Gabapentin was developed as an anticonvulsive drug and adjuvant for treating generalized or partial epileptic seizures resistant to conventional therapies.1 It is also one of the new generation antiepileptic drugs that have antinociceptive and antihyperalgesic properties.2 Its use in acute postoperative pain management and to decrease postoperative analgesic consumption has been evaluated in several studies.3–13 In neurosurgical patients, inadequate analgesia may lead to agitation, hypertension, shivering, and vomiting. These events are potentially harmful, mainly because of a risk of intracranial bleeding. Adequate postoperative analgesia could therefore reduce complications and shorten recovery.
Despite the lack of definitive evidence that prophylactic anticonvulsant therapy is useful, neurosurgeons often administer anticonvulsant medication prophylactically to patients with brain tumors.14,15 If one drug has both antiepileptic and analgesic effects, its use could provide important advantages for patients undergoing craniotomy. In this study, we aimed to understand the postoperative effectiveness of gabapentin on acute postoperative pain when it is used for antiepileptic prophylaxis in patients undergoing craniotomy for supratentorial tumor resection. In our clinic, patients having a craniotomy are routinely given antiepileptic prophylaxis. For this purpose, the drug most widely used in neurosurgical clinics is phenytoin.15 Therefore, the control group comprised patients who were administered phenytoin.
This study was approved by the Institutional Ethics Committee. After giving written informed consent, 80 patients undergoing elective supratentorial craniotomy for tumor resection in the supine position were enrolled. Patients were eligible for enrollment if they were 18-60 yr old; had no clinically significant cardiovascular disease; no hepatic, renal, or peptic ulcer disease; no asthma or mental disability; and no history of substance abuse or bleeding diathesis. Patients who were more than 20% of their ideal body weight; those who had a brain tumor larger than 30 mm in diameter (because of the tendency for a prolonged emergence from anesthesia); those with a Glasgow Coma Scale score of <15 points; patients with neurological deficits (precluding their use of a patient-controlled analgesia [PCA] device); and patients taking tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, or neuroleptic or antiepileptic drugs were excluded. Patients with known allergy to any of the study medications, or any patients with preoperative aphasia or dysphasia, and those with symptoms identical to antiepileptic-related side effects (somnolence, dizziness, asthenia, nystagmus, ataxia, headache, fatigue, skin rash, light headedness, nausea, and vomiting) were also excluded. Furthermore, patients who might need postoperative drainage were excluded because any change in intracranial pressure could cause pain.
The patients were randomly assigned to two study groups of 40 patients each. The PCA device and the visual analog scale (VAS) were explained to the patients during their preoperative visit.
In Group G (n = 40), we administered 1200 mg (3 × 400 mg) oral gabapentin (Neurontin, 400-mg capsule, Pfizer, Goedecke GmbH, Germany), and in Group P (n = 40), we administered 300 mg (3 × 100 mg) oral phenytoin (Epanutin, 100-mg capsule, Pfizer, Istanbul, Turkey) per day for 7 days before surgery. Antiepileptic control plasma concentrations were measured 1 day before surgery, just before the antiepileptic drug intake in the morning. After oral intake of the antiepileptic drug, any antiepileptic-related side effects (somnolence, dizziness, asthenia, nystagmus, ataxia, headache, fatigue, skin rash, light headedness, nausea, vomiting, etc.) were recorded. On the morning of surgery, antiepileptic dosages were administered to all patients. All operations were planned in the morning as a first operation. All patients started receiving dexamethasone 1 day before the surgery and continued for about 1 wk postoperatively. All antiepileptic drugs were continued for about 6 mo to 1 yr in patients with meningiomas. They were not discontinued in patients with glial tumors postoperatively.
