Is lidocaine patch as effective as intravenous lidocaine in pain and illus reduction after laparoscopic colorectal surgery? A randomized clinical trial.

OBJECTIVE: To evaluate the efficacy of lidocaine patch applied around wound in laparoscopic colorectal surgery in reduction of postoperative pain and illus compared to intravenous lidocaine infusion and placebo.
BACKGROUND: Postoperative illus and pain after colorectal surgery is a challenging problem associated with increased morbidity and cost. Inflammatory response to surgery plays crucial rule in inducing postoperative illus. Systemic local anesthetics proved to have anti-inflammatory properties that may be beneficial in preventing ileus added to its analgesic actions. The lidocaine patch evaluated in many types of pain with promising results. We try to evaluate the patch in perioperative field as a more simple and safe technique than the intravenous route.
MATERIALS AND METHODS: Prospective, randomized, controlled study was conducted, comparing three groups. Group 1 (placebo) received saline infusion, group 2 received i.v. lidocaine infusion after induction of anesthesia, 2 mg/min if body weight >70 kg or 1 mg/min if body weight <70 kg, group 3 received lidocaine patch 5%, three patches each one divided into two equal parts and applied around the three wounds just before induction. Data collected were, pain scores (VAS), morphine consumption, return of bowel function, pro-inflammatory cytokines plasma levels and plasma lidocaine level.
RESULTS: Pain intensity (VAS) scores at rest and during coughing were significantly lower during the first 72 h postoperative in i.v. lidocaine group and patch group compared to the placebo group. Mean morphine consumption were significantly lower in the i.v. lidocaine group and patch group compared to placebo group. Return of the bowel function was significantly earlier in i.v. lidocaine group in comparison to the other groups. Proinflammatory cytokines (IL6, IL8, and C3a) were significantly lower in i.v. lidocaine group compared to the other two groups.
CONCLUSION: The lidocaine patch was equal to i.v. lidocaine infusion in decreasing pain scores and morphine consumption but not in acceleration of bowel function return.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Nearly all patients go through bowel resection surgery suffer from postoperative paralytic illus, temporary cessation of bowel motility that prevents effective intestinal contents transit, although the course usually self-limiting it is associated with increase in postoperative morbidity and length of the hospital stay.[1234]

The pathophysiology of postoperative ileus is multifactorial and includes neuronal mechanism in the acute phase and inflammatory mechanism in the late phase. So, management of postoperative ileus must be multimodal to face the different mechanisms.[5678]

Local anesthetics exert their actions as local anesthesia and antiarrhythmic through Na channels blocking but still have many other important actions through other receptors (e.g., m1 muscarinic receptors) that occur at very low plasma levels compared to levels needed for Na channels blocking, one of these actions is the anti-inflammatory effect against surgical stress response.[9101112]

Targeting the inflammatory pathway get interest in many clinical studies that prove the modulating effects of local anesthetics on the inflammatory system associated with stress response of surgery.[8910]

Several randomized studies found that i.v. lidocaine shortens duration of postoperative ileus and some of it reported decreased postoperative pain with i.v. lidocaine, so they recommended i.v. lidocaine as a safe, simple, and less invasive method for management of postoperative ileus and equal to postoperative epidural analgesia.[10131415]

The lidocaine patch 5% (Lidoderm®, Endo Pharmaceuticals, Chadds Ford, PA), a targeted peripheral analgesic is Food and Drug Administration (FDA) approved for treatment of postherpetic neuralgia, while efficacy in other nonneuropathic pain conditions has also been reported.[16]

In our study, we try to evaluate the efficacy of a 5% lidocaine patch application to control postoperative pain and enhancing return of the bowel function in patients go through laparoscopic colorectal surgery.

MATERIALS AND METHODS

This study was approved by the ethics committee of Tanta university hospital, Egypt, and informed consent was obtained from each patient.

Thirty patients, ASA I to III, undergoing elective colorectal surgery enrolled in the study. Exclusion criteria were known allergy to lidocaine, respiratory or cardiac dysfunction, arrhythmia, treatment with antiarrhythmic drugs, inflammatory bowel disease (Crohn's disease or ulcerative colitis) hepatic, renal, and chronic use of analgesics or corticosteroids.

Patients randomly assigned to one of three equal groups, placebo group (group 1), i.v. lidocaine infusion (group 2) and lidocaine patch (group 3).

