Intravenous Lidocaine for Neuropathic Pain: A Retrospective Analysis of Tolerability and Efficacy

Pain Medicine 2014; 2015; : 16: 531 536 Wiley Periodicals, Inc. NEUROPATHIC Intravenous Lidocaine PAIN SECTION for Neuropathic Pain: A Retrospective Analysis of Tolerability Brief and Efficacy Research Article Intravenous Lidocaine for Neuropathic Pain: A Retrospective Analysis of Tolerability and Efficacy Paul Hutson, PharmD,* Miroslav Backonja, MD, and Hanna Knurr, PharmD* *School of Pharmacy, University of Wisconsin, Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; CRILifetree Research, Salt Lake City, Utah, USA Reprint requests to: Paul Hutson, PharmD, School of Pharmacy, University of Wisconsin, 2220f Rennebohm Hall, 777 Highland Avenue, Madison, WI 53705, USA. Tel: (608)-263-2496; Fax: (608)-265-5421; E-mail: paul.hutson@wisc.edu. Disclosure information: Paul Hutson has no potential conflicts to disclose. Miroslav Backonja has no potential conflicts to disclose. Hanna Knurr has no potential conflicts to disclose. Abstract Objectives. This study was designed to describe the efficacy and toxicity of intravenous (i.v.) lidocaine infusions for the treatment of neuropathic pain initially administered at a flat-rate trial dose of 500 mg over 30 minutes. Setting. Academic, tertiary care hospital and infusion center. Methods. Data were retrospectively collected and analyzed for efficacy, correlations between infusion rates with adverse effects, patterns of infusion rate adjustments, and infusion frequencies. Results. The average rate for all infusions was 9.1 mg/min. Efficacy was seen in 45 patients (65%), and all but eight patients (12%) required infusion rate reductions from the initial test rate of 16.7 mg/ min due to adverse effects. Fifty-five patients experienced adverse effects, with light-headedness as the most frequently reported side effect. Conclusion. The flat-dose trial used under the University of Wisconsin Health protocol for i.v. lidocaine administration did not cause serious adverse events, but few patients who responded to this trial dose tolerated subsequent infusions at the trial rate. Due to the lack of serious adverse events, administering an aggressive trial dose to elicit an analgesic response appears to be rational. If patients show a benefit from the trial dose, the need for reductions in infusion rate of subsequent doses should be anticipated. Key Words. Intravenous Lidocaine; Toxicity; Neuropathic Pain; Infusion Rate Background Chronic pain is a debilitating disorder that significantly decreases quality of life when inadequately managed. Neuropathic pain results from damaged or diseased nociceptive pathways of the nervous system and is characterized by spontaneous ongoing pain and by allodynia and hyperalgesia to various internal and external stimuli. There are various etiologies of neuropathic pain, and clinical manifestations are frequently variable in the scope and complex in presentation. A patient s response to therapy is unpredictable, and many patients struggle to achieve satisfactory pain relief and control in spite of modern pain management. Typically patients will trial regimens of opioids, antidepressants, and anticonvulsants in attempts to control neuropathic pain [1]. However, according to studies of neuropathic pain secondary to diabetic neuropathy and other etiologies when treated with drugs that relieve neuropathic pain, only 30% patients will achieve even partial relief of their pain symptoms with these medication regimens [2]. One of the proposed pathophysiological mechanisms that contribute to neuropathic pain is an upregulation of 5311

