986
Regional Anesthesia and Pain Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy [L’administration préventive de gabapentine diminue la douleur postopératoire d’une discectomie lombaire] Chandra Kant Pandey MD, Surabhi Sahay PDCC, Devendra Gupta PDCC, Sushil Prakash Ambesh Ram Badan Singh PDCC, Mehdi Raza MD, Uttam Singh PhD, Prabhat Kumar Singh MD
Purpose: We investigated whether the preemptive use of gabapentin, a structural analogue of gamma amino butyric acid could reduce postoperative pain and fentanyl consumption in patients after single-level lumbar discoidectomy. Methods: Fifty-six ASA I and II patients were randomly allocated into two equal groups to receive either gabapentin 300 mg or placebo two hours before surgery. After surgery, the pain was assessed on a visual analogue scale (VAS) at intervals of 0–6, 6–12, 12–18, and 18–24 hr at rest. Total fentanyl consumption in the first 24 hr after surgery was also recorded. Fentanyl 2 µg·kg–1 intravenously was used to treat postoperative pain on patients’ demand. Results: Patients in the gabapentin group had significantly lower VAS scores at all time intervals of 0–6, 6–12, 12–18, and 18–24 hr than those in the placebo group (3.5 ± 2.3, 3.2 ± 2.1, 1.8 ± 1.7, 1.2 ± 1.3 vs 6.1 ± 1.7, 4.4 ± 1.2, 3.3 ± 1.1, 2.1 ± 1.2; P < 0.05). The total fentanyl consumed after surgery in the first 24 hr in the gabapentin group (233.5 ± 141.9, mean + SD) was significantly less than in the placebo group (359.6 ± 104.1; P < 0.05). Conclusion: Preemptive gabapentin 300 mg po significantly decreases the severity of pain postoperatively in patients who undergo single-level lumbar discoidectomy.
MD,
Objectif : Vérifier si l’usage préventif de gabapentine, analogue structurel de l’acide gamma amino-butyrique, pouvait réduire la douleur postopératoire et la consommation de fentanyl dans les cas de discectomie lombaire à un seul niveau. Méthode : Cinquante-six patients d’état physique ASA I et II, répartis au hasard en deux groupes égaux, ont reçu soit 300 mg de gabapentine, soit un placebo, deux heures avant l’opération. Après l’opération, la douleur a été évaluée selon une échelle visuelle analogique (EVA) de 0–6, 6–12, 12–18 et 18–24 h au repos. La consommation totale de fentanyl pendant les 24 premières heures postopératoires a aussi été notée. Une dose iv de 2 µg·kg–1 de fentanyl a été utilisée pour traiter la douleur postopératoire sur demande. Résultats : Les patients sous gabapentine ont eu des scores significativement plus bas à l’EVA, pour toutes les mesures aux intervalles de 0–6, 6–12, 12–18 et 18–24 h, que ceux du groupe placebo (3,5 ± 2,3 ; 3,2 ± 2,1 ; 1,8 ± 1,7 ; 1,2 ± 1,3 vs 6,1 ± 1,7 ; 4,4 ± 1,2 ; 3,3 ± 1,1 ; 2,1 ± 1,2 ; P < 0,05). La consommation postopératoire totale de fentanyl pendant les 24 premières heures a été significativement plus faible avec la gabapentine (233,5 ± 141,9, moyenne + écart type) qu’avec le placebo (359,6 ± 104,1 ; P < 0,05). Conclusion : L’administration préventive de 300 mg po de gabapentine diminue significativement la sévérité de la douleur postopératoire chez les patients qui subissent une discectomie lombaire à un seul niveau.
