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Lack of Analgesic Effect Induced by Ropivacaine Wound Infiltration in Thyroid Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial

Miu, Mihaela MD*; Royer, Catherine MD*; Gaillat, Carmen MD*; Schaup, Barbara MD*; Menegaux, Fabrice MD, PhD; Langeron, Olivier MD, PhD*; Riou, Bruno MD, PhD; Aubrun, Frédéric MD, PhD§

doi: 10.1213/ANE.0000000000001041
Regional Anesthesia: Research Report

BACKGROUND: Surgical site infiltration with local anesthetic reduces analgesic requests in various types of surgeries. Because thyroid surgery may induce severe postoperative pain, we tested the hypothesis that ropivacaine surgical site infiltration would significantly decrease postoperative administration of morphine in patients undergoing thyroid surgery.

METHODS: We performed a double-blind, placebo-controlled superiority trial to assess the efficacy of surgical site analgesia with ropivacaine (10 mL, 75 mg) performed at the end of thyroid surgery in adult patients. The primary end point was the proportion of patients not requiring IV morphine in the postanesthesia care unit.

RESULTS: One hundred sixty-three patients completed the study, 85 in the placebo group and 88 in the ropivacaine group. The proportion of patients requiring morphine administration in the postanesthesia care unit (55% vs 53%, P = 0.80), the dose of IV morphine administered (5.6 ± 6.1 vs 5.5 ± 6.0 mg, P = 0.90), the total dose of opioids administered (expressed as oral morphine equivalent dose: 64 ± 27 vs 69 ± 29 mg, P = 0.20), and the visual analog pain scale over the first 24 hours were not significantly different between groups. The incidence of adverse events (36% vs 39%, P = 0.88), morphine-related adverse events (19% vs 17%, P = 0.84), serious adverse events (0% vs 2%, P = 0.50), and the patient satisfaction scores (9 ± 1 vs 9 ± 1, P = 0.70) was not significantly different between the 2 groups.

CONCLUSIONS: Surgical site analgesia with ropivacaine at the end of thyroid surgery is not associated with any significant analgesic benefit.

Published ahead of print October 26, 2015

From the Departments of *Anesthesia and Critical Care, General Surgery, and Emergency Medicine, Pitié-Salpetrière Hospital, Pierre et Marie Curie University, Paris, France; and §Department of Anesthesia and Critical Care, Croix-Rousse Hospital, Claude Bernard Lyon 1 University, Lyon, France.

Accepted for publication August 21, 2015.

Published ahead of print October 26, 2015

Funding: Support was provided solely from institutional and/or departmental sources. The study was supported by the Délégation Régionale de la Recherche Clinique (N° P061002), Assistance Publique-Hôpitaux de Paris (Paris, France).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Frédéric Aubrun, MD, PhD, Département d’Anesthésie-Réanimation, Hôpital de la Croix-Rousse, 103, Grande Rue de la Croix Rousse, 69004 Lyon, France. Address e-mail to frederic.aubrun@chu-lyon.fr.

Thyroid surgery may induce severe postoperative pain, particularly in the early postoperative hours.1 The mean pain level after thyroidectomy was estimated at 69 on a 0- to 100-mm visual analog pain scale (VAS),2 and values between 55 and 78 have been noted in another study, depending on the intraoperative opioid regimen used.3 Thyroid surgery per se and opioid requirement have been recognized as risk factors for postoperative nausea or vomiting, which are a major complaint of the patients and may increase the risk of postoperative bleeding requiring emergency surgery,2–5 which is a rare but life-threatening complication in thyroid surgery. Thus, attempts should be made to both decrease postoperative pain and limit opioid consumption in the postoperative period in patients undergoing thyroid surgery.

Surgical site infiltration with local anesthetic reduces analgesic requests in various types of surgeries, including inguinal herniorrhaphy, breast surgery, and iliac bone graft harvest.6,7 In addition to sophisticated techniques such as combined superficial and deep cervical blockade, the simple method of surgical site infiltration with local anesthetic has been suggested to reduce postoperative pain and opioid consumption after thyroid surgery.2,4,8–10

Thus, we performed a double-blind, placebo-controlled superiority trial to assess the analgesic efficacy of surgical site infiltration with ropivacaine (10 mL, 75 mg) performed at the end of surgery in patients undergoing thyroid surgery. We tested the hypothesis that ropivacaine infiltration significantly increased the proportion of patients who did not require additional morphine in the postoperative period.

