Comparative study of single dose pre-emptive pregabalin vs. Placebo for post-operative pain relief in middle ear surgery

Objectives: The present study was designed to evaluate effect of Pregabalin on pain scores and analgesic requirements in middle ear surgeries. Methods: ASA physical status I-III adults scheduled for elective middle ear surgery under general anesthesia were taken for study. Postoperative pain severity was assessed using VAS. Two study groups were designed. Group P (Study Group) received oral Pregabalin capsule (150 mg) while Group   C (Control group) received oral placebo capsule one hour before surgery. The primary outcome was pain score in the recovery unit and patients were followed for 24 hours. Results: Pain scores were significantly lower in pregabalin group as compared to placebo group especially after 1 and 4 hours. More number of patients was sedated in pregabalin group compared to placebo. Conclusions: It can be concluded from our study that single dose preoperative pregabalin improves analgesia in early postoperative period and reduces analgesic consumption but with increased sedation without respiratory depression.

IJBAR (2014) 05 (03) www.ssjournals.com The primary end points were the pain scores during first 24 hours post operatively. Other end points include total diclofenac dose and adverse events.

Discussion
Pain during and after surgery can lead to sensitization and consequently over-sensitivity to pain, it can also transform post-operative acute pain into chronic pain. Relieving pain during an operation by administering opioids is a common practice, which can also result in undesirable side effects. In order to scale down these side effects, other non-opioid drugs can be utilized. Pregabalin is an analogue of gammaaminobutyric acid (GABA) which can be effective in dealing with post-operative pain. Studies also suggest that gabapentin 3 has a satisfactory effect in alleviating post-operative pain. Pregabalin has been introduced as the new gabapentinoid with a higher efficacy and more desirable pharmacological profile than gabapentin. Therefore, it seems that pregabalin could be a better choice in alleviating post-operative pain.

Dose
In a review done by Zhang et al; five trials with six treatment arms used a perioperative pregabalin dose of less than 300 mg/ day and combined data showed a statistically significant opioid-sparing effect of pregabalin. 1 Paech et al 2 did not observe any reduction in analgesic requirement after 100 mg pregabalin after gynec surgeries. The dose was lower compare to other studies which resulted in no effect of pregabalin on analgesia. Agrawal et al 4 gave patients a 150 mg dose of pregabalin, before a laparoscopic cholecystectomy under general anesthesia to relieve pain. The pain intensity was significantly lower in the group receiving pregabalin, than in the control group. We used same dose of 150 mg pregabalin as routinely surgeons at our institute infiltrate the operating site with xylocaine adrenaline, so less analgesia is needed.

Visual analogue scale
Balaban et al 5 studied randomized placebo controlled trial of pregabalin on post-operative pain intensity after laparoscopic cholecystectomy. They concluded that post-operative pain scores were significantly lower in pregabalin group as compared to placebo group.
Chang et al administrated pregabalin 150 mg 1 hr before and 12 hrs after an operation, but they did not find statistically significant differences in post-operative pain scores in these two groups.
Mathieson et al 8 studied effect of oral pregabalin 300 mg one hour before surgery. They studied effects of pregabalin in two different painful surgeries like hip arthroplasty and abdominal hysterectomy. No statistically significant difference was found in both groups of pregabalin and placebo.
Ghai et al 6 studied randomized controlled trial to study effect of pregabalin and gabapentin on post-operative pain after abdominal hysterectomy. They concluded that post-operative pain scores were decreased with single pre-operative dose of both pregabalin and gabapentin after initial hour of recovery which was consistent with our study. There was no difference after initial hour. They concluded that it may be due to the fact that both drugs have a relatively shorter half-life and given as single dose pre-operatively.
Kim et al 7 studied effect of pregabalin on post-operative pain after mastectomy. Assessment of pain scores were done in both pregabalin and placebo group 1, 6, 24 and 48 hours after surgery. VAS scores were significantly lower in pregabalin group as compared to placebo group in initial 8 hours.
In our study patients were given oral pregabalin 150 mg 1 hr before surgery. Post-operative pain was assessed in the recovery room with the help of visual analogue scale (VAS) 0,1,2,4,8,12 and 24 hrs post-operatively. Pain scores were significantly lower in pregabalin group as compared to placebo group especially after one and four hrs which is concurrent with the many of the studies stated above.
The difference in results may be due to variation in the pain depending on surgery and whether it is visceral or somatic. In our study for ear surgery, pregabalin was effective in reducing VAS scores.

