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ANALGESIA

Gabapentin Attenuates Late but Not Early Postoperative Pain After Thyroidectomy with Superficial Cervical Plexus Block

Nicolas Brogly, MD^*, Jean-Michel Wattier, MD^*, Grégoire Andrieu, MD^*, Daliana Peres, MD^*, Emanuel Robin, MD, PhD^*, Eric Kipnis, MD, PhD^*, Laurent Arnalsteen, MD, Béatrice Thielemans, DPharm, Bruno Carnaille, MD, PhD, François Pattou, MD, PhD, Benoît Vallet, MD, PhD^*, and Gilles Lebuffe, MD, PhD^*

From the *Department of Anesthesiology and Intensive Care-Section of Pain, Department of Pharmacology, Department of Endocrine and General Surgery, Claude Huriez University Hospital, rue Michel Polonovski, 59037 Lille cedex, France.

Address correspondence and reprint requests to Gilles Lebuffe, MD, PhD, Department of Anesthesiology and Intensive Care-Section of Pain, Claude Huriez University Hospital, rue Michel Polonovski, 59037 Lille cedex, France. Address e-mail to g-lebuffe{at}chru-lille.fr.

Abstract

BACKGROUND: Preoperative oral gabapentin has been shown to reduce postoperative pain. However, the effects of gabapentin as an adjunct to regional anesthesia is unclear and its effects on chronic pain remains unknown. In patients undergoing thyroidectomy, we investigated the effects on early and late (at 6 mo) postoperative pain of preoperative oral gabapentin as an adjunct to superficial cervical plexus block (SCPB).

METHOD: Fifty consecutive consenting patients were randomized to receive either 1200 mg of gabapentin (Group G) or placebo (Group P) 2 h preoperatively. Preoperative anxiety was assessed on a numeric scale from 0 to 6. A SCPB was performed after a standardized induction of anesthesia. The primary outcome, analgesic drug consumption, was assessed during the procedure and postoperatively in the postanesthesia care unit and after discharge to the ward. Over the first 24 h, pain levels at rest and during swallowing were measured on a numeric scale from 0 to 10. If the pain level was more than 4/10 at rest, patients received 1 g/6 h of IV paracetamol and/or 50 mg/6 h of IV tramadol as a rescue analgesic treatment in the interval. The day before operation and 6 mo after thyroidectomy, included patients were asked to answer a neuropathic pain diagnostic questionnaire.

RESULTS: Population characteristics, preoperative anxiety, intraoperative drug consumption, procedure duration, and postoperative care unit stay were comparable in both groups. Analgesic consumption during the first 24 postoperative hours was similar in both groups (G: 3 [0–5] doses/24 h; P: 3 [1–5] doses/24 h; P = NS), as well as pain at rest (G: 2,2 [0.2–3.7]; P: 2 [0–6.3]; P = NS), and during swallowing (G: 2.8 [0.4–8.9]; P: 3 [1.4–6.3]; P = NS]). Eight patients had a diagnostic questionnaire score more than 3, 6 mo after operation versus 2 in preoperative period (P = 0.04). Such delayed neuropathic pain complaints were reported in seven patients receiving SCPB alone and only in one patient receiving both SCPB and preoperative adjunctive oral gabapentin. (P = 0.01).

CONCLUSION: Oral preoperative administration of gabapentin did not modify immediate pain management in thyroidectomy patients receiving SCPB, but prevented delayed neuropathic pain at 6 mo.

