|Year : 2015 | Volume
| Issue : 3 | Page : 437-442
A comparative study between a small dose of ketamine, lidocaine 1%, and acetominophen infusion to decrease propofol injection pain
Ayman A Elsayed MD 1, Ayman A Rayan2
1 Department of Anesthesia, Faculty of Medicine, Ain shams University, Cairo, Egypt
2 Department of Anesthesia, Menoufia University, Menoufia, Egypt
|Date of Submission||14-Jul-2014|
|Date of Acceptance||10-Oct-2014|
|Date of Web Publication||29-Jul-2015|
Ayman A Elsayed
Anesthesia Department, Faculty of Medicine, Ain Shams University, Abbassia, Cairo 11381
Source of Support: None, Conflict of Interest: None
Background and objectives
Pain during the injection of propofol is one of its drawbacks. The aim of this prospective, randomized and double-blinded study was to compare ketamine (K), lidocaine (L) 1%, and paracetamol (P) infusion as pretreatment before propofol injection regarding pain during injection.
Patients and methods
A total of 200 patients aged between 20 and 60 years, ASA I or II physical status, were randomly assigned into four equal groups. All patients received pretreatment solutions made up in 20-ml syringes with isotonic saline 0.9%. All the patients were pretreated over a period of 20 s. In group K, patients received ketamine 0.5 mg/kg. In group L, patients received lidocaine 0.5 mg/kg. In group P, patients received paracetamol (perfagan 10 mg/ml) 2 mg/kg. In group C (which served as a control group), patients received isotonic saline. We placed a rubber tourniquet on the forearm for 50 s to occlude the venous blood before giving the study drug. A blinded researcher assessed the patient's pain on propofol injection using a four-point scale, hemodynamics, the incidence of complications, and the dose of propofol used to induce anesthesia.
There was a significant increase in the pain in group L compared with group K and group P. Also, there was a significant increase in the pain in group C compared with all other groups. After propofol injection, there was a significant decrease in the mean arterial pressure in P, L, and C groups in comparison with the baseline values. There was a significant decrease in the propofol dose for the induction of anesthesia in the ketamine group in comparison with the other groups.
Pretreatment with paracetamol 2 mg/kg, ketamine 0.5 mg/kg, and lidocaine 0.5 mg/kg were significantly effective in attenuating the pain of propofol. However, pretreatment with lidocaine 0.5 mg/kg was the least effective and pretreatment with paracetamol 2 mg/kg was the most effective in attenuating propofol pain. The incidence of complications was not significant in all groups.
Keywords: ketamine, lidocaine, paracetamol, propofol
|How to cite this article:|
Elsayed AA, Rayan AA. A comparative study between a small dose of ketamine, lidocaine 1%, and acetominophen infusion to decrease propofol injection pain. Ain-Shams J Anaesthesiol 2015;8:437-42
|How to cite this URL:|
Elsayed AA, Rayan AA. A comparative study between a small dose of ketamine, lidocaine 1%, and acetominophen infusion to decrease propofol injection pain. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2021 Oct 26];8:437-42. Available from: http://www.asja.eg.net/text.asp?2015/8/3/437/161731
| Introduction|| |
Propofol has been widely used to induce general anesthesia. Pain during injection is one of its drawbacks. Chemically, propofol (2,6-diisopropyl phenol) belongs to the group of phenols, and so propofol can irritate the skin, the mucous membrane, and the venous intima  .
The most common method used to decrease propofol injection pain is the usage of lidocaine  . Some ideas are suggested, such as a decrease in the pH of the lidocaine-propofol mixture, which decreases the concentration of propofol in aqueous phase with less pain  . Another mechanism is the lidocaine effect as a local anesthetic itself  . It is proved that the formulation of the drug plays an important role in the incidence and the severity of propofol pain  . Larsen et al.  stated that a recent formulation of propofol (a 10% emulsion of fat formulated with medium-chain and long-chain triglycerides) might be associated with lesser pain upon injection. Microemulsion of propofol produces more severe and frequent pain during injection than lipid emulsion propofol  .