From the Departments of Anaesthesiology and Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. Address correspondence to: Dr. Chandra Kant Pandey, Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. Phone: 0091-522-2668700, ext. 2490; Fax: 0091-522-2668017, attention to Dr. C.K. Pandey; E-mail:
[email protected] Manuscript assessed January 27, 2004. 1st revision accepted March 11, 2004. Final revision accepted August 2, 2004. CAN J ANESTH 2004 / 51: 10 / pp 986–989
Pandey et al.:
987
PREEMPTIVE GABAPENTIN
G
ABAPENTIN, a structural analogue of gamma-amino butyric acid, has been used as an anticonvulsant and antinociceptive drug but its mode of action is not well understood.1 After a single 300 mg oral dose, the mean maximum plasma gabapentin concentrations are attained in two to three hours.2 Absorption kinetics of gabapentin is dose-dependent, possibly due to a saturable transport system. The bioavailability of a single 300 mg oral dose of gabapentin is 60% and decreases with increasing dose. It is not metabolized in humans and eliminated from the body by renal clearance. The elimination half-life of gabapentin is about five to seven hours after a single oral dose.2 Gabapentin has demonstrated potent antihyperalgesic proprieties in preclinical and clinical studies, without affecting acute nociception.3,4 In experimental studies gabapentin suppressed experimentally induced hyperalgesia. Intrathecal administration reduced tactile allodynia after incision, and reduced mechanical hyperalgesia in a rat model of postoperative pain.5 In human volunteers, gabapentin demonstrated substantial inhibitory effects not only on the development but also on established secondary allodynia and hyperalgesia resulting from sensitization of the skin with heat and capsaicin.6 The magnitude of this effect was comparable with the effect observed with remifentanil, but without affecting the acute nociceptive threshold and with only moderate side effects.7 The rationale behind preemptive analgesia is that antinociceptive treatment started before surgery is more effective in reducing postoperative pain than treatment started in the early postoperative period.8 As gabapentin has a substantial inhibitory effect on the development and establishment of allodynia and hyperalgesia, we investigated whether the preemptive use of gabapentin could reduce postoperative pain and fentanyl requirements in the initial 24 hr after singlelevel lumbar discoidectomy. Material and methods The Institute’s Ethics Committee approved this study and written informed consent was obtained from each participant. Fifty-six patients, ASA physical status I and II, of both sexes scheduled for single-level lumbar disc surgery were recruited. The exclusion criteria were: body weight exceeding 20% of the ideal body weight; those older than 70 yr or younger than 18 yr; history of drug or alcohol abuse; impaired kidney or liver functions; patients with spondylolisthesis undergoing spinal plating or those with additional pathology of the spine; and patients who had received analgesics within 48 hr before surgery.
All patients received oral lorazepam 0.04 mg·kg–1 the evening before surgery and the morning of surgery. Patients were randomly assigned into two equal groups of 28 each using a computer generated table of random numbers to receive oral gabapentin 300 mg or matching placebo two hours before surgery. Anesthesia was induced with propofol 2 mg·kg–1 and fentanyl 2 µg·kg–1, lidocaine 1.5 mg·kg–1 and vecuronium bromide 800 µg·kg–1. Anesthesia was maintained with a propofol infusion 100 to 200 µg·kg–1·min–1 and 70% nitrous oxide in oxygen and intermittent vecuronium when indicated. After completion of surgery, neuromuscular blockade was reversed with atropine 0.02 mg·kg–1 and neostigmine 0.04 mg·kg–1 and patients were extubated when adequate spontaneous ventilation was established. After surgery a senior resident, who was not the part of the anesthesia team, recorded the pain score every two hours on a visual analogue scale (VAS; 0–10 cm) at rest. From these pain score data, the maximum pain scores during the time intervals of 0–6, 6–12, 12–18 and 18–24 hr were considered for statistical analysis. Patients received fentanyl 2 µg·kg–1 on demand. The total rescue analgesic requirement in the first 24 hr was recorded. The data were entered into the statistical software package SPSS 9. The mean ± SD from maximum pain scores for all patients in both groups at time intervals of 0–6, 6–12,12–18 and 18–24 hr were calculated. Similarly, total fentanyl consumption in each group was calculated. On the assumption that a 25% difference in fentanyl consumption between the groups would be of clinical interest, the study required 22 patients in each group for a power ß = 80% and α = 0.05. A value of P < 0.05 was considered significant. VAS scores were analyzed with two-factor ANOVA for repeated measures. The total fentanyl consumed in each group (mean ± SD) in 24 hr was compared using an unpaired t test.
TABLE I Demographic variables (mean + SD) Groups
Age in yr
Weight in kg Male/female
Gabapentin 38.5 ± 7.7 60.6 ± 9.5 (n = 28) Placebo 39.1 ± 11.6 59.0 ± 11.1 (n = 28)
Duration of anesthesia (hr)
20/8
3.4 ± 0.4
18/10
3.6 ± 0.4
No significant difference between groups.
988
CANADIAN JOURNAL OF ANESTHESIA
TABLE II Visual analogue scale scores and total fentanyl consumption (µg) Groups
0–6 hr
6–12 hr
12–18 hr
18–24 hr
Total 24 hr fentanyl consumption (µg)
Gabapentin (n = 28)
3.5 ± 2.3*
3.2 ± 2.1*
1.8 ± 1.7*
1.2 ± 1.3*
Placebo (n = 28)
6.1 ± 1.7
4.4 ± 1.2
3.3 ± 1.1
2.1 ± 1.2
233.5 ± 141.9* (n = 28) 359.6 ±104.1 (n = 28)
*P < 0.05 vs placebo group.