Group 1: received i.v. saline infusion.

Group 2: received i.v. lidocaine infusion after induction of anesthesia, 2 mg/min if body weight >70 kg or 1 mg/min if body weight <70 kg.

Group 3: for every port entry site from the three in ports of laparoscope, patients received three lidocaine patches 5% (Lidoderm®, Endo Pharmaceuticals, Chadds Ford, PA). Each patch measured 10 cm × 14 cm and contains (700 mg), was divided into two equal parts, six parts applied two of it around one port entry site that marked before sterilization and just before induction of anesthesia. The patches not changed until removed after return of bowel function or on the maximum at fifth postoperative day.

At the day before surgery all patients were instructed how to rate pain intensity on a visual analog scale (VAS), identifying 0 as “no pain” and 10 as “worst imaginable pain.”

Each patient requested to record the first appearance of flatus and inform staff nurse, bowel sounds heard four times per day and time to first appearance recorded by resident on duty and time to first defecation postoperatively recorded.

All patients received the same general anesthetic technique. No premedication was used. General anesthesia was induced with i.v. fentanyl (2 m/kg) and propofol (2.0-2.5 mg/kg). Orotracheal intubation was facilitated by cisatracurium (0.15 mg/kg) and patients were maintained with 1.5-2% isoflurane.

The hemodynamic parameters, mean blood pressure, heart rate (HR) and SpO2, and respiratory rate (RR) were recorded before operation, intra-operatively every 15 min, then at 2, 4, 8, 12, and then every 6 h postoperatively.

In the recovery room pain intensity assessed using visual analog scale (VAS), identifying 0 as, no pain, and 10 as, worst imaginable pain, any patient has pain score >3 treated by fentanyl 30-50 mic every 15 min or morphine 2 mg every 20 min as needed.

In the ward patients treated with patient controlled anesthesia (PCA) set on morphine 2 mg on demand with lock time 10 min and maximum dose 10 mg/h.

Pain VAS scores at rest and during coughing were recorded postoperatively at 1, 4, 12, and then every 12 h through the study.

Morphine consumption recorded and calculated daily.

The time of first flatus, first bowel sounds and first postoperative defecation were recorded.

Plasma level of lidocaine evaluated after 1 h of starting infusion or patch apply, 12 h after surgery then once per day in the following days, if >5 μg/mL the infusion stopped or the patch removed, also if any signs of toxicity (neurological or cardiovascular) appeared and the plasma level evaluated again (the chromatography technique used).

Plasma levels of inflammatory cytokines (IL6, IL8, IL10, TNFα, and C3a) estimated, preoperative, 1, 24, and 48h postoperative.

The study intervention stopped with return of bowel function (i.v. infusion stopped or patch removed).

If bowel function did not return on the fifth day i.v. lidocaine or patch stopped but the patient not excluded from the study.

Patient with abnormal postoperative course or surgical complication excluded from the study.

Statistical analysis

At the conclusion of the study, data were cleaned and exported for analysis to SPSS 15 (SPSS Inc, Chicago IL, USA). Results are expressed as mean ± SD unless indicated number (%).

Differences between the three groups, in VAS pain scores, morphine consumption, bowel sounds, time to first passage of flatus, time to first defecation, plasma levels of pro-inflammatory cytokines, ASA physical status and demographic data were compared using one-way analysis of variance ANOVA followed by the posthoc Bonferroni test.

Differences to preoperative value in proinflammatory cytokines within the same group were analyzed using student t-test.

Differences were considered significant if P < 0.05.

RESULTS

Thirty patients undergone laparoscopic colorectal surgery were randomized and assigned equally to three groups, three patients excluded from the study one in each group because of surgical complications lead to changes in postoperative plane.

Group 1: Control group (i.v. saline) nine patients, group 2 (i.v. lidocaine) nine patients, and group 3 (lidocaine patch) nine patients.

The three groups were comparable in demographic data [Table 1] and intraoperative parameters [Table 2].

Table 1

Demographic and clinical data of the three studied groups

Table 2

Intraoperative parameters

Pain intensities at rest and during coughing differed significantly between groups. Means of VAS scores at rest and during coughing was significantly lower in groups 2 and 3 compared to group 1 in the first 72 h (P = 0.021, P = 0.032, P = 0.037, P = 0.041, P = 0.047, P = 0.044, P = 0.048, P = 0.042 respectively) but did not reach significant difference in the following postoperative hours.

