Effect of pretreatment with lidocaine, intravenous paracetamol and lidocaine-fentanyl on propofol injection pain: comparative study

Abstracts

JUSTIFICATIVA E OBJETIVOS: Foi realizado estudo duplamente encoberto, aleatório, para avaliar a eficácia do tratamento prévio, por via venosa, com lidocaína, paracetamol (Perfalgan®) ou lidocaína associada ao fentanil na redução da dor causada pela injeção de propofol. MÉTODOS: Imediatamente após a oclusão venosa com torniquete de borracha foi feita a administração venosa de 4 mL de lidocaína a 1% (Grupo L, n = 50), 4 mL de paracetamol (Perfalgan®) (40 mg) (Grupo R, n = 50), lidocaína a 2% associada a 100 µg de fentanil (Grupo LF, n = 50) ou 4 mL de solução fisiológica a 0,9% (Grupo P, n = 50; grupo-controle com placebo) a 200 adultos. A liberação da obstrução venosa foi feita após 60 segundos, sendo seguida da administração venosa de propofol, 2,5 mg.kg-1 a uma velocidade de 0,5 mg.s-1 através de cateter 20G inserido na veia do dorso da mão. A avaliação da dor foi feita durante a injeção de propofol. Ela incluiu movimentos da mão, expressão verbal espontânea de dor, caretas e gemidos durante a injeção de propofol. RESULTADOS: Lidocaína-fentanil (70% sem dor) e lidocaína (68% sem dor) foram mais eficazes na redução da dor causada pela injeção de propofol do que o paracetamol (54% sem dor) e o placebo (36% sem dor) (p < 0,05). A diferença na redução da incidência de dor causada pela injeção de propofol entre a lidocaína e lidocaína-fentanil não foi significativa. O paracetamol foi muito superior ao placebo (p < 0,05). CONCLUSÕES: O propofol é um anestésico amplamente utilizado. Lidocaína e lidocaína-fentanil administrados como tratamento prévio, na forma de retenção venosa durante 60 segundos, antes da administração do propofol reduziram de forma acentuada a dor causada pela injeção de propofol, enquanto o paracetamol (Perfalgan®) reduziu discretamente essa mesma dor.

ANESTÉSICOS, Venoso; COMPLICAÇÕES, dor à injeção

SCIENTIFIC ARTICLE

Effect of pretreatment with lidocaine, intravenous paracetamol and lidocaine-fentanyl on propofol injection pain. Comparative study^*

Efectos del tratamiento previo con lidocaína, paracetamol y lidocaína-fentanil intravenosos en el dolor causado por la inyección de propofol. Estudio comparativo

Khaled M. El-Radaideh

Professor-Assistente de Anestesiologia, MD, Facharzt Division of Anesthesia and Surgical ICU, King Abdullah University Hospital, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Performed a randomized, double blind study to assess the efficacy of intravenous (IV) pretreatment with lidocaine, IV paracetamol (Perfalgan^®) or lidocaine mixed with fentanyl in reducing propofol injection pain.

METHODS: Immediately after venous occlusion with a rubber tourniquet on the patient's arm IV lidocaine 1% 4 mL (Group L, n = 50), IV paracetamol (Perfalgan^®) 4 mL (40 mg) (Group R, n = 50), lidocaine 2% mixed with 100 µg fentanyl (Group LF, n = 50) or normal saline 4 mL (Group P, n = 50; as placebo control) was given to 200 adult patients. The release of the venous occlusion was done after 60s and followed by intravenous administration of propofol 2.5 mg.kg^-1 at rate of 0.5 mg.s^-1 through a 20G catheter inserted in hand dorsum vein. Pain assessment was made during the propofol injection. This included movement of hand, spontaneous verbal expressions of pain, frowning, and moaning during the injection of propofol.

RESULTS: Lidocaine-fentanyl (70% pain free), and lidocaine (68% pain free) significantly reduced propofol injection pain more than paracetamol (54% pain free) and more than placebo (36% pain free) (p < 0.05). The difference in reducing the incidence of propofol injection pain between lidocaine and lidocaine-fentanyl did not reach statistical significance. There was a significant superiority of paracetamol compared to placebo (p < 0.05).

CONCLUSIONS: Propofol, a commonly used anesthetic. Given as a venous retention pretreatment 60 seconds before propofol, lidocaine and lidocaine-fentanyl were found to significantly reduce the propofol injection pain, whereas IV paracetamol (Perfalgan^®) slightly reduced the propofol injection pain.