Pain management has evolved in the last 10 yr. Multimodal approaches have resulted in lower postoperative pain levels by using combinations of various analgesic techniques.1 Other strategies intended to modulate the triggering of pain by operative stimuli such as preemptive analgesia, described in the 1980s,2 in which analgesics were administered before the onset of noxious stimulation, reduced intra and postoperative opioid requirements. More recently, the concept of preventive analgesia extends the concept of multimodal analgesic treatment into the postoperative period in order to prevent peripheral and central sensitization.3 Preincisionnal administration of local anesthetics provides a peripheral action on primary hyperalgesia at the site of the lesion, whereas drugs such as gabapentin administrated preoperatively have a selective effect on the nociceptive process involving central sensitization.4 The central neuronal sensitization contributes to the mechanical hyperalgesia surrounding the wound in postoperative patients. In a recent review, preoperative oral gabapentin was found to be effective in reducing pain intensity and opioid consumption.5 However, both its efficacy as an adjunct to local anesthetics which decrease hyperalgesia at the incision site and its efficacy in preventing postoperative neuropathic chronic pain remain unclear.

The antinociceptive effects of gabapentin result, in part, from an action on the ₂ subunits of voltage-dependent Ca²⁺ channels,6 which are up-regulated in the dorsal root ganglia and spinal cord after peripheral injury.4 Gabapentin-induced antihyperalgesia would be the consequence of decreased glutaminergic transmission in the spinal cord and inhibition of voltage-operated Ca²⁺ channels,7 thereby attenuating synaptic transmission.8 The precise mechanisms of action for gabapentin remains unknown, and additional mechanisms, other than ₂ interactions, may contribute to the effects of gabapentin.9

Local anesthetics and gabapentin have been studied separately in pain management after thyroidectomy. Andrieu et al.10 found an intraoperative opioid-sparing effect and postoperative reduction in analgesic rescue, associated with superficial cervical plexus block (SCPB). Similar results in postoperative pain management were also observed in patients receiving gabapentin preoperatively.11

The combination of SCPB with gabapentin might be of interest to reduce pain after thyroidectomy. The goal of this study was to evaluate preoperative oral gabapentin and SCPB on early (24 h), and late (6 mo) postoperative pain in patients operated on for thyroid surgery.

METHODS

This prospective, randomized, controlled, double-blind trial was approved by the ethics committee for Human Investigations of the University of Lille (France). Written informed consent was obtained from participating patients. The primary outcome was the effect of oral gabapentin on postoperative rescue analgesic consumption after a thyroidectomy performed under general anesthesia with SCPB. Secondary outcomes were the incidence of chronic neuropathic pain 6 mo postoperatively, and the potential protective role of gabapentin on such delayed pain.

Included patients were men or women aged 18 to 75 yr with an ASA score between 1 and 3, undergoing scheduled total or partial thyroidectomy without lymph node dissection. Exclusion criteria were: emergency reintervention, a contraindication to paracetamol, the presence of preoperative chronic pain with either repetitive consumption of analgesics or a level of pain of at least 3 on a numeric scale graduated from 0 (absence of pain) to 10 (maximal imaginable pain), epilepsy or history of convulsions, previous prescription of gabapentin, an incapacity to understand the protocol, noncooperating patients and patients who did not consent to the study.

The day before operation, eligible patients were asked to evaluate their preoperative pain with the numeric scale and the neuropathic pain diagnostic questionnaire (DN2).12 The DN2 detects neuropathic pain for a score of at least 3 with a sensitivity of 78% and a specificity of 80%.

The number of patients to be included in the study was calculated at 20 patients per group, based on a reduction of paracetamol consumption from 3 g to 2 g in the first 24 postoperative hours ( = 0.05 and β = 0.10), according to data from the literature showing a 33% analgesic-sparing effect with gabapentin.13 We decided to include 25 patients in each group. Post hoc power calculations were performed to determine power for the DN2 score comparisons.

Fifty patients were randomized in 2 groups to receive a dose of 1200 mg oral gabapentin (G) or a placebo (P) 2 h preoperatively. Randomization was performed by subgroups of 10 patients with a randomization table.

