A single dose of preoperative gabapentin for pain reduction and requirement of morphine after total mastectomy and axillary dissection: Randomized placebo-controlled double-blind trialVK Grover, PJ Mathew, S Yaddanapudi, S Sehgal
Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.58928
Source of Support: None, Conflict of Interest: None
Background : Gabapentin has been recently found to be useful for reducing acute postoperative pain when administered preoperatively. Although various dose regimens have been tried in different surgical settings, the minimum effective dose is not established. Aims : We aimed to evaluate the analgesic efficacy of single low dose gabapentin in patients undergoing total mastectomy and axillary dissection. Settings and Design : Prospective randomized placebo-controlled double-blind trial in a tertiary care teaching hospital. Materials and Methods : Fifty women scheduled for total mastectomy and axillary dissection were randomized to receive either gabapentin 600 mg or placebo orally 1 h preoperatively. The intraoperative and postoperative management was standardized. Postoperative pain was assessed at rest and on movement for 12 h using the numerical rating scale (NRS). Morphine was administered if NRS exceeded 30. Primary outcome measure was total morphine consumption. Statistical Analysis : The morphine consumption was compared using independent t test while pain and sedation scores were analyzed using Mann-Whitney U test. Results : Forty-six patients completed the trial. The postoperative morphine consumption was significantly less (5.8 ± 4.2 vs. 11.0 ± 3.4 mg; P < 0.001) and the median [IQR] time to first analgesic was significantly longer (90 [37.5-120] vs. 0 [0-90] min; P < 0.001) in the gabapentin group than in the placebo group. The incidence of side effects was similar in the two groups. Conclusions : A single low dose of 600 mg gabapentin administered 1 h prior to surgery produced effective and significant postoperative analgesia after total mastectomy and axillary dissection without significant side effects.
Keywords: Gabapentin, mastectomy, postoperative analgesia
Gabapentin is an anticonvulsant drug that is widely and effectively used for the treatment of chronic neuropathic pain. , Gabapentin has also been used in a few studies to relieve postoperative pain though its use in reducing acute pain is not well established.  It has been found to decrease the pain scores and analgesic requirements following total abdominal hysterectomy, , laparoscopic cholecystectomy,  spinal surgery  and ear, nose and throat (ENT) surgery.  Although the molecular mechanism of action of gabapentin is not clear, it is thought to alter the central neuronal sensitization (that amplifies postoperative pain) without affecting the pain transmission. Therefore, when used as a preemptive analgesic, gabapentin may reduce acute postoperative pain.  Our aim was to investigate the safety and efficacy of single preoperative oral administration of low dose gabapentin (600 mg) on morphine consumption (primary outcome measure) and pain scores (secondary outcome measure) in the postoperative period after total mastectomy and axillary dissection.
After approval of the Institutional Ethics Committee and written informed consent of the patients, a randomized, double-blind and placebo controlled trial was conducted in women undergoing total mastectomy with axillary dissection. Fifty American Society of Anaesthesiologists (ASA) I or II women aged 18-75 years were enrolled in the study. Patients with history of allergy to gabapentin or morphine, drug or alcohol abuse, chronic intake of analgesics or corticosteroids, intake of nonsteroidal antiinflammatory drug 24 h prior to surgery were excluded. Obese patients (Body Mass Index > 30 kg/m 2 ) and those scheduled for breast reconstructive procedure in the same sitting were also excluded.
During the preoperative evaluation, patients were familiarized with the 100 point numerical rating scale (NRS) where 0 represents no pain and 100 represents worst imaginable pain. They fasted for at least 8 h preoperatively and were premedicated with diazepam 5 mg on the night prior and on the morning of surgery.
Patients were randomly assigned to receive 600 mg of gabapentin (2 capsules of 300 mg each) (Group G) or 2 placebo capsules (Group P) orally 1 h before surgery. The placebo capsules were green capsules identical to gabapentin containing vitamin B-complex and were prepared in the hospital pharmacy. The allocation sequence was generated from a standard random number table by one of the investigators not involved in the outcome assessment. Allocation was concealed using opaque sealed coded envelopes. The anesthesiologist involved in the intra-operative anesthetic management and the investigator performing the outcome assessment were blind to the drug administered.
