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Preemptive gabapentin reduces postoperative pain and opioid demand following thyroid surgery

[L’administration préventive de gabapentine réduit la douleur postopératoire et la demande d’opioïdes à la suite d’une thyroïdectomie]

From the Department of Anesthesia and Intensive Care, Al-Sabah Hospital, Safat, Kuwait.

Address correspondence to: Dr. Yatindra Kumar Batra, Department of Anaesthesia and Intensive Care Unit, Post-Graduate Institute of Medical Education & Research, Chandigarh, India. Fax: +91-172-2744401; E-mail: ykbatra{at}glide.net.in

	Abstract

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Purpose: Gabapentin is reported to possess antihyperalgesic and antiallodynia properties. Recently, reports have indicated that gabapentin may have a place in the treatment of postoperative pain. In this study, we sought to determine whether preemptive use of gabapentin reduced postoperative pain and morphine demand following thyroidectomy.

Methods: In this prospective, randomized, double-blind clinical trial, we gave gabapentin 1200 mg or placebo two hours prior to induction of anesthesia to patients undergoing elective thyroidectomy. Post-thyroidectomy pain was assessed on a visual analogue scale at rest and during swallowing in the first 24 hr postoperatively. All patients received morphine 3 mg iv every five minutes until visual analogue scale scores were 4 or less at rest, and 6 or less with swallowing. Total morphine consumption for each patient was recorded from zero to 24 hr postoperatively.

Results: Thirty-seven patients in the gabapentin group and 35 patients in the placebo group completed the study. Overall, pain scores at rest and during swallowing in the gabapentin group were significantly lower when compared with the placebo group. Total postoperative morphine consumption in the gabapentin group was 15.2 ± 7.6 mg (mean ± SD) vs 29.5 ± 9.9 mg in the placebo group (P < 0.001). No significant differences in side effects were observed between groups.

Conclusions: Preoperative gabapentin decreased pain scores and postoperative morphine consumption in patients following thyroid surgery.

	Introduction

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POST-THYROIDECTOMY pain perception likely includes many components linked to the deep and superficial layers of the wound, intraoperative neck position and wound drainage. This pain is usually treated with non-steroidal anti-inflammatory drugs or opioids. In one study, the mean pain score reported after thyroidectomy was 6.9 on a visual analogue scale (VAS) from 0 to 10, and 90% of patients required morphine.¹ Among the most frequent complaints of postoperative pain treatment is opioid-induced nausea and vomiting. Combination of opioids with non-steroidal anti-inflammatory drugs reduces the incidence of side effects either by reducing opioid requirements or by improving analgesia.

The concept of preemptive analgesia, which is an analgesic treatment initiated before, as opposed to after the surgical procedure, was introduced to protect the central nervous system from deleterious effects of noxious stimuli, and the patient from the resulting allodynia, and increased pain.² Gabapentin is a structural analogue of gamma-amino butyric acid, which was introduced in 1994 as an antiepileptic drug, particularly for partial seizures.^3,4 It alleviates pain and/or prevents acute nociceptive and inflammatory pain both in animals and volunteers, especially when given before trauma.^5,6 Recently, several reports have indicated that gabapentin may have a place in the treatment of postoperative pain.^7–9 To date, the potential effect of gabapentin on acute, postoperative pain following thyroidectomy has not been evaluated in clinical practice. The aim of the present study, therefore, was to determine the efficacy of gabapentin in managing acute postoperative pain in patients undergoing thyroid surgery.

	Material and methods

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The study was approved by Institutional Ethics Committee and informed written consent was obtained from all patients. American Society of Anesthesiologists physical status I–II adults scheduled for elective thyroid surgery under general anesthesia were eligible for the study. Excluded were patients with known allergy to gabapentin, a history of drug or alcohol abuse, chronic pain or daily intake of analgesics or corticosteroids, diabetes or impaired kidney function. All patients were instructed preoperatively on the use of VAS using a ruler (VAS; 0 cm = no pain to 10 cm = the worst possible pain). Each patient received oral diazepam 10 mg one hour prior to surgery. The study was double-blind, randomized and placebo-controlled. The study drugs were prepared by the pharmacy into identical capsules using a computer – generated randomization schedule. They were packed in sequentially numbered packages which were given to the recruited patients in the same order by a trained nurse who was not involved in any other part of the study. Patients received oral gabapentin 1200 mg (neurontin 400-mg capsule; Pfizer, Goedecke GmbH, Germany) or oral placebo capsules two hours before surgery.

