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The Analgesic Effect of Paracetamol When Added to Lidocaine for Intravenous Regional Anesthesia

Sen, Huseyin, MD*; Kulahci, Yalcin, MD; Bicerer, Enis, MD*; Ozkan, Sezai, MD*; Dagl, Guner, MD; Turan, Alparslan, MD‡§

doi: 10.1213/ane.0b013e3181b0fedb
Regional Anesthesia: Research Reports
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BACKGROUND: In this study, we evaluated the effect of paracetamol on sensory and motor block onset time, tourniquet pain, and postoperative analgesia, when added to lidocaine in IV regional anesthesia (IVRA).

METHODS: Sixty patients undergoing hand surgery were randomly and blindly divided into three groups. All groups received IVRA lidocaine (3 mg/kg) diluted with saline to a total volume of 40 mL. Group 1 received IVRA lidocaine plus IV saline, Group 2 received IVRA lidocaine and paracetamol (300 mg) admixture plus IV saline, and Group 3 received IVRA lidocaine plus IV paracetamol (300 mg). Sensory and motor block onset time, tourniquet pain, and analgesic use were assessed during operation. After tourniquet deflation, visual analog scale (VAS) scores at 1, 2, 4, 6, 12, and 24 h, the time to first analgesic requirement, total analgesic consumption in first 24 h, and side effects were noted.

RESULTS: Onset of motor block was shorter and recovery of motor and sensory block was significantly longer in Group 2 (P < 0.05). Intraoperative VAS scores at intraoperative 20, 30, and 40 min were significantly lower in Group 2 (P < 0.05). Intraoperative fentanyl consumption (78 ± 12, 58 ± 14, 78 ± 11 μg, respectively) and the number of patients who required fentanyl for tourniquet pain (13 patients, 3 patients, 9 patients, respectively) were significantly less in Group 2 (P < 0.05). Time to postoperative fentanyl administration was also prolonged (15 ± 6, 25 ± 5, 15 ± 4 min, respectively) in Group 2 (P < 0.05). The quality of surgical anesthesia was better in Group 2 (P < 0.05). Postoperative VAS scores and time of initial analgesic requirement were similar among groups; however, the total amount of diclophenac use was less in Group 2 (P < 0.05).

CONCLUSION: The addition of paracetamol during IVRA with lidocaine decreased tourniquet pain, increased anesthesia quality, and decreased postoperative analgesic consumption.

From the Departments of *Anesthesiology and Reanimation, and †Plastic and Reconstructive Surgery, Gülhane Military Medical Academy Haydarpaşa Training Hospital Üsküdar, İstanbul, Turkey; ‡Department of Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, Kentucky; and §Department of Outcomes Research, The Cleveland Clinic, Cleveland, Ohio.

Accepted for publication May 11, 2009.

Supported by institutional and departmental sources at GATA Haydarpaçsa Eğitim Hastanesi.

Address correspondence and reprint requests to Dr. Alparslan Turan, Department of Anesthesiology and Perioperative Medicine, 530 S. Jackson St., University Hospital, Louisville, KY 40202. Address e-mail to alparslanturan@yahoo.com.

IV regional anesthesia (IVRA) is easy to administer, reliable, and cost-effective for short operative procedures of the extremities performed on an ambulatory basis.1 However, there are some disadvantages of IVRA, including delayed onset of action, poor muscle relaxation, and rapid onset of pain at the operative site after the tourniquet has been deflated.2 Additives such as opioids and muscle relaxants have been combined with local anesthetics to improve these problems.3 Although various nonsteroidal antiinflammatory drugs (NSAIDs), such as ketorolac,4 tenoxicam,5 and aspirin6 in IVRA, have been demonstrated to successfully improve analgesia, there are no clinical studies evaluating paracetamol when added to lidocaine for IVRA.

Paracetamol (acetaminophen) possesses very little antiinflammatory activity, and studies suggest the possibility that the site of action of its antinociceptive effect may be in the central nervous system.7 However, several studies have demonstrated peripheral antinociceptive properties of paracetamol in different pain models.8,9 Perfalgan (10 mg/mL, Bristol-Myers Squibb, France) is an injectable paracetamol solution and was introduced into clinical practice in 2002.

In this study, we evaluated the effect of an IV solution of paracetamol when added to lidocaine in IVRA for elective hand surgery and also compared it with IV administration. Our aim was to investigate the sensory and motor block onset and recovery time, quality of anesthesia, intraoperative and postoperative hemodynamic variables, and pain.

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METHODS

After ethics committee approval and informed written consent, 60 ASA physical status I–II patients scheduled for hand surgery were included in the study. Patients with Reynaud disease, sickle cell anemia, and a history of allergy to any drug used were excluded from the study. Patients were randomized to three groups with 20 patients in each. A randomization list was generated, and identical syringes containing each drug were prepared by an anesthesia assistant not involved in the study.

