Gabapentin, an antiepileptic drug, is effective in the treatment of chronic neuropathic pain . The drug administered to diabetic patients with peripheral diabetic neuropathy reduces pain when compared to control . It is also efficacious for those patients exhibiting pain due to postherpetic neuralgia .
Gabapentin may be effective in acute postoperative pain and may decrease opioid requirements [4-6]. In fact, a pharmacokinetic and a pharmacodynamic interaction exists between gabapentin and morphine, resulting in an increased analgesic effect of morphine . Perioperative treatment with gabapentin after breast surgery for cancer decreased postoperative analgesic requirements . Also, multimodal analgesia with gabapentin and local anaesthetics was associated with less analgesic requirements, less acute postoperative pain and a lower incidence of chronic pain 3 months after breast surgery for cancer .
Several studies investigated the effect of gabapentin on postoperative pain and analgesic requirements following abdominal hysterectomy. With a total dose of 3000 mg given perioperatively, the drug reduced the analgesic requirements after abdominal hysterectomy . Gabapentin in a dose of 1200 mg given 1 h before surgery decreased pain scores and analgesic consumption during the first 24 h after abdominal hysterectomy . Other studies showed conflicting results. Thus in one study, gabapentin had no effect on opioid requirements and acute postoperative pain after abdominal hysterectomy. However, the incidence of patients who experienced late pain 1 month postoperatively was lower in the gabapentin vs. the control group .
Infiltration of the surgical wound with local anaesthetics may produce short-lasting analgesia. Several studies reported continuous or intermittent administration in the wound area with conflicting results regarding pain scores and opioid sparing effects. In patients having cholecystectomy, continuous postoperative wound perfusion with bupivacaine 0.5% for 24 h was associated with lower pain scores when compared with normal saline infusion . Also, patients undergoing cholecystectomy or splenectomy who received postoperatively bupivacaine 0.5% 10 mL twice daily for 3 days exhibited less pain and required less opioids . However, in another study, patients receiving a continuous infusion of bupivacaine 0.5% 150 mL over 60 h after cholecystectomy had no better analgesia when compared with normal saline . Levobupivacaine 12.5 mg h−1 administered intraperitoneally for 24 h after abdominal hysterectomy decreased pain and analgesic requirements . Also bupivacaine wound installation after abdominal hysterectomy had an opioid sparing effect . In other studies, bupivacaine 0.5% continuous wound infusion was not efficacious in reducing pain or analgesic requirements after abdominal hysterectomy or after surgery for gynaecologic oncology [18,19].
The present study was designed to investigate the effect of the combination of oral gabapentin given perioperatively and of ropivacaine administered into the wound as a continuous infusion on analgesic needs as well as on acute and late postoperative pain after abdominal hysterectomy. Our hypothesis was that combination of oral gabapentin and subcutaneous local anaesthetic infusion into the wound area would decrease analgesic requirements and postoperative pain.
After obtaining approval from the Hospital Ethics Committee, 60 females ASA I or II, admitted to Aretaieio Hospital for abdominal hysterectomy for no malignant disease, from 30 August 2004 until 11 October 2005, were recruited for the study. Patients were assessed the day before surgery and gave their written informed consent to participate. They were informed about the visual analogue score (VAS) for pain scoring, the PCA technique apparatus and how to use it. Exclusion criteria were age ≥59 yr, body weight more than 20% of the ideal, abnormal haemoglobin values due to fibromyoma bleeding, abnormal electrocardiogram (ECG), chronic pain, nervous system disease, and treatment with analgesics, sedatives, anxiolytics, hypnotics, antidepressants and calcium channel blockers during the last week.
