Ain-Shams Journal of Anaesthesiology

ORIGINAL ARTICLE
Year
: 2014  |  Volume : 7  |  Issue : 2  |  Page : 138--142

Evaluation of the optimum preemptive dose of gabapentin and its postoperative morphine-sparing effect after debridement of burned patient


Hesham Elazzazi, Rafik Atalla 
 Department of Anesthesia and Intensive Care, Ain Shams University, Cairo, Egypt

Correspondence Address:
Rafik Atalla
Department of Anesthesia, ICU and Pain Management, Faculty of Medicine, Ain Shams University, Abbassia, Cairo 11566
Egypt

Abstract

We evaluated the optimal dose of preemptive gabapentin for postoperative pain relief after debridement of burned patient and its effect on morphine consumption during the initial 24 h after surgery. Patients were divided into seven groups to receive gabapentin 300, 600, 900, 1200, 1500, 1800, and 2100 mg 1 h before surgery. After surgery, patients were transferred to the postanesthesia care unit. Pain scores were recorded at time points of 2, 6, 12, 18, and 24 h in postanesthesia care unit on a visual analog scale (VAS: 0-10 cm). Patients received patient-controlled analgesia (morphine), and total morphine consumption during the initial 24 h was recorded. Data were entered into statistical software package SPSS 9.0 for analysis. Patients who received gabapentin 600, 900, 1200, 1500, and 1800 mg had lower VAS scores at all time points than patients who received gabapentin 300 mg. Increasing the dose of gabapentin from 1500 to 1800 mg did not decrease the VAS score nor it decreased morphine consumption. Thus, gabapentin 1500 mg is the optimal preemptive dose for postoperative pain relief following debridement of burn patients.



How to cite this article:
Elazzazi H, Atalla R. Evaluation of the optimum preemptive dose of gabapentin and its postoperative morphine-sparing effect after debridement of burned patient.Ain-Shams J Anaesthesiol 2014;7:138-142


How to cite this URL:
Elazzazi H, Atalla R. Evaluation of the optimum preemptive dose of gabapentin and its postoperative morphine-sparing effect after debridement of burned patient. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Nov 30 ];7:138-142
Available from: http://www.asja.eg.net/text.asp?2014/7/2/138/133348


Full Text

 Introduction



Acute pain is a symptom that signals real or imminent tissue damage. Effective management of acute pain is not only required for ethical reasons, but also to modify the response to burn injury [1]. The magnitude of the injury response is proportional to the degree of tissue damage and leads in turn to a number of physiological changes, promoting catabolism, increasing sympathetic activity, immunosuppression, and other adverse effects [2]. Burn patients have extreme pain and opioids are the main agents used for analgesia. Opioids can have several adverse effects and have been partially effective in controlling the pain associated with burn injury [3],[4].

Gabapentin 1-(amino methyl) cyclohexaneacetic acid is a novel anticonvulsant drug that is active in a variety of animal seizure models and prevents partial seizures and generalized tonic-clonic seizures. g-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in mammalian brain, and seizures occur if GABA synapses are blocked [5]. A variety of GABA-enhancing drugs such as GABA agonists, GABA modulators (e.g. benzodiazepines), drugs converted metabolically to GABA, GABA uptake inhibitors (e.g. tiagabine), and inhibitors of GABA degradation (e.g. vigabatrin) prevent seizures. The similarity in chemical structures between gabapentin and GABA also suggests a functional relationship [6],[7].

It is likely that its analgesic effects result from an action at the a1, d1 subunits of the voltage-dependent Ca 2 channel for which it has substantial affinity and is upregulated in the dorsal root ganglia and spinal cord after peripheral nerve injury as can be produced by surgical incision [8]. Gabapentin may produce analgesia by binding to an inhibiting presynaptic voltage-dependent Ca 2 channels, decreasing calcium influx and inhibiting the release of neurotransmitters including glutamate from the primary afferent nerve fibers that activate pain-responsive neurons in the spinal cord [9],[10].

 Aim of the study



To our knowledge, gabapentin has been used in doses ranging from 300 to 2100 mg preemptively for acute pain management, but no clinical trial has yet established the optimal doses of gabapentin for preemptive analgesia in burn patient. Therefore, although several studies have shown gabapentin to be a beneficial addition to an opioid analgesia protocol in burns patients, what is required is to determine the lowest possible dose of gabapentin to achieve maximal pain relief but with minimal side effects.

The aim of this study was to evaluate the optimal preemptive dose of gabapentin for postoperative pain relief after debridement of burned patient and its morphine-sparing effect during the initial 24 h postoperatively.

 Materials and methods



This study was conducted at Ain Shams University hospitals on 140 patients undergoing debridement operation under general anesthesia for burn, after approval from Ain Shams University medical ethics committee in 2011. Written consent was taken from all patients.

