Postoperative pain in patients undergoing craniotomy is often underestimated and inadequately treated.1,2 A prospective study of 256 patients undergoing craniotomy demonstrated that 87% of patients experienced acute postoperative pain, of which 32% had mild pain, 44% experienced moderate pain, and 11% reported severe pain.3 Approximately, 80% of patients reported moderate to severe pain up to 48 hours after intracranial surgery4 and were often inadequately treated.5 Suboccipital and subtemporal surgical approaches may be associated with a higher incidence and severity of pain; these procedures are performed through incision and reflection of the temporalis, splenium capitis, and cervicalis muscles.4,5 However, limited studies have investigated postoperative pain and analgesia after intracranial neurosurgery from a specific approach.
Opioids are most frequently used to treat postoperative pain; however, the side effects, particularly sedation, nausea, and vomiting, influence neurological assessments and limit their use in neurosurgical analgesia.6 Therefore, multimodal analgesia using a combination of opioids and nonopioids or adjuvant analgesics to improve analgesia with few adverse effects is the optimal postoperative analgesic choice, particularly for patients undergoing craniotomy.7–9 Gabapentin is an adjuvant antiepileptic agent and has also been administered in acute postoperative pain management for gynecological surgery, lumbar spinal surgery, arthroplasty, and thoracic surgery.10–13 Only 2 studies have investigated its effects in patients undergoing craniotomy. Türe et al12 demonstrated that gabapentin (3 doses of 400 mg for 7 d) decreased total morphine consumption and lowered pain scores; nevertheless, Misra et al13 demonstrated that preoperative gabapentin (one dose of 600 mg) did not reduce pain scores or opioid consumption within 24 hours. Only one of the previous studies was designed to assess the effect of gabapentin on postcraniotomy pain. Furthermore, the primary outcome of Mirsa et al’s study was postoperative nausea and vomiting (PONV) not postoperative pain. The dose and the duration of gabapentin use may explain the difference; however, these studies did not focus on the analgesic effect of gabapentin using a single approach of craniotomy.
On the basis of the previous studies, we hypothesized that preoperative gabapentin (total dose of 1200 mg) would reduce acute postoperative-24-hour pain in patients undergoing suboccipital or subtemporal craniotomy. A randomized controlled trial was performed to test this hypothesis.
MATERIALS AND METHODS
This study was a single-center, randomized, controlled, and double-blind trial. Ethical approval was obtained from the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (number: ky2013-008-01). The trial was registered at http://www.Clinicaltrials.gov (number: NCT02306278). All participants provided their written informed consent.
Patients scheduled for an elective suboccipital or subtemporal approach craniotomy were consecutively recruited in the study. The inclusion criteria were age between 18 and 65 years and an American Society of Anesthesiologists (ASA) physical status of I or II.
Patients were excluded from the study if they met at least one of the following criteria: history of mental or psychiatric disorders, pregnancy or lactation in female patients, history of systemic malignant tumor, previous treatment using this protocol or participation in another experimental study within the previous 30 days, allergy to the drugs used in the study, body mass index (BMI)>30, and drug or alcohol addiction.
Randomization and Blinding
A computer-generated randomization table prepared by an investigator with no involvement in the trial was used. Patients were randomly assigned following simple randomization to the 2 parallel groups 24 hours before surgery with an allocation ratio of 1:1. An individual not involved in the enrollment handled the randomization list to guarantee allocation concealment.
A nurse placed four capsules of 300 mg gabapentin (Gabapentin Capsule, Enhua Pharmaceutical Limited by Share Ltd., Jiang Su, China) or placebo (capsules of identical color and size that contained vitamin B) in an envelope with a randomization code and sealed it. An anesthesiologist distributed the envelopes to the patients at the preanesthesia interview. The patients ingested 2 capsules of gabapentin or placebo orally the night before surgery and 2 hours before anesthesia induction. The nurse, anesthesiologists, patients, and outcome assessors were all blinded to the grouping. The grouping was unmasked at the end of the trial. The anesthesiologists in chief and the principal investigator jointly decided whether to unmask the grouping in cases of emergency or severe adverse events.