Ketamine has been recognized to reduce propofol pain. The exact mechanism of the analgesic effect of ketamine is not clear. However, it was suggested that it may be through N-methyl-d-aspartate receptors  . It is also possible that ketamine acts peripherally  . It is considered that ketamine when mixed with propofol can decrease the pH of the mixed solution and reduce propofol injection pain  . However, ketamine has undesired adverse effects, including sympathetic stimulation and increased secretions  .
Another drug used to decrease propofol injection pain is paracetamol (N-acetyl-p-aminophenol). It has analgesic and antipyretic properties, but without anti-inflammatory effects. The exact mechanism is unclear. However, it is multifactorial and more central than peripheral effects. It is a potent inhibitor of prostaglandin synthesis within the CNS centrally. It also acts by inhibiting the generation of impulses within bradykinin-sensitive chemoreceptors for pain  . Paracetamol inhibits both cyclooxygenase subtypes, cox 1 and cox 2, with potent antipyretic and analgesic effects, but weak anti-inflammatory activity  . Cox 3 is another paracetamol-sensitive variant of cox 1, which exists within the CNS and the vascular endothelium  .
The aim of this study was to compare ketamine, lidocaine 1%, with acetaminophen infusion to assess the grade of propofol pain experienced during the administration of the pretreatment solution and after the release of the tourniquet during propofol injection for the induction of general anesthesia.
| Patients and methods|| |
The study was approved by the institutional ethics committee in Bagedo and Erfan General Hospital in Jeddah, KSA, and a written informed consent was obtained from each patient. This study was a prospective, randomized, and double-blinded comparison of ketamine, lidocaine 1% and paracetamol infusion as the pretreatment before propofol injection. The study included a total of 200 adult patients who were admitted for elective laparoscopic cholecystectomy surgery (age range 20-60 years, ASA grade I or II). Exclusion criteria were patients with acute or chronic pain syndromes, patients receiving sedative medications, uncooperative patients, patients with communication problems, and any history of allergy to one of the medications used.
Anesthetic techniques and the study protocol
On arrival of the patient in the operating room, a 20-G cannula was inserted into a vein on the dorsum of the patient's non-dominant hand without local anesthesia. Routine monitoring (ECG, NIBP, and pulse oximeter) was applied. An isotonic saline infusion was started at a rate of 5-6 ml/kg/h before the induction of anesthesia. Baseline parameters were recorded. Oxygen saturation (SpO 2 ) was recorded every minute, whereas noninvasive BP was recorded at baseline and every 2 min after propofol injection. Desaturation was defined as SpO 2 below 92%.
We informed the patients that we would give them intravenous anesthetics that might cause pain in the forearm. After this information, we stopped the intravenous solution, and the arm with the intravenous line was raised for 20 s for gravity drainage of the venous blood. Then, we placed a rubber tourniquet on the forearm for 50 s to occlude the venous blood. Thereafter, the 200 patients were randomly divided equally into four groups using computer-generated random tables and closed envelops. Nurses who did not participate in the study prepared the drugs according to the table of randomization.
All the patients were pretreated over a period of 20 s by an anesthetist who was blinded to the patients' group allocation.
received ketamine 0.5 mg/kg (Tekam50; Hikma Pharmaceuticals).
received lidocaine 0.5 mg/kg (Lidocaine hydrochloride 2%; Jeddah, Saudi Arabia).
received paracetamol 2 mg/kg (10 mg/ml; Bristol Myers Squibb).
received isotonic saline and served as the control group.
All patients received pretreatment medication diluted in 20-ml syringes with isotonic saline 0.9%. All syringes were labeled by a blue tape. After 50 s, the occlusion was released and 40 mg propofol (1%; Fresenius Kabi, Germany) was given within 10 s. During the next 10-s pause after the injection, another anesthetist who was unaware of the study groups asked the patients to inform the grade of pain experienced during the administration of the pretreatment medication and after the release of the tourniquet using a four-point scale  :
0 = No pain.