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METHODS

This prospective study was performed from October 18, 2009, to April 16, 2010, after approval by an Ethical Committee (Comité de Protection des Personnes, CPP de Paris—Ile de France III, Paris, France), and all patients provided written informed consent. The study was conducted according to Good Clinical Practice standards and the Helsinki Declaration, and we followed the Consolidated Standards of Reporting Trials (CONSORT) recommendations for reporting of parallel-group randomized trials.11 The study has been registered at a clinical trial registry (EudraCT Number 2008-004011-35; https://eudract.ema.europa.eu).

The criteria for inclusion in the study were age >18 years, ASA physical status I to III, and scheduled thyroid surgery. The investigators verified that patients were able to understand and follow the protocol, including the VAS. The exclusion criteria included the following: ASA physical status IV to V, any chronic pain medication as opioids, nonopioid or nonsteroidal antiinflammatory drugs or corticosteroids within 10 days before surgery; pregnancy; coagulation disorders; age <18 years; infections; current or past drug use; patients’ refusal; renal insufficiency (estimated creatinine clearance <30 mL·min−1 using the Cockroft formula); sleep apnea obstruction syndrome; morbid obesity (body mass index >40 kg·m−2); known allergies; or contraindication to morphine, tramadol, acetaminophen, or ropivacaine. Patients requiring prolonged surgery with lymph node dissection for cancer, sternotomy for substernal goiters, and emergency surgery were excluded. Patients with a contraindication to droperidol (patients with known or suspected QT prolongation or hypersensitivity to the drug) were also excluded.

This was a monocentric, randomized, placebo-controlled, parallel-group, superiority trial. Patients were included in the study during the preoperative (at least 48 hours before surgery) appointment with the anesthesiologist. The following data were recorded: patient characteristics, including age, sex, weight, height, body mass index, personal history, and ASA physical status. A pregnancy test was performed in women. Preoperative biological measurements included hemoglobin, creatinine, platelet counts, prothrombin, and activated partial thromboplastin time.

Patients were randomly allocated to 1 of the following 2 groups: (1) placebo group using surgical site analgesia with 10 mL of isotonic (0.9%) sodium chloride solution; and (2) ropivacaine group using surgical site analgesia with 10 mL of 0.75% (75 mg) plain ropivacaine (Naropeine®; AstraZeneca, Rueil-Malmaison, France). The specific treatment given was presented in unlabeled plastic bottles prepared at the hospital pharmacy to ensure double-blinding and randomization. Before skin closure and using a 21-gauge needle, the surgeon blinded to the applied medications infiltrated the subcutaneous tissue, above the platysma muscle, of surgical edges uniformly with 10 mL of this unlabeled solution (5 mL in the upper edge and 5 mL in the lower edge, respectively).

All patients received the following standard care. Patients were premedicated with 50 or 100 mg oral hydroxyzine, 1 hour before surgery. Anesthesia was provided using IV target-controlled infusion of propofol and remifentanil (Orchestra® Base Primea, Fresenius Kabi, France), and patients were mechanically ventilated with a mixture of air and oxygen (50/50). Orotracheal intubation was facilitated by the administration of atracurium (0.5 mg·kg−1). Thirty minutes before the end of the surgery, all patients received 1 g of acetaminophen, 1.25 mg droperidol, and 0.1 mg·kg−1 morphine IV as part of multimodal prevention of postoperative pain after remifentanil-based intraoperative analgesia and postoperative nausea and vomiting. According to their Apfel score for postoperative nausea and vomiting risk, we used our hospital protocol that consists of IV dexamethasone administration at the induction of general anesthesia (4–8 mg) and additional droperidol (1.25 mg) at the end of surgery with 4 mg of ondansetron if required.12,13 Patients were tracheally extubated in the operating room and then transferred to the postanesthesia care unit (PACU) where they stayed for at least 2 hours, then were transferred to the surgical ward. Intraoperatively, we recorded the total dose of all IV anesthetics used and the dose of IV morphine administration.