Anesthesia was induced with fentanyl 2–3 µg·kg^–1 iv followed by propofol 2–3 mg·kg^–1 iv. Vecuronium 0.1 mg·kg^–1 was used to facilitate orotracheal intubation. Neuromuscular block was maintained with vecuronium. Mechanical ventilation was adjusted to maintain normocarbia. General anesthesia was maintained with isoflurane and 66% nitrous oxide in oxygen. The concentration of agent was adjusted to maintain adequate depth of anesthesia (stable heart rate and blood pressure) as in routine practice. No other analgesics were administered during the surgery. Fluids and blood losses were replaced according to standard prescription of the department. At the end of surgery, residual neuromuscular block was antagonized with atropine 0.02 mg·kg^–1 and neostigmine 0.04 mg·kg^–1iv. After tracheal extubation, patients were transferred to the postanesthesia care unit (PACU). Monitoring during anesthesia comprised of continuous electrocardiogram and heart rate, pulse oximetry, non-invasive arterial pressure, measurement of endtidal CO₂ and measurement of end-tidal agent concentration. All parameters were recorded at five-minute intervals.

Assessment of VAS pain scores at rest and on swallowing were made during the first hour in the PACU (T0), then at two, six, 12, 18 and 24 hr in the postoperative period. All observers involved in the postoperative pain assessment were blinded with respect to the patient’s treatment group. Morphine 3 mg iv bolus doses were given every five minutes until VAS pain scores were 4 or less at rest, and 6 or less with swallowing. The number of morphine doses used was recorded and total dose requirements (24 hr) were calculated. The following postoperative complications were recorded in the PACU and in the ward: nausea and vomiting, respiratory depression, dizziness, peripheral edema, diarrhea. Nausea was recorded by each patient as none, light, moderate or severe. The number of vomiting episodes (> 100 mL) was documented. In response to occurrence of nausea and vomiting, the patient’s nurse was instructed to administer metoclopramide 10 mg iv.

Sample size calculation was based upon mean morphine consumption level of 31.4 ± 9.24 mg in the first 24 hr, as derived from pilot data. Assuming a target of 25% morphine consumption reduced with an error of 5% and a ß error of 10%, and a two-tailed alternative hypothesis, a sample size of 30 patients per group was estimated. Demographic data were analyzed with two-sample Student’s t test. Morphine consumption and VAS scores were analyzed using a two-way ANOVA with drug administered as one factor and the time interval as the second. This was statistically significant. Consequently, unpaired t tests were performed at each time period to ascertain the pattern and magnitude of differences. The incidence of adverse events was compared by Chi-square test. Data are reported as mean ± standard deviation. A P-value of < 0.05 was considered statistically significant.

	Results

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Eighty-eight consecutive patients fulfilled the inclusion criteria for entry in the study (Figure). Ten patients were not included: eight patients did not want to participate and two patients had different surgical techniques. Seventy-eight patients were enrolled in the study; however, six of these were subsequently excluded, four in the gabapentin group and two in the placebo group. One patient each in the gabapentin and placebo groups was withdrawn because surgery was postponed. Three patients in the gabapentin group and one patient in the placebo group received another analgesic prescribed by the surgeon. Thus, data from 72 patients, 37 of 41 in the gabapentin group and 35 of 37 in the placebo group, were included and analyzed. There were no differences between groups with respect to demographic characteristics or the type and duration of thyroid surgery (Table I). The SpO₂ and intraoperative hemodynamic values were similar in the two groups. The VAS scores at rest and during swallowing were significantly lower in the gabapentin group compared with the placebo group (Table II). The total morphine consumption after surgery in the first 24 hr in the gabapentin group (15.2 ± 7.6 mg) was significantly less than in the placebo group (29.5 ± 9.9 mg), (P < 0.001). There were no pre- or postoperative differences in the frequency of nausea (P > 0.05), or episodes of vomiting between groups. In the gabapentin group, eight of 37 patients received antiemetic, compared with 11 patients of 35 patients in the placebo group. No other side effects such as ataxia, vertigo, somnolence, visual disturbances and headache were observed in either group. One patient in the gabapentin group required bladder catheterization. No patient had a respiratory rate < 10 breath·min^–1 throughout the study period.

View larger version (28K): [in this window] [in a new window]   FIGURE Flow diagram of patient distribution.