Results There was no difference in age, sex, body weight, and duration of anesthesia between the two groups (Table I). Patients in the gabapentin group had significantly lower VAS scores at all time intervals of 0–6, 6–12, 12–18, and 18–24 hr than those in the placebo group (Table II). The total fentanyl consumed after surgery in the first 24 hr in the gabapentin group (233.5 ±141.9, mean ± SD) was significantly less than in the placebo group (359.6 ± 104.1; P < 0.05; Table II). The incidence of adverse effects (nausea 5 vs 4, vomiting 3 vs 4, fatigue 1 vs 0, light headedness 1 vs 0 and dizziness 1 vs 0) was similar in the gabapentin and placebo groups. Discussion Our study shows that the preemptive administration of gabapentin 300 mg significantly reduces the incidence of pain after lumbar discoidectomy. Postoperatively, patients who received preemptive gabapentin had significantly lower pain scores in the time intervals of 0–6, 6–12, 12–18 and 18–24 hr and had significantly decreased total fentanyl requirements in the initial 24 hr in comparison to the placebo group. The analgesic efficacy of gabapentin used preemptively has been demonstrated in surgical patients.3,6,9 In a previous study, a single dose of gabapentin (600 mg) enhanced the analgesic effect of morphine but side effects appeared in approximately 40% of subjects.10 Dirks et al. gave a single oral dose of 1200 mg of gabapentin to patients undergoing a radical mastectomy. They found a substantial reduction in postoperative morphine consumption without significant side effects, similar to our findings.3 Peripheral tissue injury, such as that caused by surgery provokes two kinds of modification in the responsiveness of the nervous system: peripheral sensitization which causes a reduction in the threshold of nociceptor afferent peripheral terminals, and central sensitization which causes an activity-dependent increase in the excitability of spinal neurons.11,12 Together these changes contribute to a hypersensitivity
state which manifests as an increase in the response to noxious stimuli and a decrease in the stimulus threshold, both at the site of injury and in the surrounding uninjured tissues.11,12 The rationale for preemptive analgesia is to prevent this hypersensitization, by blocking the initial nociceptive input to the spinal cord. Gabapentin had no effect on pain transmission in normal skin but significantly reduced hyperalgesia following an experimental thermal injury or heat capsaicin sensitization.13 The pattern of activity is of considerable importance in that gabapentin may reduce pathological pain while leaving other protective nociceptive mechanisms intact.13 Animal studies have shown that although gabapentin does not affect the nociceptive threshold, it is effective in reducing both allodynia and hyperalgesia, suggesting that it has a selective effect on the nociceptive process involved in central sensitization.14,15 In a recent study it was shown that gabapentin effectively inhibits acetic acid induced nociception in a dose-related fashion, and that its antinociceptive effect also suppresses noxious-evoked release of excitatory amino acids (glutamate, aspartate, serine, glutamine and glycine) in the spinal cord.16 Although the exact mechanism of action of gabapentin is not well understood, clinical and experimental studies have demonstrated its analgesic efficacy and safety in physiological as well as in pathological pain. Our clinical study on postoperative pain also demonstrates that a preemptive 300 mg oral dose of gabapentin decreases significantly the incidence of pain postoperatively in patients who undergo lumbar discoidectomy without significant adverse effects. References 1 Abdi S, Lee DH, Chung JM. The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. Anesth Analg 1998; 87: 1360–6. 2 Goa KL, Sorkin EM. Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy. Drugs 1993; 46: 409–27.
Pandey et al.:
PREEMPTIVE GABAPENTIN
3 Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002; 97: 560–4. 4 Mao J, Chen LL. Gabapentin in pain management. Anesth Analg 2000; 91: 680–7. 5 Field MJ, Holloman EF, McCleary S, Hughes J, Singh L. Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. J Pharmacol Exp Ther 1997; 282: 1242–6. 6 Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heat/capsaicin sensitization. Anesthesiology 2002; 97: 102–6. 7 Petersen KL, Jones B, Segredo V, Dahl JB, Rowbotham MC. Effect of ramifentanil on pain and secondary hyperalgesia associated with the heat-capsaicin sensitization model in healthy volunteers. Anesthesiology 2001; 94: 15–20. 8 Kissin I. Preemptive analgesia. Why its effect is not always obvious (Editorial). Anesthesiology 1996; 84: 1015–9. 9 Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg 2002; 95: 985–91. 10 Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000; 91: 185–91. 11 Woolf CJ, Chong MS. Preemptive analgesia–treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77: 362–79. 12 Kissin I. Preemptive analgesia. Anesthesiology 2000; 93: 1138–43. 13 Gilron I. Is gabapentin a "broad-spectrum" analgesic? (Editorial). Anesthesiology 2002; 97: 537–9. 14 Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barre syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg 2002; 95: 1719–23. 15 Nicholson B. Gabapentin use in neuropathic pain syndromes. Acta Neurol Scand 2000; 101: 359–71. 16 Feng Y, Cui M, Willis WD. Gabapentin markedly reduces acetic acid–induced visceral nociception. Anesthesiology 2003; 98: 729–33.
989