The patients were randomly allocated to the gabapentin and placebo groups. In the gabapentin group, the patients received a dose of gabapentin (600 mg, orally) the night before surgery and 2 hours before anesthesia induction, respectively. The patients received vitamin B in capsules of identical color and size at the same time points in the placebo group. The preoperative visual analog scale (VAS) pain score was assessed before gabapentin administration 1 day before surgery without consumption of analgesic.
All enrolled patients were the first case of the surgical day to provide a consistent time from premedication with gabapentin to anesthesia. Peripheral venous access was established after the patients were admitted to the operating room. Routine monitoring included electrocardiograph, pulse oxygen saturation, continuous arterial pressure, end-tidal carbon dioxide partial pressure (ETCO2), and bispectral index (BIS).
Midazolam (0.05 mg/kg) was intravenously administered 10 minutes before anesthesia induction. Anesthesia was induced with propofol (1.5 to 2.5 mg/kg), sufentanil (0.3 to 0.4 µg/kg), and rocuronium (0.6 mg/kg). Mechanical ventilation was performed after tracheal intubation with a 50% fraction of inspired oxygen in the air and fresh gas at a flow rate of 2 L/min to maintain the ETCO2 between 35 and 40 mm Hg. Anesthesia was maintained with propofol, remifentanil and rocuronium. Propofol was titrated to maintain the BIS values between 40 and 50. The rate of remifentanil infusion was adjusted to maintain the mean arterial blood pressure (MAP) and heart rate (HR) fluctuations within 20% of the baseline values. Tramadol (1.5 mg/kg) and ondansetron (8 mg) were administered thirty minutes prior to the end of surgery per standard care. No additional analgesics, such as local anesthetics, or antiemetics were administered intraoperatively.
The patients were extubated after full recovery from anesthesia and transferred to the postanesthesia care unit (PACU). The patients remained in the PACU for 120 minutes and received nasal oxygen inhalation. The patients were connected to fentanyl-loaded electric analgesia pumps (Rhythmic Plus; Micrel Medical Devices S.A., Greece-European Union) for routine postoperative analgesia. PCA electric pumps were filled with fentanyl (18 µg/kg) and ondansetron (16 mg) diluted in 150 mL of normal saline (continuous basal infusion rate of 2 mL/h, no loading dose, and a 0.5-mL incremental dose with a 15-minute lockout time). Insufficient postoperative analgesia was defined as a VAS score that exceeded 60 or was >40 and lasted for 15 minutes. Patients with insufficient analgesia received intravenous tramadol (50 mg). Ondansetron (8 mg) was intravenously administered if patients vomited or reported >15 minutes of nausea.
The primary endpoint was the postoperative pain score at 24 hours. The pain score on movement (moving head gently) was assessed by the VAS by the trained investigator who was blinded to the grouping. The VAS consisted of a 100-mm line with 0 on the left extreme indicating “no pain” and 100 on the right extreme indicating “maximal pain.” The patients were instructed to describe their pain intensity using the VAS score prior to surgery.
Secondary outcomes were included as follows:
- In addition to assessment at 24 hours, the VAS scores on movement at 1 hour, 2 hours and 48 hours and the VAS during rest at the same time points after surgery were evaluated.
- Consumption of the dosage of intraoperative and postoperative analgesics and sedatives were recorded and calculated, including the intraoperative dosage of propofol and remifentanil and the postoperative PCA opioid consumption and rescue tramadol within 48 hours after surgery.
- Postoperative sedation levels at 1 hour, 2 hours, 24 hours, and 48 hours were rated by the trained investigator who was blinded to the grouping by Ramsay sedation scale scores,14 in which 1 indicated anxious and agitated and 6 indicated no response. Excessive sedation was defined as a score >4.
- The incidences of postoperative nausea, vomiting, dizziness, and rescue antiemetics were recorded at 1 hour, 2 hours, 24 hours, and 48 hours.