Premedication with 50 mg oral hydroxyzin was administered with the appropriate treatment 2 h preoperatively. General anesthesia was induced with propofol in target-controlled infusion (Diprifusor®; Fresenius Vial Master TCI; Bad Homburg; Germany), with targets ranging from 5 to 8 µg/mL, associated with IV sufentanil (0.2–0.3 µg/kg). Atracurium (0.5 mg/kg) was injected IV to facilitate orotracheal intubation. A bilateral SCPB was performed in anesthetized patients with 0.5% ropivacaine combined with 7.5 µg/mL clonidine, using the technique and the mixture described by Andrieu et al.10 Anesthesia was maintained with a target-controlled infusion of propofol at targets between 3 and 5 µg/mL and repeated boluses of 5 to 10 µg sufentanil, following the local protocol. Variations of more than 20% of systolic blood pressure and/or heart rate, compared with the preincision value, determined subsequent sufentanil bolus administration. Patients' lungs were ventilated with an oxygen/air admixture (70%/30%). Standard anesthetic variables were also collected.

At the end of operation, patients were tracheally extubated in the operating room, and transferred to the postanesthetic care unit (PACU). On their arrival in the PACU, the intensity of pain at rest and during swallowing was measured using the numeric scale. Transfer to the ward was authorized when patients presented an Aldrete score of at least 9. The time spent in the PACU was recorded.

Pain levels at rest and during swallowing, and the presence of postoperative nausea and vomiting (PONV) were evaluated every 3 h for the first 12 h, and every 6 h until the 24th h. An analgesic treatment with 1 g IV paracetamol was administered every 6 h if the pain level was at least 4 on the numerical scale at rest. If analgesia was insufficient, rescue administration of 50 mg IV tramadol was possible every 6 h. Analgesic consumption defined the primary outcome and was recorded. Before discharge from the hospital, patients were asked to evaluate their global satisfaction on a numeric scale scored from 0 (not satisfied at all) to 10 (entirely satisfied).

Six months postoperatively, all patients included in the study were contacted by mail to evaluate chronic pain using the DN2 questionnaire. Patients presenting a DN2 score of at least 3 were then interviewed by phone to understand the consequences of pain on their everyday lives. If pain constituted a handicap for them, a consult in the pain unit was proposed.

Continuous variables are reported as median (range). The differences between groups were examined with the Mann-Whitney test. Categorical variables are reported as proportions and were analyzed using the ² test or Fischer's exact test. Post hoc testing was performed according to the Bonferroni correction for multiple comparisons. A value of P < 0.05 was considered statistically significant. Graphpad Prism® for windows (version 4.00, GraphPad Software, San Diego, CA) was used to perform the statistical analysis.

RESULTS

Fifty patients were enrolled in the study between May and November 2006. All received treatment allocated by randomization. Early postoperative pain was evaluated in 22 patients in Group G and 21 patients in Group P. Seven patients were excluded, due to incomplete data (Group G: 1 case; Group P: 1 case) and protocol violations during the intraoperative period (Group G: 2 cases; Group P: 3 cases). Late postoperative pain was assessed in 47 patients, 2 subjects of the study being lost to follow-up, and another's failure to answer the questionnaire query.

Table 1 presents patient characteristics. There were no significant differences in age, gender, weight, size, ASA score, intra and postoperative variables.

The median (range) analgesic consumption during the first 24 postoperative hours was 3 (0–4) g in Group G compared to 2 (1–4) g in Group P (P = NS) for paracetamol and 0 (0–50) mg in Group G compared to 0 (0–150) mg in Group P for tramadol (P = NS). At 24 h after thyroidectomy, the total analgesic consumption (number of doses of IV paracetamol and tramadol by patient) was similar in both groups (3 [0–5] doses in Group G versus 3 [1–5] doses in Group P [P = NS]). Tramadol was required in 27.3% patients in Group G and in 23.5% in Group P (P = NS). There were no significant differences between groups for pain scores at rest and during swallowing (Fig. 1).

View larger version (28K): [in this window] [in a new window]   Figure 1. Evolution of pain at rest (A) and during swallowing (B) in the 24 first postoperative hours. The box plots indicate median, quartile (25th-75th) and the whiskers represent lower and upper adjacent values. Black circles are extreme values. Comparison between groups performed at each timepoint by Mann-Whitney test. Post hoc analysis with Bonferroni correction for multiple comparisons. Group gabapentin (G) and placebo (P); A-postanesthesia care unit (PACU): Admission in the PACU; D-PACU: Discharge from the PACU.

