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3 Q2 Q1 Q3 Q Emergency Medicine Department, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran 2 Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran Correspondence to Dr Morteza Saeedi, Shariati Hospital, North Amirabad Street, Tehran , Iran; m_saeedi@tums.ac.ir, m_saeedi_a@yahoo.com Received 24 April 2014 Revised 17 July 2014 Accepted 19 July 2014 To cite: Vahidi E, Shakoor D, AghaieMeybodi M, et al. Emerg Med J Published Online First: [ please include Day Month Year] doi: /emermed Comparison of intravenous lidocaine versus morphine in alleviating pain in patients with critical limb ischaemia Elnaz Vahidi, 1 Delaram Shakoor, 2 Mohamad AghaieMeybodi, 2 Morteza Saeedi 1 ABSTRACT Background Numerous drugs have been proposed to alleviate ischaemic limb pain, but none have been successful in relieving ischaemic pain thoroughly and rapidly. Objective To compare the effectiveness of intravenous lidocaine and intravenous morphine in decreasing pain in patients with critical limb ischaemia. Methods A randomised double-blind controlled trial was performed in 63 patients with critical limb ischaemia recruited from the emergency department between October 2012 and December 2013; 23 patients were excluded and the remainder were randomly divided into two groups of 20 patients. Patients in the lidocaine group received lidocaine infusion (2 mg/kg) while patients in the morphine group received morphine (0.1 mg/kg). Patients visual analogue pain scores (VAS), from 0 to 10, were reported before and 15 and 30 min after the infusion. Results Before the infusion the mean±sd VAS score was 7.50±1.93 in the lidocaine group and 7.65±1.92 in the morphine group. At 15 min the mean±sd VAS score in the lidocaine group was lower than in the morphine group (5.75±1.77 vs 7.00±1.83; mean difference 1.25, 95% CI to 2.405) and, at 30 min, the mean±sd VAS score in the lidocaine group was again lower (4.25 ±1.48 vs 6.50±1.73; mean difference 2.25, 95% CI to 3.282). Conclusions Lidocaine may be helpful in decreasing ischaemic pain in patients with critical limb ischaemia. Trial registration number irirct n2. INTRODUCTION Critical limb ischaemia (CLI), the most advanced manifestation of peripheral arterial disease, refers to a clinical state in which blood flow of an extremity is severely compromised, resulting in ischaemic rest pain, non-healing ulcers, gangrene and ultimately limb loss. 1 It is also associated with a remarkably high risk of cardiovascular events. 1 2 The management of CLI therefore remains a major challenge in emergency medicine. 1 Pain relief is a vital aspect of CLI treatment, especially in emergency conditions. To achieve this, various intravenously administered medications have been introduced and narcotics are most commonly used. Lidocaine, an amide-type regional anaesthetic and systemic antiarrhythmic drug, has recently been proposed as a candidate to alleviate neuropathic pain in conditions such as trigeminal neuralgia, neuroma, spinal cord injury and Key messages What is already known on this subject There is no perfect treatment for pain in patients with critical limb ischaemia. What this study adds This study introduces a new intervention for pain management in critical limb ischaemia. peripheral nerve injury Furthermore, a large body of evidence supports the use of intravenous lidocaine in treating central and visceral pain. It was proved to be successful in controlling diabetic pain, postoperative pain in abdominal surgery and painful conditions associated with malignancies Intriguingly, Froehlich et al showed that lidocaine had an inhibitory effect on ischaemic pain, producing a sustained analgesic state in ischaemic pain induced by the tourniquet technique in healthy individuals. 14 Since there has been no similar study in patients with limb ischaemia, this study compares the effect of intravenous lidocaine and morphine in controlling ischaemic pain in patients with CLI. MATERIALS AND METHODS Participants We conducted a randomised double-blind parallel group study (with 1:1 balanced randomisation) in patients with CLI recruited from the emergency department of Shariati Hospital, a tertiary referral centre, from October 2012 to December Eligible patients were aged >15 years with no exclusion criteria who were diagnosed with CLI based on their clinical findings: pain, pallor, paraesthesia and paralysis of a pulseless limb. We excluded patients with opioid addiction and prior use of intravenous opioids, pregnancy, respiratory distress, blood pressure (BP) <100 mm Hg, trauma, altered level of consciousness, dementia and other neurological problems, respiratory or cardiac conditions which contradict the use of either morphine or systemic lidocaine and a history of allergic reactions to the aforementioned agents. The diagnosis was confirmed by the treating emergency physician and the chief investigator (MS) was contacted. The subjects were randomly divided into twogroups of 20 each (figure 1): a lidocaine group and a morphine group. Randomisation was performedby means of a random double digit codes list extracted from the website Vahidi E, et al. Emerg Med J 2014;0:1 4. doi: /emermed