Forty-five minutes before the surgical procedure, patients were premedicated with IM 0.07 mg/kg of midazolam and 0.01 mg/kg of atropine. In the operating room, patients were monitored for mean arterial blood pressure (MAP), oxygen saturation (Spo2), and heart rate (HR). Two cannulae were placed: one was in a vein on the dorsum of the operative hand and the other in the opposite hand for crystalloid infusion. The operative arm was elevated for 2 min and was then exsanguinated with an Esmarch bandage. A pneumatic “double” tourniquet (Tourniquet 2800 ELC, UMB Medizin-tecknick GmbH, Germany) was then placed around the upper arm, and the proximal cuff was inflated to 250 mm Hg. Circulatory isolation of the arm was verified by inspection, absence of a radial pulse, and a loss of the pulse oximetry tracing in the ipsilateral index finger. IVRA was achieved with 3 mg/kg of lidocaine (10% Lidocaine, Aritmal, Biosel, Turkey) diluted with saline to a total of 40 mL in Group 1 (n = 20), 3 mg/kg of lidocaine plus 300 mg of paracetamol (Perfalgan 10 mg/mL, Bristol-Myers Squibb) diluted with saline to a total of 40 mL in Group 2 (n = 20), and 3 mg/kg of lidocaine diluted with saline to a total of 40 mL in Group 3 (n = 20). Groups 1 and 2 received 30 mL of saline and Group 3 received 300 mg of paracetamol IV immediately after injection of IVRA medication. The solutions were prepared by an anesthesiology assistant not involved any other part of the study. The solutions were injected over 90 s by an anesthesiologist blinded to the study drugs.

After injection, sensory block was evaluated with pinprick testing every 30 s until the start of surgery with a 22-gauge needle in the median, ulnar, and radial nerve-innervated areas of the hand and forearm.10 Motor function was assessed by asking the subjects to flex and extend their wrist and fingers; complete motor block was noted when no voluntary movement was possible.10 Sensory block onset time was noted as the time elapsed from injection of study drug to sensory block achieved in all innervated areas, and motor block onset time was the time elapsed from injection of study drug to complete motor block.

After complete sensory and motor blocks were achieved, the distal tourniquet was inflated to 250 mm Hg, the proximal tourniquet was released, and surgery was started. MAP, HR, Spo2 levels were recorded before and after the application of the tourniquet and during the operation (5, 10, 15, 20, 30, 40, and 50 min) and after release of the tourniquet by an anesthesiology resident, who did not know which medication was administered.

Pain due to the tourniquet was assessed with a 10-cm visual analog scale (VAS). Levels of sedation were assessed with the Ramsey sedation scale as follows: (1) patient is anxious and agitated or restless, or both, (2) patient is cooperative, oriented, and tranquil, (3) patient responds to commands only, (4) patient exhibits brisk response to light glabellar tap or loud auditory stimulus, (5) patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus, and (6) patient exhibits no response. Both VAS and sedation levels were recorded before and after the application of the tourniquet and during the operation (5, 10, 15, 20, 30, 40, and 50 min).

If the patient reported VAS >4, 1 μg/kg of fentanyl was given and requirement for analgesics (dose and time) was recorded. During surgery, 5 mg IV ephedrine was given for hypotension (systolic arterial blood pressure <90 mm Hg or 50 mm Hg lower than the normal value), 0.5 mg IV atropin was given for bradycardia (HR <50/min), and 4 mg IV ondansetron for nausea and vomiting. Oxygen was administered with a face mask in case Spo2 was lower than 91%. All of these complications were also recorded with respect to time.

At the end of the operation, the quality of anesthesia was graded by the anesthesiologist who was blinded to the study drug as follows: (4) excellent, no complaint from the patient (3); good, minor complaint with no need for supplemental analgesics (2); moderate, complaint that required a supplemental analgesic (1); unsuccessful, patient was given general anesthesia.11 Patient satisfaction was graded as follows: (4) excellent, (3) good, (2) moderate, (1) poor.11 Operative conditions and dryness of the operative field were qualified by the blinded surgeon as follows: (3) perfect, (2) acceptable, (1) poor, (0) unsuccessful.11

The tourniquet was not deflated before 30 min and was not inflated more than 2 h. At the end of surgery, the tourniquet deflation was performed by the cyclic deflation technique. Sensory recovery time was noted (time elapsed after tourniquet deflation up to recovery of pain in all innervated areas determined by pinprick test done every 30 s). Motor block recovery time was noted (the time elapsed after tourniquet deflation up to movement of fingers). First analgesic requirement time was also noted (the time elapsed after tourniquet release to first patient request of analgesic).

During the first 2 h in the postanesthesia care unit and later in the ward, patients were questioned by an anesthesiology resident not involved in study for nausea and vomiting, skin rash, tachycardia, bradycardia, hypotension, hypertension, dizziness, tinnitus, hypoxemia, and other side effects were noted if encountered during the postoperative 24 h in the ward. Statistical analyses were performed by Student’s t-test, χ2, and Mann–Whitney tests. Significance was determined at the P < 0.05 level.

