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Multiple lidocaine infusions for relief of neuropathic pain: systematic review and meta-analysis

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors.

The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

INTRODUCTION

Chronic pain can be broadly classified into three categories of causation: due to a tissue disorder or injury (nociceptive); due to a somatosensory disorder or injury (neuropathic pain), or a combination of nociceptive and neuropathic pain (mixed pain). Neuropathic pain due to an injury or disease affecting the somatosensory system11. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630-5. continues to be a challenging clinical problem because the pain is often severe and incapacitating22. Gilron R, Watson CPN, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ 2006; 175: 265-75. . Population studies indicate that its prevalence ranges from 7 to 10%, based on validated screening tools33. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006; 7: 281-9. .

The effectiveness of certain antidepressants, anticonvulsants, opioid analgesics, and various agents has been established in systematic reviews44. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2012; 85: S3-14. and several evidence-based guidelines for the management of neuropathic pain55. Attal N, Cruccu G, Baron R, et al. European Federation of Neurological Societies. EFNS Guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17: 1113-23. . However, these studies consistently show that less than 50% of the patients achieve adequate control of pain in the short term, and a recent prospective study, of observational results, showed that only about a quarter reached clinically significant improvement in pain and function in the long term, after up to 12 months of follow-up 66. Moulin DE, Clark AJ, Gordon MD, et al. Long term outcome of the management of chronic neuropathic pain – a prospective observational study. J Pain 2015; 16: 852-61. .

Lidocaine has the ability to block sodium channels. Therefore, it can be expected to act only in the subset of neuropathic symptoms mediated by the abnormal activation of the sodium channels77. Attal N, Rouaud J, Brasseur M, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology. 2004;62:218–225. .

Intravenous infusions of lidocaine in the dose of 5 mg kg-1 provide significant relief of pain in comparison with a placebo, for up to six hours after the infusion, with a peak of 1 to 2 hours after the infusion88. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev 2005; 19: CD003345. .

Given the short-term effect of systemic lidocaine and the intravenous route, it would not be practical for the management of pain in the long term. Given this, it is justified to evaluate, in the long term, the role of the intravenous infusions of lidocaine in the treatment of chronic neuropathic pain.

OBJECTIVE

The goal of this assessment is to identify the efficacy and safety of multiple infusions of lidocaine in the relief of pain in patients with neuropathic pain, in comparison with a placebo.

METHODS

The clinical question is: What is the impact of therapy with multiple infusions of lidocaine on outcomes of pain relief for up to four weeks and adverse events in the treatment of patients with neuropathic pain, compared with a placebo?

The eligibility criteria for the studies are:

  1. An adult patient with neuropathic pain due to any cause;

  2. Treatment with multiple applications of intravenous lidocaine compared with placebo therapy;

  3. Outcomes - pain relief for up to four weeks and adverse events;

  4. Excluded outcomes - evaluation of relief of pain in the period immediately after the infusion, i.e., soon after the infusion and up to 1-3 days after the infusion;

  5. Randomized clinical trial;

  6. No time or language restrictions;

  7. Full text available for access.

The search for evidence was carried out the virtual databases Medline/Pubmed using the following search strategy - (Intravenous OR infusions OR infusion OR parenteral OR systemic) AND (lidocaine OR lignocaine) AND (Pain OR fibromyalgia OR Neuralgia OR Peripheral Nervous System Diseases OR Neuromuscular Diseases OR Nervous System Diseases OR Neuropathic Pain OR Neuralgia, Postherpetic OR Diabetic Neuropathies OR Peripheral Nerve Injuries ) AND Random*; and on CENTRAL / Cochrane with the search strategy - (Intravenous OR infusions OR infusion OR parenteral OR systemic) AND (lidocaine OR lignocaine) AND (neuropathic pain). The search in these databases was performed up to the month of March 2020, and a systematic review was performed according to the PRISMA recommendations.99. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Disponível em: www.prisma-statement.org.
www.prisma-statement.org...