Sample Size and Statistical Analysis
The sample size was estimated using PASS 2011 software (NCSS LLC). We calculated the sample size based on the primary outcome, which was the VAS score (0 to 100) on movement at 24 hours after surgery. Only Türe et al’s10 study was designed to assess the effect of gabapentin on postcraniotomy pain; however, the pain intensity was assessed using the VAS score (0 to 10). On the basis of the study regarding cesarean delivery, the patients received 600 mg gabapentin preoperatively, and the results indicated the mean [95% confidence interval (CI)] VAS scores were 21 mm (13 to 29) in the gabapentin group and 41 mm (32 to 51) in the placebo group at 24 hours (P=0.001). However, the intensity of pain after craniotomy is not worse than after cesarean section. The minimal clinically significant differences between groups is approximately 10 mm.15 Thus, we estimated preoperative gabapentin would reduce the VAS pain score by 10 mm on movement at 24 hours after surgery with a SD of 16.5 mm.16 A sample size of 122 would be sufficient to detect a significant difference at a test level of 0.05 and a power of 85% using Student t test, with a drop-out rate of 20%. Statistical analysis was performed using SPSS for Mac (version 20, IBM). The Kolmogorov-Smirnov test was used to test for normality. The continuous variables with a normal distribution were described as means with SDs and compared using Student t tests. Non-normally distributed continuous variables were described as medians with interquartile ranges (IQRs) and compared using Mann-Whitney U or Friedman tests. Categorical variables were described as numbers with percentages and compared using Pearson χ2 or Fisher exact tests. A 2-tailed P<0.05 was considered statistically significant for these outcomes. The postoperative VAS on movement and at rest, sedation score, and cumulative PCA opioid dosages were compared by analysis of variance of repeated measures. If the overall effect exceeded statistical significance, the between-group difference at each time point was compared using a nonparameter test with Bonferroni correction.
A total of 209 patients were screened for eligibility from December 2014 to December 2015 in Beijing Tiantan Hospital, Capital Medical University. A total of 122 eligible patients were randomly allocated to the 2 groups. The recruitment flow chart is presented in Figure 1. Furthermore, we also assessed the pain score at 3 months after craniotomy, which will be reported in another paper.
The demographics and baseline characteristics were comparable between the 2 groups (Table 1). The pathology type, operative approach, tumor size, duration of surgery and anesthesia, and time to tracheal extubation were all similar between the 2 groups (Table 1).
Gabapentin significantly decreased the overall postoperative pain score both at rest (P=0.001) and on movement within 48 hours (P=0.000) compared with the placebo group. Moreover, the postoperative VAS score, including at rest and on movement at 1 hour, 2 hours, and 24 hours, was significantly lower in the gabapentin group than in the placebo group after the Bonferroni correction (Table 2). The difference in the VAS score on movement at 24 hours was the most substantial among the 4 time points (9.1; 95% CI, 13.5-4.6; P=0.000). However, there was no significant difference in the VAS scores at rest or movement at 48 hours.
Gabapentin significantly decreased the total consumption of intraoperative propofol (0.7 mg/kg/h; 95% CI, 0.0-1.4; P=0.021) and remifentanil (1.3 µg/kg/h; 95% CI, 0.1-2.6; P=0.025). The cumulative PCA opioid dosage and the number of patients who required rescue tramadol were similar between the 2 groups (Table 3). Gabapentin significantly decreased the incidence of vomiting (16.5%; 95% CI, 1.3-31.6%; P=0.047) and the number of patients who required rescue antiemetics (18.5%; 95% CI, 2.6-34.5%; P=0.033) within 48 hours. The incidence of nausea and dizziness were similar in the 2 groups. Gabapentin increased the overall postoperative sedation score (P=0.012), particularly at 2 hours (0.2; 95% CI, 0.0-0.4; P=0.015) after Bonferroni correction. However, no excessive sedation (score >4) was identified in either group.
This study was a single-center, randomized, controlled, and double-blind trial. We aimed to investigate the effects of gabapentin on postoperative acute analgesia in patients undergoing craniotomy via suboccipital or subtemporal approaches. The results demonstrated that preoperative oral gabapentin significantly decreased the acute postoperative pain scores both at rest and on movement within 24 hours and reduced the intraoperative sedative and analgesic requirements. However, gabapentin increased the postoperative sedation level at 2 hours.