1 = Mild pain (pain reported only in response to question).
2 = Moderate pain (pain reported in response to question and accompanied by behavioral signs reported spontaneously).
3 = Severe pain (strong vocal response or facial grimace, tears, arm withdrawal).
After complete assessment, general anesthesia was completed by variable doses of propofol till loss of eyelash reflex. The dose of propofol used per kilogram was assessed till loss of eyelash reflex. After that, fentanyl 2 mg/kg was given intravenously. The tracheal intubation was facilitated with 0.5 mg/kg atracurium, and anesthesia was maintained with sevoflurane 2% and nitrous oxide 50% in oxygen with controlled mechanical ventilation.
The primary outcome of the study was propofol-induced pain experienced during the administration of ketamine, lidocaine 1%, and acetaminophen infusion during the administration of the pretreatment solution and after the release of the tourniquet during propofol injection for the induction of general anesthesia.
The secondary outcome was to detect the incidence of complications such as emergence reactions and secretions, which were recorded by asking the patient after recovery from anesthesia.
Sample size calculation was performed by the GPower version 3.1.5 computer software  . It revealed that at least 50 patients were needed in each group for the detection of at least a 10% change in the rate of propofol-induced pain, assuming its incidence is 80% (effect size = 0.25) with a power of 0.9 and a significance level (α error) of 0.05.
Data were analyzed using SPSS version 16.0 computer software (SPSS Inc., Chicago, Illinois, USA). Numerical variables were presented as mean and SD, whereas categorical variables were presented as the frequency (%). One-way analysis of variance was used for between-group comparisons of numerical variables. Within-group comparisons for such variables were performed using repeated-measures analysis of variance. The χ2 -test was used for comparisons of categorical variables. Tukey's HSD test was used as post-hoc test for pair-wise comparisons. A P-value of less than 0.05 was considered statistically significant.
| Results|| |
Two hundred patients completed the study. Regarding their demographic data, there were no significant differences between all groups as shown in [Table 1].
Regarding the incidence of pain after injection of the pretreatment drugs, there were no significant differences between all groups. Pretreatment with lidocaine, ketamine, and isotonic saline solutions produced pain (two patients in each group), whereas no pain was experienced in the paracetamol group. Data analysis showed that all the studied drugs were significantly effective in attenuating propofol injection pain. There was a significant increase in pain in group L compared with group K and group P. Also, there was a significant increase in pain in group C compared with all other groups. However, there was no significant difference between group K and group P regarding the incidence of pain [Table 2].
|Table 2: The incidence and the severity of pain after propofol injection in the different groups|
Click here to view
Regarding hemodynamics, there was no significant difference between baseline measurements in the mean arterial pressure in all groups. After propofol injection, there was a significant decrease in the mean arterial pressure in the paracetamol, the lidocaine, and the control groups in comparison with the baseline values. However, there was no significant difference experienced between the ketamine group and the baseline values as shown in [Figure 1].
Regarding desaturation, there was no significant difference between all groups.
|Figure 1: Comparison between the different groups regarding the mean arterial pressure (MAP).|
Click here to view
No emergence agitation was experienced in any group, except the ketamine group (4%; 2/50), which was not significant in comparison with the other groups. Four patients in the ketamine group experienced increased secretions, but this was again not statistically significant between all the studied groups. Regarding the dose of propofol that was used for the induction of general anesthesia, there was a significant decrease in the ketamine group in comparison with the other groups as shown in [Table 3].
|Table 3: The incidence of complications and the dose of propofol used for the induction of general anesthesia in the studied groups|
Click here to view
| Discussion|| |
In this study, the primary aim was to compare ketamine, lidocaine 1%, with acetaminophen infusion to decrease propofol pain. We observed that pretreatment with paracetamol 2 mg/kg, ketamine 0.5 mg/kg, and lidocaine 0.5 mg/kg were significantly effective in attenuating the pain of propofol. However, pretreatment with lidocaine 0.5 mg/kg was the least effective, and pretreatment with paracetamol 2 mg/kg was the most effective in attenuating propofol pain.
