A Prospective, Observational Study to Evaluate the Role of Gabapentin as Preventive Analgesic in Thyroidectomy under General Anesthesia.

BACKGROUND: Effective management of postoperative pain is a part of well-organized perioperative care, which helps in reduced morbidity and improved patient satisfaction. Preventive analgesia can reduce acute and chronic pain by blocking the noxious inputs to pain pathways, preventing sensitization. Studies have reported efficacy of gabapentin as a preventive analgesic in perioperative pain. In this study, we aimed to determine whether preoperative gabapentin reduced postoperative pain and tramadol consumption after thyroidectomy under general anesthesia.
MATERIALS AND METHODS: Sixty patients scheduled for thyroidectomy were allocated to two groups of thirty each for this prospective, observational study. Patients in Group A and Group B received oral gabapentin 600 mg (6 × 10-4 kg) and diazepam 10 mg (1 × 10-5 kg), respectively, 2 h prior to surgery. Tramadol was given as rescue analgesic for postoperative pain with a verbal rating score of two. The analgesic efficacy of preoperative gabapentin was assessed in terms of postoperative pain scores at rest or swallowing, time to first rescue analgesic, and total tramadol consumption for 24 h. Ramsay sedation score and side effects of drug were also looked into.
RESULTS: Postoperative pain scores and total tramadol consumption were significantly lower in Group A during 24 h (P = 0.00). Time to first rescue analgesic was significantly prolonged in Group A (P = 0.001). Side effects were comparable.
CONCLUSION: Oral gabapentin is effective as a preventive analgesic in reducing postoperative pain and tramadol consumption after thyroidectomy under general anesthesia.

INTRODUCTION

Acute postoperative pain continues to be undermanaged despite the use of new drugs and delivery modalities. The literature reveals that up to 75% of postsurgical patients have reported pain, and 80% of these patients experienced severe acute pain during a hospital stay.[1] Uncontrolled postoperative pain may produce detrimental acute and chronic effects.[2] The attenuation of perioperative pathophysiology through reduction of nociceptive inputs to the central nervous system and optimization of perioperative analgesia may decrease complications and facilitate recovery during the immediate postoperative period.[3]

A variety of medications, neuraxial blocks, and regional analgesic techniques are available for the treatment of postoperative pain. The analgesic benefits of controlling postoperative pain are generally maximized when a multimodal strategy is implemented.[4] Opioids the most commonly used analgesic in the perioperative setting are prone for multiple untoward side effects. Recent guidelines of American Society of Anesthesiologists (ASA) Task Force 2012 recommend maximizing nonopioid agents and using opioids as adjuncts when needed.[5]

Timing of intervention is also clinically important. Preventive analgesia includes any regimen given at any time during the perioperative period that is able to control pain-induced sensitization. The older terminology of preemptive analgesia referred to an analgesic intervention that preceded a surgical injury still remains an important component of preventive analgesia.[4]

Gabapentin, the drug used in the present study, was introduced as an antiepileptic drug and subsequently reported to have antihyperalgesic and antiallodynic properties.[6] It has a high affinity for the α2δ subunit of presynaptic voltage-gated calcium channels, which inhibit calcium influx and subsequent release of excitatory neurotransmitters in the pain pathways thereby preventing central sensitization.[7] Several studies have assessed its efficacy in the postoperative pain management.[89101112131415161718192021] Studies assessing the efficacy of low dose of 6 × 10−4 kg gabapentin on postthyroidectomy pain were not done before. The present study was conducted to determine whether preoperative administration of 6 × 10−4 kg gabapentin is effective in decreasing pain and analgesic requirements after thyroidectomy.

MATERIALS AND METHODS

After getting approval from Institutional Ethics Committee, a prospective, observational study was conducted at our institution over a period of 1 year from August 2013. Based on the assumption from our previous clinical observation a reduction of pain scores by 25% was clinically relevant, sample size was calculated with a type 1 error of 5% and power 90%.[8]

Sixty patients in either sex, of age 18–45 years, weight between 50 and 70 kg, and of ASA’ physical status 1–2 scheduled for elective thyroidectomy under general anesthesia were selected for the study.

Thyroid swelling with pressure or toxic symptoms and malignancies were not considered for this study. Patients with renal or hepatic impairment, known allergy to gabapentin, chronic pain disorders, and pregnant and lactating women were also excluded from the study.

A written informed consent in local language was obtained from the patient and relatives. Preoperatively, patients were familiarized on the use of verbal rating scale for the assessment of pain, having four grades of pain - no pain (0), mild pain (1), moderate pain (2), and severe pain (3).

The patients were allocated into two groups - Group A and Group B. Two hours prior to surgery, Group A patients were given gabapentin 600 mg (6 × 10−4 kg), and Group B patients were given diazepam 10 mg (1 × 10−5 kg) orally as a placebo by the physician in the premedication room. After drug administration, patients were monitored in the observation room.

