Evaluation of gabapentin and dexamethasone alone or in combination for pain control after adenotonsillectomy in children.

BACKGROUND: Different methods and many drugs have been used to control the post-operative pain. In this study, we evaluate the role of gabapentin premedication and/or dexamethasone in management of post-operative pain following adenotonsillectomy in children.
MATERIALS AND METHODS: In a double-blind randomized study, 120 children were subjected for adenotonsillectomy classified into three equal groups. Group G: Gabapentin 10 mg/kg was given orally 2 h before induction of anesthesia (Gabapentin syrup 250 mg/5 ml. Group D: Children in this group received placebo pre-operatively and received dexamethasone 0.15 mg/kg intravenously after induction of anesthesia, but before surgery. Group C: Children in this group received combination of oral gabapentin 10 mg/kg 2 h before induction of anesthesia and intra-operative 0.15 mg/kg dexamethasone intravenously. All children underwent general anesthesia. Pain score was assisted post-operatively 2 h, 4 h, 6 h, 8 h, 12 h and 18 h after recovery using face, legs, activity, cry, consolability scale.
RESULTS: Pain score in Group C and Group G was significantly less at 4 h, 6 h and 8 h post-operatively than in Group D (P < 0.05). At 12 h, the pain score in Group C was significantly less than Group G and Group D (P < 0.05). And no significant changes were observed in pain score at 18 h post-operatively between all groups (P > 0.05). The time to first analgesia was longer in the Group C than in Group G and Group D and the time to first analgesia was significantly longer in Group G than in Group D (P < 0.05). The total amount of pethidine was less in Group C and Group G than in Group D (P < 0.05). The incidence of post-operative nausea and vomiting was statically insignificant among all groups and no reported post-operative bleeding.
CONCLUSION: Gabapentin 10 mg/kg premedication combined with intra-operative dexamethasone 0.15 mg/kg prolongs the post-operative analgesia following adenotonsillectomy in children and decreases the amount of pethidine used post-operatively with no reported adverse effects or increase in the incidence of post-operative bleeding.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Tonsillectomy is the most commonly performed surgical procedure in the otolaryngology practice. The more important complications of this operation are intra-operative blood loss, post-operative hemorrhage and post-operative pain.[1]

Poorly controlled pain can result in increased catabolism, increased heart rate, blood pressure, respiratory rate, immunosuppression[2] and coagulation disturbances.[3] Pain and post-operative nausea and vomiting (PONV) prolong recovery, discharge time and contribute to unexpected readmission after out-patient surgery, also lead to poor patient satisfaction, impair quality of recovery and increase health care costs.[4]

Corticosteroids have been used as anti-inflammatory and anti-immunological agents. Corticosteroids act by suppressing arachidonic acid production through lipocortin-induced phospholipase inhibition, which inhibits both prostaglandins and leukotrienes.[5] It also prevents the production of cytokines, which play a role in the mechanism of inflammatory pain.[6] Gabapentin was introduced in 1993 as an adjuvant anticonvulsant drug for the treatment of refractory partial seizures. Subsequently, it was shown to be effective in treating a variety of chronic pain conditions. Gabapentin use has more extended into the management of more acute conditions, particularly in the peri-operative period.[7]

Gabapentin has the role in post-operative analgesia, pre-operative anxiolysis, prevention of chronic post-surgical pain, attenuation of hemodynamic response to direct laryngoscopy and intubation, prevention of PONV and post-operative delirium.[8]

The aim of this clinical study was to evaluate the role of gabapentin premedication in the management of post-operative pain following adenotonsillectomy in children.

MATERIALS AND METHODS

This study was carried out on 120 children American Society of Anesthesiologists I and II who underwent adenotonsillectomy after obtaining approval from the hospital ethics committee and a written informed consent from the parents of each child. Their age ranged between 4 and 6 years. Exclusion criteria included diabetes, cardiac conduction anomalies, liver and/or kidney disease, hypersensitivity to drugs used, peritonsillar abscess, swallowing disorder, epilepsy or previous treatment with gabapentin or steroids uses. Tonsillectomy dissection was performed using the bipolar diathermy and was performed in all patients by the same surgeon. Patients were randomly allocated equally (40 patients in each group) into three groups. The randomization was performed using sealed numbered envelopes indicating the group of each patient. A blind nurse who did not participate in patients’ follow-up read the number and made group assignments.

The process of inclusion in the study went on until the requested number of patients was reached.

Group G: Gabapentin 10 mg/kg (gabapentin 250 mg/5 mL, Pfizer) was given orally mixed with juice to make its taste accepted 2 h before induction of anesthesia (Gabapentin syrup 250 mg/5 mL.[9]

Group D: Received placebo (free juice) 2 h before induction of anesthesia and received 0.15 mg/kg dexamethasone intravenously after induction of anesthesia but before surgery.