Premedication was omitted. All patients received preoperatively the drugs determined by the study protocol (capsules of gabapentin or placebo). In the operating room, a peripheral vein was catheterized with a 16-G catheter and metoclopramide 10 mg and droperidol 0.750 mg were administered intravenously (i.v.). Intraoperatively ECG, heart rate (HR), non-invasive blood pressure, pulse oximetry, end-tidal carbon dioxide, and desflurane-inspired and end-tidal concentrations were monitored (S/5TM Anesthesia Monitor; Datex-Ohmeda Division, P.O. Box 900, FIN-00031, Finland). Patients were also attached to a bispectral index monitor (BIS A-2000; Aspect Medical Systems, Inc., Newton, MA, USA).
Anaesthesia was induced with propofol 2.5 mg kg−1 and morphine 0.1 mg kg−1. Cis-atracurium 0.15 mg kg−1 was given to facilitate tracheal intubation and muscle relaxation during surgery. To maintain anaesthesia, we administered desflurane in a 50% oxygen and 50% nitrous oxide mixture. Desflurane inspired concentrations were adjusted to maintain BIS values between 40 and 50. We titrated anaesthesia using BIS; hence both groups were exposed to similar anaesthetic effects on the cortex and probably exhibited similar levels of consciousness to respond to the VAS scoring questions during the early recovery period. Increases in systolic blood pressure higher than 30% of the preoperative value should be treated with nitroglycerin infusion. However, patients with increased systolic blood pressure and tachycardia should be treated with clonidine and excluded from further evaluation.
All operations were performed during the morning list, and all were performed via a Pfannenstiel incision. During uterus excision, paracetamol 1200 mg was given i.v. within 20 min. At the end of the procedure and before skin and subcutaneous tissue closure, the surgeon placed the distal end of a three-hole epidural catheter (Portex Ltd, UK) subcutaneously with the tip in the middle of the wound. The proximal end of the catheter was connected to an elastomeric pump (Baxter S.A.; Baxter Healthcare Corporation, Deerfield, IL, USA) filled with 60 mL of ropivacaine 0.75% or normal saline with a continuous infusion of 2 mL h−1.
Randomization was carried out with sealed opaque envelopes containing numbers from a computer-generated table, with even numbers assigning the patient to the treatment group and odd numbers to the control group. Patients blindly assigned to the treatment or to the control group received identical gabapentin 400 mg or placebo capsules 6 hourly, starting at 12.00p.m. the day before surgery and continuing for 7 postoperative days, the seventh day included. Therefore before start of surgery, each patient received a total dose of gabapentin 1600 mg or an equal number of placebo capsules. Placebo capsules were prepared as described in previous studies [8-9,12]. The treatment group also received subcutaneously ropivacaine 0.75% and the control group received normal saline via the epidural catheter attached to an elastomeric pump as described above; the subcutaneous infusion lasted for the first 30 postoperative hours.
Group assignment, distribution of the capsules to the patients according to group assignment, and filling the pump with local anaesthetic or normal saline was carried out by an independent anaesthesiologist who did not participate in the study and was not aware of the study protocol.
Postoperative analgesia and pain assessment
During the first 48 h, all patients had access to i.v. morphine using a PCA device allowing delivery of 1 mL of morphine with a lockout interval of 7 min (Freedom5®; Vygon, B.P. 7, 95440 Ecouen, France). This device is not interrogated regarding the number of demands. The PCA solution contained morphine 1 mg mL−1. From the third to the seventh postoperative day, patients consumed Lonalgal® tablets (30 mg of codeine plus 500 mg of paracetamol) on demand with a 6 h dosing interval.
Consumption of analgesics was recorded 2, 4, 8, 24 h postoperatively as well as on the mornings of the second to the seventh postoperative day. Pain intensity at rest and after coughing three times was recorded at the same time points using a 100 mm VAS, 0 corresponding to no pain and 100 to intolerable worst pain. Regarding assessment of late pain, thus pain 1 month after surgery, patients were instructed before discharge from the hospital to record pain and analgesic consumption at home after surgery. Patients requiring analgesics at home due to surgery were instructed to receive paracetamol 500 mg four times a day for 3 consecutive days. In case of lack of pain relief, they were instructed to contact us by phone. One month later, patients were interviewed by phone and asked to answer the following questions: (a) whether they experienced pain due to surgery including the day of the interview, (b) whether they had decreased or absent sensation around the incision area, and (c) whether they consumed analgesics as instructed since hospital discharge.