Toward the end of 2 h, the patients were taken to the theater, ASA’ standard monitors were attached and vital parameters were checked. Patients were given 1 × 10−6 kg pethidine and 0.1 × 10−6 kg ondansetron/kg of body weight intravenously.

After preoxygenation and precurarization with vecuronium, anesthesia was induced with propofol. Succinylcholine was used to facilitate intubation. Anesthesia was maintained with 66% N2O in O2 and propofol infusion. Neuromuscular block was maintained with vecuronium. No other analgesics were administered during the surgery. At the end of surgery, residual neuromuscular block was reversed, the patients extubated after full recovery and they were monitored in the Postanesthesia Care Unit (PACU). Once they met the modified Andretti criteria for discharge from PACU, they were sent to the postoperative ward.

Postthyroidectomy pain was assessed on a verbal rating scale at rest or during swallowing in the first 24 h; at 2 h intervals in the initial 8 h, 4 h intervals till 16 h, and then at 24 h. Time of reaching PACU is taken as 0 h. Injection tramadol 1×10-4 mg/kg of body weight was given intravenously if verbal rating scale was 1 or more. If pain was not relieved, incremental doses of tramadol 0.5 × 10−6 kg up to a maximum dose of 2 × 10−6 kg/kg of body weight were given. Additional doses of ondansetron intravenously were given if the patients had complaints of nausea and vomiting. The time to requirement of first rescue analgesic and total tramadol consumption in 24 h postoperatively were recorded.

Sedation as a side effect was assessed by Ramsay sedation score. Side effects such as dizziness, ataxia, and fatigue were also looked into.

The observations made were tabulated and analyzed using Statistical Package for Social Sciences software version 18 (SPSS Inc. 2009, Chicago, IL, USA). Demographic data were analyzed with two-sample Student's t-test. Pain scores were analyzed using independent t-test. Tramadol consumption over 24 h period was analyzed by Chi-square test. The incidence of adverse events and sedation scores were compared by Chi-square test. Data were reported as a mean ± standard deviation (SD). A P < 0.05 was considered statistically significant.

RESULTS

The demographic data were analyzed with two sample Student's t-test. Both groups were comparable with respect to age, gender, body weight, and duration of surgery as shown in Table 1 (P = 0.8, 0.16, 0.06, and 0.08, respectively).

Table 1

Demographic data

Postoperative pain was assessed during the 24 h period at timely intervals using verbal rating scale, and the data were analyzed using independent sample test as shown in Figure 1. Significant P < 0.05 was obtained for a time period up to 4 h and thereafter in the 8–12 h period.

Figure 1

Comparison of mean pain scores

The mean duration to request for rescue analgesia in minutes was compared between groups as shown in Table 2. Independent t-test showed a significant P < 0.05.

Table 2

Duration of analgesia

Regarding the total postoperative tramadol consumption, the mean requirement was 63.45 + 34.7 mg in Group A. In the Group B, it was 111.83 mg with an SD of 24.65 [Figure 2]. An independent sample test was applied for the analysis and the P value was found to be 0.000, indicating a high significance.

Figure 2

Postoperative tramadol requirement

Sedation scores were assessed using Ramsay sedation score. All patients in Group A and 29 in Group B had a score of 2, and Chi-square tests showed an insignificant P = 0.313.

Regarding side effects, three patients in Group A and four patients in Group B had dizziness. Pearson's Chi-square test was applied and an insignificant P = 0.688 was obtained.

DISCUSSION

Postoperative pain is considered as acute pain due to the surgical trauma, which leads to release of inflammatory mediators, neurotransmitters, and neurotrophins. These, in turn, activate peripheral nociceptors which will initiate transduction. Noxious stimuli transduced by peripheral nociceptors are transmitted by Aδ and C fibers to dorsal horn of spinal cord, where integration and complex modulations occur.[4] Some impulses evoke segmental reflex responses, others transmitted to higher centers through spinothalamic and spinoreticular tracts induce suprasegmental and cortical responses to produce the perception and affective component of pain. Continuous and intense noxious stimuli from the periphery result in central sensitization leading to hypersensitivity and hyperexcitability.[4] Neuronal hypersensitivity and nociception after surgical incision are mainly maintained by afferent barrage of sensitized nociceptors across the postoperative period.[22] Thus, it is suggested that both analgesic and antihyperalgesic interventions are necessary in a postsurgical setup. The peripheral nociceptive stimuli also cause a neuroendocrine stress response, affecting various systems of our body leading to increased perioperative morbidity and mortality.[4] Failure to relieve pain is ethically unacceptable. An adequately relieved postoperative pain helps to optimize patient recovery and minimize complications.