We extracted the following data from the studies: name of the author and year of publication, study population, intervention and comparison methods, pain scores as mean (SD), the absolute number of adverse events, and time of follow-up.

Randomized clinical trials will have their risk of biases analyzed according to the following criteria: randomization, blinded allocation, double-blinding, losses, prognostic characteristics, presence of relevant outcome, time for the outcome, the method for outcome measurement, sample size calculation, early interruption, presence of other biases.

The results were expressed by the difference of the mean (SD) of the pain scores, or the risk of adverse events between therapy with multiple lidocaine infusions and a placebo treatment. No distinction was made on the severity of each adverse event. The confidence level adopted was 95%.

The results of the studies included will be meta-analyzed by RevMan 5.31010. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. , and the difference in overall risk or mean will be the final measurements used to support the synthesis of evidence that will answer the clinical question of this review.

The quality of evidence will be graded as high, moderate, low, or very low using the GRADE instrument1111. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University, 2015 (developed by Evidence Prime, Inc.). Available from gradepro.org.
gradepro.org...
and taking into account the risk of bias, the presence of inconsistency, vagueness or indirect evidence in the meta-analysis of the outcomes (pain relief and adverse events), and the presence of publication bias.

RESULTS

The search for evidence retrieved 1,031 papers, of which 30 studies on intravenous lidocaine therapy were selected based on their title and abstract, for the treatment of patients with various etiologies of neuropathic pain, in comparison with a placebo. The 30 studies were accessed for analysis of the full text. Of the 30 studies, three (parallel RCTs) were selected, for meeting all the eligibility criteria, to support this assessment1212. Vlainich R, Issy AM, Sakata RK. Effect of intravenous lidocaine associated with amitriptyline on pain relief and plasma serotonin, norepinephrine, and dopamine concentrations in fibromyalgia. Clin J Pain 2011;27:285-8. PMID: 21178598

13. Albertoni Giraldes AL, Salomão R, Leal PD, Brunialti MK, Sakata RK. Effect of intravenous lidocaine combined with amitriptyline on pain intensity, clinical manifestations and the concentrations of IL-1, IL-6 and IL-8 in patients with fibromyalgia: A randomized double-blind study. Int J Rheum Dis. 2016;19:946-953. PMID: 27309886
- 1414. Kim YC, Castañeda AM, Lee CS, Jin HS, Park KS, Moon JY. Efficacy and Safety of Lidocaine Infusion Treatment for Neuropathic Pain: A Randomized, Double-Blind, and Placebo-Controlled Study. Reg Anesth Pain Med 2018;43:415-424. PMID: 29381569 ; the grounds for exclusion and the list of studies excluded are available in the references, Figure 1 ANNEXES The selection of retrieved from the virtual databases of scientific information is detailed in the flowchart below: FIGURE 1. FLOWCHART TABLE 4. PAPERS EXCLUDED AND REASON FOR EXCLUSION AFTER READING THE FULL TEXT Study Reason for exclusion Moulin DE, et al. 2019 Crossover RCT without data from the first phase , and Table 5 in the ANNEXES ANNEXES The selection of retrieved from the virtual databases of scientific information is detailed in the flowchart below: FIGURE 1. FLOWCHART TABLE 4. PAPERS EXCLUDED AND REASON FOR EXCLUSION AFTER READING THE FULL TEXT Study Reason for exclusion Moulin DE, et al. 2019 Crossover RCT without data from the first phase .

The population included is of 110 patients with neuropathic pain who underwent therapy with infused lidocaine over a period of one hour, once a week, for 4 weeks (N=55), compared to a placebo (n =55), and followed-up to measure the outcomes of pain relief and adverse events after 4 weeks ( Table 1 ).