General anesthesia was induced with propofol 1.5-2.5 mg/ kg. Vecuronium 0.1mg/kg was given to facilitate tracheal intubation. Morphine in a dose of 0.1mg/kg intravenously was used for analgesia during the surgery. Intra-operative monitoring consisted of continuous electrocardiogram, noninvasive blood pressure (NIBP) and pulse oximetry and end-tidal carbon dioxide. Anesthesia was maintained with propofol infusion at a rate of 75-100 mg/kg/minute, titrated according to the blood pressure. Rescue analgesic (morphine 0.05 mg/kg intravenously) was administered during the procedure in the event of hypertension or tachycardia exceeding 20% of the baseline after ensuring adequate muscle relaxation and anaesthesia. Intravenous ondansetron 4mg was given 30 min before the end of surgery. The infusion of propofol was terminated at skin closure. At the end of surgery, neuromuscular blockade was antagonized with 0.05 mg/kg neostigmine and 0.02 mg/kg atropine and the trachea extubated.
Patients were shifted to postanesthesia care unit (PACU) postoperatively. Pain, sedation, nausea, vomiting and other side effects were assessed every 30 min for the first 2 h and then at two hourly intervals for next 10 h (i.e. until 12 h post-op). Pain was assessed at rest and on movement (supine to sitting position) using NRS. Morphine in the dose of 0.05 mg/ kg was administered in case NRS exceeded 30. Total morphine consumption during this 12-h period was recorded. No other analgesic was administered during the study period.
Sedation was assessed using the Observer's Assessment of Alertness/Sedation scale (OAA/SS).  Nausea and number of episodes of vomiting were recorded. Ondansetron 4 mg i.v was administered if patient experienced severe nausea or an episode of vomiting. Patients were observed for other side effects of gabapentin, namely, dizziness, headache, visual disturbances and light-headedness.
A sample size of 22 patients per group was needed to detect at least 20% decrease in postoperative morphine consumption at a significance level of 5% and power of 90%. We included a total of 50 patients to account for possible attrition. Data were checked for normality prior to analysis.
The continuous data are expressed as mean ± standard deviation and nonparametric data as median and interquartile range. The demographic data in the two groups were compared using two sample Student's t test. The morphine consumption in the two groups was analyzed using independent t test. The pain and sedation scores in the two groups were analyzed using Mann-Whitney U test. The incidence of side effects was compared using Chi-square test. All analyses were performed using SPSS v13.0 for Windows (SPSS Inc., Chicago IL) and a P < 0.05 was taken to be significant.
Fifty patients were enrolled in this study, 23 patients in placebo group and 27 in gabapentin group [Figure 1]. Four patients were excluded as the surgery was postponed due to lack of time, resulting in 21 patients in placebo and 25 in gabapentin groups. The demographic data were comparable in the two groups [Table 1]. The intra-operative morphine requirement was similar in both the groups [Table 1].
Postoperative morphine consumption was 48% less in gabapentin group than placebo group, which was statistically significant. Also, time to first rescue analgesia was significantly longer in gabapentin group than placebo group [Table 2]. The median postoperative pain scores at rest as well as on movement were higher in placebo group than gabapentin group at most of the measurement times [Figure 2] and [Figure 3].
The sedation scores were similar in the two groups. The overall incidence of postoperative vomiting was 30.4% and was similar in the two groups. The incidence of nausea was also similar [Table 3]. The other side-effects like headache, dizziness and light-headedness were comparable between the two groups.
We found that preemptive administration of a single oral dose of 600 mg of gabapentin led to a decrease in postoperative analgesic requirement and pain scores as compared to placebo without undue sedation or other side effects. A decrease in opioid requirement in gabapentin-treated patients has been shown in patients undergoing hysterectomy, , laparoscopic cholecystectomy,  discectomy,  nephrectomy,  and thyroid surgery.  There is mounting evidence from two meta analyses supporting analgesic and opioid sparing effects of gabapentin in the peri-operative period similar to our findings. , The commonly used regimen of gabapentin for postoperative analgesia is either single dose of 1200 mg ,,, or multiple doses of 300-600 mg. , Pandey et al., demonstrated ceiling effect of 600 mg of gabapentin in a dose-response study in lumbar discectomy and no additional benefit at 900 mg or 1200 mg.  As the surgical stimulation is different, the analgesic requirements may vary following different surgical procedures. The earlier study in mastectomy used single oral dose of 1200 mg of gabapentin preoperatively and found it to be effective in relieving postoperative pain.  We had planned to assess the analgesic effect of a lower dose in mastectomy and therefore, ours is the first study to demonstrate the postoperative analgesic efficacy of single low dose (600 mg) of gabapentin in mastectomy.