Group C: Received combination of both gabapentin 10 mg/kg orally mixed with juice to make its taste accepted 2 h before induction of anesthesia pulse 0.15 mg/kg dexamethasone after induction of anesthesia but before surgery, we suppose that The combination of both gabapentin and dexamethasone would provide a synergistic effect and prolog the post-operative analgesia also prolog time to first analgesic request. The significant of combination of gabapentin and dexamethasone in reducing the postoperative pain better than individual administration of each drug was mentioned by Koc s et al.,[10] and Rasmussen ML et al.[11]

Anesthesia technique

General anesthesia was induced by inhalational technique with halothane in oxygen. After the patients’ loss of consciousness, intravenous line was installed and standard patient monitoring (electrocardiogram, non-invasive arterial pressure, heart rate, pulse oximetry and end-tidal CO2) was applied. Patients in Group D and C received 0.15 mg/kg dexamethasone intravenously after induction of anesthesia but before surgery and all patients received 1 μg/kg fentanyl and ringer's solution 10 ml/kg/h during surgery. Central orotracheal intubation was performed and anesthesia was maintained with halothane in oxygen. After the surgeon had completed the operation, oropharyngeal suction was performed under direct vision, all patients were extubated in tonsillectomy position with or without nasopharyngeal or oropharyngeal airway in place to prevent airway obstruction, especially in patients with obstructive sleep apnea.

Measurements

The pain intensity was assisted by a person who was blind to study by using face, legs, activity, cry, consolability (FLACC) scale[12] [Table 1] graded from 0 to 10 (0 = no pain, 10 = the worst possible pain in the following time 2 h, 4 h, 6 h, 8 h, 12 h and 18 h after recovery.

Table 1

FLACC scale

Post-operative analgesia was given to all patients depending on pain score. If the value was less than 5, rectal paracetamol 20 mg/kg was given if the value was more than 5, pethedine 0.5 mg/kg was given intravenously and recorded. The time to the first dose of analgesia and the total amount of pethedine used was recorded in all patients. Post-operative complications as nausea, vomiting or bleeding were recorded.

Patients were discharged post-operatively when they had no or mild pain (FLACC <3), were able to tolerate clear fluids and soft food and had no bleeding and or nausea or vomiting.

Statistical analysis

A sample size of 40 patients will be sufficient to detect a 30% reduction in the post-operative analgesics requirements between the study groups assuming a power of 80% and a significance level of 5%. All data are expressed as mean ± standard deviation. To determine the pattern of changes in individual variables in each group during various phase of study, an analysis of variance for repeated measure was performed. P < 0.05 was considered to be statistically significant. Unpaired t-test was used to compare between both groups and Mann–Whitney U-test was used for pain scores.

RESULTS

This study was carried out on 120 patients divided into three equal groups, 40 children in each group. The groups were comparable as regards to demographic data including age, gender, weight and duration of anesthesia [Table 2]. Time to first request for analgesia was significantly longer in Group C than in Group G and Group D and the time was significantly longer in Group G than Group D (14.5 ± 3.54 h, 7.95 ± 2.06 h, 5.85 ± 1.87 h, respectively) P < 0.05 [Table 2].

Table 2

Demographic data; pethidine consumption; time of first analgesic requirement; duration of anesthesia and incidence of PONV

The amount of pethidine was less in Group C than Group G and Group D and the amount of pethidine was significantly less in Group G than in Group D (5.31 ± 4.45 mg, 8 ± 10.05 mg, 16.25 ± 11.57 mg, respectively (P < 0.05) [Table 2].

Pain score after 2 h was statistically insignificant between all groups (P > 0.05) whereas pain score at 4 h, 6 h and 8 h in Group C and Group G was significantly less when compared to Group D (P < 0.05). Furthermore, the value of pain score was significantly less in Group C when compared with Group G (P < 0.05) [Table 3].

Table 3

The value of pain score

The incidence of PONV was comparable in all groups and treated by Metoclopramide 0.15 mg/kg and if PONV still persisted, ondansetron 0.1 mg/kg would be administered. Use of opioid analgesics increased risk of emetic episodes. In the present study, there was no correlation between pethidine doses and incidence of PONV.

DISCUSSION

Tonsillectomy is one of the most commonly performed operations in children. It carries significant post-operative pain which if not treated well can cause significant risk including, increasing heart rate, blood pressure, respiratory rate, difficulty swallowing, increase the risk of post-operative bleeding and prolong the hospital stay.

