alexa Lidocaine Infusion: A Promising Therapeutic Approach for Chronic Pain | OMICS International
ISSN: 2155-6148
Journal of Anesthesia & Clinical Research

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Lidocaine Infusion: A Promising Therapeutic Approach for Chronic Pain

Enas Kandil1*, Emily Melikman1 and Bryon Adinoff2*

1Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

2Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA

*Corresponding Authors:
Enas Kandil
Department of Anesthesiology and Pain Management
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd
Dallas, Texas 75390, USA
Tel: (214) 645-8450
Fax: (214) 645-8451
E-mail: [email protected]
 
Bryon Adinoff
Department of Psychiatry, University of Texas Southwestern Medical Center
5323 Harry Hines Blvd, Dallas, Texas 75390, USA
Tel: (214) 645-6975
E-mail: [email protected]

Received date: December 13, 2016; Accepted date: January 06, 2017; Published date: January 11, 2017

Citation: Kandil E, Melikman E, Adinoff B(2016) Lidocaine Infusion: A Promising Therapeutic Approach for Chronic Pain. J Anesth Clin Res 8:697. doi: 10.4172/2155-6148.1000697

Copyright: © 2017 Kandil E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Opioid abuse is a national epidemic in the United States, where it is estimated that a prescription drug overdose death occurs every 19 minutes. While opioids are highly effective in acute and subacute pain control, their use for treatment of chronic pain is controversial. Chronic opioids use is associated with tolerance, dependency, hyperalgesia. Although there are new strategies and practice guidelines to reduce opioid dependence and opioid prescription drug overdose, there has been little focus on development of opioid-sparing therapeutic approaches. Lidocaine infusion has been shown to be successful in controlling pain where other agents have failed. The opioid sparing properties of lidocaine infusion added to its analgesic and antihyperalgesic properties make lidocaine infusion a viable option for pain control in opioid dependent patients. In this review, we provide an overview of the opioid abuse epidemic, and we outline current evidence supporting the potential use of lidocaine infusion as an adjuvant therapeutic approach for management of chronic pain.

Introduction

Chronic pain is a debilitating condition that frequently requires treatment with high doses of opioids [1]. Chronic pain affects as many as 116 million adult Americans each year with an annual estimated cost of 635 billion dollars or more in medical costs and lost wages [2]. A generalized definition of chronic pain is “Pain that extends beyond the expected period of healing” [3]. The temporal definition of chronic pain varies, but it is often described as pain that persists for more than 3 months or more than 6 months. According to the NIH, pain is one of our most pressing national public healthcare problems and as a result chronic pain was named by the NIH as the “silent epidemic” [4]. The prevalence of chronic pain is hard to assess due to the complexity of chronic pain and variance in the definition [5].

Despite advances in the specialty of pain management, chronic pain continues to be on the rise. Results from the 2012 National Health Interview Survey showed that about 25.3 million U.S. adults (11.2%) had pain almost every day for the preceding 3 months, with a staggering 40 million adults (17.6%) complained of significant or severe pain [6]. In an effort to raise awareness of the prevalence of chronic pain, the American Pain Society endorsed pain as fifth vital sign in 1999. Since this endorsement, there has been an escalating rise in the number of opioid prescriptions for chronic non-cancer pain where opioids have become the standard of care for moderate to severe pain [6-9]. This shift in practice is clearly reflected in the dramatic increase in the medical use of the four most common used opioids for pain. Since 1997, for example, morphine use has increased by 73%, hydromorphone by 96%, fentanyl by 226% and oxycodone by 403% [10]. Despite their frequent use, opioids are only partially effective for short-term pain relief and have highly variable effectiveness in the long term relief (greater than 6 months) of pain [11].

Thus far, there has been little progress on for alternative noninvasive therapeutic strategies for chronic pain patients maintained on opioids. Rightfully so, much of the effort has been focused on improving patient compliance and prescription practices. Therefore, the approach to the current opioid abuse epidemic requires not only implementation of safer practice guidelines, but also novel therapeutic approaches. In the current review, we provide an overview of the magnitude of the current epidemic of prescription opioid abuse and outline the potential of lidocaine infusion as a viable therapeutic strategy for pain control in opioid dependent patients, where lidocaine infusion has the potential to markedly reduce the dependence on opioids both in the acute and chronic settings.

Opioid Use Disorder

In concurrence with the dramatic increase of opioid prescriptions, the incidence of opioid use disorder has risen. It is currently a major health problem in the United States with increasing morbidity and mortality due to misuse and abuse [12,13]. Recent reports have outlined the rise in opioid use, abuse, and overdose deaths due to prescription opioid medications [14]. Currently more than 1300 deaths due to overdose per year involve prescription opioids. Deaths from drug overdose are now the leading cause of death among persons aged 35 to 54, surpassing motor vehicle accidents [15]. The rise in opioid related problems led the FDA to propose a risk evaluation and mitigation strategy (REMS) for all long acting and immediate release opioids. The advisory panel also urged that education for safe prescribing of opioids be made mandatory for prescribing physicians [16]. A shift in clinical practice in the form of leniency in opioid prescription patterns has occurred gradually over last 20 or more years. This has resulted in a staggering increase in number of opioid sales, prescription drug abuse overdoses, and admission to substance abuse programs. Responding to these concerns places a burden on pain treating providers as they strive to properly address the patient’s needs while finding the right balance avoiding under prescribing, over-prescribing, while monitoring for misuse and abuse [17]. In 2015 all hydrocodone-containing products became schedule II drugs, making it more difficult to overprescribe and preventing many mid-level pain management providers for administering them without physician oversight. The impact this change will have on the issue remains to be seen.

Adverse effects of long-term opioid use

Long-term treatment with opioids can result in numerous and dangerous side effects including tolerance, addiction, dependency, immune modulation, and abnormal pain sensitivity [18]. Thus, whereas opioids were initially considered a solution for chronic pain, they have further exacerbated the problem [19]. A more cautious approach towards escalating doses of opioids is now being advised as evidence clearly suggests that prolonged use of high dose opioid is neither safe nor effective [18].