Key Words: ANESTHETICS, Intravenous: propofol; COMPLICATIONS: pain on injection.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Se realizó estudio doblemente encubierto, aleatorio, para evaluar la eficacia del tratamiento previo, intravenoso (IV), con lidocaína, paracetamol (Perfalgan^®) o lidocaína asociada con fentanil en la reducción del dolor causado por la inyección de propofol.

MÉTODOS: Inmediatamente después de la oclusión venosa con un torniquete de goma, se hizo la administración intravenosa de 4 mL de lidocaína a 1% (Grupo L, n = 50), 4 mL de paracetamol (Perfalgan^®) (40 mg) (Grupo R, n = 50), lidocaína a 2% asociada con 100 µg de fentanil (Grupo LF, n = 50) o 4 mL de solución fisiológica (Grupo P, n = 50; grupo control con placebo) a 200 adultos. La liberación de la obstrucción venosa fue hecha después de 60 segundos, siendo seguida de la administración intravenosa de propofol, 2,5 mg.kg^-1 a una velocidad de 0,5 mg.s^-1 a través de un catéter de 20G insertado en la vena del dorso de la mano. La evaluación del dolor fue hecha durante la inyección de propofol. Ella incluyó movimientos de la mano, expresión verbal espontánea de dolor, muecas y gemidos durante la inyección de propofol.

RESULTADOS: Lidocaína-fentanil (70% sin dolor) y lidocaína (68% sin dolor) fueron más eficaces en la reducción del dolor causado por la inyección de propofol que el paracetamol (54% sin dolor) y el placebo (36% sin dolor) (p < 0.05). La diferencia en la reducción de la incidencia de dolor causada por la inyección de propofol entre la lidocaína y la lidocaína-fentanil, no fue estadísticamente significativa. El paracetamol fue significativamente superior al placebo (p < 0,05).

CONCLUSIONES: El propofol es un anestésico ampliamente utilizado. La lidocaína y lidocaína-fentanil administrados como tratamiento previo, en la forma de retención venosa durante 60 segundos, antes de la administración del propofol redujeron significativamente el dolor causado por la inyección de propofol, mientras que el paracetamol IV (Perfalgan®) redujo discretamente ese mismo dolor.

INTRODUCTION

Propofol is a commonly used agent for the induction of general anesthesia, especially for outpatient surgical procedures. The pain on injection is still the major problem with propofol. Many methods have been used to prevent or to alleviate pain on injection caused by propofol such as applying propofol in different temperature ^1-4, lidocaine mixed with propofol ^5,6, lidocaine pretreatment without ⁷ or with tourniquet ⁸. Furthermore, multiple agents have been administered such as metoclopramide ⁹, nitroglycerin ¹⁰, procaine ¹¹, prilocaine ¹², opioids ⁷ and ketorolac ^13,14 with variable results. Recent and early studies showed that temporary venous occlusion following premedication with lidocaine did indeed diminish the intensity of pain ^15,16.

The purpose of this study was to assess the efficacy of the pretreatment with lidocaine and lidocaine mixed with fentanyl and IV paracetamol on diminish pain associated with the injection of propofol after temporary venous occlusion using an increased volume to 4 mL instead of the commonly used 2 mL.

METHODS

After ethical approval by the local Research Ethics Committee and after obtaining a written informed consent from all patients, 200 ASA physical status I–III aged 21–73 yr patients scheduled for elective gynecological, urological or general surgical procedures were entered into this double-blind, randomized, placebo-controlled study.

Exclusion criteria were refusal of consent, heart failure, renal failure and liver dysfunction. Patients taking sedatives, analgesics, central nervous system (CNS) depressants or anti-seizure medication, or with a history of intolerance or adverse reactions to the medications used in the study were also excluded from the study.

A total of 200 patients (50 patients each group) were randomized by a sealed envelope system to be pretreated either with 4 mL lidocaine 1% (Group L) or with 2 mL lidocaine 2% mixed with 2 mL fentanyl (Group LF) or 4 mL IV paracetamol (Group R) or with 4 mL isotonic sodium chloride solution as placebo (Group P) followed by propofol 2.5 mg.kg^-1 after 60 seconds of venous occlusion. On arrival to the anesthesia room all patients received a 20G intravenous catheter in the dorsum of the hand. Standard monitoring was used throughout the study and the surgical procedure, including non-invasive blood pressure, heart rate and pulse oximetry.

The venous occlusion of 60s for all groups was done on the arm at a distance of about 8 cm proximal the anticubital fosse using a 2.5 cm wide rubber tourniquet.

After 60 seconds the tourniquet had been released 2.5 mg.kg^-1 propofol were injected at rate of 0.5 mL.s^-1.

