Gabapentin is an anticonvulsant drug, which has been used to treat painful neuropathy in patients with diabetes mellitus, postherpetic neuralgia and neuropathic pain in general . Neuropathic pain may follow breast cancer surgery [2,3]. Gabapentin administered before breast surgery for cancer and continued for 10 days decreased cumulative analgesic requirements. The drug also decreased chronic pain characterized as burning 3 months postoperatively. One dose of gabapentin reduced postoperative pain and analgesic requirements after spinal surgery . The drug is considered to be safe, with minor adverse effects and minor interactions with other drugs . In healthy volunteers gabapentin 1200 mg given by mouth decreased mechanical allodynia in acute inflammation but did not reduce heat pain threshold .
Prevention of early postoperative pain should include interventions and strategies to prevent chronic neuropathic pain development. Unfortunately, the focus of most studies investigating postoperative pain has been limited to assess pain for a few hours after surgery only. Nevertheless, development of postoperative neuropathic pain influences patients' life negatively, and has social and economical consequences for the individual and her family. Though previous studies have investigated the effect of gabapentin on postoperative pain after hysterectomy, postoperative follow up of pain was limited to 24 h [7-9].
Our hypothesis was that gabapentin may reduce analgesic requirements after abdominal hysterectomy, and that the drug may attenuate pain experienced by the patients even 1 month after surgery. The present study was designed to assess the effect of gabapentin on pain intensity and analgesic requirements during the first 5 postoperative days after abdominal hysterectomy. The issue of late pain 1 month after surgery and the effect of gabapentin on this type of pain was also investigated.
The study was approved by the Hospital Ethics Committee and adhered to the Helsinki declaration. Sixty patients, physical status ASA I or II, scheduled for abdominal hysterectomy for benign disease, were recruited for the study. Exclusion criteria were body weight exceeding 20% of the ideal body weight, age older than 55 yr, malignancy, central or peripheral nervous system disease, chronic pain condition, consumption of analgesics, sedatives, antidepressants or calcium channel blockers. During the preoperative visit, patients signed the informed consent and were informed about the visual analogue score (VAS) for pain scoring.
Patients did not receive any premedication except for the drugs determined by the study protocol (placebo or gabapentin). In the operating room, patients were attached to a bispectral index (BIS) monitor and a standard haemodynamic monitoring (electrocardiogram, pulse oximetry, heart rate, non-invasive blood pressure). Intraoperatively, end-tidal carbon dioxide and sevoflurane concentration were also monitored. After preoxygenation for 3-4 min, anaesthesia was induced with fentanyl 5 μg kg−1, thiopentone 4-5 mg kg−1 followed by cis-atracurium 0.15 mg kg−1 to facilitate tracheal intubation and to provide muscle relaxation. To maintain anaesthesia, we administered sevoflurane in a 50% oxygen and 50% nitrous oxide mixture. The inspiratory sevoflurane concentration was titrated to maintain a BIS value between 40 and 50. Abdominal hysterectomy was performed through a Pfannenstiel incision.
Randomization, postoperative analgesia and pain assessment
Patients were randomly assigned to the control or the gabapentin group to receive placebo or gabapentin 400 mg capsules every 6 h, starting at 12.00p.m. the day before surgery and continuing for 5 days postoperatively, including the fifth day. Randomization was done with sealed envelopes containing numbers from a computer-generated randomization list, odd numbers for the control and even numbers for the gabapentin group. Placebo consisted of matching sugar capsules and prepared by the hospital pharmacy. Two bottles labelled as A and B contained the gabapentin and placebo capsules, respectively.
Postoperative analgesia for the first 48 h consisted of intravenous (i.v.) patient controlled analgesia (PCA) device with morphine. A morphine 1 mg mL−1 solution was prepared to fill the PCA device (Freedom5®; Vygon, B.P. 7, 95440 Ecouen, France). This pump allows delivery of 1 mL with a lockout interval of 7 min and is not interrogated regarding the number of demands. During the third, fourth and fifth postoperative day, patients had free access to Lonalgal® tablets, each tablet containing 500 mg of paracetamol and 30 mg of codeine. During the morphine PCA period, patients received i.v. metoclopramide 10 mg three times a day and pantoprazol 40 mg once a day.
Pain intensity was recorded at rest and during coughing. Pain at rest with the patient in the supine position and after coughing three times was assessed with a 100 mm VAS with 0 corresponding to no pain and 100 corresponding to intolerable pain. We recorded VAS scores 2, 4 and 8 h postoperatively as well as from the first to the fifth postoperative day. Pain assessment at days 1-5 was done between 8 and 9.00a.m. At the same time we recorded the consumption of morphine or Lonalgal® tablets.