Hutson et al. sodium channels in nociceptors. The change in channel density on nociceptor membranes creates an electrochemical environment that causes neurons to reach their depolarization threshold more rapidly, which leads to increased nociceptive signaling. Lidocaine, a sodium channel blocker, may modulate neuropathic pain by decreasing the function of these sodium channels, reversing the effects of sodium channel upregulation [3]. Parenteral intravenous (i.v.) lidocaine administration for the off-label treatment of resistant neuropathic pain has been occurring in clinical practice since the 1950s [4]. Specifically, recent studies have found i.v. lidocaine therapy to be effective in treating neuropathic pain associated with spinal cord injury [5], diabetic neuropathy [2], central pain syndrome [6], chronic regional pain syndrome [7], and postherpetic neuralgia [8]. Additionally, i.v. lidocaine infusions have an opioid sparing effect during the postoperative period when administered during abdominal surgery [9]. The safety characteristics of i.v. lidocaine have been well established. The most common adverse effects seen with i.v. lidocaine include light-headedness, dizziness and confusion, lethargy, nausea and vomiting, vision changes, and perioral numbness [2 15]. Because of its antiarrhythmic effects, patients receiving lidocaine infusions are typically screened for conduction defects via electrocardiogram (ECG) prior to lidocaine administration. Patients at a heightened risk for arrhythmia should not receive lidocaine infusions. No studies have reported arrhythmias due to i.v. lidocaine for neuropathic pain. A statistically significant increase in mean blood pressure when compared with placebo [7,10] was the only reported cardiac effect. This result was reported in two studies as an increase of 10 15 mm Hg in both mean systolic and mean diastolic blood pressure during or after lidocaine infusion. However, the duration of this elevation in blood pressure and its clinical significance was not reported. Although several studies have investigated i.v. lidocaine in neuropathic pain therapy, there is no consensus for dosing and administration of i.v. lidocaine. Some studies have found that the effect of lidocaine on neuropathic pain may be dose related [2,7,8,11]. There is currently no best practice or recommended guideline for the use of lidocaine infusions in this patient population. At the University of Wisconsin (UW) health infusion centers, a lidocaine infusion trial protocol has been in place for several years. All patients undergoing lidocaine infusion therapy for neuropathic pain are administered 500 mg lidocaine in 100 ml of normal saline over 30 minutes (16.7 mg/min) for their first infusion to establish whether the patient responds to and tolerates the treatment. This trial dose is higher and the duration of infusion is shorter than what is seen in most studies (Figures 1 and 2). Based upon the response of each patient to this test infusion, the patient and physician form a plan for future infusions (frequency, dose, and rate). The objective of this Number of infusions 700 600 500 400 300 200 100 0 retrospective chart review was to assess the practice of a fixed trial dose protocol of more rapidly infused lidocaine. Methods 69 256 414 116 583 A chart review of patients receiving i.v. lidocaine infusions for the indication of chronic neuropathic pain between January 2011 and December 2011 from any Health center was performed. Patients who received lidocaine for cardiac arrhythmias were excluded. Each eligible patient s lidocaine infusion history was analyzed retrospectively from their very first infusion to the most recent infusion. The UW Health Sciences Institutional Review Board approved this study. Per the UW lidocaine infusion protocol, patients with an established neuropathic pain diagnosis were screened with a 12-lead ECG for conduction abnormalities prior to beginning i.v. lidocaine therapy. An i.v. infusion of 500 mg lidocaine over 30 minutes was administered as the initial trial dose. All patients were observed closely, and a physician was immediately available over the 30-minute infusion. An observation period of 30 minutes was enforced 82 1 128 0-2 2-4 4-6 6-8 8-10 10-12 12-14 14-16 16-18 Rate in mg/min Figure 1 Distribution of lidocaine infusion rates in the analyzed cohort. The initial trial infusion rate (solid black bar) is 16.7 mg/min. % of patients with AE 100 80 60 40 20 0 0 0.1 0.2 0.3 0.4 0.5 0.6 Infusion rate (mg/min*kg) Figure 2 Cumulative percentage of patients who experienced an adverse effect at or below the indicated infusion rate. 2532