Postoperative pain management was standardized. The patients received 1 g of IV acetaminophen every 6 hours during the first 24 hours. In PACU, a nurse trained in pain assessment interviewed the patients every 10 minutes for the first hour postoperatively. The patients were asked to rate pain at rest using a (0–100 mm) VAS and to localize their pain (cervical versus other sites). When VAS was >30 mm, IV morphine was titrated every 5 minutes in 2-mg increments (3 mg if weight >60 kg) until pain relief was achieved (VAS ≤30).14 The morphine titration protocol was stopped if nausea or vomiting occurred, if the patient was too deeply sedated (>2 on Ramsay scale of sedation), or if he/she presented apnea, desaturation, or a respiratory rate <10/min.14 In the PACU, we recorded the following variables: the VAS score at admission to the PACU, the delay between the admission and the first VAS score over 30 mm recorded at rest, the amount of IV morphine titration, the use of rescue analgesia, the incidence of nausea or vomiting, the sedation score, and the length of stay in the PACU. The transfer to the ward was authorized when patients presented an Aldrete score of at least 9 and if no surgical complication was noted. Pain level was assessed before leaving PACU.

In the surgical ward, the pain scores were assessed every 4 hours until 24 hours after the end of surgery. The pain management included scheduled administration of acetaminophen every 6 hours and if severe pain occurred (VAS > 40 mm), 50 mg of tramadol was given (every 6 hours if needed), with rescue administration of subcutaneous morphine (0.1 mg·kg−1 every 4 hours) if pain relief was not achieved using acetaminophen and tramadol. Nausea, vomiting, antiemetic requirements, sedation, and respiratory scores, and other adverse events including hypocalcemia, hematoma, and tingling and/or paresthesia were recorded. Before discharge from the hospital, patients were asked to evaluate their global satisfaction about pain management on a numeric scale ranging from 0 (not satisfied at all) to 10 (entirely satisfied).

The main end point was the proportion of patients who did not require additional IV morphine administration in the PACU. The secondary efficacy end points were the dose of IV morphine administered in the PACU, the proportion of patients receiving tramadol and subcutaneous morphine, the VAS and the incidence of adverse events over the first 24 hours, the time between extubation and the first VAS score over 30 mm, the length of stay in PACU, and patient satisfaction rating. We also calculated the total opioid dose administered during the first 24 hours expressed as an equivalent of oral morphine dose (1 mg of IV morphine = 3 mg of oral morphine; 5 mg of tramadol = 1 mg of oral morphine).

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Statistical Analysis

The following assumptions were made to calculate the number of patients to be included. In a preliminary study, we observed that the proportion of patients who did not require additional morphine in the postoperative period is 23%. Assuming an α risk of 0.05, a β risk of 0.10, we calculated that 88 patients per group would be required to demonstrate that ropivacaine is able to increase this proportion to 46% at least (nQuery Advisor 4.0; Statistical Solutions Ltd., Cork, Ireland). No interim analysis was performed. Randomization was performed using a random number table equilibrated every 10 patients without stratification.

The statistical plan was decided a priori. The main analysis was performed using an intention-to-treat approach, but we also reported a per-protocol analysis only for the primary outcome. Continuous variables are reported as mean ± SD and were compared using the Student t test and repeated measure analysis of variance. Because delays to first VAS score over 30 mm were thought to be not normally distributed, they were reported as medians and lower and upper quartiles. To compare the delays between groups, we considered the time until the first VAS achieved 30 mm as an event occurrence and used a log-rank test to compare the 2 event curves.

Categorical variables are reported as number of patients and proportions and the compared using the χ2 test or Fisher exact test when appropriate. We performed a multivariate analysis using logistic regression to assess variables (sex, age, ASA physical status, previous surgery, chronic pain in past or preoperative neck pain, and treatment group) associated with the occurrence of a VAS > 30 mm or postoperative morphine titration in the PACU and calculated the odds ratio (OR) and its 95% confidence interval (CI). All P values were 2-tailed, and a P value of <0.05 was considered significant. SAS version 9.2 (SAS Institute, Cary, NC) was used to perform the statistical analysis.

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RESULTS

We included 176 adult patients undergoing elective thyroid surgery under general anesthesia. Three patients were not randomly allocated, and thus, 173 patients were considered in the intention-to-treat analysis, 85 in the placebo group and 88 in the ropivacaine group (Fig. 1). Patient characteristics and intraoperative data were similar in both groups (Table 1). In the per-protocol analysis, 4 patients in the placebo group and 6 patients in the ropivacaine group were excluded because of major violation of the protocol (lymph node dissection, early reintervention for hematoma, study interrupted, IV morphine titration not performed, VAS not appropriately recorded, and IV morphine titration inappropriately interrupted). Thus, 163 patients completed the study in the per-protocol analysis, 81 in the placebo group and 82 in the ropivacaine group.