Among 47 patients who completed chronic pain questionnaires after 6 mo, 8 presented a DN2 score of at least 3 compared to 2 patients in the preoperative period (P = 0.04). A significant decrease of the total score and of the number of patients presenting a score of at least 3 was observed in Group G with a Post hoc power at 80% (Table 2). There was a trend toward greater burning sensation and numbness in Group P without reaching statistical significance (Table 2). Among eight patients with a DN2 of at least 3 after 6 mo, only 1 patient (2%) had a persistent pain complaint by the time an interview over the phone was organized and this patient benefited from a pain consult.

DISCUSSION

Rescue analgesic consumption and pain during the first 24 h were not affected by a single preoperative dose of gabapentin 1200 mg administered 2 h before thyroidectomy under general anesthesia with SCPB. Adverse effects were negligible. Delayed pain of low intensity was, however, observed 6 mo after surgery, mainly in patients who did not receive gabapentin.

There were several study limitations. First, postoperative pain scores were low overall, suggesting that our hypothesis of a 33% reduction in analgesic consumption with treatment based on previous data was too optimistic. More patients would have been necessary to reveal an analgesic-sparing effect of gabapentin. A reduction of 10% in analgesic consumption would have required 200 patients per group. The clinical relevance of such a study for immediate postoperative pain management after thyroidectomy seems, however, difficult to determine. Second, gabapentin's antihyperalgesic effects cannot be totally excluded, as the area of mechanical hyperalgesia surrounding the wound was not assessed. Third, the use of regional anesthesia itself could prevent delayed postoperative pain, but14 the use of SCPB in all patients suggests that the lower incidence of delayed postoperative pain in the group receiving gabapentin as an adjunct to SCPB was due to gabapentin.

A meta-analysis reported the benefit of a single dose of gabapentinoïdes (gabapentin or pregabalin) on postoperative opioid consumption and pain. According to studies, 300 mg to 1200 mg gabapentin reduced morphine consumption from 20% to 60%.5 Al Mujadi et al.11 demonstrated the efficacy of 1200 mg gabapentin given 2 h before thyroidectomy under general anesthesia. Pain levels at rest and during swallowing, as well as opioid consumption, were reduced in treated patients (48% compared with nontreated patients).11

In the present study, pain levels were low with SCPB, probably attenuating any expected additional analgesic effects of gabapentin. Similar data were found in upper humeral/scapular orthopedic surgery performed under interscalenic block.15 In addition to decreasing pain levels by regional anesthesia, the interaction between regional anesthesia and gabapentin might also explain the absence of any discernable additional analgesic effect of gabapentin in our study. Indeed, blockage of nociceptive stimulus by regional anesthesia may prevent central sensitization limiting the effects of gabapentin. In the case of thyroidectomy, SCPB blocked the nociceptive influx and permitted an opioid-sparing effect,10 which reduced the effects of gabapentin on morphine consumption as demonstrated by others.16 A gabapentin-induced antihyperalgesic effect cannot, however, be eliminated since no specific evaluation of mechanical hyperalgesia surrounding the wound was performed.17

The addition of gabapentin to regional anesthesia provided analgesic benefit when regional anesthesia did not cover the area in which hyperalgesia developed. Gabapentin was efficient in patients operated on for abdominal hysterectomy with a wound infiltration of local anesthetics,18 allowing a reduction of analgesic consumption, compared to placebo. Gynecological surgery is responsible for an intense pain with mechanical hyperalgesia, due to the wide stimulation of the peritoneum. Parietal infiltration with local anesthetics only has a local effect on the incisionnal area, whereas gabapentin, with its systemic diffusion and central action, acts on secondary hyperalgesia leading, in this case, to a significant decrease of pain intensity.

