Comparative study between 2 different doses of pregabalin and lidocaine on pain following propofol injection: A double-blind, randomized clinical consort study.

BACKGROUND: Propofol, an intravenous anesthetic, often causes pain on injection, which can be very distressful to patients. We investigated the analgesic effect of pregabalin on pain following propofol injection, compared with lidocaine.
METHODS: In a randomized, double-blind, prospective trial, 120 patients were randomized into 3 groups of 40 each; who received oral placebo and intravenous lidocaine 40 mg with venous occlusion for 1 minute (group L, n = 40), oral pregabalin 75 mg and intravenous normal saline with venous occlusion for 1 minute (group LP, n = 40), and oral pregabalin 150 mg and intravenous normal saline with venous occlusion for 1 minute (group HP, n = 40) as pretreatment, followed by administration of 1% propofol 0.5 mg/kg. Pain intensity was measured on a 4-point scale (0 = no, 1 = mild, 2 = moderate, and 3 = severe pain). Any side effects associated with pretreatment substances were recorded during the first 24 hours after surgery.
RESULTS: A total of 120 patients completed this trial. Demographic data were similar between groups. The incidence of pain following propofol injection was significantly reduced in group HP (50%) and group L (55%) compared with group LP (92.5%) (P < 0.05, respectively). The incidences of moderate pain in group HP (12.5%) and group L (15%) were significantly decreased compared with group LP (37.5%; both, P < 0.05). There were no significant differences in the incidence of side effects such as headache and dizziness between groups.
CONCLUSION: Pretreatment with oral pregabalin 150 mg and intravenous lidocaine 40 mg with venous occlusion equally reduced pain from propofol injection.

RCT Entities:   Population Interventions Outcomes

Introduction

Propofol (2, 6-diisopropylphenol) is a widely used intravenous anesthetic agent to induce general anesthesia.[ However, pain following propofol injection is one of distressful adverse effects of propofol, which occurs in 60% to 80% of patients receiving propofol via peripheral vein on the dorsum of hand.[ Several methods including pretreatment with lidocaine with venous occlusion or premixed lidocaine with propofol have been tried to attenuate pain during propofol injection. Among these methods, pretreatment with lidocaine with venous occlusion is the most effective method in preventing pain following propofol injection.[ However, unfortunately this treatment could not abolish the pain. It is reported that the amount of free propofol in the aqueous phase of the emulsion is positively associated with injection pain. Therefore, propofol long-chain triglycerides (LCT)/medium-chain triglycerides (MCT) was introduced in attempts to prevent injection pain by reducing the concentration of aqueous-free propofol.[ However, pain can occur up to 47% during injection of propofol-LCT/MCT.[ It was demonstrated that pretreatment with lidocaine with venous retention before injection of propofol LCT or lidocaine premixed in propofol LCT were more effective in reducing pain than a more expensive reformulation of propofol-LCT/MCT.[

Pregabalin, a synthetic molecule derived from gamma-amino butyric acid (GABA) inhibitor, has anticonvulsant and analgesic effects. Pregabalin is recommended as first-line treatments for neuropathic pain disorders.[ In addition, this agent is known to be effective for treatment of incisional inflammatory pain. Many studies demonstrated that preoperative administration with pregabalin effectively decreased pain severity and opioid requirement after various surgeries.[ However, up to date, there is no study about the effect of pregabalin on pain following propofol injection. Therefore, we evaluated the effect of pretreatment with oral pregabalin 75 and 150 mg on pain from propofol injection, compared with intravenous lidocaine 40 mg with venous occlusion.

Methods

Patients and exclusion criteria

A total of 120 patients (20–60 years) with American Society of Anesthesiologists physical status I or II were studied. Patients with a history of adverse response to any drugs, renal or cardiac disease, neurologic deficits and psychiatric disorders, active alcohol or drug usage, or intake of any sedatives, analgesics, or anticonvulsants within 24 hours before surgery were excluded.

Anesthesia and data collection

The present study was approved by the Ethics Committee of Kyungpook National University Hospital (KNUH 2015-03-037-001), and informed written consent was obtained from all patients. This study was registered in the ClinicalTrials.GOV (NCT02668094).

Using a computerized randomization table, patients were randomly assigned to 1 of 3 groups (Fig. 1). The lidocaine group (group L, n = 40) received oral placebo capsules containing sugar, pregabalin 75 group (group LP, n = 40) received oral pregabalin 75 mg, and pregabalin 150 group (group HP, n = 40) received oral pregabalin 150 mg at 2 hours before the anesthetic induction, respectively. The placebo and pregabalin were provided in identical white capsules by a pharmacist who was not involved in this study.

Figure 1

Flow diagram of the study.

Preanesthetic sedative or analgesic was not administered. On arrival at the operating room, standard monitoring devices including noninvasive blood pressure, electrocardiogram, and pulse oximetry were applied, and a 22-ga cannula was placed into the vein on the dorsum of the nondominant hand. After venous occlusion using a rubber tourniquet, patients in group LP and HP received 2 mL of normal saline and patients in group L received 2 mL of 2% lidocaine intravenously, respectively. A physician who was not involved in this study prepared identically coded syringes. After 1 minute, venous occlusion was released and propofol 0.5 mg/kg was administered at the rate of 0.5 mL/s using syringe pump.[ Pain following propofol injection was assessed by a study blinded anesthesiologist using a 4-point scale: 0 = no (negative response to questioning), 1 = mild pain (pain reported only in response to questioning without any behavioral signs), 2 = moderate pain (pain reported in response to questioning and accompanied by a behavioral signs or pain reported spontaneously without questioning), and 3 = severe pain (strong vocal response or response accompanied by facial grimacing, arm withdrawal, or tears).[ Thereafter, propofol 1.5 mg/ kg was administered for induction of anesthesia. After loss of an eyelash reflex, rocuronium 0.8 mg/kg was injected and tracheal intubation was performed. Anesthesia was maintained by a mixture of air and oxygen supplemented with sevoflurane and continuous infusion of 0.05 to 0.3 μg/kg/min of remifentanil. During the first 24 hours after surgery, any side effects (e.g., dizziness, drowsiness, and visual disturbance) were assessed by a blinded investigator.