Emerging evidence reveals a more complex and wide range of side effects associated with long-term opioid use that are often overlooked. In addition to tolerance, there is also an increase in pain perception due to neuronal plasticity at the spinal dorsal horn level or more central in the rostroventral medulla and hippocampus [20]. Opioids in animal and humans have also been found to widely affect neuroendocrine functions. In a review by Vuong et al. most of the studies found seemed to highlight the acute changes in the neuroendocrine function despite chronic changes being more relevant. Opioids were found to increase growth hormone and decrease luteinizing hormone, leading to hypogonadism and weight gain [21]. The immune suppression effects of opioids have been known since 1890, when morphine was shown to decrease the resistance to bacterial infection in guinea pigs [22,23]. Immune cells express classic and novel opioid receptors, which are believed to be the site of the non-proliferative action of opioids [23,24], and long-term opioids have been shown to compromise optimal function of the immune response system. The clinical effects of opioids on the immune system are of particular concern in immunecompromised patients such as HIV infected patients and the elderly [25]. Opioids also increase the risk of pneumonia in older adults; the odds of developing pneumonia were found to be 1.38 in elderly opioid users (95% CI=1.08-1.76) versus non-opioid users. Despite the risk being highest in the first 14 days of opioid use, there was an increased risk of pneumonia with long acting opioids had a higher odds ratio (OR) (3.43 (95% CI=1.44-8.21) versus non-opioid users, as for shortacting opioids, OR was 1.27 (95% CI=0.98-1.64) versus non opioid users. In the same population the risk of pneumonia was not seen with other similar drugs such as benzodiazepines [26].

Chronic exposure to opioids increase pain and neuronal plasticity

In order to develop innovative treatment strategies for chronic pain, mechanistic understanding of the underlying pathology is paramount. A critical determinant of the pathophysiology of chronic pain is the maladaptive inflammatory response, which mediates and propagates chronic pain long after the initial insult subsides. At the spinal cord level, macrophages and lymphocytes have been shown to invade the dorsal root ganglia (DRG) after acute injury in rodents [27]. Macrophages and lymphocytes are essential for initial healing; however, problems arise when their presence persist at the DRG after healing. These cells secrete proinflammatory cytokines that generate spontaneous impulses in sensory nerves. Continuous and spontaneous firings of sensory nerves lead to the generation or progression of acute pain into chronic neuropathic pain [27]. Proinflammatory cytokines play a significant role in peripheral and central sensitization causing increased severity and duration of pain [28].

The chronic administration of opioids increases levels of circulating inflammatory cytokines interleukin 1B (IL1B), interleukin 6 (IL6), and tumor necrosis factor (TNF), all of which lead to hyperalgesia and increased pain [29]. Unfortunately, the chronic use of anti-inflammatory drugs to counteract this response is suboptimal and is associated with a marked increase in adverse effects including gastrointestinal, renal, and cardiovascular complications, with a resultant significant increase in morbidity and mortality. Therefore, there is a significant disconnecting between the escalating use of opioids for chronic pain and the toxic effects of opioids upon inflammatory processes (Figure 1).

anesthesia-clinical-research-central-sensitization

Figure 1: Role of opioids in development of central sensitization.

A plausible strategy to interrupt the vicious cycle of pain, inflammation and hyperesthesia is using efficacious, non-opioid medications for the treatment of chronic pain. This evidence calls for a newer pharmacotherapeutic approach that effects peripheral and central sites of action and could ultimately reverse this neuroplasticity. Such a drug could potentially relieve pain in opioid dependent patients and potentially be used as an adjuvant treatment in opioid abuse treatment programs to prevent relapse.

Systemic Lidocaine for Treatment of Neuropathic Pain

Lidocaine infusion has been used to treat some acute and chronic pain conditions. It was first used for treatment of neuropathic pain due to burns in 1943 [30]. Since then lidocaine has only been tested in a few studies on a small number of chronic pain patients, such as patients with diabetic neuropathy and complex regional pain syndromes [31,32]. In neuropathic pain, the pathophysiology involves the modification of expression of sodium channels leading to the plasticity of responses responsible for the generation of inappropriate pain [33]. Lidocaine attenuates peripheral nociceptors sensitization and central hyperexcitability through its sodium channel blocking action [33].

Lidocaine also has other modes of actions that explain its clinical role in treating peripheral and central pain. It has potent antiinflammatory properties that are more potent than traditional antiinflammatory drugs, with fewer side effects [34,35]. Through its antiinflammatory property, lidocaine infusion has been shown to reduce circulating inflammatory cytokines [34]. The role of inflammatory cytokines is recognized in the process of secondary hyperalgesia and central sensitization [27]. Lidocaine infusion is specifically effective in relieving the mechanical allodynia and hyperalgesia associated with chronic neuropathic pain. This process is believed to occur through a central mechanism of action (Figure 2) [36].

anesthesia-clinical-research-prevention-central-sensitization

Figure 2: Role of lidocaine in prevention of central sensitization.

Wallace et al. [37] evaluated the effects of I.V. lidocaine on sensory thresholds in complex regional pain syndrome (CRPS) patients. Patients received IV of lidocaine and diphenhydramine 1 week apart. The investigators measured pain scores and performed neurosensory testing. The results of this study indicated that intravenous lidocaine affects cold stimuli-related pain more significantly than mechanical pain. This demonstrates that lidocaine may primarily exert its effect on sensory processing as opposed to conduction blockade. Attal et al. [38] showed that intravenous lidocaine significantly reduced spontaneous pain and mechanical hyperalgesia. The same group also showed in a separate study [39] that lidocaine reduced neuropathic pain but did not change dynamic mechanical pain thresholds in non-neuropathic areas. Taken together, these results suggest lidocaine exerts a central modality-specific effect rather than a general pain-relieving effect. Importantly, these findings suggest that is critical to avoid reliance on visual analogue scale as a single method of assessing response to lidocaine.