Before the induction of general anesthesia, standard monitors (electrocardiogram, arterial blood pressure cuff, and pulse oximeter probe) were placed. A bispectral index (BIS) sensor (Aspect Medical Systems, Part 186-0106, Norwood, MA) was placed in the frontal area with consideration for the location of the surgical incision. Anesthesia was induced with 4-6 mg/kg thiopental and titrated remifentanil in doses of 0.5-1 μg/kg, and muscle relaxation was achieved with 0.15 mg/kg cisatracurium. The trachea was intubated and mechanical ventilation was started (oxygen/air; oxygen 50%). A 20-gauge catheter was placed in the radial artery, and the esophageal and skin temperatures and end-tidal carbon dioxide levels were monitored. Anesthesia was maintained with the titration of remifentanil (0.1-0.25 μg · kg−1 · min−1) and propofol infusion (75-200 μg · kg−1 · min−1). The remifentanil and propofol infusion rates were changed at the discretion of the anesthesiologist to keep the BIS between 40 and 50 and the hemodynamic variables stable. Muscle relaxation was maintained using cisatracurium in boluses (0.02 mg/kg). Drugs such as furosemide and antibiotics were administered IV as required by the surgeon.
In Group P, routine scheduled doses of phenytoin were administered IV during the surgery. In Group G, a nasogastric tube was placed and a scheduled dose of gabapentin was administered during the surgery. Gastric insufflation and gastric aspiration were avoided because of their relation to postoperative nausea and vomiting. Propofol was discontinued after dural closure, and remifentanil was discontinued after the removal of the three-pin head holder. After propofol was discontinued, if hemodynamic changes occurred (mean arterial blood pressure or heart rate >20% of baseline, movements of the patient’s hand or arm), we administered a bolus of remifentanil titrated in doses of 0.5-1 μg/kg, and the dose of remifentanil was increased. Any residual neuromuscular block was reversed by using neostigmine and atropine when appropriate.
We recorded the duration of surgical closure, duration of surgery and anesthesia, total propofol and remifentanil doses, and anesthetic and surgical side effects. The time from the beginning of dural closure to the end of skin closure was defined as the surgical closure time. The duration of anesthesia was defined as the time from induction to the discontinuing of remifentanil. The tracheal extubation time was defined as the time from discontinuing remifentanil to safe extubation when the patient opened their eyes, obeyed commands, and resumed adequate respiration.
We planned to tracheally extubate patients at the end of the procedure in the operating room, then transfer them to the postanesthesia care unit where they were connected to the PCA device (Abbott Pain Management, North Chicago, IL). A nurse anesthetist, who was unaware of the study, recorded each patient’s pain and sedation scores (0 h). Postoperative pain was assessed with the VAS score (0 = no pain and 10 = worst pain imaginable). When the VAS score was more than 3, morphine was titrated to a maximum dose of 0.1 mg/kg IV, and then a morphine PCA was set to deliver 1-mg doses with an 8-min lockout and no background infusion. Any problems (uncontrolled pain, sedation, obtundation, and respiratory arrest) required the PCA device to be discontinued.
The VAS and Ramsay sedation scores, total and cumulative morphine consumption, and any nausea, vomiting, seizure activity, or other adverse effects were noted at 0, 15, 30 min, and 1, 2, 4, 6, 12, 24, and 48 h postoperatively. At the patient’s request, or if nausea, retching, or vomiting occurred, ondansetron (4 mg, IV) was administered. The number of patients requiring ondansetron was recorded.
During the postoperative period, the nasogastric tube was removed when patients could swallow and were fully awake, and routine scheduled doses of gabapentin were administered orally.
If we assume that a 10% difference in morphine consumption between the groups is clinically relevant, the study required 30 patients in each group for a power β = 80% and α = 0.05. To compensate for potential exclusions or withdrawals, we decided to include 10 more patients in each group.
All variables were tested for normal distribution by using Kolmogorov-Smirnov test. Student’s t-test and χ2 tests were used for comparison for means of the variables and normally distributed data. Morphine consumption at different time intervals was compared with repeated measures of analysis of variance. Mann-Whitney U-test was used to analyze the VAS and sedation scores of the groups. Correlations between the variables were done with Spearman rho correlation test. The results of these analyses were expressed as the mean ± sd. Sedation and VAS scores are reported as median and interquartile ranges. A P value of <0.05 was considered significant.
Eighty patients were asessed for eligibility but only 75 completed the study. In Group G, two patients had severe side effects related to gabapentin during the preoperative period and one patient’s surgical procedure was changed preoperatively. In Group P, after antiepileptic therapy was initiated, one patient wished to be withdrawn from the study just before surgery and one developed transient neurological symptoms postoperatively (hemiparesis). These five patients were withdrawn from the study. Thirty-seven patients in Group G and 38 patients in Group P completed the study.