Sample size estimation
Initial sample size estimation showed that approximately 30 patients were needed in each group to detect a clinically relevant reduction of analgesics by 30% with a power of 0.80 and a level of significance of 5%. Standard deviations estimated from the initial sample size were 4.89 mg and 2.93 mg for the treatment and the control group, respectively. The assumed α error was 0.05.
To compare patients' characteristics we used t-tests for normally distributed parameters (age and weight) and U-tests for abnormally distributed parameters (height and duration). A linear mixed model on the logarithm of VAS at rest and VAS after cough was fit in order to assess treatment differences over time. This model has time and treatment as fixed effects and a random effect for subject in order to allow for correlation between repeated measurements on the same individual. The same model was applied on the logarithm of the cumulative morphine consumption. For Lonalgal® tablets consumption, a generalized estimated equations model was fit to allow for abnormal distribution over time. In all the above models, an interaction term between time and treatment was included to assess whether the differences between the two groups were constant over time. If a significant effect was found, post hoc comparisons adjusted for Bonferroni's test were carried out to assess at which time point the two groups were different. Pain, absent or decreased sensation and analgesic requirements 1 month postoperatively were compared between the two groups with the χ2-test. All the analyses were performed with Stata version 6.0 (Stata Corp., College Station, TX, USA).
The treatment and control groups did not differ in age (40 ± 7.3 vs. 40 ± 7.7 yr), height (163 ± 5 vs. 164 ± 6 cm) or body weight (63 ± 9 vs. 64 ± 7.2 kg), respectively. The duration of surgery was also similar (101 ± 25.8 min in the treatment group vs. 109 ± 26.5 min in the control group). In one patient in the gabapentin group, intraoperative systolic blood pressure increased more than 30% of the preoperative value during pulling the uterus; this was treated with nitroglycerine infusion until the manipulations were discontinued. One patient in the control group developed hypertension and tachycardia. This patient received clonidine and no data were collected as clonidine has analgesic properties and might interfere with the study protocol. In two patients, the subcutaneous epidural catheter was removed accidentally during changing the dressing. The number of patients we lost for follow-up after group assignment and the reasons are shown in Figure 1.
Cumulative morphine consumption at 2, 4, 8, 24 and 48 h postoperatively was 11 ± 3.2, 13 ± 4.4, 15 ± 5.8, 22 ± 9.1 and 31 ± 13.2 mg in the treatment group. At the same time points, the control group consumed 15 ± 5.7, 20 ± 6.8, 23 ± 7.7, 35 ± 13.8 and 50 ± 20.5 mg of morphine. Overall morphine consumption differed significantly between the two groups (estimated coefficient = −0.40, 95% confidence interval (CI) −0.59 to −0.21; P < 0.001) (Fig. 2).
During the postoperative days 3–7, the treatment group consumed a median of 0 (range, 0–3), 0 (0–2), 0 (0–1), 0 (0–1) and 0 (0–2) Lonalgal® tablets (Boehringer Ingelheim Hellas, Athens). At the same time points, the control group consumed 0.5 (0–4), 1 (0–3), 0 (0–3), 0.5 (0–4) and 0 (0–2) Lonalgal® tablets, respectively. The tablets consumed by the treatment group were significantly fewer than those in the control group (z = 2.54, P = 0.011).
The overall mean VAS values at rest did not differ significantly between the two groups (estimated coefficient = 0.11, 95% CI −0.07 to 0.29; P = 0.24). The two groups did not differ significantly in mean VAS values at rest at any time point (P value for time by treatment interaction = 0.71) (Fig. 3).
We found no significant difference in overall mean VAS values after cough between the treatment and control groups (estimated coefficient = 0.08, 95% CI −0.08 to 0.25; P = 0.33). Moreover, the two groups did not differ in mean VAS values after cough at any point in time (P value for time by treatment interaction = 0.36) (Fig. 4).