Parenteral Intravenous Lidocaine for Neuropathic Pain post infusion to assess adverse effects. Patients were educated on common lidocaine side effects, signs of a serious reaction, and instructed to rate their pain (pain severity scoring range of 1 to 10, with 10 being worst imaginable pain). Based upon patient response and tolerance of the trial infusion, the patient and physician chose to continue, discontinue, or adjust the dose and assign a frequency to the infusions. Data collected from each patient s medical record included dates of treatment, indication, type of infusion, dose, infusion time, adverse events, action taken as a result of an adverse event, duration of treatment, frequency of infusions, reason for discontinuation, pain scores, and vital signs that were taken preinfusion, during infusion, and postinfusion. Results A total of 69 patients who were administered i.v. lidocaine infusions at UW Health sites met inclusion criteria (Table 1). Data from 1,650 lidocaine infusions administered to these patients were analyzed. Only 262 (15.8%) of the infusion documentations included both pre- and postinfusion pain scores. The average change in 0 10 pain score was 3.6 out of 10 (standard deviation [SD] 1.7). IV Lidocaine Trial Fifty-eight of the 69 patients underwent their first dose at the institution s default dose of 500 mg infused over 30 minutes. Fifteen of the 58 did not tolerate the full trial infusion dose or required a rate reduction due to adverse events. Although the initial target dose was 500 mg, due to slowed or stopped lidocaine infusions, the actual dose administered averaged 364 mg (SD 78 mg), and the average infusion rate was 9.10 mg/min (SD 3.31 mg/min). Table 1 Patient demographics Treatment with Intermittent i.v. Lidocaine Infusions Only 23 (51%) of the 45 subjects continuing infusions remained at the trial infusion rate of 16.7 mg/min. Of those 23 subjects, only eight continued all subsequent infusions at this rate. Excluding each patient s initial trial infusion, 89% of infusion rates were between 4 and 14 mg/min (mean 9.1 mg/min). Dose reductions were required in 26 (57.8%), and rate reductions were required in 38 (82%) of the 45 patients that continued infusions after the first dose. The average interval at which patients received infusions was every 19.4 days. Only 38 (2.3%) of 1,650 infusions were stopped early or slowed due to adverse effects (Table 2). The average rate of these 38 infusions was 13.4 mg/min. Adverse effects occurred in 55 (79.9%) patients (average rate 13.2 mg/ min). Light-headedness was the most common adverse event, and all infusion-related toxicities were reversible. Compared with previous literature, adverse event incidence in patients receiving lidocaine at the trial rate (16.7 mg/min) was higher than the adverse event incidence in all but one other study. The average change from preinfusion to postinfusion vital signs were a slight drop in heart rate ( 3.8 bpm [SD 8.5]), systolic blood pressure ( 3.2 mm Hg [SD 21.2]), and diastolic blood pressure ( 0.6 mm Hg [SD 10.1]). Discussion The off-label use of lidocaine infusion for neuropathic pain is relatively uninvestigated, and it is difficult to discern the dose that will maximize patient analgesia while avoiding the risk of toxicity. This descriptive summary provides information about lidocaine dosing patterns in response to patient tolerance. Age (median and range) 57 years (12 91 years) Weight (average and range) 90.1 kg (33 140 kg) Body surface area (Mosteller method) (average and range) 2.07 m 2 (1.19 2.64 m 2 ) Body mass index (average and range) 32.0 (15.9 67.1) Type of neuropathy Central pain syndrome 2 CRPS 24 Diabetic peripheral neuropathy 8 Fibromyalgia 3 Ischemic neuropathy 1 Malignant cancer pain 5 Median nerve neuropathy 1 Mononeuritis multiplex 1 Multiple sclerosis 2 Neuropathic pain (unspecified) 10 Postherpetic neuralgia 4 Poststroke pain 1 Posttraumatic or surgical pain 5 Sensory neuropathy 1 Trigeminal neuralgia 1 Patients without a specific diagnosis are categorized into the general category of Neuropathic Pain (unspecified). 5333