Gabapentin is an anticonvulsant drug with analgesic effects. Several studies have indicated the effect of gabapentin on postoperative analgesia; however, the timing and dosage of gabapentin are topics of continuous debate. A single dose before10,17,18 or after surgery19 was initially applied in the research of postoperative pain. Multiple doses before and after surgery were also administered.20,21 The dosage of gabapentin administered varied and included 300 mg/d,18 600 mg/d,10,17 1200 mg/d,22 and 1500 mg/d.23 Similarly, the effects on postoperative analgesic were also different. Gabapentin relieved postoperative pain only with a dosage of 300 mg in patients undergoing arthroscopic surgery,18 whereas the dosage of 1200 mg gabapentin was not effective after thoracotomy surgery.24 These studies indicated the analgesic effect of gabapentin was closely associated with different types of surgery and the dosage administered.25 Gabapentin is absorbed slowly after oral administration. The time to the maximal plasma concentration after oral administration is approximately 3 hours, and the half-life elimination is approximately 6 hours.26 Both the time to reach the peak concentration and to eliminate the drug in the cerebrospinal fluid are substantially longer than those in the plasma.27 Animal experiments demonstrated that preemptive gabapentin treatment was more effective and provided a longer duration of analgesia than postoperative administration.28 Prophylactic use of gabapentin reduced postoperative pain in several surgical settings, including tonsillectomy, nasal surgery, abdominal hysterectomy, and lumbar spinal surgery,25 which is consistent with our study. In the current study, 2 doses (600 mg per dose) of gabapentin were administered. The first dose was administered orally at 10 PM the day before surgery, and the other dose was administered 2 hours before anesthesia induction. The time between the first dose and surgery was approximately 10 hours, which guaranteed that the plasma concentration of gabapentin had reached an analgesic level during the period of skull opening. The other dose of gabapentin further enhanced the effective plasma and cerebrospinal fluid concentrations during the entire period to 24 hours after surgery.
In general, the mechanisms related to the analgesic effect of gabapentin mainly involved mediating the α2-δ subunit of presynaptic calcium channels, inhibiting neuronal calcium influx, reducing the release of excitatory neurotransmitters (glutamate, substance P, and calcitonin), and inhibiting the pathway of pain conduction.29–31 Decreased release of excitatory neurotransmitters modulated the down-regulation of peripheral hyperexcitability in spinal dorsal horn neurons induced by peripheral noxious stimulation, which would suppress hyperalgesia and central sensitization. Hyperalgesia and central sensitization might activate peripheral nociceptors and play a crucial role in pain amplification.32 In addition, gabapentin stimulated the descending noradrenergic pathway to produce antinociception and inhibit postoperative hypersensitivity.33 In the current study, we determined that gabapentin decreased the intraoperative consumption of remifentanil and the VAS score at 1 and 2 hours after surgery, which might be mainly associated with the direct inhibition of pain transmission by gabapentin. In addition, gabapentin lowered the VAS score at 24 hours after surgery. On the basis of the pharmacokinetics, the concentrations of gabapentin in the plasma and cerebrospinal fluid were minimal at 24 hours after surgery because of the preoperative administration; thus, the analgesic effects of gabapentin might result from the inhibition on hyperalgesia and central sensitization.
Postoperative pain from craniotomy is closely related to the scalp, temporalis and cervicalis muscles, soft tissue, and dura. The site of surgical incision substantially impacts the incidence and severity of postoperative pain and the requirements for analgesics.34 Suboccipital and infratemporal approaches produce the highest incidences of postoperative pain.6,35 Türe and colleagues assessed 80 patients with supratentorial tumor who received 1200 mg/d gabapentin daily up to 1 week before craniotomy, compared with 300 mg/d phenytoin. The study demonstrated that gabapentin decreased the pain scores 1 hour postoperatively; however, no effects at 2 hours to 48 hours were identified.12 Several potential reasons for the negative effect at 24 hours included the positive control decreasing the between-group difference and 64% of patients undergoing a pterional approach, which was associated with less pain than infratentorial procedures. Misra et al13 administered a single dose (600 mg) of gabapentin 2 hours before craniotomy and determined there was no effect on the incidence of postoperative pain within 24 hours. However, the primary endpoint was postoperative nausea, and the sample size might be insufficient to estimate the impact on the pain score. In addition, the surgical approaches were diverse and were not similar to the current study. In the current study, gabapentin significantly decreased the intraoperative remifentanil dosage and the pain score within 24 hours, which is consistent with Türe and colleagues’s study.