Postthyroidectomy pain has many components linked to the deep and superficial layers of the wound, intraoperative neck position, and wound drainage. It includes pain from neck incision, intraoperative cervical hyperextension that causes postoperative cervical myalgia, irritation, and laryngeal discomfort caused by frequent tracheal stimulation and movements of the endotracheal tube during surgical manipulation. Pain also results from cervical drains which are kept in place for 24 h.[23] Mean pain scores in the range of 6.9 on a visual analog scale (VAS) from 0 to 10 has been reported following thyroidectomy in previous studies.[24]

Pain due to cervical myalgia, laryngeal, and tracheal irritation can more or less be effectively controlled by sedative and muscle relaxant properties of diazepam. Because of this, we chose diazepam as an active placebo.

In a similar active, placebo, controlled, double-blind, randomized study by Rorarius et al., analgesic efficacy of gabapentin 1200 mg given preoperatively for patients undergoing vaginal hysterectomy was evaluated using oxazepam 15 mg as an active placebo. Gabapentin reduced the need for additional postoperative pain treatment by 40% during the first 20 postoperative hours. However, oxazepam was more effective in relieving preoperative anxiety than gabapentin.[13]

Preventing central sensitization with intensive multimodal analgesic interventions could reduce the intensity or can eliminate acute postoperative pain.[25] Preventive analgesia broadly includes any regimen given at any time during the perioperative period that is able to control pain-induced sensitization.[4] Recent guidelines of ASA Task Force 2012 recommend maximizing nonopioid agents and using opioids as adjuncts when needed.[5] Considering the possibility of a drug which significantly improves the quality of opioid analgesia, reduces opioid requirements, relieves anxiety, with no respiratory depression, no effect on renal function, gastric mucosa, and platelets will be worthwhile.

Gabapentin which was introduced as an antiepileptic drug was subsequently reported to possess antihyperalgesic and antiallodynic properties.[6] The mechanism of antihyperalgesic action may be a result of the postsynaptic binding of gabapentin to the α2δ subunit of voltage-gated calcium channels, which inhibit calcium influx and subsequent release of excitatory neurotransmitters in the pain pathways, thereby preventing central sensitization. Allodynia and hyperalgesia are also present after surgery and trauma due to the peripheral and central sensitization. Other possible mechanisms include its effects on N-methyl-D-aspartate receptors, sodium channels, monoaminergic pathways, and the opioid system.[6]

Gabapentin is well-absorbed orally, peak plasma level achieved in 2–3 h, not metabolized, eliminated unchanged in urine, with an elimination half-life of 4.8–8.7 h.[2526] Clinically relevant drug interactions are nil. It is not metabolised, excreted unchanged in urine.[27]

Clinical studies with gabapentin for postoperative analgesia were done before. In a study by Al-Mujadi et al., preemptive use of gabapentin as a single dose of 1200 mg 2 h prior to thyroidectomy significantly reduced the VAS scores at rest and during swallowing when compared to placebo group.[9]

Oral administration of gabapentin approximately 2 h before surgery appears rational in attaining maximal plasma concentration at the time of surgical stimuli. The recommended dose of gabapentin for the treatment of neuropathic pain was 300–1200 mg three times daily. We opted 600 mg as the dose because Pandey et al., in their study for the evaluation of optimal dose of gabapentin for postoperative pain relief after lumbar discectomy, found that increasing the dose of gabapentin from 600 to 1200 mg had no additional benefit.[10]

Mean pain scores were significantly reduced in first 4 h (P = 0.000) and again at 8–12 h (P = 0.001) postoperatively in our study. Although the comparison of mean pain scores between two groups was insignificant from 4 to 8 h, it was noticed that only six patients in Group A had pain by this time, while in Group B, all the thirty patients had a dose of rescue analgesic by 6 h. A decrease in pain score in the 6–8 h period in Group B patients may be explained on the basis of this.

In the 8–12 h period, there was a marked increase in the mean score in Group B patients. This may be explained on the basis that the effect of the first dose of tramadol received by the Group B was waning off, so they demanded a second dose. Here, the statistical analysis by Pearson's Chi-square test showed a P = of 0.001, which was significant.

We got a score of 2, indicating moderate pain, right from the immediate postoperative period for six patients in Group B. However, in Group A, a score of 2 was reported only 12–16 h postoperatively, that too only for seven patients. Approximately, 47% of the patients in Group A had their first demand of analgesic only during this period. While in Group B, many had a second dose of rescue analgesia by this time.

After 12 h, mean pain scores of Group A (0.80 ± 0.805) were more than Group B (0.73 ± 0.907), but it was statistically insignificant (P = 0.764). After 16 h, most of the patients in both the groups had no pain; they were sitting comfortably and able to take oral fluids. An interesting observation was that three of the patients in Group A did not have pain during the entire study period.

