Prophylactic gabapentin for prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: A randomized, double-blind, placebo-controlled study

Abstract

Background: Gabapentin is an antiepileptic drug. Its antiemetic effect is demonstrated in chemotherapy-induced acute and delayed onset of nausea and vomiting in breast cancer patients. Aim: To evaluate the antiemetic effect of gabapentin on incidence and severity of postoperative nausea and vomiting in laparoscopic cholecystectomy. Settings and Design: Double-blind, randomized, placebo-controlled study. Materials and Methods: Two hundred and fifty patients of ASA physical status I and II, scheduled for laparoscopic cholecystectomy were randomly assigned into two equal groups to receive 600 mg gabapentin or matching placebo two hours before surgery. Standard anaesthesia technique was used. Fentanyl was used as rescue postoperative analgesic. Ondansetron 4 mg was used intravenously as rescue medication for emesis. The total number of patients who had nausea or vomiting, and its severity and total fentanyl consumption in the first 24 hours were recorded. Statistical Analysis: "Z test" was used to test the significance of severity of post-operative nausea and vomiting between groups. Fentanyl consumed in each group (Mean±SD) within 24 hrs was compared using student t test. P value< 0.05 was considered significant. Results: There were no demographic difference between the two groups. Incidence of post-operative nausea and vomiting within 24 hrs after laparoscopic cholecystectomy was significantly lower in gabapentin group (46/125) than in the placebo group (75/125) (37.8% vs 60%; P =0.04). There was a significantly decreased fentanyl consumption in gabapentin group (221.2±92.4 µg) as compared to placebo group (505.9±82.0 µg; P =0.01). Conclusion: Gabapentin effectively suppresses nausea and vomiting in laparoscopic cholecystectomy and post-operative rescue analgesic requirement.

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Original Article
Prophylactic gabapentin for prevention of postoperativeProphylactic gabapentin for prevention of postoperative
Prophylactic gabapentin for prevention of postoperativeProphylactic gabapentin for prevention of postoperative
Prophylactic gabapentin for prevention of postoperative
nausea and vom iting in patients undergoing nausea and vom iting in patients undergoing
nausea and vom iting in patients undergoingnausea and vom iting in patients undergoing
nausea and vom iting in patients undergoing
laparoscopic cholecystectom y: A random ized, double­laparoscopic cholecystectom y: A random ized, double-
laparoscopic cholecystectom y: A random ized, double-laparoscopic cholecystectom y: A random ized, double-
laparoscopic cholecystectom y: A random ized, double-
blind, placebo-controlled studyblind, placebo-controlled study
blind, placebo-controlled studyblind, placebo-controlled study
blind, placebo-controlled study
Pandey CK, Priye S, Ambesh SP, Singh S, Singh U, Singh PK
Departments of
ABSTRACTABSTRACT
ABSTRACTABSTRACT
ABSTRACT
Anaesthesiology and
Background: Gabapentin is an antiepileptic drug. Its antiemetic effect is demonstrated in chemotherapy-
Biostatistics, Sanjay Gandhi
Postgraduate Institute of
induced acute and delayed onset of nausea and vomiting in breast cancer patients.
Medical Sciences,
Aim: To evaluate the antiemetic effect of gabapentin on incidence and severity of postoperative nausea and
Lucknow - 226014, India
vomiting in laparoscopic cholecystectomy.
Settings and Design: Double-blind, randomized, placebo-controlled study.
Correspondence:
Materials and Methods: Two hundred and fifty patients of ASA physical status I and II, scheduled for laparoscopic
Chandra Kant Pandey,
E-mail:
cholecystectomy were randomly assigned into two equal groups to receive 600 mg gabapentin or matching
ckpandey@sgpgi.ac.in
placebo two hours before surgery. Standard anaesthesia technique was used. Fentanyl was used as rescue
postoperative analgesic. Ondansetron 4 mg was used intravenously as rescue medication for emesis. The
total number of patients who had nausea or vomiting, and its severity and total fentanyl consumption in the
first 24 hours were recorded.
Statistical Analysis: “Z test” was used to test the significance of severity of post-operative nausea and vomiting
between groups. Fentanyl consumed in each group (Mean±SD) within 24 hrs was compared using student t
test. P value< 0.05 was considered significant.