Hutson et al. Table 2 Adverse effects reported as the percentage of patients who experienced each side effect Side Effect Percentage of Patients Affected Average Infusion Rate at which Side Effect Occurred (mg/min) Total 79.7 13.1 Arrhythmia 0 N/A Clumsiness/incoordination 18.8 11.1 Confusion 2.9 12.8 Delirium 1.4 11.7 Dizziness/vertigo 30.4 13.0 Headache 8.7 13.5 Light-headedness 44.9 14.5 Metallic taste 1.4 16.7 Muscle twitching 1.4 7.8 Nausea/vomiting 15.9 11.6 Peri-oral numbness 23.2 13.7 Peripheral numbness/dyesthesias 8.7 13.4 Sedation/lethargy 13.0 13.4 Speech disturbance 23.1 15.3 Tingling 2.9 16.7 Tinnitus 5.8 16.7 Other 39.1 14.4 Side effects were reported by the either the patient or the administering nurse. The average infusion rate of the infusion that the patient experienced the adverse effect is reported in mg/min. Efficacy Though there was a reduction in pain assessment scores, only 15% of infusions contained sufficient data to compare pre- and postinfusion pain score ratings. Additionally, many patients reported that the point at which they experienced maximal pain relief was 24 hours after the infusion was administered. Therefore, the efficacy of lidocaine infusions is arguably better reflected by the percentage of patients who continued therapy (indicating efficacy as well as tolerability of lidocaine infusions). The 1,579 of 1,650 infusions (95.7%) were repeat infusions for subjects, indicating that those who experienced benefit from the lidocaine infusions continued to see some effect, in some cases for 200 or more infusions. Most patients received subsequent infusions at lower rates than the trial rate, suggesting that efficacy was maintained for many patients even when doses are reduced. This also indicates that adverse effects occur at a higher frequency at higher infusion rates but can be effectively overcome by a decrease in infusion rate. Infusion Rate and Toxicity The distribution of lidocaine infusion rates (Figure 1) suggests that the most commonly tolerable, effective lidocaine infusion rate is between 4 and 12 mg/min. Only eight patients tolerated the trial infusion rate for all continued infusions, and no patients received an increase in dose or rate above the trial rate of 16.7 mg/min. The average rate of infusions that elicited an adverse event was reported was 13.1 mg/min (Table 3). The trial infusion rate for lidocaine described here is aggressive, and it is unlikely that most patients will tolerate repeated lidocaine infusions at 16.7 mg/min. However, the use of a high-dose trial infusion is an efficient way to determine whether a patient s neuropathic pain will respond to lidocaine. Additionally, toxicities at this and other infusion rates were not life threatening and quickly reversible. There was a single report of one subject that admitted to the emergency department as a result of an adverse effect mid-infusion in this review. However, this adverse effect (hypoglycemia) is not an adverse effect associated with lidocaine infusions and was considered circumstantial and not directly due to the infusion. There have been no side effects related to clinically apparent cardiac arrhythmias, indicating that these doses of infused lidocaine do not achieve levels in cardiac tissues high enough to cause cardiotoxic effects. However, patients at our institution are not monitored with telemetry during infusion. The most common side effects seen were transient light-headedness, dizziness/ vertigo, and clumsiness/incoordination. All of these resolved within the 30 minute postinfusion observation period. The decrease in mean blood pressure after lidocaine infusion was minimal and contrasts with a significant increase that was reported in two randomized controlled trials [7,10]. Comparison of Trial Infusions vs Maintenance Infusions The primary differences between initial trial infusions and subsequent maintenance infusions are the rate of infusion 4534