4 Figure 1 CONSORT flow diagram. Q9 by the chief investigator. Only the chief investigator was aware of the assignment. Both the patients and the emergency specialists who identified the patients were blinded to the injected medication. Drug administration The patients were interviewed and the method of drug administration, visual analogue pain score (VAS; where 10 represented the worst imaginable pain and 0 was pain-free) and possible complications were explained to them and informed written consent was obtained. Demographic data including age, sex and comorbidities were collected through a questionnaire by the emergency physician. Subsequently, a 12-lead ECG and vital signs including BP, respiratory rate, pulse rate and VAS score were taken by the emergency physician who was blinded to the treatment arm. In the lidocaine group, lidocaine solution (2 mg/ kg) was slowly administered intravenously over 5 min. Lidocaine was diluted using a 10 ml syringe which contained 5 ml lidocaine 2% and 5 ml water (1 ml=10 mg lidocaine). To maintain the same infusion volumes, for patients who needed more than 100 mg lidocaine we decreased the diluting water volume so 1 ml of solution would contain more than 10 mg of lidocaine. In the morphine group, morphine solution (0.1 mg/kg) was slowly administered intravenously over 5 min using a 10 ml syringe containing 10 mg morphine and 9 ml water (1 ml=1 mg). Both the drugs and their appropriate doses according to patients weight and treatment code were prepared by the triage nurse and administered by the emergency physician. Throughout the infusion, pulse oximetry, BP, heart rate and ECG were observed and recorded. Patients were requested to express their degree of pain using the VAS score, before and 15 and 30 min after initiation of the infusion. In case of failure and no decrease in VAS scores in either group after 30 min, the infusion would be stopped and fentanyl would be administered. The rate of fentanyl infusion was 1 2 macro/kg administered and titrated to the effect. During the infusion, patients were monitored for adverse effects and, if they occurred, the protocol was to report the incident and stop the infusion. Statistical analysis and sample size calculation In order to produce one degree difference in the mean VAS pain score, which is considered a clinically significant change, with power of 80%, CI of 0.05 and SD of 1.1, a sample size of 20 per treatment group was calculated by means of the following formula: n ¼2 ðz1 a=2 þ Z 1 b Þ 2 SD 2 =ðm 1 m 2 Þ 2 n ¼2 ð0:96 þ 0:84Þ 2 ð1:1þ 2 =1 n ¼20 All data were analysed using SPSS V.18 software. In order to evaluate the normal distribution of quantitative data such as VAS score, we conducted a Kolmogronov Smirnov (KS) test. We Q Vahidi E, et al. Emerg Med J 2014;0:1 4. doi: /emermed

5 Table 1 Demographic features of study groups Lidocaine group(n=20) Morphine group(n=20) Sex Women 9 (56.2%) 7 (43.8%) Men 11 (45.8%) 13 (54.2%) Age, years 63.95± ±12.22 Hypertension 5 (25%) 8 (40%) Diabetes mellitus 2 (10%) 4 (20%) then performed the independent t test to compare our quantitative data, which had a normal distribution, with 95% CI. All the descriptive data are given as mean±sd. RESULTS During the study period 63 patients were diagnosed with CLI and 23 patients were excluded: five patients had respiratory distress, five had BP below 100 mm Hg, three were suffering from dementia and other neurological problems, six patients were addicted to opioids and four patients had cardiac problems for which lidocaine was contraindicated. The remaining 40 patients were randomly divided into two groups of 20 each (table 1). The mean ages of the lidocaine and morphine groups were similar (63.95±11.66 years and 63.80±12.22 years, respectively). The lidocaine group included 11 men and 9 women and the morphine group included 13 men and 7 women. Their comorbidities are shown in table 1. The mean pain