TABLE 1
CHARACTERISTICS OF THE STUDIES INCLUDED

Regarding the risks of bias of the 3 studies included1212. Vlainich R, Issy AM, Sakata RK. Effect of intravenous lidocaine associated with amitriptyline on pain relief and plasma serotonin, norepinephrine, and dopamine concentrations in fibromyalgia. Clin J Pain 2011;27:285-8. PMID: 21178598

13. Albertoni Giraldes AL, Salomão R, Leal PD, Brunialti MK, Sakata RK. Effect of intravenous lidocaine combined with amitriptyline on pain intensity, clinical manifestations and the concentrations of IL-1, IL-6 and IL-8 in patients with fibromyalgia: A randomized double-blind study. Int J Rheum Dis. 2016;19:946-953. PMID: 27309886
- 1414. Kim YC, Castañeda AM, Lee CS, Jin HS, Park KS, Moon JY. Efficacy and Safety of Lidocaine Infusion Treatment for Neuropathic Pain: A Randomized, Double-Blind, and Placebo-Controlled Study. Reg Anesth Pain Med 2018;43:415-424. PMID: 29381569 , 2 of them presented uncertainty in the blinded allocation and two uncertainty in double-blinding. Two did not carry out analysis by intention to treat ( Table 2 ).

TABLE 2
NEUROPATHIC PAIN THERAPY WITH MULTIPLE LIDOCAINE INFUSIONS. DESCRIPTION OF THE RISK BIASES OF THE STUDIES INCLUDED

All studies assessed the outcome of pain relief for up to four weeks after multiple infusions and adverse events ( Table 3 ). The overall risk of bias among the studies is moderate.

TABLE 3
STUDY RESULTS FOR THE OUTCOME OF DEATH.

The three studies allowed the assessment of the outcome of neuropathic pain relief for up to 4 weeks, comparing infused lidocaine once a week, for 4 weeks, with a placebo (saline solution 0.9%); there was no difference in pain reduction between the two groups (MD -0.96; 95% CI -2.02 to 0.11; p = 0.08, I2= 33%), Figure 2 .

FIGURE 2
COMPARISON FOREST PLOT: 1 LIDOCAINE VERSUS PLACEBO, OUTCOME: 1.1 PAIN RELIEF AFTER 4 INFUSIONS (ONCE A WEEK) OF LIDOCAINE.

ADVERSE EVENTS

The three parallel RCTs included in this review do not allow to assess the safety of IV lidocaine due to a lack of data; therefore, the result of a systematic review with meta-analysis1515. Zhu B, Zhou X, Zhou Q, Wang H, Wang S, Luo K. Intra-Venous Lidocaine to Relieve Neuropathic Pain: A Systematic Review and Meta-Analysis. Front Neurol 2019 18;10:954. PMID: 31620064 , which included crossover studies that evaluated the relief of neuropathic pain (various etiologies) soon after the infusion and up to 1-3 days after the infusion will be used to answer the clinical question. Dizziness, drowsiness, perioral paresthesia, nausea, headache, dysarthria, dry mouth, metallic taste were some of the most common side effects observed in the studies included in this meta-analysis. Three hundred and seventeen patients received lidocaine, while 318 received a placebo. One hundred and thirty-two patients (41.6%) in the lidocaine group experienced adverse events, in comparison with 53 patients (16.7%) in the placebo group (increase in the absolute risk of 25%, 95% CI 18.1 to 31.7%; NNH = 4, 95% CI 3 to 6).


QUALITY OF EVIDENCE: OUTCOME OF PAIN RELIEF IN 4 WEEKS

SYNTHESIS OF EVIDENCE

In patients with neuropathic pain, infused lidocaine once a week, for 4 weeks, compared with a placebo (saline solution 0.9%) showed no difference in pain reduction in up to 4 weeks. Moderate quality of evidence.

Intravenous lidocaine increases the risk of adverse events (any) in 25% (95% CI 18 to 31%) in comparison with a placebo (saline solution 0.9%), and it is necessary to treat 4 patients for one to present an adverse event (95% CI 3 to 6). Low quality of evidence.