In a meta-analysis, Tremont-Lukats et al. [40] noted that there is a wide variation of doses and durations of lidocaine administration for treatment of neuropathic pain, nevertheless the authors concluded that while low doses of lidocaine did not confer benefit over placebo, higher doses showed modest effect on the VAS. This meta-analysis highlights the need for standardized lidocaine administration protocols.

An important randomized, double blind, placebo-controlled clinical trial was controlled clinical trial was conducted in patients with neuropathic pain by Gottrup et al. [41]. In this study, patients were randomized to 0.24 mg/kg ketamine, to 5 mg/kg lidocaine or saline infusion, and the effect on on going or evoked pain (brush or pin-prick) was assessed. The results demonstrate that ketamine reduced both on going and evoked pain, while lidoaine only reduced pain-prick evoked pain. These results add to previous studies that highlight the complexity of the mechanism of neuropathic pain, and the need for carefully designing pain assessment techniques.

Finnerup et al. [42] assessed the role of lidocaine in spinal cord injury-associated neuropathic pain in a randomized control trial, again using a 5 mg/kg infusion protocol. The results confirmed previously observed effects of lidocain infusion on evoked pain in neuropathic pain patients, where lidocain infusion was found to decrease both evoked and spontaneous neuropathic pain. The authors concluded that the results are consistent with a central sodium-blocking effect of lidocain infusion.

Another interesting study was conducted by Viola et al43, which examine the long-term effect of lidocain infusion in patients with diabetic neuropathy. The investigators used the McGill Pain Questionnaire (MPQ) and found that lidocaine infusion markedly reduced both pain severity and quality at 14 and 28 days post infusion. This is a remarkable finding that highlights the long-lasting effect of lidocaine infusion in pain modulation that should be explored further in other indications.

In a retrospective multivariant analysis of patients that underwent lidocaine infusions, Carroll et al. [44] reported that both severity of pain and age of the patient influenced the likelihood of response to intravenous lidocaine infusion. They found that each point increase of pain (in an 11-point scale) increased the odds of responding to lidocaine by approximately 29%, while decade of life increased the odds by 36%. Not only are these results supportive of the role of lidocaine in severe pain, but also add age as an important characteristic of patients that are more likely respond to lidocaine, which can help guide future study designs.

Lidocaine infusion may be beneficial in other difficult to treat neuropathic syndromes such as fibromyalgia. A significant improvement was observed by Schafranski et al. [45] in the Fibromyalgia Impact Questionnaire FIQ scores, the Health Assessment Questionnaire, and visual analog scale (VAS) for pain. This improvement was sustained at 30 days after the last infusion. As for back pain, Park et al. [46] investigated the effects of intravenous lidocaine on neuropathic pain items of failed back surgery syndrome (FBSS) which the pain that occurs as result of abnormal impulse originated from the dorsal root ganglion and spinal cord. In this study, the authors demonstrated that 1 mg/kg, or 5 mg/kg of IV lidocaine, and placebo (attributed to small small size) improved pain in patients with neuropathic pain attributable to FBSS, however 5 mg/kg was significantly more effective. This study supports the lack of effect of low dose lidocaine infusion.

Tanen et al. [47] compared intravenous lidocaine to ketorolac for the emergency department treatment of acute radicular low back pain. Patients received either 100 mg lidocaine or 30 mg ketorolac intravenously over 2 min and changes in VAS scores was evaluated at 60 min and 1 week after treatment. In this study, the authors found that intravenous lidocaine did not improve pain associated with acute radicular low back pain. The difference between findings in this study and others previously discussed is not clear, but may be related to the protocol of infusion, or the type of pain. As outlined earlier, there is generally no consistent protocol for lidocaine infusion in the literature, which might underpin the discrepancy of observed results. The aforementioned studies are summarized in Table 1 [37-39,41-43,45-54].