The mechanism of the pain caused by propofol injection remains unclear. Scott et al.  suggested two mechanisms for this pain: the first is direct irritation and the second is an indirect effect through the kinin cascade. Bradykinin produces local vasodilatation, and it increases the permeability, which may increase the contact with free nerve endings. Iwama et al.  supported this idea through pretreatment with a kallikrein inhibitor before propofol injection, and the pain was abolished.
There are several factors that affect the propofol injection pain including the site, the size of the vein, the speed of injection and its concentration in aqueous phase, and the temperature of the propofol syringe material  . The incidence of propofol pain on injection has been reported to be up to 90% if a vein on the dorsum of the hand is used  .
Multiple pharmacological and physical approaches have been used to decrease propofol injection pain. These approaches include premixture or pretreatment of propofol with lidocaine, ketamine  . However, none of these approaches is effective in abolishing the pain completely.
The use of a tourniquet was considered as an important tool in the isolation of the arm veins from the rest of the circulatory system to study the peripheral action of the drug in the absence of its central action. We applied a rubber tourniquet for only 50 s. This time was based on a meta-analysis that concluded that the proper method for the prevention of propofol pain was to apply the tourniquet for a period of 30-120 s with intravenous lidocaine 0.5 mg/kg  . Also, this short interval of 50 s between ketamine pretreatment and propofol injection may indicate the peripheral local anesthetic action, which modulates the afferent pathway of the pain pathway rather than a central analgesic effect  .
Lidocaine is an amide local anesthetic, which acts reversibly through excitable membranes in the arm  . Pang et al.  , in their study, administrated 60 mg intravenous lidocaine, and the pain incidence was 11%, which was different from the current study (40%). This difference may be attributed to the fact that the dosage used in their study (60 mg) was higher than that used in this study (0.5 mg/kg), with an average dose around 35 mg (in our study). In contrast, there are several studies supporting our study, such as Turan et al.  , who administered 0.5 mg/kg intravenous lidocaine, and the incidence of pain was 33.3%, and also the study conducted by Agarwal et al.  . Picard and Tramèr  concluded that the most effective method for the prevention of propofol injection pain was to give lidocaine 0.5 mg/kg while applying the tourniquet to the forearm for a period 30-120 s before the injection. However, unfortunately, using this technique alone had a high failure rate of about 40%.
A study conducted by Canbay et al.  showed that lidocaine 50 mg is more effective than paracetamol 50 mg. However, paracetamol 50 mg was effective in reducing propofol injection pain compared with the control group. The overall incidence of propofol injection pain after paracetamol injection in that study was 22% compared with 8% in the lidocaine group and 64% in the control group. In the current study, the incidence of pain in groups pretreated with paracetamol 2 mg/kg was 12%, compared with 16% in the ketamine group, 40% in the lidocaine group, and 84% in the control group.
The usage of ketamine in small doses for attenuating propofol-associated injection pain has been reported in adults  . It was reported that the incidence of pain after propofol injection was about 26-46% after pretreatment with ketamine without the use of tourniquet when using ketamine at a dose 0.1-0.2 mg/kg  . This was different from the current study, which proved that propofol injection pain after pretreatment with ketamine was 16%. This difference may be attributed to the lower dose of ketamine used in the previous study and the cancellation of the venous occlusion (no tourniquet was used). In accordance to our study, Zhao et al.  reported that the frequency of propofol injection pain was 14.9% after pretreatment with ketamine at a dose of 0.5 mg/kg despite the fact that propofol was injected after only 15 s of ketamine injection, unlike in our study (50 s). Hence, further studies are needed to evaluate the exact time between the injection of the pretreatment study drug and propofol  . Other previous reports using only a 30-s interval with smaller doses of ketamine (0.1-0.5 mg/kg) did not eliminate the pain completely. However, the usage of a larger dose of ketamine 1 mg/kg could eliminate the pain completely  . A study conducted by Wang et al.  found that ketamine at ~0.3 mg/kg was effective in the elimination of popofol pain. Koo et al.  proved that 100 mg/kg ketamine given just before propofol injection decreased the possibility and the intensity of pain more than smaller doses (10 and 50 mg/kg)
Polat et al.  proved that lidocaine 40 mg, metoclopromide, ketamine (100 μg kg -1 ) and ramifentanil are equally effective in treatment and attenuating of propofol pain. This result was different from our result that proved that ketamine was more effective in the treatment of propofol pain than lidocaine. However, this difference may be attributed to the low dose of ketamine used in that study (100 mg/kg in comparison with 0.5 mg/kg in our study)  .