Previous clinical trials with preoperative administration of gabapentin showed promising results on postoperative pain relief.[891011121314]

In a randomized, double-blind study, in patients for laparoscopic cholecystectomy, Pandey et al. concluded that preemptive use of gabapentin significantly reduces postoperative pain and rescue analgesic requirement in laparoscopic cholecystectomy.[11]

Turan et al. found significantly reduced VAS scores for 20 h postoperatively in abdominal hysterectomy with 1200 mg gabapentin 1 h before surgery.[12] Rorarius et al. also found that gabapentin 1200 mg given in patients for vaginal hysterectomy reduced postoperative analgesics by 40% for 20 h.[13]

Mathiesen et al. had searched MEDLINE, the Cochrane Library, and Google Scholar for double-blind, randomized, placebo-controlled trials of gabapentin for postoperative pain relief compared with placebo in adults undergoing a surgical procedure. Qualitative and quantitative analysis were done, and in 12 of 16 studies with data on postoperative opioid requirement, 24 h consumption was significantly less with gabapentin.[14] Gabapentin 300 mg 2 h before internal fixation tibia showed reduced pain in a study by Panah Khahi et al.[15]

Ajori et al. with 600 mg preoperative gabapentin got significantly reduced postoperative pain after abdominal hysterectomy for 24 h.[16]

Yu et al. found gabapentin to be effective throughout the first postoperative day in lumbar spinal surgery.[17]

In our study, we noticed a significant reduction in the additional analgesic demand for about 10 h (636 min with an SD of 318.6) postoperatively in the gabapentin group, compared to 1.9 h (114 ± 50.6 min) in the other.

The WHO pain ladder is a three-step approach for symptomatic pain relief mainly for cancer pain, which can also be applied for postoperative pain. As per step 2 of this approach, weak opioids are recommended for mild-to-moderate pain. Since postthyroidectomy pain is a moderate surgical pain, we decided to use tramadol, a weak opioid, for postoperative analgesia.

Tramadol is a synthetic opioid that exhibits weak μ-agonist activity and also inhibits reuptake of serotonin and norepinephrine. Tramadol is effective in moderate postoperative pain. Use of tramadol in intravenous patient-controlled analgesia (PCA) results in similar pain scores when compared with that from intravenous PCA opioids, but the side effect profile is different between the two groups. Advantages of tramadol for postoperative analgesia include a relative lack of respiratory depression, major organ toxicity, and depression of gastrointestinal motility and a small potential for abuse (1 case/100,000 patients).[28] In a randomized, double-blind, placebo-controlled clinical study to assess the efficacy of preemptive oral pregabalin for prolonging postoperative analgesia in modified radical mastectomy, tramadol 1 mg/kg intravenously was used as first rescue analgesic.[29]

Regarding the total tramadol consumption in the 24 h postoperative period in this study, there was a significant difference between the two groups. The mean requirement was 111.83 ± 24.65 mg in the placebo group and 63.45 ± 24.65 mg in the gabapentin group. This difference was statistically significant (P = 0.000).

In the study by Turan et al., on spinal surgery the PCA morphine consumption reduced from 42.8 ± 10.9 to 16.3 ± 8.9 mg on administration of gabapentin.[18]

Alayed et al. in a systematic review and meta-analysis, in patients for abdominal hysterectomy under general anesthesia, found that preemptive administration of gabapentin is effective in reducing postoperative pain scores, narcotic consumption, nausea, and vomiting.[19]

Mahoori et al. also found a beneficial effect for gabapentin on postoperative pain relief and analgesic demand in patients after inguinal herniorrhaphy.[20]

In our study, majority of patients in both groups did not experience any significant side effects. Only three in Group A and four in Group B had complained of dizziness in the sitting position. Regarding sedation, a Ramsay sedation score of 2 was observed in both groups of patients. These results were in congruence with the previous studies.

There are studies with conflicting results also. Siddiqui et al. found that preoperative administration of 600 mg gabapentin in patients undergoing major bowel surgery does not reduce postoperative pain scores, opioid consumption, or opioid-related side effects.[21]

The pathophysiology of postoperative pain might be of different origin according to different surgical sites. Hence, clinical trials with the same drug in different surgeries are needed to claim a definite benefit.

The inference from this study is that gabapentin when administered 2 h prior to surgery significantly decreased the pain for an average period of 10 h postoperatively with a concomitant reduction in the tramadol requirement. There were no significant side effects.

Ideally, postoperative pain should be assessed in terms of pain at rest and pain during movement separately. One major limitation of our study is that such a separate assessment of pain at rest and during swallowing was not done.

CONCLUSION

Preoperative administration of gabapentin 6 × 10−4 kg significantly reduces the postoperative pain during the first 10 h following thyroidectomy. There is a concomitant reduction in the postoperative analgesic requirement. There are no significant side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.