Type of pain Study Condition treated Method Number of subjects Intervention Outcome Conclusion Adverse events
Central Attal et al. Neuropathic pain Randomized double blind Crossover, 3-wk washout 16 IV Lidocaine, 5 mg.kg-1, 30 min Intensity of spontaneous ongoing pain Lidocaine > Placebo Supraspinal mechanisms of lidocaine actions are demonstrated by its effectiveness in hemispheric lesions and central pain. Lightheadedness (44%)
Central Kvarnstrom, Spinal Cord Injury with Pain Below Injury Level Randomized, double-blind three treatment Crossover 10 IV lidocaine 2.5mg.kg-1, 40 min Ketamine (0.4 mg/kg IV) vs. Lidocaine (2.5 mg/kg IV) vs. Placebo (NS) over 40 min visual analogue scale (VAS). Sensory function, sensory tests and temperature thresholds. Lidocaine = Placebo No significant difference in response between both groups in VAS spontaneous pain scores and evoked allodynia. 4/10 Drowsiness, perioral paresthesia 5 somnolence, 1 dizziness, 2 out of body sensation, change in hearing, 2 paresthesias.
Peripheral Kvarnstrom Long lasting, Posttraumatic, neuropathic pain Randomized double blind, crossover 12 Ketamine (0.4 mg/kg IV) vs. Lidocaine (2.5 mg/kg) vs. placebo infused over 40 min Visual analogue scale (VAS) Warm and cold perception as well as heat and cold pain thresholds Sensibility to touch was also tested Lidocaine = Placebo No significant difference in VAS resting score between lidocaine and placebo; no significant difference in any evoked VAS scores 9 somnolence, 5 light-headedness,4 "out of body sensation", 3 nausea, 2 pruritus, 2 paresthesia.
Central Finnerup Spinal cord injury Crossover Double-blind Placebo controlled 24 IV Lidocaine 5 mg.kg-1 or placebo, 30 min Visual Analog Scale and quantitative sensory testing. Lidocaine > Placebo For pain at and below the level of injury irrespective of the presence or absence of evoked pain. 11 somnolence, 7 dizziness, 7 dysarthria, 7 lightheaded, 3 blurred visions.
Peripheral Tremont-Lukats Peripheral neuropathic pain Parallel 32 1, 3, and 5 mg.kg.hr-1, 6 h   Lidocaine > Placebo Placebo: 6/7 lidocaine (all doses): 21/23.
Peripheral Wallace Complex regional pain syndrome (CRPS I and II) with a prominent allodynia Crossover 1 week washout 16 IV lidocaine and diphenhydramine separated by 1 week by increases in plasma levels of lidocaine of 1, 2, and 3 µg.ml-1. Spontaneous and evoked pain scores, neurosensory testing within the painful area was measured. Lidocaine caused a significant elevation of the hot pain thresholds in the painful area and decreased response to stroking and cool stimuli in the allodynic area. Significant decrease in pain scores to cool stimuli at all plasma levels and the spontaneous pain at the highest plasma level. Delirium, nausea
Peripheral Wu Post-amputation pain: phantom limb or stump pain Crossover, 24-h washout 32 11 cases Stump pain alone, 9 cases phantom pain alone, and 11 with both IV Lidocaine 1 mg.kg-1 bolus, followed a 4 mg.kg-1 infusion vs. morphine 0.5 mg.kg-1 bolus 0.02 mg.kg-1 infusion vs. active placebo diphenhydramine, 10 mg bolus IV  40 mg infusion). All infusions lasted 40 min. Phantom and stump pain ratings, sedation scores, and 0-100 visual analog scale (VAS). Lidocaine > Placebo for stump but not phantom pain. Lidocaine = Morphine > Placebo in self-reported ratings of pain and satisfaction for stump pain. No adverse events reported. 1/32 withdrawn because of no pain before treatment.
Peripheral Attal  Pain-related to postherpetic neuralgia or traumatic nerve injury Randomized controlled double-blind, Crossover 22 IV Lidocaine 5 mg.kg-1 30 min vs. placebo while 16 patients subsequently received mexiletine on an open basis titrated from 400 to 1,000 mg per day (mean 737 mg/day). Spontaneous pain and Quantitative sensory testing. Change in mechanical dynamic allodynia and static (punctate) mechanical allodynia/hyperalgesia, but not thermal allodynia and hyperalgesia. Five of 22 patients were pain free with lidocaine, 11 of 22 had 50% reduction of spontaneous pain, and 12 of 22 had 33% reduction of spontaneous pain. Somnolence, lightheadedness and perioral numbness, which were present in 16 of 22 patients.
Peripheral Lemming PNP Whiplash disorder Crossover 33 IV Lidocaine 5 mg.kg-1 30 min Ketamine (0.3 mg/kg infused over 30 min) vs. Lidocaine vs. morphine vs. placebo (NS)   No significant difference in response between all treatment arms; all treatment arms did illicit partial response No reported adverse events
Peripheral Viola Diabetic PNP Previous responders to lidocaine Crossover Double-blind, Placebo controlled 4 week wash out 15 5 and 7.5 mg.kg-1, 4 h Lidocaine (5 mg/ml IV) vs. Lidocaine (7.5 mg/ml IV) vs. placebo (NS), 5ml/kg over 4 h x 1 each four week washout. Pain perception with McGill Pain Questionnaire (MPQ), hours of sleep, fasting blood glucose, and use of other pain-relieving medication. Lidocaine > Placebo Both doses of lidocaine decreased MPQ resting pain scores compared to placebo; effect lasted up to 28 days post-infusion. 1 patient reported lightheadedness with 7.5 mg/ml infusion
Peripheral Gottrup Nerve injury pain Randomized Placebo-controlled Crossover 20 IV infusion of ketamine (0.24 mg.kg-1), lidocaine (5 mg. kg-1), or saline for 30 min. Effects on spontaneous and mechanical evoked pain. Lidocaine only reduced evoked pain to repetitive pinprick stimuli. Ketamine was superior to lidocaine in reducing spontaneous pain. Sixteen patients (84%) experienced side effects from lidocaine, compared with 11% in the placebo group.
Peripheral Gormsen PNP chronic neuropathic pain (peripheral nerve injury) Randomized double-blind, placebo-controlled, three-way crossover 13 IV lidocaine 5 mg/kg vs. NS1209 (AMPA Receptor antagonist 322 mg total) vs. placebo (NS) over 4 h Spontaneous current pain and pain evoked by brush, pinprick, cold, and heat stimulation No difference in any treatment arms of spontaneous current pain, both NS1209 and lidocaine exhibited significant effects on resting pain compared to placebo Drowsiness, perioral paresthesia, headache, dizziness, fatigue, discomfort, dry mouth, nausea, muscle spasm.
Peripheral Schafranski PNP Fibromyalgia Open 23 IV lidocaine 2- 5 mg/kg 2 h. Five sequential intravenous 2% lidocaine infusions with rising dosages (2-5 mg/kg, days 1-5). Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire, and a visual analog scale (VAS) for pain were applied before the first lidocaine infusion, immediately after the fifth infusion, and 30 days after the fifth infusion. A significant improvement was observed in the FIQ scores after the fifth infusion and maintained after 30 days. No adverse events reported.
Peripheral Park Failed back surgery syndrome (FBSS) Randomized controlled double-blind Crossover, 2 weeks wash out 18 Patients received each of following intravenous infusion over 1 hour at 2 weeks apart: normal saline placebo, lidocaine 1 mg/kg, and lidocaine 5 mg/kg at 60 ml/hr initially, and then titrated infusion speed while keep the heart rate <130 rates/minor 160 mmHg >systolic blood pressure >85 mmHg. VAS and neuropathic pain questionnaire. Lidocaine = Placebo in controlling neuropathic pain- related to FBSS. No adverse events reported.
Peripheral Schipper  Peripheral neuropathic pain prospective, uncontrolled, open-label 16 IV lidocaine (5 mg.kg-1) within 30 min followed by long-term oral Oxcarbazepine (900-1,500 mg.day-1) Daily numeric pain scores for a period 28 days. Prematurely aborted due to ethical reason. Lidocaine infusion well tolerated with slight paresthesias and dizziness. 6 out of 16 participants (38%) discontinued oxcarbazepine treatment due to side effects.
Peripheral Tanen  Acute radicular back pain Randomized controlled double-blind Crossover 21 lidocaine, 20 ketorolac 100 mg lidocaine or 30 mg ketorolac intravenously over 2 min. A 100-mm visual analog scale (VAS) at Time 0 (baseline), and 20, 40, and 60 minutes and 1 week. Intravenous lidocaine failed to clinically alleviate the pain associated with acute radicular low back pain. 1 in the ketorolac and 1 in the lidocaine group withdrew at the 20-min time point due to a lack of improvement in symptoms.