Before discharge from the hospital, patients were asked to record pain and analgesic consumption at home. One month later, patients were interviewed by phone for the presence of pain (yes vs. no), intensity of pain (0: none, 1: mild, 2: moderate and 3: severe pain), absence or decreased sensation (Table 1) in the surgical area and the need for analgesics since discharge. Patients were asked to touch the area around the skin incision and the area of the epigastrium and to compare between these two sensations.
Initial sample size estimation showed that approximately 30 patients were needed in each group to detect a clinically relevant decrease in cumulative morphine consumption by 30% during the first 48 postoperative hours with a power of 0.80 and level of significance 0.05. The pilot study included seven patients in each group. Standard deviations (SD) estimated from the initial sample were 4.9 mg for gabapentin and 2.9 for controls.
We compared the patient characteristics between the two groups with the unpaired t-test and cumulative morphine and Lonalgal® tablets consumption with the U-test. We used Poisson regression to compare morphine (mg) consumption over time and Lonalgal (tablets) requirements over time between groups. To assess differences in VAS scores at rest and after cough, we used repeated measures analysis of variance. Continuous data are presented as mean ± SD. For dichotomous data, we report odds ratios (OR) with 95% confidence interval (CI). The 95% CI implies that we may be 95% confident that the OR estimate lies within the range of the interval.
Control and gabapentin groups did not differ in age (42 ± 6.2 vs. 42 ± 5.6 yr), height (164 ± 6.0 vs.166 ± 5.7 cm) body weight (65 ± 6.5 vs. 66 ± 7.8 kg), or duration of surgery (109 ± 27 vs. 110 ± 30 min). Two patients discontinued gabapentin, one due to nausea and vomiting, and one due to dizziness and ataxia. These effects may have been due to the gabapentin. Since treatment was discontinued in these patients, no data on pain and analgesic consumption were collected. The flow diagram of the study is shown in Figure 1.
During the first 48 postoperative hours, the control group consumed 35 ± 15.7 mg morphine and the gabapentin group 28.4 ± 12.1 mg (P = 0.21). Cumulative morphine consumption at 2, 4, 8, 24 and 48 h was 9.7 ± 3.5, 13.4 ± 5.1, 16.9 ± 6.3, 25.7 ± 11.2 and 35.0 ± 15.7 mg in the control group, and was 9.0 ± 4.3, 10.5 ± 4.4, 13.5 ± 5.5, 20.3 ± 7.9 and 28.4 ± 12.1 mg in the gabapentin group (F = 2.86, df = 1, P = 0.09) (Fig. 2).
During days 3-5, the control group consumed a median (range) of 1.0 (0-6) Lonalgal® tablets and the gabapentin group 2.0 (0-9) (P = 0.35). Lonalgal® consumption during the third, fourth and fifth postoperative day was 1.0 (0-4), 0.5 (0-2) and 0 (0-3) tablets in controls and was 1.0 (0-4), 1.0 (0-3) and 0 (0-2) tablets in the gabapentin group (z = 0.81, P = 0.42). The VAS scores at rest and after cough did not differ between groups (F = 0.92, df = 1, P = 0.34 and F = 0.56, df = 1, P = 0.46, respectively) (Figs 3 and 4).
Pain 1 month postoperatively
The number of patients with pain, with absent or decreased sensation and of those who needed analgesics 1 month after surgery are shown in Table 2. Patients who received gabapentin were significantly less likely to experience pain 1 month after surgery than those in the control group; OR 0.16 (95% CI, 0.05-0.53). Patients treated with gabapentin were also significantly less likely to experience high pain intensity 1 month after surgery; OR 0.36 (95% CI, 0.16-0.82).
In an attempt to prevent chronic pain after surgery for breast cancer, gabapentin was found to decrease postoperative analgesic requirements and pain at abduction of the ipsilateral arm . In the present study we did not find a significant effect of gabapentin on splanchnic pain after abdominal hysterectomy. Requirements of morphine during the first 48 postoperative hours and of Lonalgal® tablets during days 3-5 did not differ between the two groups. However, the incidence of pain at 1 month was significantly reduced in the gabapentin-treatedgroup.