Results: There were no demographic difference between the two groups. Incidence of post-operative nausea
and vomiting within 24 hrs after laparoscopic cholecystectomy was significantly lower in gabapentin group
(46/125) than in the placebo group (75/125) (37.8% vs 60%; P=0.04). There was a significantly decreased
fentanyl consumption in gabapentin group (221.2±92.4 µg) as compared to placebo group (505.9±82.0 µg;
P=0.01).
Received : 01-12-05
Conclusion: Gabapentin effectively suppresses nausea and vomiting in laparoscopic cholecystectomy and
Review completed : 23-01-06
post-operative rescue analgesic requirement.
Accepted : 23-02-06
PubMed ID :?
J Postgrad Med 2006;52:97-101
KEY WORDS: Antiemetic, gabapentin, post-operative nausea, vomiting?
Posto-perative nausea and vomiting (PONV) are among the proteins and is not metabolized in humans. After a single oral
most common complications following anaesthesia and surgery. dose of 300 mg, mean maximum plasma concentrations are
The etiology of PONV is complex and is dependent on a variety attained in 2-3 hr. Absorption kinetics of gabapentin are dose­
of factors including the technique of anaesthesia patients’ dependent, possibly due to a saturable transport system.[3] The
demographics and type and site of surgery. Laparoscopic
bio-availability of a single 300 mg oral dose of gabapentin is
cholecystectomy has emerged as a popular alternative to
60% and decreases with increasing dose. Elimination of
traditional cholecystectomy in the management of
gabapentin is by renal clearance and the elimination half life
cholelithiasis.[1] It is reported that nearly 53-72% of patients is about 5-7 hr after a single oral dose of 200 to 400 mg.[3]
require antiemetic therapy after laparoscopic
cholecystectomy.[1,2]
Recently an open clinical study demonstrated the anti-emetic
effect of gabapentin in chemotherapy-induced acute (within
Gabapentin, a structural analog of gamma amino butyric acid 24 hr) and delayed onset (days 2-5) of nausea and vomiting in
(GABA) is an antiepileptic drug.[3] It does not bind with plasma
breast cancer.[4] In the present clinical study, we have evaluated
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� Panday et al: Gabapentin for prevention of postoperative nausea and vom iting
the antiemetic effect of gabapentin on the incidence and
severity of PONV in patients who underwent laparoscopic
cholecystectomy.
Materials and Methods
We recruited 250 patients of ASA physical status I and II, of
both sexes scheduled for elective laparoscopic cholecystectomy
for a double-blind, prospective, randomized and placebo­
controlled study (sample size was determined on the
assumption that the incidence of PONV is 70% following
laparoscopic cholecystectomy and treatment with gabapentin
would decrease it by 20%. For 90% of power of the test, 125
patients were required in each group). The exclusion criteria
were: body weight more than 20% of the ideal body weight;
those older than 60 years or younger than 18 years or smokers;
history of drug or alcohol abuse; history of hypersensitivity to
any drug, history of peptic ulcer disease or of bleeding diathesis
or patients taking antacids; impaired kidney or liver functions;
patients who had received antiemetics within 24 hr before
scheduled surgery or received sedatives other than those
determined by protocol, menstruating, pregnant or lactating
females, patients who had history of motion sickness, patients
on anti-depressants or calcium channels blockers or patients
on whom laparoscopic cholecystectomy was converted into
open cholecystectomy [Figure 1].
The day before surgery, all patients were visited for pre­
anaesthesia assessment and to explain the study protocol. All
patients received oral lorazepam 2 mg the evening before
surgery and the morning of surgery. Patients were randomly
divided into two equal groups using a computer generated table
of random numbers, to receive the medication orally two hours
before surgery. Patients enrolled in the Gabapentin group
received 600 mg of gabapentin; while those in the placebo
group received a placebo (capsule similar to gabapentin).