One of the 27 patients in the treatment group and five of the 24 patients in the control group (4% and 21%, respectively) had nausea. The difference between the two groups was not statistically significant (x2 = 0.058, continuity correction 0.144). One patient in each group vomited, two patients in the control group presented bronchospasm after induction, and one patient in the treatment group complained about dizziness and sedation. None of the patients presented wound infection. All patients were ambulated the next morning and discharged from hospital on the fourth postoperative day.
Fewer patients treated with gabapentin and subcutaneous infusion of local anaesthetic experienced pain 1 month after surgery compared with the control group (P = 0.045). However, the number of patients with absent or decreased sensation around the wound and the number of patients who required analgesics at home the first month after surgery did not differ between the two groups (P = 0.92 and P = 0.36, respectively) (Table 1). None of the patients called for insufficient pain relief at home.
Our results show that the combination of oral gabapentin and an infusion of ropivacaine into the surgical wound significantly decrease postoperative morphine requirements and late postoperative pain after abdominal hysterectomy.
Several studies have investigated the effect of gabapentin on acute postoperative pain. The drug given perioperatively decreased analgesic requirements after breast surgery for cancer [8,9]. A single dose of gabapentin after spinal surgery decreased morphine consumption and pain in the early postoperative period . However, in these studies, surgery also involved nervous tissue like discectomy, spinal fusion or axillary gland dissection where the brachial plexus is injured.
Mechanisms suggesting that gabapentin may be effective in acute postoperative pain involve pharmacokinetics and pharmacodynamics of the drug. A single oral dose of 1200 mg given to volunteers exposed to thermal injury decreased mechanical allodynia . The drug at clinically relevant concentrations decreases the membrane voltage activated calcium currents in primary afferent neurons and the release of neurotransmitter by sensory neurons, producing analgesia .
Further investigations suggested that gabapentin had an effect on splanchnic postoperative pain. Gabapentin 1200 mg given 2.5 h preoperatively decreased the analgesic requirements of fentanyl during the first 20 h after vaginal hysterectomy by 40% . A much lower dose of gabapentin, i.e. 300 mg given 2 h before laparoscopic cholecystectomy, also decreased fentanyl requirements during the first 24 h after surgery . A single dose of 1200 mg given 1 h before abdominal hysterectomy decreased tramadol consumption and pain scores for 24 h after surgery . Dierking and colleagues found that gabapentin given pre- and post-operatively during the first 24 postoperative hours in a total dose of 3000 mg decreased morphine consumption after abdominal hysterectomy by 32% without an effect on pain scores . In a recent study, gabapentin 1200 mg or rofecoxib 50 mg per day decreased opioid requirements and improved postoperative pain to a similar degree . These results are not reproducible by all studies. Premedication with gabapentin 300 mg had no effect on postoperative pain following laparoscopic cholecystectomy . Administration of gabapentin 400 mg 6 hourly, starting 18 h before surgery and continued for 5 postoperative days, did not influence postoperative pain or analgesic needs. However, fewer patients experienced pain 1 month after surgery and the intensity of pain was reduced in the gabapentin treated group .
On the other hand, local anaesthetic infusion in the wound area may have an opioid sparing effect. Gupta and colleagues reported that levobupivacaine 0.25% 5 mL h−1 given intraperitoneally at the end of abdominal hysterectomy exhibited a significant opioid sparing effect . Similarly, bupivacaine 0.25% wound installation above the superficial abdominal fascia decreased the opioid requirements and nausea in the first 24 h after abdominal hysterectomy . These results are not consistent with the results of other studies. Continuous wound infusion of bupivacaine 0.5% into the incisional wound had no effect on PCA morphine consumption after abdominal hysterectomy . Also, bupivacaine 0.5% continuous wound infusion into the deep subcutaneous space was not efficacious for postoperative analgesia after laparotomy in gynaecologic oncology . Despite the controversy regarding each analgesic technique on its own, our results show that the combination of the two methods reduced analgesic requirements and decreased the incidence of late pain 1 month postoperatively.
