months		48 hours and 3 months post operation		Calculate postoperative (24 hours) morphine consumption		Not documented
Kranke et al. 2015		Systematic review of randomized control trial		Postsurgical pain various surgeries (namely laproscopic and open abdominal surgeries)		Varied based on study		Varied based on study		NA		Benefits and risks of perioperative IV lidocaine infusiony on pain and recovery in patients undergoing various surgical procedures.		Varied based on study		Reduction of length of hospital stay, postoperative nausea, intraoperative and postoperative opioid requirements		Not documented
Rekatsina et al. 2021		randomized, placebo-controlled, double-blind with 3 arms		Abdominal hysterectomy or myomectomy		1.5 mg/kg lidocaine over 10 minutes preoperatively then 1.5 mg/kg lidocaine intraoperatively until final stitch		sodium chloride 0.9%		N/A		Cumulative morphine consumption and postoperative pain at rest and cough		48 hours post operation		Anesthetic (sevoflurane) consumption, nausea/vomiting, postoperative sedation, time to first passage of flatus/stool, mobilization, sleep quality, satisfaction, discharge time		Hypotension, bradycardia

Table 2. Evidence for Fibromyalgia.

Author and Study year		Study design		Pathology		Intervention Group		Control group/Placebo		Adjunctive Pain treatment		Primary outcome		Duration of effects		Secondary outcome		Adverse effect
McCleane, Gary. 2013		Randomized, double-blind, placebo controlled cross-over study		Fibromyalgia related pain		960 mg of lidocaine over 24 hrs (1x)		“Placebo” infusion (1x)		“Analgesic” tablets		Pain relief		3 weeks post-treatment		Amount of Additional Analgesic Consumption*		Nausea, flu-like symptoms
Vlainich et al. 2011		Randomized, double-blind, prospective, comparative study		Fibromyalgia related pain		240 mg of lidocaine infused over 1 hr (4x) + 25 mg Amitriptyline QD		125cc Saline infusion over 1 hr (4x) + 25 mg Amitriptyline QD		Amitriptyline		Pain relief*		No significant pain relief observed		Plasma serotonin*, norepinephrine*, and dopamine*		None
Giraldes et al. 2016		Randomized, double-blind, prospective, comparative study		Fibromyalgia related pain		240 mg of lidocaine infused over 1 hr (4x) + 25 mg Amitriptyline QD		125cc Saline infusion over 1 hr (4x) + 25 mg Amitriptyline QD		Amitriptyline + Paracetamol PRN + Tramadol PRN		Pain relief*		No significant pain relief observed		Fibromyalgia Impact Questionnaire*, Plasma level IL-1, IL-6, and IL-8*		None
Vlainich et al. 2010		Randomized, double-blind, prospective, comparative study		Fibromyalgia related pain		240 mg of lidocaine infused over 1 hr (4x) + 25 mg Amitriptyline QD		125cc Saline infusion over 1 hr (4x) + 25 mg Amitriptyline QD		Amitriptyline		Pain relief*		No significant pain relief observed		# Tender points*, fatigue*, sleep disorder*, edema*, morning stiffness*		None
Schafranski et al. 2009		Prospective open trial		Fibromyalgia related pain		2 mg/kg (day 1), 3 mg/kg (day 2), 4 mg/kg (day 3), 5 mg/kg (Day 4 + 5) of lidocaine infused over 2 hrs		No control group		Maintained regular analgesic medication schedule		Pain relief		30 days post-treatment		Health Assessment Questionnaire*, Fibromyalgia Impact Questionnaire		None
Posner, Israel. 1994		Randomized, prospective, comparative study		Fibromyalgia related pain		240 mg of lidocaine infused over 30 minutes (4x)		Control group without lidocaine treatment		Maintained regular analgesic medication schedule including Alprazolam, ketoprofen, capsaicin cream, IV glutethimide, local trigger point injections		Pain relief		During 4 week treatment period		Patient global assessment*		Dizziness

Table 3. Evidence for IV Lidocaine for Cancer Pain.

Author and Study year		Study design		Pathology		Intervention Group		Control group/Placebo		Adjunctive Pain treatment		Primary outcome		Duration of effects		Secondary outcome		Adverse effect
Sharma et al. 2009		Randomized, double-blind, placebo-controlled, crossover study		Cancer related opioid refractory pain		2 mg/kg bolus + 2 mg/kg slow infusion over 1 hour (1x)		Saline infusion (1x)		Morphine (PRN rescue dose)		Pain relief		9.34 +/− 2.58 days		N/A		Tinnitus, perioral numbness, sedation, light headedness, headache
Ellemann et al. 1989		Randomized, double-blind, placebo-controlled, crossover study		Cancer related neuropathic pain		5 mg/kg infusion over 30 minutes (1x)		Saline infusion (1x)		Paracetamol, ketobemid, acetylsalicylic acid, ibuprofen, opiates (Regular scheduled regimen)		Pain relief*		No significant pain relief observed		N/A		Transient drowsiness
Bruera et al. 1992		Randomized, double-blind, placebo-controlled, crossover study		Cancer related neuropathic pain		5 mg/kg infusion over 30 minutes (1x)		“Placebo” infusion (1x)		Opioid (regular scheduled regimen)		Pain relief*		No significant pain relief observed		Mean number of extra PRN opioid doses*		None