Dizziness, drowsiness, perioral paresthesia, nausea, headache, dysarthria, dry mouth, metallic taste are some of the most common side effects.

DISCUSSION

A large number of trials tested IV lidocaine for neuropathic pain; however, most included few patients (<30) and reported the use of a diverse range of dosages and times of infusion. These studies also assessed pain scored after several periods of time, and most evaluated the efficacy of IV lidocaine in the period immediately post-infusion and in a single dose, while only 4 assessed lidocaine transfused over a period of 4 weeks, to study its persistent effect in the long term.

Our assessment suggests that the effect of lidocaine in humans is transitory and does not last for a long period of time, which can be explained by the pharmacokinetics of the drug. It starts acting between 30 and 60 min and its effects can last from 2 to 6 hours after the end of the infusion, after which the analgesic effect disappears quickly88. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev 2005; 19: CD003345. .

Based on the retrieved results, we have shown that patients receiving IV lidocaine are more prone to adverse events in comparison with placebo; however, no serious adverse event was reported.

It was not possible to perform a subgroup analysis based on the specific etiology of neuropathic pain, considering the limited number of studies available.

ANNEXES

The selection of retrieved from the virtual databases of scientific information is detailed in the flowchart below:


FIGURE 1. FLOWCHART
TABLE 4. PAPERS EXCLUDED AND REASON FOR EXCLUSION AFTER READING THE FULL TEXT
Study Reason for exclusion
Moulin DE, et al. 2019 Crossover RCT without data from the first phase

REFERENCES

  • 1
    Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630-5.
  • 2
    Gilron R, Watson CPN, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ 2006; 175: 265-75.
  • 3
    Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006; 7: 281-9.
  • 4
    Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2012; 85: S3-14.
  • 5
    Attal N, Cruccu G, Baron R, et al. European Federation of Neurological Societies. EFNS Guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17: 1113-23.
  • 6
    Moulin DE, Clark AJ, Gordon MD, et al. Long term outcome of the management of chronic neuropathic pain – a prospective observational study. J Pain 2015; 16: 852-61.
  • 7
    Attal N, Rouaud J, Brasseur M, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology. 2004;62:218–225.
  • 8
    Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev 2005; 19: CD003345.
  • 9
    Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Disponível em: www.prisma-statement.org.
    » www.prisma-statement.org
  • 10
    Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  • 11
    GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University, 2015 (developed by Evidence Prime, Inc.). Available from gradepro.org.
    » gradepro.org
  • 12
    Vlainich R, Issy AM, Sakata RK. Effect of intravenous lidocaine associated with amitriptyline on pain relief and plasma serotonin, norepinephrine, and dopamine concentrations in fibromyalgia. Clin J Pain 2011;27:285-8. PMID: 21178598
  • 13
    Albertoni Giraldes AL, Salomão R, Leal PD, Brunialti MK, Sakata RK. Effect of intravenous lidocaine combined with amitriptyline on pain intensity, clinical manifestations and the concentrations of IL-1, IL-6 and IL-8 in patients with fibromyalgia: A randomized double-blind study. Int J Rheum Dis. 2016;19:946-953. PMID: 27309886
  • 14
    Kim YC, Castañeda AM, Lee CS, Jin HS, Park KS, Moon JY. Efficacy and Safety of Lidocaine Infusion Treatment for Neuropathic Pain: A Randomized, Double-Blind, and Placebo-Controlled Study. Reg Anesth Pain Med 2018;43:415-424. PMID: 29381569
  • 15
    Zhu B, Zhou X, Zhou Q, Wang H, Wang S, Luo K. Intra-Venous Lidocaine to Relieve Neuropathic Pain: A Systematic Review and Meta-Analysis. Front Neurol 2019 18;10:954. PMID: 31620064

Publication Dates

  • Publication in this collection
    03 July 2020
  • Date of issue
    May 2020

History

  • Received
    22 May 2020
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