The patients of placebo group (n = 50) received 4 mL 0.9% normal saline. The patients of Group L (n = 50) were pretreated with 4 mL lidocaine 1% (total = 40 mg). The patients of Group LF (n = 50) were pretreated with 2 mL lidocaine 2% (total = 40 mg) and 2 mL fentanyl (total = 100 µg) while the patients of Group R (n = 50) were pretreated with 4 mL paracetamol (total = 40 mg). Four different Anesthesiology residents of the last year of training were involved in this study. The anesthesiologist, who was blind to the content of the study syringe, assessed the pain on injection associated with propofol. These included movement of hand, spontaneous verbal expressions of pain, frowning, and moaning during the injection.

This study proposes that the pretreatment with increased volume of lidocaine and mixing the lidocaine with fentanyl and paracetamol after temporary venous occlusion will diminish the pain on injection associated with propofol.

Data are presented as mean and standard deviation or as group percentages. Statistical evaluation was done with the Students t and Chi-square tests, incorporating Fishers Exact test where appropriate. Differences were considered statistically significant at p < 0.05.

Statistical calculations were performed using the Statistical Package for the Social Sciences Software Program version 13 (SPSS^®, Inc).

RESULTS

Of the 200 patients enrolled in this study, 50 patients were randomly assigned to each treatment group. The groups did not differ in age, gender, ASA physical status, bodyweight and height (Table I).

Propofol injection triggered pain in 32 patient's in Group P (64%), 16 patients in Group L (32%), 15 patients in Group LF (30%) and 23 patients in Group R (46%).

Compared with the placebo group, there was significantly less pain noted by the patients of Group L (36% pain free versus 68%; p < 0.05), the patients of Group LF (36% pain free versus 70%; p < 0.05) and the patients of Group R (36% pain free versus 54%; p < 0.05).

There was no significant difference between L and LF groups in reducing pain on injection of propofol (68% pain free versus 70%; p > 0.05) (Figure 1).

DISCUSSION

The tourniquet isolates the arm veins from the rest of the circulation. This is useful for studying the peripheral actions of a drug in the absence of its central effect ⁸.

The mechanism by which propofol causes pain on injection remains unclear ¹⁴, although Scott et al. ¹⁷ have suggested an enzyme cascade, possibly the kallekrein-kinin cascade. This suggestion was supported by Iwama et al. ¹⁷, who demonstrated that the pretreatment with kallekrein inhibitor inhibited the propofol injection pain.

The main finding of this study is that intravenous pretreatment with lidocaine; IV paracetamol and mixture of lidocaine with fentanyl reduced the pain caused by intravenous propofol injection.

Lidocaine and mixture of lidocaine with fentanyl were effective in reducing the incidence of propofol injection pain, although the difference did not reach statistical significance.

Paracetamol was also effective in reducing the incidence of propofol injection pain, but significantly less than lidocaine and mixture of lidocaine with fentanyl.

The incidence of pain on injection of propofol has been reported to be 70% ^15,19. In this study 64% of the subjects in the placebo group complained of pain at the site of injection. This correlated with the results of other studies ^20,21.

Lidocaine, a local anesthetic, reversibly blocks peripheral nerve pathways through the action on excitable membranes in the arm ⁸. It was found a diminished incidence of pain with lidocaine 40 mg IV pretreatment injected as a Bier's block. In this study 32% of the patients in the lidocaine group complained of pain following the injection of propofol. This finding is consistent with the results of Schaub et al. ¹⁵.

The primary clinical effect of fentanyl as an opioid is related to its interaction with opiate receptors centrally and with larger dose could have a local anesthetic effect ^22,23.

To use this local effect of fentanyl it was mixed with lidocaine in Lidocaine-Fentanyl group. It was found in this study that the effectiveness of lidocaine mixed with fentanyl in reducing propofol injection pain is similar to that of lidocaine.

Perfalgan^® solution (10 mg.mL^-1) contains the active ingredient paracetamol for the short-term treatment of moderate pain and for the short-term treatment of fever ²⁴. In this study it was aimed to use the analgesic effect of paracetamol intravenously given before propofol injection after 60 seconds of venous occlusion. In the group pretreated with IV paracetamol 23 patients (46%) complained of pain associated with propofol injection.

In conclusion, there was a significant superiority of IV paracetamol compared to placebo whereas lidocaine and lidocaine mixed with fentanyl significantly reduced propofol injection pain compared to IV paracetamol and to placebo.

The addition of fentanyl to lidocaine does not seem to be a good method to increase the effectiveness of lidocaine in reducing the propofol injection pain.

Lidocaine 40 mg retained in tourniquet-occluded vein for 60 seconds effectively reduces the incidence of pain caused by propofol injection.