 Patient selection



Exclusion criteria

Age above 60 years or below 20 years.Burn surface area more than 25% of the total body surface area.History of drug or alcohol abuse.History of hypersensitivity to any drug.Uncontrolled concomitant medical disease (diabetes mellitus, hypertension, and impaired kidney or liver functions).Burned pregnant women.

Study groups

This study was a single-blind randomized controlled study in which patients were allocated into seven equal groups according to the dose of gabapentin given preoperatively. Patients were randomly assigned into seven equal groups using a computer-generated table of random numbers to receive the medications. All patients received their medications 1 h preoperatively, and results were collected during the first 24 h postoperatively.

Group I patients received one capsule of gabapentin 300 mg.

Group II patients received two capsules of gabapentin 300 mg each (total 600 mg).

Group III patients received three capsules of gabapentin 300 mg each (total 900 mg).

Group IV patients received four capsules of gabapentin 300 mg each (total 1200 mg).

Group V patients received five capsules of gabapentin 300 mg each (total 1500 mg).

Group VI patients received six capsules of gabapentin 300 mg each (total 1800 mg).

Group VII patients received seven capsules of gabapentin 300 mg each (total 2100 mg).

Anesthetic protocol

Patient consent was taken for our medication and complete explanation of the study protocol and for the use of PCA (infusion) pump for morphine administration. Complete explanation of the visual analog scale (VAS) was given, with zero scale revealing no pain and gradual increase in pain intensity with the scale reaching maximum pain perception at a score of 10. In addition, complete explanation of the sedation scale (Ramsay) used in patient assessment was provided, with grades 1 and 2 revealing mild degree of sedation, grades 3 and 4 revealing moderate sedation, and grades 5 and 6 denoting severe degree of sedation. Drugs used were gabapentin given as 300 mg capsules (Neurontin; Pfizer, Cairo, Egypt) and morphine 20 mg morphine sulphate ampoules (Misr Pharmaceutical Company, Egypt).

On the day of surgery, patients received oral gabapentin with 50 ml water about 1 h earlier than the expected time of surgery. Antiaspiration measures such as 10 mg metoclopromide (primpran) and 50 mg ranitidine (zantac) were given intravenously slowly 1 h before induction. On arrival to the operating room, standard monitoring by HP monitors was applied: ECG limb lead II, noninvasive arterial blood pressure, capnography, and peripheral oxygen saturation (SPO 2 ).

Anesthesia was induced with propofol 2 mg/kg, morphine 0.1 mg/kg, and lidocaine 1.5 mg/kg. Intubation of trachea was facilitated with atracurium 0.5 mg/kg, using PVC endotracheal tube with an internal diameter of 7-8 mm. Anesthesia was maintained with isoflurane 1-2 vol%. Neither local nor regional anesthesia was performed. No sedative premedication other than gabapentin was administered.

Postoperative analgesic protocol

After arrival to the postanesthesia care unit, pain intensity was assessed using a visual pain scale; when patients were alert enough to use a PCA pump, morphine titration was started. PCA pump was set to deliver bolus doses of morphine 1 mg/ml with an incremental dose of 1.5 mg, a lockout interval of 10 min, a 4 h limit of 20 mg, and no background infusion. Rescue medication for breakthrough pain in patients with high VAS (scores more than 3-4) using paracetamol 1 g/6 h intravenously was given when needed.

Evaluation criteria included hemodynamic stability measuring arterial blood pressure, heart rate, and oxygen saturation (and need for supplemental oxygen), in addition to pain score (VAS) measured at rest and during mobilization. Total morphine consumption during the first 24 h postoperatively was measured in addition to the total dose of paracetamol consumption. The incidence of side effects such as nausea and vomiting [also number of patients who consumed antiemetic (ondansetron)] during the first 24 h postoperative, respiratory depression (detected by respiratory rate and by oxygen saturation using pulse oximetry), and sedation with no mild, moderate, and severe degree with respect to the Ramsay sedation scale were also measured.

Statistical analysis

Data were collected, coded, tabulated, and then analyzed using SPSS computer software, version 19.0. Numerical variables were presented as mean and SD, whereas categorical variables were presented as number of patients and percentage. Between-groups analysis of numerical variables was performed by one-way analysis of variance and Tukey's HSD test as a post-hoc test for pairwise multiple comparisons, whereas the c2 -test was used for categorical data analysis. Any difference with P-value less than 0.05 was considered statistically significant.

 Results



From October 2011 to August 2013, 140 consecutive patients undergoing debridement for burn, who fulfilled the inclusion criteria, were included in the study. All patients allocated were able to complete the study. The data from 140 patients were analyzed.

Demographic data

The seven groups did not differ in demographic data. The groups were comparable with respect to age, sex, duration of surgery, weight, and ASA status.