Post-operative Diclofenac requirement
Patients with pain scores of 3 or more were given inj. diclofenac sodium 75 mg. Number of diclofenac doses required were calculated and total analgesic consumption were recorded in 24 hrs. It was observed that total numbers of patients requiring diclofenac were significantly lower in pregabalin group as compared to placebo group.
Several studies have been done on pre-operative pregabalin use and post-operative analgesic consumption which have similar results as compared to our study.
Gilron I 10 et al concluded that Pregabalin reduced movement evoked pain with additional lower analgesic consumption and this lead to enhanced functional recovery post-operatively.
Zhang et al 1 in their study reported that there was statistically significant difference in opioid consumption during first 24 hours after surgery. They concluded that pregabalin had opioid sparing effect in first 24 hours. Reduction in the opioid requirement resulted in decreased incidence of post-operative nausea and vomiting.
Jokela et al 11,12 did two different studies on pregabalin. In first study they gave 300 mg oral pregabalin pre-operatively in patients undergoing laparoscopic hysterectomy. They concluded that pre-emptive pregabalin reduced post-operative oxycodone consumption with improved analgesia. In second study they gave 150 mg pre-emptive pregabalin in patients undergoing minor gynaecological surgery. They concluded that there was no difference in the amount of post-operative analgesics required.
Ghai et al 11 concluded that time to first analgesic requirement was longest in pregabalin group as compared to gabapentin group which may be due to quicker onset and better analgesia due to pregabalin.

Side effects
In our study, only side effect that was statistically significant in pregabalin group was sedation. Patients of pregabalin group had sedation in early post-operative periods. These patients had complained of mild sleepiness but patient responded normally to verbal commands. No respiratory depression was seen. Other side effects that were seen with pregabalin group were vomiting and dizziness.
Ghai et al 6 concluded that incidence of side effects did not differ in both groups except sedation and somnolence that were significant in pregabalin group.
Zhang et al 1 concluded that the incidence of postoperative vomiting was significantly lower with the use of pregabalin. This might be related to the decreased use of opioids after surgery and the consequent decrease in opioid-related adverse effects. The incidence of visual disturbance, however, was significantly higher in the pregabalin group. There were also more patients with sedation, dizziness, and headache in the pregabalin group, although no statistically significant differences were observed. These side-effects are well known and have been reported in various chronic pain trials. Therefore, pregabalin should be used with caution in ambulatory surgery. Side-effects may also influence the use of opioids. It is possible that over the more sedated patients in the pregabalin group will use less opioid. They reported that incidence of visual disturbances was high in pregabalin group.
Sharaswat et al 13 in their study concluded that most common side effects that were seen with pregabalin were sedation and somnolence in the early post-operative period that subsided over 2-3 hours.
Alimian et al 14 in their study concluded that apart from sedation, nausea and vomiting were also seen in pregabalin group but much less than in the control group. So, it was not statistically significant. Other side effects that were commonly seen with pregabalin group like dizziness and visual disorder were not seen in any of our patients.
Few limitations of our study were that we did not observe long term effect on chronic pain as gabapentinoids are known to reduced hyper sensitization to surgical pain; they may have effect on chronic pain. Our sample size is small. We did not analyze data on first demand of analgesic.

Conclusion
Our clinical study demonstrated that pre-emptive oral pregabalin reduces diclofenac requirement post-operatively which was significantly lower as compared to placebo group. Only side effect that was statistically significant was sedation which was higher in pregabalin group as compared to placebo group. So, it can be concluded from our study that single dose preoperative pregabalin improves analgesia in early postoperative period and reduces analgesic consumption but with increased sedation without respiratory depression.