Chronic pain is common after operations such as herniorrhaphy, mammar or thoracic surgery.19 After inguinal hernia surgery, 10% of patients develop chronic pain and 2% to 4% have severe pain at 3 and 6 mo. To our knowledge, no study has described the incidence of late pain after thyroidectomy. Moreover, no validated score has been used to diagnose late postoperative pain. Classically, chronic pain is diagnosed by phone interviews evaluating a painful experience 1 to 6 mo after operation,20,21 the need for repeated analgesic treatments, and sensations surrounding the wound.18,20,22,23 Pain intensity, from 0 to 10, at rest and during swallowing, was evaluated at the time of the interview, and the week before.24

DN2 is an easy-to-use score which does not require a clinical examination, and which was validated for the diagnosis of neuropathic chronic pain.12 In our study, DN2 revealed neuropathic pain at 6 mo in 17% of patients after thyroidectomy. Pain intensity was low with mainly burning and numbness sensations. Only one patient (2%) had persistent pain when called back, but did not suffer from severe handicap or major consequence in his everyday life. These data confirm the possibility of chronic pain after an operation associated with immediate low postoperative pain.14 For Kehlet et al.,19 the afferent nervous damage in the operative wound explains, in part, delayed postoperative pain.

Our preliminary data suggest that gabapentin may potentially decrease the incidence of chronic pain after thyroidectomy. As predominant neuropathic pain was observed, its antihyperalgesic properties via an action on dorsal horn hyper-excitability induced by tissue lesions25,26 should assist in this protective effect.27 Fassoulaki et al. reported a reduction of burning sensation at 1 mo after an administration of 400 mg gabapentin for 10 days, beginning from the day before a mastectomy with axillary lymph node resection.20 Patients receiving a combination of gabapentin, EMLA cream and an intraoperative infiltration of the wound with ropivacaine developed less chronic pain and consumed less analgesics at 3 mo but not at 6 mo than those who received placebo.23 After an abdominal hysterectomy, 1600 mg gabapentin daily for 5 days started the day before operation, reduced postoperative pain after 1 mo, whereas no benefit was found in the early postoperative period.22 Others did not observe benefits from gabapentin for the prevention of late pain at 1 and 3 mo.21,24

The optimal dose, timing and duration of gabapentin for preventing both acute and chronic postoperative pain remain to be elucidated. Pandey et al. found that increasing the dose from 300 mg to 600–1200 mg improved the analgesic-sparing requirement without any difference between the higher doses.28 No study indicates the superiority of pre and/or postoperative administration even if gabapentin's pharmacokinetic properties favor treatment initiation one16 or 2 h before surgery.11 Finally, the duration of gabapentin administration might be adjusted according to the type of surgery leading to prolonged postoperative treatment for surgery-induced high pain intensity.4

No major adverse effect was observed with the administration of gabapentin. The incidence of PONV was low (2%) compared to the study of Andrieu et al.,10 who described 31% of patients with this complication. This result probably relates to the exclusion of volatile anesthetics from their anesthetic protocol. Gabapentin was suggested to have a protective effect from PONV,29 but this effect is most likely due to the morphine-sparing effect, than to an intrinsic effect of the molecule.13 Time spent in the PACU tended to be longer in patients treated with gabapentin. This is certainly related to the sedative effect of gabapentin, which is the most common side effect of the molecule, with an approximate incidence of 3%, according to Tiippana et al.5

In conclusion, our study did not show an early sparing effect of gabapentin on the administration of rescue analgesics after thyroidectomy performed under combined general anesthesia and SCPB. However, neuropathic postoperative pain was observed 6 mo after thyroidectomy and our preliminary data indicate that the frequency may be decreased by preoperative administration of gabapentin, and warrant further investigation in a properly powered clinical trial.

Footnotes

Accepted for publication June 20, 2008.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Brogly, N. Articles by Lebuffe, G. Search for Related Content PubMed PubMed Citation Articles by Brogly, N. Articles by Lebuffe, G. Related Collections Postanesthetic Care Unit Pain Medicine Clinical Pharmacology Regional Anesthesia Pharmacology