We demonstrated a statistically significant effect of preoperative gabapentin on VAS scores, with changes between 4 to 9 mm, which was slightly lower than the clinically meaningful change in the VAS score of 10 mm (100 mm in total) reported in other literature.15 In addition, gabapentin did not reduce PCA opioid consumption and rescue tramadol use. The reason for this finding includes the adequate intraoperative analgesia provided by the long-acting opioid (sufentanil) during skull opening, the tramadol administered 30 minutes before the end of surgery and the relatively high background infusion rate used for PCA in both groups. Consequently, the analgesic effect of preoperative gabapentin might be weakened by intraoperative and postoperative concomitant analgesia and, although VAS scores were reduced, PCA opioid consumption and rescue tramadol use were not influenced.
Gabapentin is often well-tolerated with few side effects, which are dose-dependent. The long-term high-dose use of gabapentin may increase the risks of dizziness and sedation. Therefore, we administered a low-dose twice, including on the night before surgery and 2 hours before anesthesia induction, to achieve an effective concentration and avoid serious postoperative sedation. In the current study, no patients exhibited severe sedation (scores >4). However, the low-dose gabapentin increased the postoperative sedation depth at 2 hours. In addition, gabapentin decreased the intraoperative propofol infusion dose, which is administered as a sedative. It might also be a result of mediating α2-δ subunits of presynaptic calcium channels in the central nervous system, inhibiting neuronal calcium influx, and reducing the release of excitatory neurotransmitters, which are synergistic with the sedative effect of propofol. In addition, gabapentin might reduce the surgical stress response by reducing the release of sympathetic adrenal hormones, such as catecholamines, which may also be involved in the reason for the reduction of intraoperative propofol.36 Therefore, when preoperative gabapentin is administered as a multimodal analgesic, the intraoperative anesthesia depth should be monitored and postoperative sedation should be evaluated during the early recovery period.
We also determined that the incidence of vomiting and the number of patients who required rescue antiemetics during the first 48 hours were significantly lower in the gabapentin group, which are in accordance with the results from Misra and colleagues’s study. On the basis of the literature, gabapentin could reduce the incidence of vomiting through tachykinin (NK-1) antagonism and decreasing the release of the tachykinin neurotransmitter substance P.37,38 In addition, an opioid sparing effect of gabapentin was expressed as the decreased intraoperative consumption of remifentanil, which partly attributed to its antiemetic effect.
There are several limitations of the study. First, the postoperative acute pain was evaluated using the VAS. Pain should also be assessed using objective measurements, such as serum catecholamine levels. However, VAS assessment of postoperative pain is the primary measurement tool for assessing pain and is well accepted in clinical practice.39 Second, the perioperative opioid applied for analgesia was not consistent. However, it is routine to provide intraoperative analgesia by combining long-acting (sufentanil and fentanyl) and short-acting opioids (remifentanil) and postoperative analgesia by tramadol to avoid opioid-related side effects. Third, vitamin B might provide adjuvant analgesia from the recent study.40 However, in our study, we applied vitamin B as the placebo and did not combine vitamin B with gabapentin, which would not confound the antinociceptive effects of gabapentin; however, it may lead to an underestimation of the analgesic effect of gabapentin. Finally, it was a single-center study, and the clinical practice might not be the same as other medical centers.
In summary, preoperative gabapentin administration reduced the acute postoperative pain score within 24 hours, decreased the incidence of vomiting, and increased the sedation level in patients undergoing craniotomy by a suboccipital or subtemporal approach. Further multicenter studies are required to test the efficacy and safety of gabapentin for postoperative analgesia in the long term and also to help to identify the optimal dosing regimen for perioperative analgesia.
The authors gratefully thank the Department of Anesthesiology, Beijing Tiantan Hospital, with a special acknowledgment to the colleagues of the Department of Neurosurgery, for their support and cooperation.
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