Parenteral Intravenous Lidocaine for Neuropathic Pain Table 3 Comparison of reports of Lidocaine for Treatment of Neuropathic Pain Study Patients (N) Study Type Lidocaine Dose(s) Infusion Duration Average Rate (mg/min/kg) UW Lidocaine trial dose 56 Retrospective chart review trial doses only UW Lidocaine all infusions 69 Retrospective chart review Varied. Mean: 364 mg Attal [6] 16 Randomized, double blind, placebo trial Attal [13] 22 Randomized, double blind, placebo trial Baranowski [8] 24 Randomized, double blind, placebo 500 mg 30 minutes 0.185 Varied, Average: 45.1 minutes 0.101 5 mg/kg 30 minutes 0.167 5 mg/kg 30 minutes 0.167 1 mg/kg 5 mg/kg Ivo [12] 31 Placebo controlled trial 6 mg/kg, 18 mg/kg 30 mg/kg 2 hours 0.00829 0.0417 6 hours 0.0167 0.05 0.083 Bolus: 0.2 Infusion: 0.05 Dirks [5] 25 Placebo, 6.25 mg/kg 85 minutes: 2 mg/kg IV bolus over 10 minutes, followed by infusion 3 mg/kg/h for 85 minutes Finnerup [10] 24 Randomized, double blind, placebo 1 mg/kg 5 mg/kg Koppert [9] 12 Randomized, double blind, placebo 1.0 mg/kg injection and 1.5 mg/kg/h infusion Kvarnstrom [14] 12 Randomized, double blind, placebo Kvarnstrom [3] 10 Randomized, double blind, placebo 30 minutes 0.033 0.167 Varied based on surgery time: started 0.025 30 minutes before incision, ended 1 hour post op. Bolus: 0.1 Infusion: 0.05 2.5 mg/kg 40 minutes: 1 mg/kg during 10minutes and then 1.5 mg/kg during 30 minutes 2.5 mg/kg 40 minutes: 1 mg/kg during 10 minutes and then 1.5 mg/kg during 30minutes Bolus: 0.1 Infusion: 0.05 Lidocaine infusion regimens and adverse effects of the UW Health s protocol for lidocaine when used for neuropathic pain are contrasted with the other reports of lidocaine infusion regimens and adverse effects. The UW infusions are reported both as total infusions and as a subgroup of the portion of infusions that were administered at the trial infusion rate. 5355

Hutson et al. and the incidence of adverse event. The average infusion rate of maintenance infusions was 8.8 mg/min, nearly a 50% reduction from the trial infusion rate. The rate of adverse effects per infusion in the maintenance infusions was 3.3% vs an incidence rate of 88% in the trial infusions. Though not all patients required rate reductions for maintenance infusions, the majority of patients continued their maintenance infusions at a reduced infusion rate and successfully decreased the incidence of adverse effects. The mean rate of all infusions in this retrospective review was 9.10 mg/min, which was higher than many rates seen in other lidocaine infusion studies (Table 3), and the trial infusion rate for first time lidocaine infusions (16.7 mg/min) was higher than rates used in all but one other study [5]. When the incidence of adverse event was correlated with average rate/kg bodyweight, lower rates of infusion were associated with lower side effect incidence across multiple studies (Figure 2). Another health center reported successful use of lidocaine for neuropathic pain using a trial infusion protocol followed by a continuous infusion. This institution used weight-based dosing to determine the initial trial infusion (1 3 mg/kg) over 20 30 minutes or 0.033 mg/kg/min to 0.15 mg/kg/min [15]. Thereafter, responders lidocaine infusion rates were titrated to the lowest rate that maintaining analgesic efficacy, typically around 0.0167 mg/kg/min 0.033 mg/kg/min. Lidocaine serum levels were measured with results well below the toxic threshold of 6 μg/ml. Similarly, reversible adverse events of light-headedness and peri-oral numbness were anecdotally noted [15]. In conclusion, adverse effects occur more commonly at higher i.v. lidocaine infusion rates. The flat-dose trial used under the UW Health protocol for i.v. lidocaine administration did not cause serious adverse events, but few patients who responded to this trial dose tolerated subsequent infusions at the initial trial rate. Starting with an aggressive trial dose to elicit an analgesic response appears to be rational, given the lack of serious adverse events noted in this study and in other similar series of short lidocaine infusions. If patients show benefit from the trial dose, the need for reductions in infusion rate of subsequent doses should be anticipated. References 1 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 2010;85(suppl 3):S3 14. 2 Wallace MS, Laitin S, Licht D, Yaksh TL. Concentration-effect relations for intravenous lidocaine infusions in human volunteers: Effects on acute sensory thresholds and capsaicin-evoked hyperpathia. 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