Table 1

Table 1

Figure 1

Figure 1

The proportion of patients requiring morphine titration in the PACU, the dose of morphine administered, the proportion of patients requiring tramadol or subcutaneous morphine, and the total dose of opioids administered over the 24-hour postoperative period were not significantly different between the 2 groups (Table 2). In the multivariate analysis, to assess variables associated with IV morphine in the PACU, only women required IV morphine more frequently (OR, 3.10; 95% CI, 1.46–6.60; P = 0.003), whereas treatment group was not significant (OR, 0.80; 95% CI, 0.46–1.58; P = 0.61). In the per-protocol analysis, the proportion of patients requiring morphine in the PACU remained not significantly different between the placebo and ropivacaine groups (57% vs 54%; P = 0.69).

Table 2

Table 2

The VAS scores registered immediately after tracheal extubation were comparable in the placebo and ropivacaine groups (7 ± 18 vs 7 ± 18 mm; P = 0.89), as well as the VAS at PACU admission (25 ± 28 vs 20 ± 24 mm; P = 0.60), and the proportion of patients with a VAS > 30 mm (66% vs 68%; P = 0.75). The median time until the first VAS score achieved 30 mm was also comparable (36 [20–120] vs 44 [23–75] minutes; P = 0.96).

The VAS during the first 24 postoperative hours was not significantly different between groups (Fig. 2). In the multivariate analysis, to assess variables associated with the occurrence of a VAS > 30 mm in the PACU, only women had more pain (OR, 1.65; 95% CI, 1.02–2.66; P = 0.04), whereas treatment group remained nonsignificant (OR, 0.94; 95% CI, 0.65–1.37; P = 0.77). The proportion of patients who reported cervical pain was not significantly different between groups (28% vs 35%; P = 0.32).

Figure 2

Figure 2

The incidence of morphine-related adverse effects, all adverse events, and serious adverse events was similar in both groups. No significant differences regarding hypocalcemia, hematoma, or dysphonia were observed between groups (Table 3).

Table 3

Table 3

There were no significant differences between the placebo and the ropivacaine groups in the length of stay in the PACU (130 [125–137] vs 125 [120–134] minutes; P = 0.06). The patient satisfaction score was recorded in only 59 patients in the placebo group and 52 patients in the ropivacaine group: there was no significant difference in the patient satisfaction score between the 2 groups (9 ± 1 vs 9 ± 1; P = 0.70).

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DISCUSSION

In this randomized double-blinded, placebo-controlled trial, we observed that surgical site analgesia with ropivacaine performed by the surgeon at the end of thyroid surgery did not significantly reduce the proportion of patients requiring morphine when compared with placebo. The pain scores, IV morphine requirement in the PACU, total opioid consumption over 24 hours, and incidence of adverse effects were also not significantly different between groups.

Surgical site analgesia with local anesthetic is a simple, safe, cost-effective technique. It is not time-consuming and has a high acceptance by both patients and surgeons. We choose the surgical site analgesia for pain relief because it can be done by the surgeon with a single injection and does not require a specific technique such as superficial cervical plexus block with specific anatomic landmarks.15 It can be done under general anesthesia, and the analgesic efficacy is well documented in other type of surgery, such as inguinal herniorrhaphies or superficial breast surgery.6,7

The analgesic efficacy of surgical site infiltration in thyroid surgery (which may cause considerable postoperative pain16,17) has been investigated in only a very few published studies.2,4,8–10,18 In an unblinded small sample (n = 20 per group) sized study, Gozal et al.2 reported a significant reduction in pain scores and morphine consumption during the first postoperative day with bupivacaine (10 mL, 50 mg). In another unblinded and small sample (n = 19–20 per group) sized study, Bagul et al.8 compared a preincision infiltration of bupivacaine (10 mL, 50 mg) with a group without any infiltration and reported a significant reduction in pain scores at 6 hours postoperatively, a difference that disappeared at 24 hours. In a double-blind small sample sized (n = 25 per group) study, Motamed et al.4 assessed ropivacaine (15 mL, 20 mg) surgical site analgesia and observed a significant decrease in pain scores and morphine requirement in the PACU without further significant difference in the surgical ward. The low dose of ropivacaine used in this study may have contributed to its limited effects.4 Karamanlioglu et al.9 compared surgical site analgesia with ropivacaine (10 mL, 75 mg), lornoxicam, or their combination and observed that pain scores, time to first analgesic requirement, and total pethidine consumption were significantly improved in the combination group. Ayman et al.10 compared surgical site analgesia with bupivacaine (10 mL, 50 mg) or ropivacaine (10 mL, 75 mg) and no infiltration and observed a decrease in postoperative pain with ropivacaine but not bupivacaine, but this effect was only significant at 1 hour and no longer detectable at 4 hours.10