Table 1. Summary of randomized trials of lidocaine infusion for neuropathic pain.

Evidence for use of systemic lidocaine for perioperative pain

Intravenous local anesthetic infusions have been used safely for pain control in the perioperative setting since the early 1950’s [55-57]. Lidocaine given intravenously in subanesthetic doses selectively blocks pain transmission in spinal cord [58], while peripherally decreasing spontaneous neuronal discharge from A delta and C fibers thus decreasing transmission of nociceptive pain [59,60]. Lidocaine has a high hepatic extraction ratio; plasma clearance is 10 ml/kg/min in patients with normal hepatic function and blood flow. Therefore, weight dosing should take into account hepatic function and hepatic blood.

Analgesia with lidocaine infusion is more effective when the intravenous lidocaine infusion is preceded by a 1-2 mg/kg bolus dose [61,62] which is likely due to achieving a faster therapeutic steady state concentration. Benefits of perioperative lidocaine infusion are range from improved VAS pain scores, opioid sparing effect and decreased hospital length of stay [62]. These benefits seem to be more important in abdominal procedures where lidocaine infusion facilitated faster return of bowel function and early hospital discharge [63,64]. These benefits suggest that lidocaine infusion is effective in relieving visceral pain, which is consistent with results seen in animal visceral pain models [65] These results are less pronounced in orthopedic procedures, cardiac surgery, and tonsillectomy cases [66]. Despite extensive research on perioperative lidocaine infusion, its benefits for non-visceral procedures, dosing, timing, and duration of infusion still need to be studied through more randomized controlled trials [66]. Table 2 outlines some of the most recent randomized controlled trials using intravenous lidocaine infusion for perioperative pain [67]. These studies are summarized in Table 2 [36,64,68-89].