There were no significant differences between group 2 and 3 [Tables 3 and 4].

Table 3

Visual analog scale pain scores at rest

Table 4

Visual analog scale pain scores during coughing

Morphine consumption [Table 5] from first to fifth day postoperative was significantly lower in groups 2 and 3 compared to control group 1 (P = 0.037, P = 0.026, P = 0.042, P = 0.048, P = 0.044, respectively) but without difference between group 2 and 3.

Table 5

Morphine consumption

The return of bowel function [Table 6] bowel sounds, time to first flatus and time to first defecation postoperative were significantly earlier in group 2 (i.v. lidocaine) compared to group 1(control) and group 3 (lidocaine patch) (P = 0.021, P = 0.034, P = 0.046, respectively) but, without difference between groups 1 and 3.

Table 6

Time to return of bowel function (hours)

The mean plasma lidocaine levels were higher in-group 2 compared to group 3 with range of (1.04-3.7 μg/mL vs. 0.11-1.08 μg/mL) but, both groups did not endure adverse events of local anesthetic toxicity (neurologic symptoms or cardiovascular).

The plasma levels of inflammatory cytokines (IL6, IL8, C3a) [Table 7] significantly increased in the three groups compared to preoperative values. There were significantly lower levels in group 2 (i.v. lidocaine group) compared to placebo group 1 and group 3 (lidocaine patch) [IL6 (P = 0.009), IL8 (P = 0.021), C3a (P = 0.034)] but, without difference between groups 1 and 3. TNFα cytokine did not differ from preoperative value in the three groups.

Table 7

Comparison of plasma levels of pro-inflammatory cytokines

DISCUSSION

This study demonstrates that administration of lidocaine by intravenous route or skin patch significantly lowers pain scores and morphine consumption in patients undergoing laparoscopic colorectal surgery.

The intravenous lidocaine significantly accelerates return of bowel function (time to first flatus, bowel sounds, and first postoperative defecation) compared to control group and patch group while the lidocaine patch failed to enhance return of the bowel function.

In addition, the proinflammatory cytokines (IL6, IL8, C3a) were significantly lower in i.v. lidocaine group versus the other two groups, while the lidocaine patch group not differs from the control group.

To provide effective analgesia after major surgery may be a challenge. Pain and postoperative ileus linked to each other as they result from multiple factors such as surgical trauma, liberation of inflammatory mediators and sympathetic stimulation activating inhibitory reflexes while treatment of pain by opioid shares in production of ileus.[1718]

Protocols to accelerate postoperative recovery “fast-track” are clinically novel requirement. This advance includes combinations of techniques planned to reduce surgical stress, manage pain, and help early feeding and mobilization.[19] The introduction of nonopioid analgesics to control perioperative pain with visceral operations is of particular interest, and the administration of intravenous lidocaine infusions for this target recently received attention as an analgesic intervention.[910131415]

Several studies discussed and proved the anti-inflammatory and modulating effects of local anesthetics on the inflammatory cascade occur with surgery. As inflammation plays a crucial role in postoperative ileus, intravenous local anesthetics may produce their beneficial effects on accelerating gastrointestinal motility by targeting different steps within this inflammatory cascade. Perioperative administration of lidocaine significantly attenuated the surgery-induced elevation of complement and proinflammatory cytokines, such as IL-8 and IL-6 that is well known for its role in maintaining postoperative ileus.[891011131415]

This explains our results in i.v. lidocaine group where there were significantly lower levels of inflammatory cytokines and accelerated return of bowel function.

The target of the present study was to find a simpler and safer method for lidocaine administration than i.v. rout to avoid iatrogenic mistakes. Therefore, we designed this study to evaluate the lidocaine patch as a substitute to i.v. lidocaine. Because of its proven efficacy and safety profile, the lidocaine patch 5% has been recommended as a first-line therapy for the treatment of the neuropathic pain of post herpetic neuralgia[2021] and in other pain conditions as myofascial pain,[22] low back pain,[23] carpal tunnel syndrome,[24] osteoarthritis,[25] peripheral neuropathy,[26] and leg ulcers.[27]

The systemic absorption from the lidocaine patch was minimal in healthy adults when four patches applied for up to 24 h/day.[21]