It is likely that a 0.5 mg/kg ketamine dose may have some central effects. Ketamine is one of the important factors that may cause emergence agitation. It is accompanied with adverse psychological effects and other adverse effects at significantly higher doses  .
Indeed, two patients in group K experienced emergence agitation.
Regarding hypotension, there were no significant differences between L, P, and C groups, with a significant difference between these groups and the K group. This may be attributed to the activation of the sympathetic nervous system by ketamine. As a consequence, BP is increased  , which may attenuate the hypotensive effect of the propofol injection in our study. The frequencies of desaturation in group L, group P, group K, and group C were 16, 12, 8, and 12%, respectively. There was no significant difference between all groups, with the least occurrence in group K. The doses of propofol used for induction were lower in group K compared with group L, group P, and group C. These differences between group K and the other groups were significant. This is may be attributed to the sedative analgesic effect of ketamine  .
A potential criticism of our methodology is the presence of a placebo group as the primary aim of the study was to compare the three active treatment groups without the need of placebo groups. Also, it is obvious that the incidence of pain on injection in the control patients reported by Picard and Tramèèr  ranged from 54 to 100%, which is arguably too wide to judge the comparison and it was not comfortable to the patients.
| Conclusion|| |
We observed that pretreatment with paracetamol 2 mg/kg, ketamine 0.5 mg/kg, and lidocaine 0.5 mg/kg were significantly effective in attenuating the pain caused by propofol. However, pretreatment with lidocaine 0.5 mg/kg was the least effective and pretreatment with paracetamol 2 mg/kg was the most effective in attenuating propofol pain. Incidences of complications were not significant between all the study drugs. Further studies may apply variable doses of paracetamol to other age groups to assess its effect in attenuating propofol injection pain.
| Acknowledgements|| |
Conflicts of interest
| References|| |
Kay B, Rolly G. I.C.I. 35868, a new intravenous induction agent. Acta Anaesthesiol Belg 1977; 28:303-316.
Nicol ME, Moriarty J, Edwards J, Robbie DS, A'Hern RP. Modification of pain on injection of propofol- a comparison between lignocaine and procaine. Anaesthesia 1991; 46:67-69.
Eriksson M, Englesson S, Niklasson F, Hartvig P. Effect of lignocaine and pH on propofol-induced pain. Br J Anaesth 1997; 78:502-506.
Larsen B, Beerhalter U, Biedler A, Brandt A, Doege F, Brün K, et al. Less pain on injection by a new formulation of propofol? A comparison with propofol LCT. Anaesthesist 2001; 50:842-845.
Tan CH, Onsiong MK, Kua SW. The effect of ketamine pretreatment on propofol injection pain in 100 women. Anaesthesia 1998; 53:302-305.
Hui TW, Short TG, Hong W, Suen T, Gin T, Plummer J. Additive interactions between propofol and ketamine when used for anesthesia induction in female patients. Anesthesiology 1995; 82:641-648.
Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia 1988; 43:492-496.
Munsterhjelm E, Munsterhjelm NM, Niemi TT, Ylikorkala O, Neuvonen PJ, Rosenberg PH Dose-dependent inhibition of platelet function by acetaminophen in healthy volunteers. Anesthesiology 2005; 103:712-717.