	Discussion

TOP Abstract Introduction Material and methods Results Discussion References

Pain following thyroidectomy results from cervicotomy, intraoperative cervical hyperextension that causes postoperative muscular cervicalgia, and irritation and laryngeal discomfort caused by frequent tracheal stimulation and movements of the endotracheal tube during surgical manipulation.¹⁰ In addition, pain can also be caused by cervical drains, which are kept in place for 24 hr. Patients after thyroidectomy require acute pain control during the first day after thyroid surgery. A combination of opioid and non-opioid analgesic drugs has been shown to improve the quality of postoperative analgesia following thyroid surgery. In one study, Basto et al. found perioperative administration of ketoprofen and proparacetamol was associated with a reduction in pain scores and morphine requirements after thyroid and parathyroid surgery.¹¹ Gozal et al. reported markedly reduced opioid requirements following local wound infiltration of bupivacaine 0.5% prior to skin closure in patients undergoing thyroidectomy.¹ In another study, bilateral superficial blocks significantly reduced pain intensity in the postoperative period after thyroid surgery.¹² Aunac et al. demonstrated the analgesic advantages of bilateral superficial and deep cervical blocks administered before thyroid surgery, and found a significant reduction of intraoperative requirements of anesthetics and analgesics and medications.¹³

The dose we studied (1200 mg) is within the limits of a single dose in the treatment of neuropathic pain, as the recommended dose is 300 to 1200 mg three times daily.¹⁴ We administered gabapentin prior to surgery on the basis of findings in laboratory animals that pretreatment with gabapentin is more effective and longer lasting than post-treatment. Pretreatment with a single dose of gabapentin blocked the development of hyperalgesia (which is N-methyl-D-aspartate mediated NMDA) and tactile allodynia [which is -amino-3-hydroxy-5-methyl-4-isoxazolaproprionate (AMPA) and metabotropic receptor-mediated] for up to two days in a rat model of postoperative pain, while gabapentin one hour after intervention reduced symptoms for only three hours.¹⁵ Previous clinical studies with gabapentin for postoperative analgesia have shown promising results. A single dose of oral gabapentin 1200 mg administered preoperatively resulted in 50% reduction in movement related pain two and four hours after radical mastectomy.⁷ Oral gabapentin 1200 mg administered one hour before surgery decreased pain scores in the early postoperative period and post-operative morphine consumption in spinal surgery patients, while decreasing morphine-associated side effects.¹⁶ In an another study, gabapentin 3000 mg administered before and during the first 24 hr after abdominal hysterectomy reduced morphine consumption by 32%, without significant effects on pain scores at rest or during mobilization.¹⁷ Rorarius et al. demonstrated that a single dose of 1200 mg gabapentin given two to 2.5 hr before induction of anesthesia reduced the need for additional postoperative pain treatment by 40% during the first 20 postoperative hours in patients undergoing vaginal hysterectomy.¹⁸ Our results are consistent with these studies. Pain scores at rest and during swallowing were significantly reduced in gabapentin-treated patients. Despite differences in surgical procedures, a significant effect of gabapentin on postoperative analgesic requirements was observed in most of the above studies.

Thyroid surgery carries a major risk of nausea and vomiting because it is cervicofacial surgery. In a study of 118 patients, the frequency of nausea and vomiting during the 24 hr after thyroid surgery was 54%.¹⁹ In our series, 21.6% of the patients required antiemetics in the gabapentin group as compared to 31.4% in placebo group. The lower scores of postoperative nausea and vomiting in the gabapentin-treated patients compared to the placebo group might be due to the diminished need for postoperative pain treatment with morphine, or because of an antiemetic effect of gabapentin itself.¹⁸ As documented previously, patients in the immediate postoperative period are exposed to side-effects not only from postoperative analgesics, but also from anesthesia and surgery, and this may have masked side-effects due to gabapentin per se.⁷ Oral administration of gabapentin approximately two hours before surgery appears rational in order to attain maximal plasma concentration at the time of surgical stimuli. Gabapentin crosses rapidly the blood-brain barrier and consequently, its concentration in brain tissue, where it exhibits its effect, is nearly as high as in blood.²⁰ Dierking et al. found a significant inverse relationship between plasma levels of gabapentin two hours postoperatively, thus indicating a dose response effect.¹⁷ Gabapentin has been reported as an anxiolytic drug in previous studies.^21,22 Reducing preoperative anxiety with gabapentin may have contributed to the improved postoperative analgesia and to reduced morphine requirements because there is a possible association between preoperative anxiety and post-operative pain.²³ In addition, studies have shown a synergistic effect of morphine and gabapentin in both animal experiments and humans.⁵ In rats, gabapentin prevents the development of morphine tolerance and partially reverses established tolerance.²³ A number of hypotheses explaining gabapentinopioid interactions have been proposed, including gabapentin inhibition of glutamate release, nitric oxide synthetase activation, dynorphin-induced allodynia, or postsynaptic calcium entry.²³ However, the real challenge in the clinical setting is not simply to minimize the dose of analgesic drug, but to minimize long-term complications and occurrence of chronic pain syndromes within weeks or months after surgery.

In conclusion, our findings suggest that gabapentin should be considered a potentially useful adjunctive, antihyperalgesic agent for the treatment of acute post-operative pain in patients undergoing thyroidecomy.

	Footnotes

 
Accepted for publication September 1, 2005. Revision accepted September 30, 2005.

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