In our study, we use either gabapentin 10 mg/kg 2 h before anesthesia or dexamethasone 0.15 mg/kg after induction of anesthesia and before the surgical procedure or combination of both drugs for controlling the post-operative pain following adenotonsillectomy in children. The mechanism of gabapentin on neuropathic pain is thought to involve voltage-gated N-type calcium ion channels. It is thought to bind to the alpha 2_ delta subunit of the voltage-dependent calcium channel in the central nervous system. This reduces calcium influx into the nerve terminals and decreases the release of neurotransmitters like glutamate.[1314] The glucocorticoids block both the cyclooxygenase and the lipooxygenase pathway in the inflammatory chain reaction. Thus, these compounds may be effective in reducing pain. Another potential benefit of steroid use is the apparent post-operative antiemetic effect by inhibiting the phospholipase enzyme.

Both gabapentin and dexamethasone had different mechanism of action in the management of acute pain. Hence, if they are used together they will have a synergistic effect, prolong the time of post-operative analgesia, decrease the amount of pethedine used and allow early return to normal life.

In this study, we compare the analgesic effect of gabapentin versus dexamethasone alone or in combination with each other in patients underwent adenotonsillectomy and we found that the patients in Group C had less pain score, time to first analgesia was prolonged and the amount of pethidine was less than in Group G and Group D. The incidences of PONV were insignificant between all groups. No side-effects related to gabapentin or dexamethasone was reported in our study.

This finding is constant with the study of Mikkelsen et al., who reported that, patients who received gabapentin showed a reduced the amount of opioid used in the first 24 h after tonsillectomy in adult patients.[15]

A study done by Jeon et al., also concluded that premedication with gabapentin decreased post-tonsillectomy pain during the swallowing in adult patients.[16]

The analgesic effect of gabapentin was reported by Dirks et al., who reported a decrease in pain following a single dose of gabapentin in patients underwent mastectomy.[17]

Furthermore Fassoulaki et al., concluded that the patients undergone surgery for cancer breast who received gabapentin before operation had less pain score and the amount of codeine used was also reduced than the control group.[18]

Turan et al., also conclude that gabapentin provided a significant analgesic benefit for intra-operative and post-operative pain relief in patients undergoing ambulatory rhinoplasty or endoscopic sinus surgery.[19]

In our study, the adverse effect related to gabapentin (dizziness, sedation and headache) were not reported. This in contrast with other studies[1520] the authors in this studies report different complication related to gabapentin such as dizziness, vomiting, gait disturbance and sedation, which occurred significantly than placebo.

We believe that the reported complications associated with gabapentin in previous studies may be related to the dose and the duration of gabapentin as increasing the dose and duration would increase the side-effects. One study used 1800 mg/day of gabapentin and suggested that these side-effects were probably caused by 5 days of continuous ingestion of gabapentin at relatively high doses.[15] The other study used 1800 mg/day pre-operatively and 3 days after the operation.[20]

In our study, we used a single dose 10 mg/kg before operation. This does is relatively smaller than the dose used by other studies and this may be the cause we have not reported these side-effects. Jeon et al.,[16] also found no significant differences in adverse effects in patients who received gabapentin 1200 mg once pre-operatively and placebo.

A study by Mohammadi and Seyedi[21] showed that oral premedication with oral 300 mg of gabapentin reduces Post-operative pain and morphine consumption after abdominal surgery.

The analgesic effect of dexamethasone was investigated by different studies Kaan et al.,[22] Steward et al.,[23] Windfuhr,[24] and Al-Shehri[25] all these studies concluded pre-operative dexamethasone use significantly reduces early post-tonsillectomy pain, improves oral intake and facilitates meeting the discharge criteria while using standard anesthesia technique and sharp dissection tonsillectomy without any significant side-effects.

The 2009 guidelines of the Association of Pediatric Anesthetists of Great Britain and Ireland conclude that in patients undergoing tonsillectomy, dexamethasone 0.15 mg/kg provided good reduction in post-operative vomiting with no adverse effects.[26]

As regard to post-operative bleeding, in our study the use of dexamethasone was not associated with increasing risk of post-operative bleeding after adenotonsillectomy. Our result was constant with different studies.[27282930]

Other study[31] found that dexamethasone has a significant and dose-dependent antiemetic effect and decreases the need for rescue analgesia with non-steroidal anti-inflammatory drugs. However, it cannot be excluded that dexamethasone, possibly through inhibition of wound healing, increases the risk of post-operative bleeding in this specific setting.

Vomiting is common after tonsillectomy and may be induced not only by swallowed blood and oropharyngeal irritation, but also by opioids.[32] In the present study, there was no significant difference between the study groups with respect to the incidence of vomiting.

Based on current studies, it appears that gabapentin reduces the post-operative analgesic requirement, but the optimal dose devoid of side-effects needs to be identified when gabapentin is used.

CONCLUSION

Gabapntin 10 mg/kg administrated orally 2 h before adenotonsillectomy in children combined with dexamethasone 0.15 mg/kg after induction of anesthesia significantly decreased the post-operative pain score and pethidine requirements with no reported side-effects, but the optimal dose devoid of side-effects needs to be identified when gabapentin is used alone or in combination.