Remy C, Marret E, Bonnet F. State of the art of paracetamol in acute pain therapy. Curr Opin Anaesthesiol 2006; 19:562-565.
McCrirrick A, Hunter S. Pain on injection of propofol: the effect of injectate temperature. Anaesthesia 1990; 45:443-444.
Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007; 39:175-191.
wama H, Nakane M, Ohmori S, Kaneko T, Kato M, Watanabe K, Okuaki A Nafamostat mesilate, a kallikrein inhibitor, prevents pain on injection with propofol. Br J Anaesth 1998; 81:963-964.
Tan CH, Onsiong MK, Tan CH, Onsiong MK, Tan CH, Onsiong MK, Kua SW. Pain on injection of propofol. Anaesthesia 1998; 53:468-476.
King SY, Davis FM, Wells JE, Murchison DJ, Pryor PJ. Lidocaine for the prevention of pain due to injection of propofol. Anesth Analg 1992; 74:246-249.
Kaabachi O, Chettaoui O, Ouezini R, Abdelaziz AB, Cherif R, Kokki H. A ketamine-propofol admixture does not reduce the pain on injection compared with a lidocaine-propofol admixture. Paediatr Anaesth 2007; 17:734-737.
Picard P, Tramèr MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg 2000; 90:963-969.
Koo SW, Cho SJ, Kim YK, Ham KD, Hwang JH. Small-dose ketamine reduces the pain of propofol injection. Anesth Analg 2006; 103:1444-1447.
Lai YY, Chang CL, Yeh FC. The site of action of lidocaine in intravenous regional anesthesia. Acta Anesthesiol Sin 1993; 53:468-476.
Pang WW, Mok MS, Huang S, Hwang MH. The analgesic effect of fentanyl, morphine, meperidine, and lidocaine in the peripheral veins: a comparative study. Anesth Analg 1998; 86:382-386.
Turan A, Memis D, Kaya G, Karamanlioglu B. The prevention of pain from injection of propofol by dexmedetomidine and comparison with lidocaine. Can J Anaesth 2005; 52:548-549.
Agarwal A, Raza M, Dhiraaj S, Pandey R, Gupta D, Pandey CK, et al. Pain during injection of propofol: the effect of prior administration of butorphanol. Anesth Analg 2004; 99:117-119.
Canbay O, Celebi N, Arun O, Karagöz AH, Saricaoðlu F, Ozgen S Efficacy of intravenous acetaminophen and lidocaine on propofol injection pain. Br J Anaesth 2008; 100:95-98.
Barbi E, Marchetti F, Gerarduzzi T, Neri E, Gagliardo A, Sarti A, Ventura A Pretreatment with intravenous ketamine reduces propofol injection pain. Paediatr Anaesth 2003; 13:764-768.
Zhao GY, Guo Y, Bao SM, Meng LX, Zhang LH. Prevention of propofol-induced pain in children: pretreatment with small doses of ketamine. J Clin Anesth 2012; 24:284-288.
Furuya A, Matsukawa T, Ozaki M, Nishiyama T, Kume M, Kumazawa T. Intravenous ketamine attenuates arterial pressure changes during the induction of anaesthesia with propofol. Eur J Anaesthesiol 2001; 18:88-92.
Wang M, Wang Q, Yu YY, Wang WS. An effective dose of ketamine for eliminating pain during injection of propofol: a dose response study. Ann Fr Anesth Reanim 2013; 32:e103-e106.
Polat R, Aktay M, Ozlü O. The effects of remifentanil, lidocaine, metoclopramide, or ketamine pretreatment on propofol injection pain. Middle East J Anaesthesiol 2012; 21:673-677.
Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med 2008; 26:985-1028.
Tomatir E, Atalay H, Gurses E, Erbay H, Bozkurt P. Effects of low dose ketamine before induction on propofol anesthesia for pediatric magnetic resonance imaging. Paediatr Anaesth 2004; 14:845-850.
Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981; 53:27-30.
[Table 1], [Table 2], [Table 3]