Postoperative pain and effective analgesic treatment after laparoscopic cholecystectomy has remained a clinical challenge. Levetiracetam, a novel broad spectrum antiepileptic, has shown analgesic properties in animal models and human volunteers.1,2 The aim of the present study was to evaluate the effect of levetiracetam on pain intensity and analgesic consumption after laparoscopic cholecystectomy.
This prospective, randomised, double-blind, placebo-controlled study was carried out after obtaining approval from the local ethical committee on 2 December 2013 (Institutional Ethical Committee, Nazareth Hospital, Memo No: NH/CMO/IEC/13-7) and written informed consent from all patients. The study protocol was registered prospectively at clinical trial registry of India (CTRI/2013/12/004255). Total 120 patients, aged 18 to 70 years, of ASA physical status I and II, scheduled for laparoscopic cholecystectomy, were included in the study. Exclusion criteria were BMI less than 19 and more than 35 kg m–2, known sensitivity to the study drugs, inability to tolerate oral medication or understand pain score, history of severe cardiac, renal, hepatic and respiratory disease as well as patients on chronic pain medication, anticonvulsants or antidepressants.
A resident doctor not participating in the trial prepared the randomisation sequence using ‘research randomiser’ software (http://www.randomizer.org/) before starting the study.
The patients were randomly assigned into two groups to receive a tablet of either placebo or levetiracetam 500 mg. (Brand name: Leveroxa, Manufacturer: Ranbaxy; Laboratories Limited, Gurgaon, India). A nurse, not participating in the study, gave one tablet in sequentially numbered, sealed, opaque envelopes to all the patients 2 h before surgery, after assessing preoperative anxiety by means of visual analogue score (VAS), where 0 indicated no anxiety and 100 indicated the worst imaginable anxiety. Patients, investigators and outcome assessors were not aware of the type of medication that had been given.
All patients received the same standardised general anaesthetic. Acute postoperative pain both at rest and during movement (on coughing) was assessed using VAS on which 0 indicated ‘no pain’ and 100 represented ‘worst imaginable pain’. Pain scores were recorded 0, 1, 3, 6, 18 and 24 h postoperatively, where 0 indicated arrival at postoperative care unit. Postoperative analgesia was maintained with infusion of paracetamol 1 g eight hourly. Patients requiring more analgesic or reporting VAS scores more than 30 received 50 mg of intravenous (i.v.) tramadol as rescue analgesic.
Primary outcome was the severity of postoperative pain as assessed by VAS scores at rest. Postoperative VAS on movement, rescue analgesic requirements and incidence of side effects such as generalised weakness, irritability, agitation, emotional liability, confusion, increased reflexes or paraesthesia were secondary outcomes.
The superiority sample size was calculated on the basis of VAS for pain assessment following laparoscopic cholecystectomy, reported previously.3 Assuming that levetiracetam would decrease VAS score by 30% (from 50 to 35) [standard deviation (SD 28)], level of significance α = 0.05 and power analysis β = 0.20 revealed that 55 patients should be enrolled in each group. We enrolled 60 patients in each group to minimise the effect of dropouts or missing data.
Mann–Whitney U test was used to compare the two groups in terms of age, BMI, duration of surgery, level of preoperative anxiety, postoperative pain and total dose of rescue analgesia. Chi-square test was done to detect significant difference between the two groups with respect to male: female ratio and the proportion of patients who did not receive adequate pain relief. Data were presented as median (interquartile range, IQR), numbers (n) and percentages (%). The package SPSS 17.0 (SPSS Inc, Chicago, Illinois, USA) and Graphpad Instat were used for statistical analysis. P value less than 0.05 was considered significant. The method of analysis incorporated the intention-to-treat principle.
Both groups were comparable regarding patient characteristics, preoperative level of anxiety and duration of surgery. Postoperative pain intensity at rest and on movement in terms of VAS scores did not differ between the groups (Table 1). Forty patients in the control group and 42 patients in the levetiracetam group required rescue analgesia. Median (min-max) doses of rescue analgesic were 50 mg (0 to 150 mg) and 50 mg (0 to 250 mg) of tramadol in the control and the levetiracetam groups, respectively, and there was no significant difference between the groups. (Mann–Whitney U statistics = 1670.0, P = 0.5146). No adverse effects were observed in either of the groups.
Levetiracetam binds to the SV2A (a synaptic vesicle glycoprotein), inhibiting calcium channels and reducing neurotransmitter release.4 The precise mechanism of its analgesic action is unknown. Levetiracetam may exert its antihyperalgesic action through various receptors such as GABAA, opioid, 5-HT and α2 adrenoreceptors.5 In an experimental animal study, levetiracetam administered to rats at the dose of 540 mg kg−1 produced an antihyperalgesic effect in two models of human neuropathic pain.1 In another trial, 1500 mg levetiracetam significantly increased pain threshold in healthy volunteers.2 On the contrary, the present study for the single dose of 500 mg failed to demonstrate an analgesic effect of levetiracetam. Similar results were reported by another study in which levetiracetam failed to reduce postmastoidectomy pain.6
The strength of the study is in the lack of previous randomised controlled trials investigating the effect of levetiracetam on postoperative pain. The low dose of levetiracetam we used is the limitation of our study. A clinical study investigating the effect of levetiracetam on the generalised social anxiety started with low doses and increased doses over a week.7 Anticipating a possible increase in the incidence of untoward effects, we avoided administering a higher single dose of levetiracetam. However, a dose–response study is required to prove or refute the role of levetiracetam as analgesic adjuvant in various types of acute or chronic pain.
In conclusion, the result of the present study showed that 500 mg of levetiracetam when given preoperatively did not decrease postoperative pain or analgesic requirements after laparoscopic cholecystectomy.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: all support was provided by Nazareth Hospital.
Conflict of interest: no conflict of interest was declared by authors.
1. Ardid D, Lamberty Y, Alloui A, et al. Antihyperalgesic effect of levetiracetam in neuropathic pain models in rats. Eur J Pharmacol
2. Enggaard TP, Klitgaard NA, Sindrup SH. Specific effect of levetiracetam in experimental human pain models. Eur J Pain
3. Agarwal A, Gautam S, Gupta D, et al. Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy. Br J Anaesth
4. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antepileptic drug levetiracetam. Proc Natl Acad Sci U S A
5. Micov A, Tomić M, Popović B, Stepanović-petrović R. The antihyperalgesic effect of levetiracetam in an inflammatory model of pain in rats: mechanism of action. Br J Pharmacol
6. Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Effect of levetiracetam on the postmastectomy pain syndrome. Eur J Neurol
7. Stein MB, Ravindran LN, Simon NM, et al. Levetiracetam in generalized social anxiety disorder: a double-blind, randomized controlled trial. J Clin Psychiatry