Hypothetically, treating acute postoperative pain preoperatively may prevent or attenuate persistent postsurgical pain . In fact very few studies have investigated the effect of gabapentin on late or chronic postsurgical pain [8-9,12]. Postsurgical neuralgia usually involves thoracic procedures such as mastectomy, thoracotomy or sternotomy and is attributed to direct nerve injury during surgery . During abdominal surgery, nerve injury is less frequent and the prevalence of postsurgical neuralgia is much lower [28,29].
Data from the recent literature indicate that gabapentin may decrease opioid requirements and pain after surgery; it therefore has a potential role as postoperative analgesic . As gabapentin prevents central sensitization, which occurs after surgical trauma, its use may also have an impact on postsurgical late pain. Regarding local anaesthetic administration, subfascial perfusion was found to be more efficacious than subcutaneous, perfusion . However, the investigators administered a bolus dose of a local anaesthetic via a catheter. Continuous infusion of local anaesthetics, as in our study, allows continuous diffusion of the anaesthetic and eventually a steady state concentration in the wound area.
In a multimodal regime, gabapentin and local anaesthetic decreased the incidence of chronic pain due to breast surgery for cancer and the number of patients requiring analgesics during the first 3 months postoperatively . In a previous study we found that with gabapentin alone fewer patients experienced pain 1 month after abdominal hysterectomy, although there was no effect on the analgesic requirements and acute splanchnic pain immediately after surgery . A combination of two different treatments proved efficacious in decreasing opioid requirements as well as the incidence of late pain after abdominal hysterectomy. As a consequence, in the treatment group 4% of the patients complained about nausea vs. 21% of the controls. The higher incidence of nausea in the control group was not significant as all patients received prophylactic antiemetics. We consider antiemetic prophylaxis a prerequisite, as a significant incidence of nausea or vomiting would influence the blinding of the study, indicating a higher morphine consumption.
Although the aim of the study was to investigate the analgesic effect of multimodal analgesia, the lack of separate groups treated with local anaesthetic infusion alone and gabapentin alone is a limitation of the study. The present study is based on the results of our previous study  aiming, along with the gabapentin effect on late postoperative pain, to affect also the pain and/or the analgesic needs immediately after surgery. The multimodal analgesic regime aims also at an opioid sparing effect along with satisfactory analgesia. We did not measure incision pain and visceral pain separately as other investigators  but pain at rest and pain elicited by coughing. However, pain due to coughing has, as a main component, deep visceral pain.
Older age and obesity were chosen to be excluded as these two patient characteristics may influence the kinetics of the anaesthetics and analgesics we administered. We chose the ropivacaine 0.75% solution as surgeons and ourselves prefer for the same dose of local anaesthetic to keep the infusion volume as low as possible.
In conclusion, a combination of wound catheter allowing infusion of local anaesthetic and gabapentin decreased postoperative analgesic requirements after abdominal hysterectomy. This combination may also ameliorate late pain. The present study design does not evaluate the effect of the local anaesthetic infusion alone on acute and chronic pain and does not allow evaluation of the potentially favourable outcome with gabapentin alone. Negative phenomena such as decreased or absent sensation were not ameliorated. Further research is mandatory to establish whether this regimen should be endorsed for clinical practice.
We thank the statisticians Ms Katerina Dimitriou (B.Sc.) and Mr Vasili Nikolaou (M.Sc.) for their invaluable help in the statistical analysis of the data. Support was provided solely from institutional sources.
1. Dworkin RH, Backonja M, Rowbotham MC et al
. Advances in neuropathic pain. Diagnosis, mechanism, and treatment recommendations. Arch Neurol
2. Backonja M, Beydoun A, Edwards KR et al
. for the Gabapentin Diabetic Neuropathy Study group. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA
3. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L, for the Gabapentin Postherpetic Neuralgia Study Group. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA
4. Rowbotham DJ. Gabapentin: a new drug for postoperative pain? Br J Anaesth
5. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med
6. Ho K-Y, Gan TJ, Habib AS. Gabapentin and postoperative pain – a systematic review of randomized controlled trials. Pain
: 91–101. Available online July 2006.