Author Condition treated Study method Number of subjects Intervention Outcome Conclusion Adverse events
Koppert Major abdominal surgery Prospective, randomized, and double-blinded study 40 IV lidocaine 2% (bolus 1.5 mg/kg in 10 min followed by an IV infusion of 1.5 mg / kg/ h), vs. saline placebo. The infusion started 30 min before skin incision and was stopped 1 h after the end of surgery. Postoperative pain ratings (numeric rating scale of 0–10), morphine consumption (patient-controlled analgesia). Patients who received lidocaine reported less pain during movement and needed less morphine during the first 72 h after surgery -Opioid-sparing effect was most pronounced on the third postop day, IV lidocaine may have a true preventive analgesic activity, most likely by preventing the induction of central hyperalgesia. No adverse events reported.
Wu Laparoscopic cholecystectomy Double-blind and randomized. 100 Co-treatment with  dextromethorphan (DM) and intravenous lidocaine. (a) chlorpheniramine maleate (CPM) IM 20 mg and IV normal saline (N/S); (b) DM 40 mg IM and IV N/S (c) CPM 20 mg IM and IV lidocaine 3 mg/ kg/ h (d)DM40 mg IM and IV lidocaine All treatments were administered 30 min before skin incision. Visual analog scale pain scores at rest and during coughing, time to meperidine request, total meperidine consumption, and the time to first passage of flatus after surgery. DM group exhibited the best pain relief and fastest recovery of bowel function. Patients in the DM and lidocaine groups had significantly better pain relief than those in the CPM group. No adverse events-related to the lidocaine infusion, except an occasional arrhythmia in 1 patient.
Kuo Colonic surgery for colon cancer Randomized 60 Thoracic epidural (TE) and IV lidocaine. TE group received lidocaine 2 mg kg followed by 3 mg.kg/h epidurally and an equal volume of IV normal saline. The lidocaine group received the same amount of lidocaine IV and normal saline epidurally. The control group received normal saline via both routes. All started 30 min before surgery and were continued throughout. Cytokines IL6, IL8, and IL1RA. Return of bowel function .VAS pain scores at rest (A) and during coughing. TE and IV lidocaine lower opioid consumption, allow earlier return of bowel function and lesser production of cytokines. TE was superior than IV lidocaine during 72 h after colonic surgery. None reported, 3 patients had occasional bradycardia in the IV lidocaine group.
Kaba Laparoscopic colectomy Randomized placebo controlled 40 IV lidocaine (bolus injection of 1.5 mg/kg at induction of anesthesia, then a continuous infusion of 2 mg/kg/h intraoperative and 1.33 mg/kg /h for 24 h postoperatively Control: Saline. Postoperative pain scores, opioid consumption, fatigue scores time to first flatus, defecation, and hospital discharge Improvement in postop analgesia, fatigue, and bowel function. These benefits are associated with a significant reduction in hospital stay Nausea 4 patient in saline 1 patient in lidocaine group, Vomiting 2 saline group, none lidocaine group
Herroeder Abdominal surgery Double-blinded, randomized, and placebo- controlled trial 60 IV lidocaine bolus (1.5 mg/kg) followed by a continuous lidocaine infusion (2 mg/min) until 4 h postoperatively. Length of hospital stay, gastrointestinal motility, and the inflammatory response after colorectal surgery. Lidocaine significantly accelerated return of bowel function and shortened length of hospital stay by one day. No difference could be observed in daily pain ratings Wound healing and surgically related skin irritation in both lidocaine and placebo group
Martin Total hip arthroplasty Prospective two-center, randomized, double-blinded study 60 1.5 mg/kg IV bolus in 10 min then 1.5 mg /kg /h IV infusion or saline started 30 min before incision, stopped at 1h after skin closure. Postoperative pain and modified nociceptive pain threshold No significant difference between lidocaine and placebo on pain scores, pressure pain thresholds, area of hyperalgesia, and maximal degree of active hip flexion No adverse events reported.
Lauwick Laparoscopic cholecystectomy Randomized and observer-blinded 50 At induction of anesthesia the control group (n=25) received fentanyl 3 µg.kg-1 while the lidocaine group received fentanyl 1.5  µg.kg-1 and a bolus of lidocaine 1.5 mg.kg-1 followed by a continuous infusion of lidocaine 2 mg.kg-1.hr-1. The amount of fentanyl required in the PACU to establish and to maintain visual analogue scale pain scores <3. Reduction in opioid consumption in the PACU and intraoperative requirements of desflurane. No adverse events reported.
McKay Ambulatory Surgery Randomized double blind, placebo-controlled trial 67 At induction, all patients received 1.5 mg/kg of lidocaine by slow IV push. The lidocaine infusion (2 mg/kg/h or equivalent volume of saline as placebo), started immediately after induction of anesthesia and continued until 1 h after arrival in the PACU. Pain and time to discharge from recovery Length of postanesthesia care unit (PACU) stay did not differ between groups. Intraoperative opioid use was significantly less in the lidocaine group, both in the PACU and during the total study period but not after discharge. No adverse events reported.
El-Tahan Cesarean delivery Randomized 90 Lidocaine 1.5 mg.kg-1 IV. bolus 30 min before induction, followed by an infusion of 1.5 mg.kg-1.h-1 until 1 h after surgery (n=45), or saline placebo (n=45). Hemodynamic and hormonal responses. Perioperative lidocaine is safe and effective in attenuating the maternal stress response to surgery for cesarean delivery. No adverse events reported.
Yardine Transabdominal hysterectomy Randomized, placebo-controlled 60 Lidocaine + PCEA group received an IV bolus injection of 2 mg/kg lidocaine followed by a continuous IV infusion of 1.5 mg/ kg/h saline. PCEA group a bolus and infusion of saline. Surgery ensued 20 min after lidocaine bolus. At completion of surgery, the lidocaine and saline infusions were terminated Pain intensity, VAS scores at rest and during coughing in the first 8 hours. Immune reactivity during the postoperative period Improves immediate postoperative pain management and reduces surgery-induced immune alterations. No adverse events reported.
Baral Upper abdominal surgery Randomized 60 Lidocaine 2% (intravenous bolus 1.5 mg/kg followed by an infusion of 1.5 mg/kg/h), and 30 patients received normal saline. The infusion started 30 min before skin incision and stopped 1 h after the end of surgery. Postoperative pain intensity at rest and movement, analgesic requirement diclofenac assessed at the interval 15 minutes for 1 h then 4 hourly up to 24 h. Lidocaine decreases postoperative pain intensity, and reduces the postoperative analgesic consumption No adverse events reported.
Cui Thoracic surgery Randomized 40 Lidocaine (33.0 mcg/kg/min and Saline control in propofol-remifentanil-based anesthesia. Postoperative pain and morphine requirements. Pain scoring a four-point verbal rating scale, and a visual analogue scale. Morphine requirement in the PACU and morphine consumption via PCA. Reduction in morphine requirements, postoperative pain and intraoperative propofol use. No adverse events reported.
Bryson Abdominal hysterectomy Randomized, blinded placebo-controlled trial 90 IV bolus lidocaine of 1.5 mg/kg followed by an infusion of 3 mg/kg/hr, Control matching placebo. The primary outcome discharge from hospital on or before the second postoperative day (POD2). Secondary outcomes: opioid use, pain scores, quality of recovery, and recovery of bowel function Intraoperative administration of intravenous lidocaine did not reduce hospital stay or improve objective measures of analgesia and recovery. Subjective symptoms of local anesthetic toxicity (lightheadedness, tinnitus, dysguesia, etc.) were reported by 21 (46%) of the control patients compared with only 11 (26%) of the lidocaine patients.