Pain scores

Our results demonstrated that there was a decrease in VAS score when the dose of gabapentin was increased from 300 to 1500 mg, but increasing the dose of gabapentin to greater than 1500 mg could not demonstrate a further decrease in VAS at rest and also during mobilization [Table 1].{Table 1}

Morphine consumption

Our results demonstrated that there was a gradual decrease in morphine consumption with increasing dose of preemptive gabapentin given, as increasing the dose of gabapentin from 300 to 600 mg caused decrease in morphine consumption from 15.2 ± 3.6 to 12 ± 2.5 mg/24 h. Further increasing the dose of gabapentin to 900 mg also caused a decrease in morphine consumption to 10 ± 2.2 mg/24 h [Table 2].{Table 2}

Group V with 1500 mg gabapentin given preoperatively showed much lower morphine consumption about 8.1 ± 2.1. Group VI receiving 1800 mg gabapentin showed no more significant reduction in morphine consumption when compared with the previous group. Hence, increasing the dose of gabapentin beyond 1500 mg did not cause any further reduction in morphine consumption in the first 24 h postoperatively.

Total paracetamol consumption

Our results demonstrated that there was a gradual decrease in paracetamol consumption with increasing dose of preemptive gabapentin given, as increasing the dose of gabapentin from 300 to 600 mg caused decrease in paracetamol consumption from 3.2 ± 0.6 to 2.2 ± 0.5 g/24 h. Further increasing the dose of gabapentin to 900 mg also caused a decrease in paracetamol consumption to 1.5 ± 0.2 g/24 h [Table 3].{Table 3}

Group V with 1500 mg gabapentin given preoperatively showed much lower paracetamol consumption about 0.5 ± 0.3 g/24 h. Group VI receiving 1800 mg gabapentin showed no more significant reduction in paracetamol consumption when compared with the previous group. Hence, increasing the dose of gabapentin beyond 1500 mg did not cause any further reduction in paracetamol consumption in the first 24 h postoperatively.

Side effects

Nausea and vomiting

Morphine-related nausea and vomiting were mostly seen in group I receiving the lowest dose of gabapentin 300 mg, with 50% of patients suffering from nausea and about 40% of patients suffering from vomiting, and 20% of patients in that group needed antiemetic (ondansetron 4 mg intravenously over 2-5 min) to stop it. Group II with slight higher dose of gabapentin of 600 mg showed decrease in the percentage of patients suffering from nausea to 35%, and about 25% suffered from vomiting. Group III with patients receiving 900 mg gabapentin showed further decrease in these side effects, with 30% of patients suffering from nausea and only 20% suffering from vomiting. Group V showed that only 10% of patients suffered from nausea and only one patient suffered from vomiting [Table 4].{Table 4}

Sedation

Recording the degree of sedation according to the Ramsay sedation score was performed, revealing that, in group I with low dose (300 mg) gabapentin, no sedation was observed; only one patient developed moderate sedation and no severe sedation was recorded. Percentage of patients showing moderate and severe sedation increased directly with increasing dose of gabapentin, with 20% of patients in group IV showing moderate sedation and about 5% showing severe sedation. In group V receiving 1500 mg gabapentin, about 25% of patients developed moderate sedation with a small increase in percentage of patients showing severe sedation. Group VII patients (2100 mg of gabapentin) recorded the highest percentage of patients with moderate and severe sedation among all groups, with more than 30% of patients in that group with moderate sedation and about 30% with severe sedation [Table 5].{Table 5}

 Discussion



The preemptive analgesic efficacy of gabapentin has been demonstrated in surgical patients. Twenty-eight publications that described the use of gabapentin in postoperative pain management were identified between 2002 and 2012. These studies reported a significant reduction in postoperative analgesic consumption when gabapentin was used preemptively in doses ranging from 300 to 2400 mg. However, differences in gabapentin dosages, the dosing regimen, and types of surgery have yielded contrasting results. This study demonstrated the efficacy of preoperative gabapentin, evaluating its optimal preemptive dose, morphine-sparing effect, and side effects for patients undergoing debridement surgery for burn.

Pain score (VAS)

The results of this study have shown that increasing dose of gabapentin from 300 to 600 mg caused a decrease in VAS score at 6 h; further increasing the dose to 900 mg caused more decrease in VAS at 6 and 12 h. Increasing the dose up to 1500 mg of gabapentin decreased VAS at 2, 6, 12, 18, and 24 h both at rest and during mobilization. However, further increasing the dose above 1500 mg did not show any further decrease in VAS.