Anaesthesia was induced with propofol 2 mg/kg, fentanyl 3
µg/kg. Intubation of trachea was facilitated with vecuronium
bromide 800 µg/kg. Anaesthesia was maintained with a propofol
infusion 100-200 µg/kg/min and 70% nitrous oxide in oxygen
and intermittent vecuronium bromide when indicated. After
completion of the surgery, neuromuscular blockade was
reversed with atropine 0.02 mg/kg and neostigmine 0.04 mg/
kg and patients were extubated when adequate spontaneous
ventilation was established and were transferred to post­
anesthesia care unit (PACU). After approximately 6 hrs of stay
in PACU, patients were transferred to their respective wards.
A senior resident, who was not part of the anesthesia team and
was blinded to the type of medication the patients had received,
recorded PONV and the amount of rescue analgesic consumed
by the patients. The PONV was defined as the subjective
unpleasant sensation associated with awareness of urge to vomit
(nausea, retching or vomiting had been grouped together). The
severity of PONV was graded as follows.[5]
No PONV
Absence of any emetic episode or nausea
Mild PONV
The patient had only mild nausea or one emetic episode or
short lasting nausea of any severity of less than 10 min which
was triggered by exogenous stimulus and no antiemetic drug
was required.
Moderate PONV
the patient had 1-2 emetic episodes or moderate or severe
nausea without exogenous stimulus and patient required
antiemetic therapy once.
Severe PONV
The patient had more than two emetic episodes or was
nauseated more than twice and administration of at least one
antiemetic was required.
Patients received patient-controlled-analgesia for their pain
management (PCA pump was set to fentanyl 1.0 mg/kg
patient’s activated dose with lockout interval of 10 minutes).
The failure of treatment was defined when the patients had
an episode of PONV within 24 hrs. The episodes of retching or
vomiting were considered as vomiting events. Patients received
ondansetron 4 mg intravenously when they demanded
antiemetics.
The Institute’s Ethics Committee approved the study protocol
and written informed consent was obtained from each
participant. The procedures followed in this were in accordance
with ethical standards of the responsible committee on human
experimentation as per Helsinki Declaration (1975, and as
revised in 2000). Patients were recruited from the department
of surgical gastroenterology from January 2003 to March 2004
till the required number of patients in each group had
completed the study.
Figure 1: Flow diagram of patient distribution
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Panday et al: Gabapentin for prevention of postoperative nausea and vom iting �
Statistical analysis
After completion of the study, the data were entered into the
statistical software package SPSS 9.0 (Chicago, USA). Data
were presented as means and standard deviation for 95%
confidence interval with 5% degree of freedom. Student ‘t’ test
was used to compare the demographic data and for the
incidence of PONV. The test of proportion “Z test” was used
to test the significance of severity of PONV between the groups.
Total fentanyl consumed in each group (Mean ± SD) within
24 hrs was compared using student t test. P value less than
0.05 was considered statistically significant.
Results
There were no demographic differences (age, weight, duration
of surgery, and gender distribution) between the gabapentin
and placebo groups [Table 1]. The incidence of PONV during
the first 24 hr in patients after laparoscopic cholecystectomy
was significantly lower in gabapentin group (46/125) 37.8%
than 60% of the placebo group (75/125) (P=0.04) but there
was no difference in the severity of PONV amongst the two
groups [Table 2]. Gabapentin achieved complete control of
established PONV (no emesis, no rescue treatment) in 79
patients whereas only 50 patients of placebo group had no
PONV (P=0.04) with absolute risk reduction of 22.2% and
relative risk reduction of 37%. The number of patients who
would have to be treated to prevent one patient from
experiencing PONV (number needed to treat, NNT) was 4.5.
The incidence of side effects in both the groups was similar
[Table 3]. However, the patients of placebo group consumed
significantly higher amount of fentanyl compared to the
patients of gabapentin group (505.9±82.0 µg vs 221.2±92.40
µg; P= 0.01) [Table 2] for their pain relief.
Discussion
Our study has demonstrated lower incidence of PONV during
the first 24 hr after laparoscopic cholecystectomy in the group
of patients who received prophylactic gabapentin 600 mg two
Table 1: The demographic data of study groups
Gabapentin (n=125) Placebo (n=125)
Age (in yrs Mean± SD) 42.8 ± 11.4 41.8 ± 11.1
Weight (Mean± SD) 58.3 ± 6.0 56.9 ± 7.2
Duration of surgery 57.7 ± 4.2 56.5 ± 5.0
(in minutes Mean± SD)
Gender Male (n) 25 18
Female (n) 100 107
hr before surgery than those who received placebo. Gabapentin
decreased the incidence of nausea and vomiting but it did not
decrease the severity of PONV. Gabapentin also decreased the
consumption of fentanyl in patients who received it
prophylactically [Table 2].