In the preoperative period, after the administration of gabapentin, seven patients had fatique (one of these had severe fatigue) and five patients were dizzy (one of whom could not be mobilized without assistance because of severe dizziness) (Table 1). In these two patients, gabapentin was stopped and the side effects diminished. Plasma samples of gabapentin were collected but could not be studied in the laboratory in three patients. These three patients were not excluded from the study. In 34 patients, the median plasma levels of gabapentin were 34 μmol/mL (range, 23-51 μmol/mL).
The demographic data and the duration of surgery, anesthesia, and surgical closure time were comparable between the groups (Table 2). In Group G, the total propofol and remifentanil doses were significantly lower than in Group P (P = 0.01). In Group G, the tracheal extubation was significantly delayed when compared with Group P (P < 0.001). In Group G, a computed tomography (CT) scan was done for two patients because of delayed extubation. The blood gases and biochemistry were within the normal range, and no surgical pathology, such as edema, bleeding, or hydrocephalus, was seen on the CT scans of these patients. There was no correlation among the extubation time and duration of anesthesia (r = 0.07, P = 0.6), surgical closure time (r = −0.1, P = 0.2), total propofol infusion (r = 0.05, P = 0.2), and total remifentanil infusion (r = 0.06, P = 0.3).
The postoperative VAS scores were significantly higher in Group P than in Group G at 15 and 30 min, and at 1 h (P < 0.001) (Fig. 1). The total and cumulative morphine consumption was significantly higher in Group P than in Group G (mg) (33 ± 17 vs 24 ± 19) during the 48-h postoperative period (P = 0.01) (Fig. 2). There was no correlation among the total morphine consumption, the surgical route (r = 0.06, P = 0.3), and the patients’ sex (r = 0.08, P = 0.2).
The postoperative sedation scores were significantly higher in Group G at 15 min, 30 min, 1 h, and 2 h (P < 0.001) (Fig. 3).
One patient in Group P had a partial seizure on postoperative Day 3. This patient’s serum phenytoin concentration was within the normal range, and levetiracetam was added to the antiepileptic therapy according to the recommendation of an epileptologist (CAB). The CT image and electroensephalography were normal and the patient recovered safely in the hospital.
After discharge from the hospital, all patients returned for examination in 1 mo. At this follow-up examination, all patients were free of seizures.
We investigated the postoperative analgesic efficiency of gabapentin started for antiepileptic prophylaxis 1 wk before craniotomy. Compared with phenytoin, gabapentin decreased the patients’ consumption of morphine and increased sedation postoperatively. However, it also delayed tracheal extubation.
The preemptive analgesic effect of gabapentin is well known.3–13 Investigators who have reported significant reductions in patients’ postoperative analgesic consumption administered preoperative gabapentin (300-1800 mg) in single or multiple dose combinations.3–13 In these studies, however, gabapentin was used for a short preoperative period. In contrast to previous studies, we began to administer 1200 mg of gabapentin per day (3 × 400 mg) 7 days before surgery to maintain an antiepileptic target plasma level. In addition, a mean 34 mmol/L plasma level of gabapentin prevented seizures and provided analgesia postoperatively. Unfortunately, none of the studies evaluating the effect of gabapentin on postoperative pain have measured the plasma level; thus, there are no available data to help determine the target analgesic and antiepileptic plasma level. If the main goal is reducing postoperative pain, however, the administration of gabapentin for 7 days preoperatively may not always be feasible, and the side effect profile should not be underestimated because it may limit its preoperative use.