scores in the two groups are shown in table 2. Baseline VAS scores were similar. After 15 min the mean VAS score was lower in the lidocaine group (mean difference between groups 1.25 (95% CI to 2.405). After 30 min the mean VAS score was again lower in the lidocaine group with the mean difference between groups 2.25 (95% CI to 3.282). The VAS pain score of four patients in the morphine group remained the same 30 min after the infusion so fentanyl infusion was started (data not shown). A comparison of physiological measures is shown in figure 2. There were no significant differences between the groups in systolic or diastolic pressure, oxygen saturation or pulse at any point in the study and the ECG remained unaffected during and after the infusion. In the lidocaine group, no side effects such as perioral numbness, nausea or light-headedness were reported and no serious complications such as hypotension, respiratory arrest or cardiac arrhythmia were observed. No side effects or complications occurred in the morphine group. DISCUSSION Over the last decades there have been various studies suggesting systemic lidocaine as an alternative for alleviating different painful conditions Despite the abundance of studies Table 2 Mean value of pain scores in the two groups Lidocaine group (N=20) Morphine group (N=20) Mean difference 95% CI of the difference Lower Upper VAS 0 min 7.50± ± VAS 15 min 5.75± ± VAS 30 min 4.25± ± VAS, visual analogue pain score. in the literature, there have been equivocal results regarding the analgesic effects of intravenous lidocaine. While it has been effective in postoperative pain associated with spinal and abdominal surgeries, it has not been helpful in patients undergoing cardiac surgery, gynaecological surgery and tonsillectomy In order to explain this incongruity, numerous theories have been proposed but the exact reason remains unclear. Our study shows that intravenous lidocaine provides a considerable analgesic state in patients with CLI. Compared with morphine, intravenous lidocaine significantly decreased the VAS scores 30 min after drug administration. Comparing VAS scores in the two groups, patients in the lidocaine group became painfree earlier than those in the morphine group. Our results are consistent with a study performed by Froehlich et al who compared the effect of intravenous lidocaine on deep ischaemic pain and superficial cutaneous pain. 14 Eighteen healthy participants received different pain stimuli including thermal, cold, electrical and ischaemic pain. Lidocaine was successful in alleviating ischaemic muscle pain but had no effect on other painful conditions apart from a slight transient effect on electrical pain. 14 These results could be explained by the mechanism of action of lidocaine. Intravenous lidocaine generates most of its analgesic action by blocking high-voltage sodium channels through nerve cell membranes. This blockade is frequency- and voltagedependent, so it aims to block conduction of the stimulated nerve while not affecting normal nerve conduction. Froehlich et al suggested that ischaemic pain may be due to stimulation of nociceptors in the ischaemic muscle which results in augmented nerve conduction in C and Aδ fibres. Systemic lidocaine may block this signal transmission. Brose et al studied three patients with terminal cancer and neuropathic pain refractory to a number of medications. 13 In a blinded study of lidocaine, opiates and placebo, significantly more relief was obtained with lidocaine. The authors also suggest that most of the pain suffered by these patients was nociceptive and transmitted through Aδ and C fibres. In addition, systemic lidocaine is successful in managing postoperative pain following abdominal and spinal surgeries This can be explained by the fact that surgical operations involve deep incisions and disrupt the vascular supply leading to ischaemia of the region. Therefore the majority of postoperative pain is nociceptive and lidocaine can block Aδ and C fibres. However, this hypothesis does not explain the ineffectiveness of lidocaine in arthroplasty and cardiac surgeries. Vingeault et al performed a meta-analysis of 29 randomised controlled trials involving 1754 patients and found a significant difference in pain control with the use of intravenous lidocaine versus opioids under general anaesthesia. 8 Among patients who received intravenous lidocaine, postoperative pain scores (at rest, during cough and movement) were lower. In another study performed by Farag et al, adults undergoing complex spinal surgery were randomly assigned to receive lidocaine or placebo and intravenous lidocaine was found to decrease postoperative pain significantly. Limitations of the study One limitation of our study was that lidocaine was not delivered by computer-assisted infusion (CAI) so we were not able to determine the plasma level at which analgesia occurred. Due to the critical condition of patients with CLI and the need for immediate surgery, follow-up for more than 30 min was not feasible. In addition, since the prevalence of CLI and Q Vahidi E, et al. Emerg Med J 2014;0:1 4. doi: /emermed