Several investigators have studied the effect of gabapentin on early postoperative pain and on analgesic requirements after abdominal surgery. Gabapentin 1200 mg given 2.5 h before induction of anaesthesia for vaginal hysterectomy reduced fentanyl consumption during the first 20 postoperative hours by 40% . The gabapentin group had significantly lower VAS pain scores 2 h postoperatively and experienced less nausea and vomiting compared with the control group. The investigators concluded that gabapentin was associated with less nausea and vomiting due to a decreased need of opioids or due to a direct gabapentin-related antiemetic effect. Also, gabapentin 1200 mg 1 h before surgery followed by 600 mg, 16 and 24 h after the initial dose (total dose 3000 mg), significantly decreased morphine requirements during 24 h after abdominal hysterectomy. The investigators did not find differences in pain scores and in adverse effects as nausea, vomiting, dizziness or sedation between the two groups . Gabapentin 1200 mg administered 1 h before abdominal hysterectomy decreased postoperative tramadol consumption during 24 h and pain scores until 20 h after surgery. Sedation and the incidence of nausea and vomiting did not differ between the control and the gabapentin treated group .
Pandey and colleagues reported that 300 mg of gabapentin 2 h before laparoscopic cholecystectomy significantly decreased the analgesic requirements of fentanyl and postoperative pain scores for 24 h postoperatively. The gabapentin group was associated with a higher incidence of sedation, nausea and vomiting compared with the control group . However, these results are not consistent with the results of a previously published study in which the same dose of gabapentin given before cholecystectomy was not effective .
All these studies [7-11] are limited by the short period of postoperative follow-up that lasted no longer than 24 h. The dose of gabapentin was given 60-150 min preoperatively and varied between 1200 mg in the hysterectomy trials and was 300 mg in the cholecystectomy study. In one study only, the drug was continued postoperatively for 24 h and up to 3000 mg. Opioids were administered intraoperatively in all studies. Postoperative analgesia was with morphine, fentanyl or tramadol.
The results of these studies are not consistent regarding postoperative pain scores, and adverse effects as nausea, vomiting, dizziness and vomiting. Nevertheless, all studies except one  demonstrated a decrease in postoperative analgesic requirements 24 h postoperatively after pretreatment with a single dose of gabapentin and in one study with repeated doses within the first 24 h.
In our study, four times daily gabapentin 400 mg was started 18 h preoperatively and was continued for 6 hourly until the fifth day postoperatively. However, there was no significant effect on analgesic requirements. Also, pain scores at rest and after cough were similar between groups. We have no explanation for the different results between our study and the studies of other investigators. In a previous study we demonstrated that gabapentin decreased the need for analgesia after breast surgery with dissection of axillary lymph nodes; this effect was observed from the second to the tenth postoperative day . As this operation was associated with manipulation and possibly injury of branches of the brachial plexus block, gabapentin was likely to have a beneficial effect on nerve injury. Splanchnic pain, as pain due to hysterectomy, differs in nature and in mechanisms from nerve originating pain.
Gabapentin given orally is transported from the gut by means of a receptor link to a saturable L-aminoacid transport mechanism . Due to the saturable absorption of gabapentin, bioavailability does not increase linearly with the dose. Bioavailability with 300 mg is 60%, and is about 40% with 600 mg . These pharmacokinetic properties of gabapentin imply that divided doses over time will be more effective than a single higher dose. Our results are consistent with the results of Gregg and colleagues who however used a lower dose of gabapentin .
In healthy volunteers undergoing the cold pressure test, 600 mg oral gabapentin had no analgesic effect compared with placebo. However, when the same dose of gabapentin when given with morphine, there was an analgesic effect. Serum levels of morphine were higher when volunteers were treated with morphine and gabapentin than when given morphine alone. Thus it appears that gabapentin increases the analgesic effect of morphine . The possible enhancement of morphine analgesia by gabapentin may be useful in decreasing the dose of morphine requirements postoperatively and its adverse effects.
Though we did not find an effect of gabapentinon the need for postoperative analgesia, we found a significantly reduced incidence and intensity of pain 1 month postoperatively. To our knowledge no other studies have investigated the impact of gabapentin on the long-term postoperative pain, except the study with breast surgery for cancer . We did not record adverse effects as drowsiness, which preoperatively is desirable and postoperatively is skewed by the effect of the general anaesthetic. One patient who received gabapentin complained about nausea or vomiting. Another patient complained about dizziness and ataxia. Both patients discontinued their gabapentin treatment and were excluded from the study. However, all patients received prophylactic metoclopramide. Since we continued gabapentin administration postoperatively, we considered essential to try to prevent nausea and vomiting to enable patients to take gabapentin by mouth.
In conclusion, gabapentin, under the conditions of the study protocol, had no effect on acute postoperative pain and analgesic requirements associated with abdominal hysterectomy. Nonetheless, patients treated with gabapentin were better off 1 month after surgery regarding the incidence and intensity of pain associated with their operation.
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Keywords:© 2006 European Society of Anaesthesiology
PHARMACOLOGY; gabapentin; morphine; paracetamol; codeine; SURGICAL PROCEDURES; abdominal hysterectomy; PAIN POSTOPERATIVE