The etiology of PONV following laparoscopic cholecystectomy
remains unclear, but is probably associated with operative
factors. These include the effect of intra-peritoneal CO2
insufflation on residual stretching and irritation of the
peritoneum.[5] Factors like age and gender of patient, obesity,
technique of anesthesia employed, presence of post-operative
pain, use of opioids for pain management and elective surgical
procedures also influence the incidence of PONV. In a clinical
study involving 17638 patients, the predictors for PONV were
derived. This study demonstrated that an increase of 10 years
in age decreased the likelihood of PONV by 13%; the risk for
men was one-third that for women; a thirty minutes increase
in the duration of anaesthesia increased the likelihood of PONV
by 59%; and general anesthesia increased the likelihood of
PONV by 11 times compared to other types of anesthesia.[6] A
study conducted by Apfel et al. in Finland and Germany
enrolling 2722 patients they identified four predictors for
PONV based on logistic regression coefficients: female gender,
history of motion sickness or PONV, non-smoking, and use of
postoperative opioids. The incidence of PONV with each of
the factors enumerated above was 10-21%, 39%, 61% and 79%,
respectively.[7] In our study both the groups were comparable
with regard to the risk of suffering PONV (gender distribution;
exclusion of patients with the history of motion sickness or
PONV or history of smoking; and use of postoperative opioids
for pain management).
Gabapentin has been reported to be effective in the treatment
of emesis in patients receiving cytotoxic drugs.[4] The precise
mechanism of gabapentin in the prevention of nausea and
vomiting induced by cytotoxic drugs is not known but mitigation
of tachykinin neurotransmitter activity has been postulated to
be useful.[8] There is evidence that tachykinins activity is part of
Table 3: Incidence of side effects in the study groups
Side effects Gabapentin group
(n=125)
Placebo group
(n=125)
Drowsiness 4 2
Itching
Light headedness
Feeling on a ‘high’
Lack of concentration
1
2
1
2
3
0
0
1
Headache 2 0
Table 2: Incidence of postoperative nausea and vomiting and its severity in study groups?
Fentanyl consumption (in µg) No PONV (n & %) PONV & its grades (n)
Mild Moderate Severe Total (n & %)
Gabapentin (n=125) 221.2 ± 92.4 79* (62.2) 9 31 6 46 (37.8)
Placebo (n=125) 505.9 ± 82.0 50 (40.0) 10 52 13 75 (60.0)
P value 0.01 0.04 0.8 0.06 0.06 0.04
Test of proportion to compare severity grades, Figures in parentheses indicate percentages, * P value <0.05 (Gabapentin VS Placebo) and power of
test 93%
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� Panday et al: Gabapentin for prevention of postoperative nausea and vom iting
the pathogenesis of chemotherapy-induced emesis in ferrets,
and a selective tachykinins-receptor antagonist improves both
acute and delayed nausea and emesis induced by
chemotherapy.[9] The etiology of PONV in patients undergoing
laparoscopic cholecystectomy is not identical to that in patients
receiving cytotoxic drugs but we assume that it may be one
probable mechanism for prevention of PONV by gabapentin.
Gabapentin has been demonstrated to decrease the opioids
consumption in postoperative as well as neuropathic painful
states.[10-14] This study also demonstrated a decrease in the
amount of fentanyl consumption in gabapentin group. In our
series the characteristics, characteristics technique of induction
and maintenance of anaesthesia and use of postoperative
analgesic were similar in both the groups. Therefore, the
difference in the incidence of the PONV between the groups
could only be attributed to gabapentin.
In conclusion, our results have demonstrated that prophylactic
use of 600 mg of gabapentin two hour before laparoscopic
cholecystectomy decreases the incidence of PONV but it does
not affect the severity of PONV. It also decreases the amount
of fentanyl required for postoperative pain management. Thus,
along with antiemetic property, it possesses analgesic property.
However, this antiemetic effect of gabapentin and its
mechanism need to be further evaluated.
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