In our study, the use of preemptive gabapentin in divided doses for 1 wk decreased morphine consumption by 28% in the first 48 h compared with phenytoin. Other studies have concluded that gabapentin reduces postoperative morphine consumption by 32%-50%.3,4,7,9,12 For example, Dirks et al.4 gave a single oral dose (1200 mg) of gabapentin to patients undergoing radical mastectomy and reported a 50% reduction in postoperative morphine consumption. In contrast, Dierking et al. administered 1200 mg of gabapentin orally to patients 1 h before surgery, followed by oral gabapentin (600 mg) 8, 16, and 24 h after the initial dose (total dose 3000 mg in 24 h) for abdominal hysterectomy. They reported a 32% reduction in morphine consumption without significant side effects.3 Our results are consistent with these studies, although all these studies differ in their gabapentin dosing regimen, type of surgery, coadministered drugs, and duration of follow-up. Blinded, randomized studies are needed to determine when to start and withdraw prophylactic gabapentin and what dose optimizes analgesic and antiepileptic efficacy, especially in neurosurgical patients.
Despite the fact that phenytoin has no known analgesic effect on acute pain control, it was the first antiepileptic drug to be used specifically for chronic pain management but is now rarely used for that application.16,17 This fact can perhaps explain why the opioid-sparing effect is less in our study when compared with some previous studies.
Patients receiving gabapentin had higher sedation scores within the first 2 h after surgery. Other investigators have also noticed the sedative effect of gabapentin.6,11,18 Despite the results of these studies, a meta-analysis reported significant sedative effects compared with placebo when the trial results were pooled but concluded, however, that this was the result of poor reporting and that most of the significance came from just two trials.16,18,19 However, in neurosurgical patients, unlike those undergoing other types of surgeries, determining the reason for sedation, delayed tracheal extubation, or unconsciousness is difficult, and the factors can relate to the patient, anesthesia, or surgery.
Consistent with the literature, we found that gabapentin decreased perioperative anesthetic requirements.10,13 A limited number of studies mention the effect of preoperatively administered gabapentin on anesthetic consumption.10,13 Koç et al.13 reported a reduction in intraoperative total remifentanil consumption with a constant propofol infusion in patients given gabapentin and dexamethasone together before varicocele surgery. Turan et al.10 showed a decrease in intraoperative total fentanyl consumption without a decrease in propofol consumption when the gabapentin was administered before ear-nose-throat surgery. These surgeries were associated with mild pain, and the depth of anesthesia was monitored with standard autonomic variables and BIS monitoring. Further studies are required to determine whether patients who receive gabapentin preoperatively require a smaller amount of anesthetic during craniotomy.
Antiepileptic prophylaxis should be determined on one hand by the risks and consequences of seizures during the immediate postoperative period, and on the other hand by the efficacy and tolerability of the drug. For prophylaxis after craniotomy, antiepileptic drugs should be easy to use, provide adequate seizure control, and generate no major side effects. Intravenous preparations are also necessary during recovery. Phenytoin has an IV form, but gabapentin does not, and gabapentin has several side effects (dizziness, fatigue, ataxia, etc.). Unfortunately, some of our patients could not continue the study because of dizziness or fatigue preoperatively. The frequency of side effects and the need to stop treatment is directly proportional to the dose, and these side effects are seen during the first days of treatment.20 In neurosurgical patients, however, it is sometimes impossible to differentiate the cause of fatigue, dizziness, and drowsiness, which are common signs related to intracranial pathology. Thus, further studies must be done with different doses of gabapentin in neurosurgical patients.
Nausea and vomiting may occur in patients after craniotomy because of the manipulation of intracranial structures, an increase in intracranial pressure, as a consequence of general anesthesia, or because of a side effect of perioperative opioid administration.21 Previous studies have found gabapentin to be associated with marked reductions in nausea and vomiting, and also the converse when gabapentin was given for postoperative pain.3,5,10,22,23 In our study, patients who received gabapentin required less antiemetic therapy than those receiving phenytoin. The reduced opioid consumption and lower VAS scores could be associated with a decreased antiemetic requirement.
In our study, gabapentin was effective in reducing acute postoperative pain. Patients receiving gabapentin had a lower anesthetic and analgesic requirement during and after craniotomy for supratentorial tumor resection. However, side effects such as delayed tracheal extubation and increased sedation occurred. The effects of varying doses of gabapentin should be investigated so as to take advantage of both the analgesic efficacy and antiepileptic effects of this drug.
The authors thank Julie Yamamato for editorial assistance and Nural Bekiroglu for statistical assistance.
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