Patients were assessed for 24 h in the postsurgical ward for MAP, HR, Spo2, VAS, and sedation 1, 2, 4, 6, 12, and 24 h postoperatively. Patients were questioned for pain and VAS >4, and 75 mg IM diclofenac was given; analgesic requirement (time and total amount) was recorded by a blinded anesthesia resident.

Initial sample size estimation showed that approximately 18 patients were needed in each group to detect a clinically relevant reduction of fentanyl consumption by 25% with a power of 0.80 and a level of significance of 5%. Statistical analysis was performed with SPSS for Windows version 11.5 (Chicago, IL). Bonferroni correction was performed to compensate for the possible effects of repeated testing. According to the distribution of the data, Kruskal–Wallis, Mann–Whitney U-test, analysis of variance, and χ2 tests were performed. Data were mean (sd), number (%), or median (min-max). A P value of <0.05 was accepted as statistically significant.

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RESULTS

All groups were similar with regard to age, sex, weight, height, ASA, surgical procedure, duration of surgery, and duration of tourniquet (Table 1). There was no statistical difference among groups when compared for MAP, HR, or Spo2 at any time either intraoperatively or postoperatively (data not presented). All patients were able to complete the study and there were no exclusions in data analysis.

Table 1

Table 1

There was no significant difference in onset of sensory block among the groups (P > 0.05); however, duration of sensory block recovery time was significantly longer in Group 2 (P < 0.05). Motor block time for onset was shorter and recovery of motor block was longer in Group 2 (P < 0.05) (Table 2).

Table 2

Table 2

Intraoperative VAS scores 20 and 30 min intraoperatively were significantly lower in Group 2 (P < 0.05) (Table 3). Intraoperative fentanyl and the number of patients who required fentanyl were significantly less in Group 2 (P < 0.05) (Table 4). First fentanyl requirement time was prolonged when compared with Groups 1 and 3 (P < 0.05) (Table 4). Sedation scores were similar among the groups in all measured times (P > 0.05).

Table 3

Table 3

Table 4

Table 4

The quality of anesthesia scores reported by the anesthesiologist was significantly higher in Group 2; however, there was no difference with the evaluation of surgeon (Table 4). Postoperative VAS scores and time of initial analgesic requirement time were similar among groups; however, the total amount of diclophenac use and number of requirements were less in Group 2 (P < 0.05) (Tables 3 and 4). Only postoperative side effect that occurred was nausea in two patients in Group 1 and three patients in Groups 2 and 3.

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DISCUSSION

A systematic review by Choyce and Peng3 suggested that NSAIDs have the most to offer as adjuncts to IVRA. NSAIDs, either as part of IVRA or wound infiltration, resulted in an analgesic benefit lasting longer than the same dose parenterally administrated. In this current study, we investigated whether the addition of paracetamol to IVRA solution decreased tourniquet pain, intraoperative opioid use, and favorably affected the sensory and motor block duration by increasing quality of IVRA. However, we were unable to demonstrate a decrease in postoperative pain scores, although the total 24 h use of postoperative diclophenac decreased.

Paracetamol is generally considered to be a weak inhibitor of the synthesis of prostaglandins. However, in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 inhibitors but, unlike the selective cyclooxygenase-2 inhibitors, paracetamol does not suppress inflammation.12,13 Several studies have suggested different mechanisms for the antinociceptive action of paracetamol, including N-methyl-d-aspartate,7 and the effect on cannabinoid receptors.9,14 The analgesic effect of paracetamol was found to be prevented by cannabinoid receptor (CB1) antagonists, suggesting the endocannabinoid system to be the long-sought mechanism of action of paracetamol.9,15 A recent study with IV paracetamol decreased propofol-induced injection pain,16 which is similar to our findings, demonstrated that paracetamol has some peripheral antinociceptive effects.

Previous studies done with ketorolac4,17 suggest better control of tourniquet pain, improved analgesia in the early postoperative period, and diminished need for analgesic supplements during the first postoperative day. Our results revealed a clinically similar analgesic effect in tourniquet pain when compared with ketorolac; however, the first analgesic request time in our study and pain scores postoperatively were not significant. Similar to ketorolac, concentrating the dose of paracetamol at the site of surgery,17 because part of IVRA resulted in better analgesic benefit than the same dose administered parenterally.

A deficiency of the current study design relates to the seemingly arbitrarily chosen dosage of the study drug (300 mg of paracetamol). The effective dose has yet to be determined. Although a higher dose of paracetamol might provide greater analgesic efficacy, it would be very difficult to prepare the IVRA solution with enough local anesthetic. To optimize the dose of paracetamol, a dose-ranging study design would be required. Another criticism of this preliminary study is that the study population involved only patients undergoing minor hand surgery procedures. Further comparative studies are clearly needed in patients undergoing other types of orthopedic surgical procedures.

In conclusion, administration of paracetamol as an adjuvant provided a significant clinical benefit by decreasing tourniquet-related pain and improving intraoperative conditions during IVRA. Intraoperative pain scores and the need for analgesic medications during and after elective hand surgery procedures were also reduced.

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