REFERENCES

Submitted em 24 de março de 2006

Accepted para publicação em 18 de setembro de 2006

• 01. Fletcher GC, Gillespie JA, Davidson JA - The effect of temperature upon pain during injection of propofol. Anaesthesia, 1996; 51:498-499.
• 02. McCulloch MJ, Lees NW - Assessment and modification of pain on induction with propofol (Diprivan). Anaesthesia, 1985;40:1117-1120.
• 03. McCrirrick A, Hunter S - Pain of injection of propofol: the effect of injectate temperature. Anaesthesia, 1990;45:443-444.
• 04. Barker P, Langton JA, Murphy P et al - Effects of prior administration of cold saline on pain during propofol injection. A comparison with cold propofol and propofol with lignocaine. Anaesthesia, 1991;46:1069-1070.
• 05. Yokota S, Komatsu T, Komura Y et al - Pretreatment with topical 60% lidocaine tape reduces pain on injection of propofol. Anesth Analg, 1997;85:672- 674.
• 06. Overbaugh R, Jone P, Nguyen A et al - Effect of mixed versus unmixed lidocaine with propofol. Internet J Anesthesiol, 2003; 7(2). www.ispub.com
• 07. Lyons B, Lohan D, Flynn C et al - Modification of pain on injection of propofol. A comparison of pethidine and lignocaine. Anaesthesia, 1996;51:394-395.
• 08. Pang WW, Mok MS, Huang S et al - The analgesic effect of fentanyl, morphine, meperidine, and lidocaine in the peripheral veins: a comparative study. Anesth Analg, 1998;86:382- 386.
• 09. Mecklem DW - Propofol injection pain: comparing the addition of lignocaine or metoclopramide. Anaesth Intensive Care, 1994; 22:568-570.
• 10. Wilkinson D, Anderson M, Gauntlett IS - Pain on injection of propofol: modification by nitroglycerin. Anesth Analg, 1993; 77:1139-1142.
• 11. Nicol ME, Moriarty J, Edwards J et al - Modification of pain on injection of propofol - a comparison between lignocaine and procaine. Anaesthesia, 1991;46:67-69.
• 12. Eriksson M - Prilocaine reduces injection pain caused by propofol. Acta Anaesthesiol Scand, 1995;39:210-213.
• 13. Smith AJ, Power I - The effect of pretreatment with ketorolac on pain during intravenous injection of propofol. Anaesthesia, 1996;51:883-885.
• 14. Huang YW, Buerkle H, Lee TH et al - Effect of pretreatment with ketorolac on propofol injection pain. Acta Anaesthesiol Scand, 2002;46:1021-1024.
• 15. Schaub E, Kern C, Landau R - Pain on injection: a double-blind comparison of propofol with lidocaine pretreatment versus propofol formulated with long- and medium-chain triglycerides. Anesth Analg, 2004;99:1699-1702.
• 16. Mangar D, Holak E - Tourniquet at 50 mmHg followed by intravenous lidocaine diminishes hand pain associated with propofol injection. Anesth Analg, 1992;74:250-252.
• 17. Scott RP, Saunders DA, Norman J - Propofol: clinical strategies for preventing the pain of injection. Anaesthesia, 1988;43:492-494.
• 18. Iwama H, Nakane M, Ohmori S et al - Nafamostat mesilate, a kallikrein inhibitor, prevents pain on injection with propofol. Br J Anaesth, 1998;81:963-964.
• 19. Picard P, Tramer MR - Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg, 2000; 90:963-969.
• 20. Nyman Y, von Hofsten K, Georgiadi A et al - Propofol injection pain in children: a prospective randomized double-blind trial of a new propofol formulation versus propofol with added lidocaine. Br J Anaesth, 2005;95:222-225.
• 21. Larsen B, Beerhalter U, Biedler A et al Less pain on injection by a new formulation of propofol? A comparison with propofol LCT. Anaesthesist, 2001;50:842-845.
• 22. Power I, Hons BSC, Brown DT et al - The effect of fentanyl, meperidine and diamorphine on nerve conduction in vitro. Reg Anesth, 1991;16:204-208.
• 23. Gissen AJ, Gugino LD, Datta S et al - Effects of fentanyl and sufentanil on peripheral mammalian nerves. Anesth Analg, 1987;66:1272-1276.
• 24. Editorial: IV paracetamol product launched. PJ online - Pharmaceut J, 2004;272:498. www.pharmj.com/Editorial/20040424/news/p498ivparacetamol.html

*

Received from King Abdullah University Hospital, Irbid, Jordan

Publication Dates

• Publication in this collection
  19 Jan 2007
• Date of issue
  Feb 2007

History

• Received
  24 Mar 2006
• Accepted
  18 Sept 2006