The pain scores at rest were significantly lower in the gabapentin group during the first 4 h, whereas the pain scores during movement were significantly lower throughout the study period. The mechanism of action of gabapentin in the postoperative period is explained as prevention or reduction of development of central neuronal hyperexcitability induced by surgical procedure.  This hypothesis is supported by our findings that evoked pain during movement, that is during augmented afferent transmission to the dorsal horn neurons, was significantly decreased, whereas the pain at rest was affected to a lesser extent. Similarly, Fassoulaki et al.,  had demonstrated that pain scores on movement during second to fifth postoperative day were lower in gabapentin group in patients undergoing mastectomy. They found no significant difference in pain scores at rest in gabapentin and placebo groups. Similar findings were also observed by Dierking et al.,  in patients undergoing abdominal hysterectomy and by Dirks et al.,  in patients undergoing mastectomy.
Another proposed mechanism of action of gabapentin is suppression of secondary hyperalgesia due to withdrawal of opioids.  Dirks et al., used remifentanyl as the intra-operative opioid which has a brief duration of action.  Thus, withdrawal of opioid action in the immediate postoperative period led to secondary hyperalgesia and this hyperalgesia was suppressed by gabapentin. The contribution of this mechanism of action in our study cannot be commented upon as we used morphine for intra-operative analgesia, which has a long duration of action extending into the postoperative period. The findings of our study would have been more meaningful if we had studied the effect of peri-operative analgesia from gabapentin 600 mg on development of chronic pain after mastectomy.
Although postoperative analgesic consumption is the primary outcome in many studies, time to first rescue analgesia is another useful outcome.  We measured the time to first rescue analgesia which was longer in the gabapentin group compared to placebo group. Also, in gabapentin group, only four out of 25 patients required morphine immediately after transfer to recovery room as compared to 19 out of 21 patients in the placebo group. Recently, McQuay et al., contended that trials that are able to achieve similar pain intensity scores with different intervention groups should in theory constitute stronger evidence.  However, they were not able to prove this hypothesis in their study. In the current study, gabapentin group consumed less morphine postoperatively and experienced less pain than the placebo group. A possible explanation could be that we administered intermittent boluses of intravenous morphine for postoperative analgesia after assessing NRS for pain. Such analgesic protocol would lead to recording of higher pain scores as analgesic is administered according to the pain score. On the contrary, a patient controlled analgesia system may ensure that the pain scores are below 30 more consistently.
The side effects of peri-operative gabapentin include dizziness, somnolence, confusion, ataxia, nausea, vomiting and headache. , In our study we found that the incidence the adverse events were comparable in the two groups. The sedation scores were also comparable. A reduction in pain score and morphine consumption would seem to predict a lower incidence of opioid-related side effects including sedation. The sedative effect of morphine, which was required in larger amount in the placebo group, was probably countered by the sedative effect of gabapentin in the treatment group.
In addition to sedation, opioids contribute to variety of postoperative adverse events including respiratory depression, pruritis, nausea, vomiting, urinary retention and cognitive dysfunction. , In a study by Dierking et al., dose of gabapentin up to 3200 mg was used and none of the patients experienced postoperative respiratory depression.  The opioid sparing effect also appears to facilitate the recovery of bowel function and may allow patient to rapidly resume activities of daily life. 
Our study is limited by the facts that the study period was only 12 h postoperatively missing out on a possible longer duration of effect of preoperative gabapentin  and the trial evaluated only 600 mg of gabapentin. A dose-ranging study is warranted to determine the lowest dose with maximum efficacy for postoperative analgesia in mastectomy.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]