6 Q Figure 2 Comparison of physiological measures. the rate of lidocaine side effects are relatively low, our sample size was not sufficient to detect adverse events. Further clinical trials with larger sample sizes and longer follow-up should therefore be performed to identify adverse events to intravenous lidocaine. CONCLUSION This study shows that intravenous lidocaine is effective in alleviating pain in patients with CLI. Since this trial included patients of all ages and both sexes, we can state that, below its toxic dose, lidocaine appears to be a safe drug with limited side effects that can be considered as one of the drugs effective for ischaemic pain in emergency conditions. Compared with narcotics, it can generate a faster and more efficient analgesic state with no further need to repeat the narcotics frequently. Contributors MS: study concept, design and supervision; EV: data gathering and supervision; DS: drafting of manuscript; MS: data analysis. Competing interests None. Patient consent Obtained. Ethics approval Ethics approval was obtained from the ethics committee of Tehran University of Medical Sciences. Provenance and peer review Not commissioned; externally peer reviewed. REFERENCES 1 Varu VN, Hogg ME, Kibbe MR. Critical limb ischemia. J Vasc Surg 2009;51: Schanzer A, Conte MS. Critical limb ischemia. Curr Treat Options Cardiovasc Med 2010;12: Sinnott CJ, Garfield JM, Strichartz GR. Differential efficacy of intravenous lidocaine in alleviating ipsilateral versus contralateral neuropathic pain in the rat. J Pain 1999;80: Chabal C, Russell LC, Burchiel KJ. The effect of lidocaine, tocainide, mexiletine on spontaneous active fibers originating in rat sciatic neuromas. J Pain 1989;38: Carroll IR, Younger JW, Mackey SC. Pain quality predicts lidocaine analgesia among patients with suspected neuropathic pain. Pain Med 2010;11: Tremont-Lukats IW, Challapalli V, McNicol ED, et al. Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg 2005;101: Maoa J, Chen LL. Systemic lidocaine for neuropathic pain relief. J Pain 2000;87: Vigneault L, Turgeon AF, Côté D, et al. Perioperative intravenous lidocaine infusion for postoperative pain control: a meta-analysis of randomized controlled trials. J Can Anesth 2011;58: Devor M, Wall PD, Catalan N. Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. J Pain 1992;48: Finnerup NB, Biering-Sørensen F, Johannesen IL, et al. Intravenous lidocaine relieves spinal cord injury pain. Anesthesiology 2005;102: Farag E, Ghobrial M, Sessler DI, et al. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery. Anesthesiology 2013;119: Kastrup J, Petersen P, Dejgard A, et al. Intravenous lidocaine infusion: a new treatment of chronic painful diabetic neuropathy. J Pain 1987;28: Brose WG, Cousins MJ. Subcutaneous lidocaine for treatment of neuropathic cancer pain. J Pain 1991;45: Froelich MA, McKeown JL, Worrell MJ, et al. Intravenous lidocaine reduces ischemic pain in healthy volunteers. Reg Anesth Pain Med 2010;35: Marchettini P, Lacerenza M, Marangoni C, et al. Lidocaine test in neuralgia. J Pain 1992;48: Insler SR, O Conner M, Samonte AF, et al. Lidociane and the inhibition of postoperative pain in coronary artery bypass patients. J Cardiothorac Vasc Anesth 1995;9: Streiebel HW, Klaettke U. Is intravenous lidocaine infusion suitable for postoperative pain management? Schmerz 1992;6: Yardeni IZ, Beilin B, Mayburd E, et al. The effect of perioperative intravenous lidocaine on postoperative pain and immune function. Anesth Analg 2009;109: Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response. A new therapeutic indication. Anesthesiology 2000;93: Nagy I, Woolf CJ. Lignocaine selectively reduces C fibre-evoked neuronal activity in rat spinal cord in vitro by decreasing N-methyl-d-aspartate and neurokinin receptor-mediated post-synaptic depolarizations; implications for the development of novel centrally acting analgesics. J Pain 1996;64: Q Vahidi E, et al. Emerg Med J 2014;0:1 4. doi: /emermed