The results of this study are not in accordance with the study by Pandey and colleagues who conducted the only study comparing different doses of gabapentin; they demonstrated that there was a decrease in VAS score and fentanyl consumption when the dose of gabapentin increased from 300 to 600 mg for postoperative pain relief after lumbar diskectomy, but increasing the dose of gabapentin to more than 600 mg could not demonstrate a further decrease in VAS scores or in fentanyl consumption [1]. In comparison with Pandey's study, our study did include a group with higher dose of gabapentin (1500 mg) aiming at significantly decreasing severity of pain and its effect on pain scores postoperatively and at side effects resulting from using this dose. Different results were obtained in two studies, which may be related to different types of surgery with different durations. In addition, different analgesic protocols were used by Pandey, such as fentanyl was used instead of morphine intraoperatively and postoperatively and oral lorazepam was given the evening before and on morning of operation. In contrast, in our study, we eliminated the use of any sedation on morning of or the evening before operation.

Total analgesic consumption

The result of our study shows that increasing the dose of gabapentin decreased morphine consumption postoperatively. However, increasing the dose of gabapentin above 1500 mg did not show any further decrease in morphine consumption postoperatively.

Results of this study are in accordance with the study conducted by Van Elstraete and colleagues who studied the effect of preemptive gabapentin on postoperative morphine consumption after posterior lumbar spinal fusion. He defined the morphine-sparing value as 30% reduction in morphine consumption. Increasing the dose of gabapentin caused more reduction in morphine consumption, evaluating ED50 of gabapentin to be 21.7 mg/kg. Large dose of gabapentin needed for spinal fusion surgery, when compared with that needed for other painful surgeries, is explained by long-term peripheral nerve root compression leading to severe central sensitization [5].

Incidence of adverse effects

When taken together, the reductions in pain scores and analgesic consumption would seem to predict a lower incidence of opioids-related side effects in the gabapentin arm with still adequate analgesia. In our study, we evaluated also the main side effect of gabapentin, which was sedation. This was demonstrated in our study as sedation risk increased with gradual increase in the dose of gabapentin. The risk for severe sedation was higher in patients receiving more than 1500 mg gabapentin when compared with other groups receiving lower doses; 30% of patients in group VII receiving 2100 mg gabapentin suffered from severe sedation. In group V receiving 1500 mg gabapentin, almost half of the patients reported no sedation and only two patients suffered severe sedation, reflecting the high safety margin of the drug at this dose.

 Conclusion



Our study demonstrated that a 1500 mg single preemptive oral dose of gabapentin significantly decreased the severity of pain occurrence until 24 h postoperatively in debridement surgeries for burn and decreased the total morphine consumption. Increasing the dose of gabapentin beyond 1500 mg did not cause any further significant reduction in the VAS scores and morphine consumption, increasing the incidence of gabapentin-related side effects such as sedation.

 Acknowledgements



Conflicts of interest

None declared.

References

1Pandey CK, Navkar DV, Giri PJ, Raza M, Behari S, Singh RB. Evaluation of the optimal preemptive dose of gabapentin for postoperative pain relief after lumbar diskectomy: A randomized, double-blind, placebo- controlled study. J Neurosurg Anesthesiol 2005; 17:65-68.
2 Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002; 97:560-564.
3 Coderre TJ, Kumar N, Lefebvre CD, Yu JSC. Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate. J Neurochem 2005; 94:1131-1139.
4 Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N: Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesthesia Analgesia 2000; 91:185-191.
5 Alain Van Elstraete, Myriam Tirault, Ignace Sandefo The median effective dose of preemptive gabapentin on postoperative morphine consumption after posterior lumbar spinal fusion. International Anesthesia research society 2008; 106:305-309.
6 Fassoulaki A, Stamatakis E, Petropoulos G, Siafaka I, Hassiakos D, Sarantopoulos C. Gabapentin attenuates late but not acute pain after abdominal hysterectomy. Eur J Anesthiol 2006; 22:136-141.
7 Dierking G. Duedahl TH, Rasmussen MI, Fomsgard JS, Moniche S, Romsing J. Effects of gabapentin on postoperative morphine consumption and pain after abdominal hysterectomy: a randomized, double-blind tria. Acta Anaesthesiol Scand 2004; 48:322-327.
8 Turan A, White PF, Karamanlioglu B. Premedication with gabapentin: The effect on tourniquet pain and quality of intravenous regional anesthesia. Anesthesia Analgesia 2007; 104:97-101.
9 Durmus M, Kdir But A, Saricicek V, Ilksen Toprak H, Ozcan Ersoy. The post-operative analgesic effects of a combination of gabapentin and paracetamol in patients undergoing abdominal hysterectomy: a randomized clinical trial. Acta Anaesthesiol Scand 2007; 51:299-304.
101Van de Vusse AC, Stomp-van den Berg SG, Kessels AH. Randomized controlled trial of gabapentin in complex regional pain syndrome type 1.BMC Neurology 2004; 4:13.