The patch delivers adequate amounts of lidocaine to block sodium channels reducing either generation or conduction of peripheral pain impulses in damaged and dysfunctional nociceptors at site of application, but insufficient amounts to block sodium channels on thick myelinated Aβ sensory fibers. It does not produce local anesthesia (the skin under the patch has normal sensation).[28] The amount systemically absorbed is 3-5% of the total dose of the patch (700 mg), mean peak blood concentration of lidocaine is about 0.13 μg/mL. The amount of drug absorbed is directly related to the skin area covered and the duration of patch application.[29]

Which while succeeded in decreasing pain scores and morphine consumption the lidocaine patch failed to decrease the levels of proinflammatory cytokines or accelerating the return of bowel function that may be referred to the minimal systemic absorption of lidocaine from the patch.

In agreement with our study the double blind, placebo controlled study,[17] in patients undergone retropubic prostatectomy under general anesthesia they received a lidocaine patch around the wound or placebo. They found significant decrease in pain scores in patch group during cough, interference of pain with their mood, walking, and breathing. As well as in our study patch did not affect return of the bowel function.

In the same line of our results, Kaba et al,[9] in their study on patients undergone laparoscopic colectomy, when administered a bolus injection of 1.5 mg/kg lidocaine at anesthesia induction, then a continuous infusion of 2 mg/kg/h for 24 h postoperatively. They found that postoperative pain scores, opioid consumption, time to first flatus, first defecation and length of hospital stay, all were significantly lower in lidocaine group versus the control group.

In a previous study, Herroeder et al,[13] found that patients undergone open colorectal surgery who received bolus 1.5 mg/kg i.v. lidocaine before anesthesia induction, followed by a continuous lidocaine infusion (2 mg/min) for 4 h postoperative, had accelerated return of the bowel function and lower plasma levels of IL-6, IL-8 and complement C3a, as our results in group 2 (i.v. lidocaine). However, against our results no difference was observed in pain scores or morphine consumption in lidocaine group. This difference may be explained by shorter time of lidocaine infusion in that study in comparison to our study.

After major abdominal surgery including prostatectomy, cystectomy, nephrectomy, and colectomy, Koppert et al,[30] examined the effects of systemic lidocaine on morphine consumption and found significant reduction in the lidocaine group, but pain at rest and time to first bowel movement were similar to the control group. They explain their results by prevention of central hyperalgesia.

With other types of surgery, Groudine et al,[14] carried out a prospective, blinded, randomized, controlled trial of i.v. lidocaine in patients undergone radical retropubic prostatectomy and found that, patients in the lidocaine group reported statistically significant differences in pain scores, faster time to first flatus and first bowel movement, and shorter hospital stays than the control group.

In a study comparing epidural bupivacaine and i.v. lidocaine in patients undergone open colorectal surgery, the researchers observed that the tow techniques are equal in enhancing return of bowel function and decreasing postoperative pain. They returned this to the anti-inflammatory effect of local anesthetics that prevent postoperative ileus. They recommended the i.v. lidocaine route to avoid risk of epidural with anticoagulants, technical difficulties with obesity, patient refusal, and simplicity of the i.v. rout.[31]

All the previous studies demonstrate the beneficial effects of the systemic lidocaine on pain reduction, morphine consumption or enhancement of the bowel function return. The beneficial effect on postoperative ileus mainly related to diminishing the inflammatory response,[1331] although associative and further mechanisms of action may exist. Since local anesthetics in the micromolar range is known to exert their anti-inflammatory actions in a time-dependent manner.[3233] In our study, we used lidocaine infusion in a low dose but longer time than most of the previous studies to get the best anti-inflammatory effects, also, we expected that lidocaine patch through its systemic absorption with stable and long time of the plasma lidocaine level may be comparable to the intravenous route which not proved. This may be explained that the systemic dose of the patch did not reach the level needed to exert the anti-inflammatory action but still this also on the side of its safety.

In conclusion, lidocaine patch 5% around the surgical wound significantly reduced pain scores and morphine consumption equal to perioperative i.v. lidocaine infusion in patients undergoing laparoscopic colorectal surgery. While i.v. lidocaine infusion significantly enhanced return of the bowel function, the lidocaine patch failed in this point. Still, the lidocaine patch modality might be a valuable adding to a multimodal approach to postoperative analgesia coupling the negligible systemic delivery and low risk of side effects or drug interactions with the simplicity of the technique.