Kang Inguinal herniorrhaphy Prospective, randomized, double-blind, placebo-controlled 64 IV bolus 1.5 mg/kg lidocaine followed by a continuous lidocaine infusion of 2 mg/kg per hour. Visual analogue scale pain scores, fentanyl consumption and the frequency at which analgesia Total fentanyl consumption (patient-controlled plus investigator-controlled rescue administration) and the total number of button pushes were significantly lower in the lidocaine group than in the control group. It is concluded that intravenous lidocaine injection reduced post-operative pain after inguinal herniorrhaphy, is easy to administer and may have potential to become routine practice for this type of surgery. The frequency of nausea was significantly lower in the lidocaine group than in the control group, but vomiting rates did not differ. Not reported any other complications.
Wongyingsinn Elective Laparoscopic Colorectal surgery Randomized Controlled Trial 60 Thoracic epidural analgesia (TEA group) or IV lidocaine infusion (IL group) (1 mg/kg per hour) with patient-controlled analgesia morphine for the first 48 hours after surgery. The primary outcome was time to return of bowel function. Postoperative pain intensity, time out of bed, dietary intake, duration of hospital stay, and postoperative complications were also recorded. Intraoperative and postoperative IV infusion of lidocaine in patients undergoing laparoscopic colorectal resection using an ERP had a similar impact on bowel function compared with thoracic epidural analgesia. No adverse events related to lidocaine. Readmission rate of 23% in both groups.
Wasiak Burn Randomized double-blind, placebo-controlled, cross-over trial 45 Lidocaine of 1.5 mg/kg/body weight followed by two boluses of 0.5 mg/kg at 5-min intervals followed by a continuous infusion. During the control condition, 0.9% sodium chloride was administered at an equivalent volume Primary end points included pain intensity as measured by verbal rating scale (VRS), time to rescue analgesia, opioid requests and consumption and overall anxiety and level of satisfaction. The clinical benefit of intravenous lidocaine for pain relief during burn wound dressing changes in terms of overall pain scores and opioid consumption was unremarkable. 29% (13 pts) complained of nausea and vomiting. 1 pt reported twitchiness.
Grady Laparoscopic Abdominal Gynecologic Procedures Randomized double-blind, placebo controlled, cross-over trial 50 Lidocaine 1mg/kg bolus in both groups followed by an infusion of lidocaine 2 mg/kg/hr. vs. placebo saline which was stopped 15-30 minutes before skin closure. 1. VAS pain score on postoperative day 3 2.Morphine requirements in PACU 3. Return of bowel function. Intraoperative lidocaine infusion improves postoperative pain levels and shortens time to return of bowel function 1 patient had protracted nausea and vomiting requiring readmission.
Wuethrich Laparoscopic renal surgery Randomized, double-blinded placebo-controlled 60 Lidocaine 1.5 mg kg bolus during induction of anesthesia, followed by an intraoperative infusion of 2 and 1.3 mg kg/h for 24 h postoperatively Primary outcome was the length of hospital stay. Secondary outcomes were readiness for discharge, opioid consumption, sedation, incidence of postoperative nausea and vomiting (PONV), return of bowel function and inflammatory and stress responses Perioperative lidocaine administration over 24 h did not influence the length of the hospital stay, readiness for discharge, opioid consumption, return of bowel function or inflammatory and stress responses 2 patients in lidocaine group had a surgical complication (need for pyelonephrostomy), and another wound infection. Postoperative delirium in one patient in the control group. No cardiac or pulmonary complications were observed
Grigoras Breast surgery. Randomized, double-blinded placebo-controlled 36 Lidocaine 1.5 mg/kg bolus followed by a continuous infusion of lidocaine 1.5 mg/kg/h or an equal volume of saline. The infusion was stopped 1 hour after the skin closure Pain scores and analgesic consumption at 2, 4, 24 hours, and then daily for 1 week postoperatively. Three months later, patients were assessed for persistent postsurgical pain (PPSP) and secondary hyperalgesia. perioperative lidocaine decreases the incidence and severity of PPSP after breast cancer surgery. Prevention of the induction of central hyperalgesia is a potential mechanism. No adverse events reported.
De Oliveira Ambulatory Laparoscopic Surgery Randomized, double-blind, placebo-controlled 70 Lidocaine 1.5 mg/kg bolus followed by a 2 mg/kg/h infusion until the end of the surgical procedure, or an equal volume of saline Primary outcome was the Quality of Recovery 40 questionnaire at 24 hours after surgery. A 10-point difference represents a clinically relevant improvement in quality of recovery based on a previously reported values on the mean and range of the Quality of Recovery-40 score Lidocaine group had a significant better quality of recovery than the control group. There was an inverse relationship between opioid consumption and the quality of recovery No adverse events reported.
Kim Lumbar surgery Randomized, placebo-controlled clinical trial 51 IV lidocaine infusion 1.5-mg/kg bolus followed by a 2-mg/kg/h infusion until the end of the surgical procedure versus normal saline infusion as a placebo. The primary outcome was the visual analog scale (VAS) (0-100 mm) pain score at 4 hours after surgery. The secondary outcomes was the frequency of the button (FPB) of PCA being pushed and fentanyl consumption after surgery The VAS scores and fentanyl consumption were significantly lower in  the lidocaine  group compared to placebo at 48 h after surgery (p<.05). Total fentanyl consumption, total FPB, length of  hospital stay, and satisfaction scores were also significantly lower in lidocaine group compared with placebo. No adverse events reported.
Tauzin-Fin Laparoscopic nephrectomy A two-phase observational study 47 I.V. lidocaine (1.5 mg/kg/h) was introduced, in the second phase, during surgery and for 24 h post-operatively. Post-operative pain scores, opioid consumption and extent of hyperalgesia were measured. Time to first flatus and 6 min walking test (6MWT) were recorded Intravenous (I.V.) lidocaine reduced post-operative morphine consumption and improved post-operative pain management and post-operative recovery after laparoscopic nephrectomy which contributed to better post-operative rehabilitation. No major adverse events reported.
Farag Complex spine surgery Randomized controlled 116 IV lidocaine (2 mg/kg/hr.) or placebo during surgery and in the PACU.  Pain scores, verbal response scale.
Quality of life at 1 and 3 months using the acute short-form (SF) 12 health survey.
IV lidocaine significantly improves postoperative pain after complex spine surgery. No serious adverse events reported.
Tikuišis Hand assisted laparoscopic colon surgery Randomized controlled 64 IV lidocaine (dose unclear) vs. placebo Visual analogue scale (VAS) scores at 2, 4, 8, 12, and 24 h after surgery. Lidocaine superior to placebo in pain score, return of bowel function, and length of hospital stay No significant  adverse events.
Peng Supratentorial craniotomy Randomized controlled 94 IV lidocaine (1.5 mg/kg) bolus and infusion at a rate of 2 mg/kg/h until the end of surgery Numeric rating scale (NRS) in PACU. Lidocaine significantly decreases the proportion of patients with acute pain after supratentorial tumor surgery in the PACU. No significant adverse events.
Zengin Elective laparotomy Randomized controlled 80 4 groups Group C, placebo capsules and normal saline infusion Group L, placebo capsules and lidocaine 1 mg⁄kg intravenous bolus dose followed by 2 mg⁄kg⁄h group P, 150 mg oral pregabalin and normal saline infusion perioperative; and group PL, 150mg oral pregabalin and lidocaine 2 mg⁄kg⁄h.   Visual analogue scale (VAS) scores, analgesic consumption, side effects, time to mobilization, time to first defecation, time to discharge and patients' satisfaction Oral pregabalin and perioperative intravenous lidocaine infusion decreased postoperative VAS scores.  Oral pregabalin decreased morphine requirement. Intravenous lidocaine infusion hastened gastrointestinal motility and mobilization, and decreased the incidence of nausea No significant adverse events.