In this study, the incidence of pain during propofol injection was primary outcome, and secondary outcomes were adverse effects of pretreatment substances.

Sample size

Based on the literatures, the incidence of pain following propofol injection is assumed as 80%.[ When a 50% reduction in pain is considered as a clinically significant endpoint, calculated minimum sample size for each group was 40 patients with a type I error of 0.05 and a test power of 80%.

Statistical analysis

Data analysis was performed using statistical software (SPSS, version 18.0 for Windows; SPSS, Chicago, IL). One-way analysis of variance was used for continuous variables. The incidences and the severities of pain following propofol injection were compared between groups with Fisher exact test or the Mann–Whitney U test, respectively. Statistical significance was accepted at P < 0.05.

Results

A total of 120 patients completed this study (Fig. 1). There were no statistical differences in demographic data (Table 1). The overall incidence of propofol injection pain was significantly decreased in group L (55%) and group HP (50%), compared with group LP (92.5%) (P < 0.05, respectively). The incidences of moderate pain in group L (15%) and group HP (12.5%) were significantly decreased, compared with group LP (37.5%; both, P < 0.05). The incidences of severe injection pain in patients receiving pregabalin 75, 150 mg, and lidocaine were 12.5%, 0%, and 0%, respectively, but there were no significant differences in the incidences of severe pain between groups (Table 2). There were no significant differences in the incidence of adverse effects such as dizziness and drowsiness during 24 hours after operation between groups (Table 3).

Table 1

Demographic data of the study population (n = 120).

Table 2

Pain during propofol injection.

Table 3

Side effects.

Discussion

In this study, pretreatment with oral pregabalin 150 mg was significantly effective in attenuating pain on propofol injection, compared to pretreatment with oral pregabalin 75 mg. Pregabalin 150 mg was compatible with intravenous lidocaine 40 mg with venous retention for preventing propofol injection pain. There were no differences in the incidence of side effects such as headache, dizziness, and drowsiness between groups.

Lipid emulsion propofol is commonly used for sedation and induction of general anesthesia. But pain from propofol injection is one of the most common adverse effects, which often distresses patients.[ The exact mechanism of pain on propofol injection is unclear. The pain following propofol injection is thought to arise from direct stimulation of nociceptive receptors or free nerve ending in the vessels by free propofol molecules.[ In addition, free propofol activates the kallikrein kinin system which releases inflammatory factors such as bradykinin, resulting in increase of permeability and dilation of vein. In this bradykinin-modified vein, contacts between free propofol and free nerve ending increases, leading to pain on injection.[ Pretreatment with various drugs including lidocaine, opioid, and nitroglycerin have been tried for the prevention of injection pain. By a systematic review conducted in 2000, pretreatment with lidocaine 40 mg plus venous occlusion was suggested as the most effective intervention for preventing pain on propofol injection.[ Pretreatment with lidocaine plus venous occlusion decreases injection pain by local anesthetic effect on vein and stabilizing the kinin cascade. However, this cannot completely alleviate pain following propofol.[ Propofol LCT/MCT which contains lower concentration of free propofol than standard propofol was introduced to reduce injection pain.[ However, despite of pretreatment with lidocaine, pain still occurs during injection of propofol-LCT/MCT.[ In the previous study, when premixed with lignocaine, there was no difference in the incidence of pain between propofol LCT and propofol LCT/MCT.[

The fundamental mechanism of action of pregabalin is the reduction of release of calcium by binding to α2-δ subunit of calcium channels, which inhibit excitatory neurotransmitter including glutamate and increase neuronal GABA levels.[ In addition, it was found that opioid spinal pathway is involved in the analgesic actions of pregabalin in mice.[ Recently, it has been used as a multidimensional analgesia for postoperative pain in various surgeries including dental, laparoscopic cholecystectomy, and spine surgery.[

Orally administered pregabalin is rapidly absorbed with maximum plasma concentrations attained with 1.3 hours and has a bioavailability of 90% with elimination half-life of 6 hours.[ Therefore, in the present study, oral pregabalin was administered 2 hours before general anesthesia. Dizziness and drowsiness are common side effects of pregabalin.[ The previous studies demonstrated that premedication with pregabalin 150 mg could be optimal dose for improving postoperative analgesia without an increase of adverse effects.[ In the present study, pretreatment with 150 mg pregabalin was effective in reducing propofol injection pain, which was comparable with pretreatment with lidocaine 40 mg with venous retention. In addition, there was no significant differences in the incidence of side effects of pregabalin such as drowsiness and dizziness between groups.

The present study had some limitations. First, placebo group was not examined to determine the baseline incidence of pain following propofol injection. Pain during propofol injection is a common clinical problem.[ Therefore, in this study, it was considered unethical that patients given propofol did not receive prophylactic analgesics. Second, in this study, premedication was not administered, which could affect pain on injection of propofol. The incidence of postoperative recall of this pain was about 50% to 87% if sedative or anxiolytic premedication was not given.[ The recall of pain during injection of propofol can decrease patient's satisfaction with anesthetic care.[ Therefore, another study will be required to investigate the postoperative recall for this pain.

In conclusion, pretreatment with oral pregabalin 150 mg and intravenous lidocaine 40 mg with venous occlusion equally reduced pain from propofol injection.