The surgical field in thyroidectomy receives its main innervation from the superficial branches of the cervical plexus that can be blocked by cutaneous infiltration of local anesthetics or more specific techniques such as bilateral superficial (or combined superficial and deep) cervical plexus block.19–25 Several placebo-controlled trials have studied the analgesic efficacy of cervical plexus block in thyroid surgery with also contradictory results.21–24 Some of these studies reported a decrease in pain scores but usually without significant decrease in analgesic requirements,22,23 whereas others did not evidence any significant analgesic effect.21 Interpretation of these studies is difficult because cervical plexus block was performed either before or after surgery. In a double-blind small sample (n = 40 per group) sized study, Eti et al.25 compared surgical site analgesia with bupivacaine (20 mL, 50 mg), cervical plexus block with bupivacaine, and placebo and also failed to observe any significant difference between the 3 groups. Our results agree with the hypothesis that locoregional techniques (wound infiltration or cervical plexus block) may not be appropriate in thyroid surgery, mainly because postoperative pain is only partly related to the surgical wound itself in thyroid surgery.

There are several limitations of our study that could explain our negative results. Although the dose and concentration of ropivacaine were comparable with those given in similar surgical settings, the surgical site analgesia, performed by the surgeon without identifying any specific anatomical landmark, may have limited the success rate. Pain scores were low in the PACU after thyroid surgery in our study, and the benefit of local surgical site infiltration may have been difficult to demonstrate afterward. It might be more relevant to perform infiltration before the surgical procedure to demonstrate a sparing effect of intraoperative remifentanil and then a decrease in morphine administration during and after the surgical procedure.

In conclusion, in a double-blind randomized placebo-controlled study, we were unable to demonstrate any significant benefit of surgical site analgesia with ropivacaine in patients undergoing thyroid surgery.

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DISCLOSURES

Name: Mihaela Miu, MD.

Contribution: This author helped in study design, conduct of the study, and data collection.

Attestation: Mihaela Miu approved the final revised manuscript.

Name: Catherine Royer, MD.

Contribution: This author helped in study design, conduct of study, and data collection. This author is designated as the archival author responsible for maintaining the study records.

Attestation: Catherine Royer approved the final revised manuscript.

Name: Carmen Gaillat, MD.

Contribution: This author helped in study design and conduct of study.

Attestation: Carmen Gaillat approved the final revised manuscript.

Name: Barbara Schaup, MD.

Contribution: This author helped in study design and conduct of study.

Attestation: Barbara Schaup approved the final revised manuscript.

Name: Fabrice Menegaux, MD, PhD.

Contribution: This author helped in study design and is the surgeon of the study.

Attestation: Fabrice Menegaux approved the final revised manuscript.

Name: Olivier Langeron, MD, PhD.

Contribution: This author helped in study design.

Attestation: Olivier Langeron approved the final revised manuscript.

Name: Bruno Riou, MD, PhD.

Contribution: This author helped in data analysis, interpretation of data, manuscripts preparation, and critical revision of the manuscript for important intellectual content.

Attestation: Bruno Riou has received the original data and the analysis reported in the manuscript and attests to the integrity of the original data and analysis reported in the manuscript.

Name: Frédéric Aubrun, MD, PhD.

Contribution: This author helped in data analysis, interpretation of data, manuscript preparation, and critical revision of the manuscript for important intellectual content.

Attestation: Frédéric Aubrun has reviewed the original data and the analysis and attests to the integrity of the original data and analysis reported in the manuscript.

This manuscript was handled by: Terese T. Horlocker, MD.

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ACKNOWLEDGMENTS

We thank David Baker, DM, FRCA (Department of Anesthesiology and Critical Care, Hôpital Necker-Enfants Malades, Paris) for reviewing the manuscript. We thank Mathieu Coudert and Nathalie Cozic (URC Pitié-Salpêrière-Charles Foix, Paris, France) for statistical analysis.

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