Table 2. Summary of randomized controlled trials of lidocaine infusion for perioperative pain.

Evidence for use of systemic lidocaine for cancer pain

Despite advances in cancer treatment, there continues to be barriers for quality end of life pain management care for cancer patients. Prevalence of cancer pain varies from 33% to 64%, depending on disease stage and prognosis, and is usually rated as moderate to severe [90]. Because of the growing appreciation for the potential role of intravenous lidocaine infusion in treating refractory pain, lidocaine has been used to treat opioid refractory cancer pain in adults and children with very few and mostly self-limiting side effects [91,92]. However, the randomized controlled trials in this area are scant. In a recent phase two pilot randomized controlled cross over clinical trial, lidocaine infusion was successful in treating opioid refractory cancer pain with a mean duration of analgesia more than the half- life of lidocaine (9.34 days) ± 2.58 after a single infusion [93].

Intravenous lidocaine infusion is an appealing option in opioid refractory cancer pain as it is inexpensive, and easy to administer. In addition, lidocaine analgesia is no associated tolerance with repeated administration, does not depend on source of pain, can be repeated as needed, and allows for discontinuation of other analgesic with consequent drug related side effects [94]. However, lidocaine infusion is not mainstream treatment for opioid refractory cancer pain as phase 4 clinical trials are needed to establish guidelines for treatment in opioid refractory pain [93]. Lidocaine toxicity at small doses has been reported in terminally ill patients despite normal liver and renal function, suggesting altered pharmacodynamics [95]. These studies are summarized in Table 3 [93,96-98].

Author Condition treated Study method Number of subjects Intervention Outcome Conclusion Adverse events
Buchanan Opioid refractory metastatic renal cell cancer Case report 1 case Lidocaine 1.8 mg/kg at a rate of 0.8 mg/kg/h. Treatment of opioid refractory cancer pain Lidocaine improved patients pain and end of life care Infusion needed to be repeated after 3 weeks due return of pain.
Ferrini Neuroectodermal tumor Breast cancer Rectal adenocarcinoma Retrospective cases series 6 cases Lidocaine ranging from 10-80 mg/h. 2 cases subcutaneous, 4 case intravenous Treatment of opioid refractory cancer pain Lidocaine improved patients pain and end of life care Lightheadedness which improved after dose reduction.
Thomas Refractory cancer pain Retrospective chart review 0f 768 hospice patients 82 receiving intravenous lidocaine, 61 patients data was analyzed. Lidocaine 1-2 mg/kg bolus followed by an infusion of 1mg/kg/h in 56 patients. 5 patients had no bolus Treatment of opioid refractory cancer pain 50 patients had major improvement in pain out of which 44% had complete resolution of their pain 5 patients had partial response 6 patients had no benefit No serious side effects reported, 26% had lethargy and somnolence.
Sharma Refractory cancer pain Randomize double blinded placebo controlled crossover 50 Lidocaine 2 mg/kg bolus over 20 min. followed by 2 mg/kg over 1 h. Magnitude and duration of pain relief. Significant improvement in pain relief of mean duration of 9.3 ± 2.58 days Significant reduction in analgesic requirements. Self-limited side effects in the form of perioral numbness, tinnitus, sedation, lightheadedness and headache.

Table 3. Summary of case reports and studies of lidocaine infusion for cancer pain.

Conclusion

In the current review, we provide a comprehensive overview of the large body of literature outlining the mechanism of action and role of lidocaine infusion in treatment of pain. Although the literature reviewed strongly supports the role of lidocaine infusion as a pain management modality, the studies reviewed vary widely in study design, patient populations, methods of pain testing, and outcomes.

Lidocaine is an amide local anesthetic with a wide range of mechanisms of action. Lidocaine, when given in a low dose intravenous infusion, successfully provides pain relief in several chronic painful conditions that have failed other treatment modalities. Lidocaine infusion is an inexpensive and relatively easily administered treatment that has been safely used with very few side effects. Lidocaine as an infusion has opioid sparing effects, blocks sodium channels, uncouples G protein, blocks NMDA receptor, reduces circulating inflammatory cytokines, and prevents secondary hyperalgesia and central sensitization.

Lidocaine infusion has been studied extensively for perioperative pain control with contradicting outcomes. These conflicting results are likely due to the limited number of patients in each study and due to the lack of standardization of study techniques. There is a paucity of studies that have assessed differences in dose, infusion protocol and adverse effects of lidocaine administration. Lidocaine infusion has been successful in treating opioid refractory pain in cancer pain patients; however randomized controlled trials are lacking. Despite its opioid sparing effect, the role of lidocaine infusion in modulating opioid dependence and addiction in patients with chronic pain is yet to be determined. Several unanswered questions need to be addressed before lidocaine infusion can be used as a mainstream treatment; including the precise dosing regimen, infusion duration and the appropriate patient selection criteria. If proven effective, lidocaine infusion can potentially be an important tool for treatment of opioid dependence.

Conflicts of Interest

The authors do not have any conflicts of interest

Acknowledgments

The support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health" under award Number KL2TR001103.

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