7. Eckhard K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg
8. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of gabapentin and mexiletin after breast surgery for cancer. Anesth Analg
9. Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg
10. Dierking G, Duedahl TH, Rasmussen ML et al
. Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind trial. Acta Anaesthesiol Scand
11. Turan A, Karamanlioglu B, Memis D, Usar P, Pamukcu Z, Ture M. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg
12. Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Chassiakos D, Sarantopoulos C. Gabapentin attenuates chronic but not acute pain after abdominal hysterectomy. Eur J Anaesthesiol
13. Chester JF, Ravindranathan K, White BD, Shanahan D, Taylor RS, Lioyd-Williams K. Wound perfusion with bupivacaine: objective evidence for efficacy in postoperative pain relief. Ann R Coll Surg Engl
14. Levack ID, Holmes JD, Robertson GS. Abdominal wound perfusion for the relief of postoperative pain. Br J Anaesth
15. Gibbs P, Purushotham A, Auld C, Cuschieri RJ. Continuous wound perfusion with bupivacaine for postoperative wound pain. Br J Surg
16. Gupta A, Perniola A, Axelsson K, Thorn SE, Crafoord K, Rawal N. Postoperative pain after abdominal hysterectomy: a double-blind comparison between placebo and local anesthetic infused intraperitoneally. Anesth Analg
17. Zohar E, Fredman B, Phillipov A, Jedeikin R, Shapiro A. The analgesic effect of patient-controlled bupivacaine wound instillation after total abdominal hysterectomy with bilateral salpingo-oophorectomy. Anesth Analg
18. Leong WM, Lo WK, Chiu JW. Analgesic efficacy of continuous delivery of bupivacaine by an elastomeric balloon infusor after abdominal hysterectomy: a prospective randomised controlled trial. Aust N Z J Obstet Gynaecol
19. Kushner DM, LaGalbo R, Connor JP, Chappell R, Stewart SL, Hartenbach EM. Use of a bupivacaine continuous wound infusion system in gynecologic oncology: a randomized trial. Obst Gynecol
20. Turan A, Karamanlioglou B, Memis D et al
. Analgesic effects of gabapentin after spinal surgery. Anesthesiology
21. Werner MU, Perkins FM, Holte K, Pedersen JL, Kehlet H. Effects of gabapentin in acute inflammatory pain in humans. Reg Anesth Pain Man
22. Sarantopoulos C, McCallum B, Kwok WM, Hogan Q. Gabapentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons. Reg Anesth Pain Med
23. Rorarius MGF, Memmander S, Suominen P et al
. Gabapentin for the prevention of postoperative pain after vaginal hysterectomy. Pain
24. Pandey CK, Priye S, Singh S, Singh U, Singh RB, Singh PK. Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laparoscopic cholecystectomy. Can J Anesth
25. Turan A, White PF, Karamanlioglu B et al
. Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg
26. Gregg AK, Francis S, Sharpe P, Rowbotham DJ. Analgesic effect of gabapentin premedication in laparoscopic cholecystectomy: a randomized double-blind placebo-controlled trial. Br J Anaesth
27. Brennan TJ, Kehlet H. Preventive analgesia to reduce wound hyperalgesia and persistent postsurgical pain: not an easy path. Anesthesiology
28. Eisenberg E. Post-surgical neuralgia. Pain
29. Nikolajsen L, Sorensen HC, Jensen TS, Kehlet H. Chronic pain following caesarean section. Acta Anaesthesiol Scand
30. Yndgaard S, Holst P, Bjerre-Jepsen K, Thomsen CB, Struckmann J, Mogensen T. Subcutaneously versus subfascially administered lidocaine in pain treatment after inguinal herniotomy. Anesth Analg