Pain on propofol injection (POPI) is a minor issue that all anesthesiologist faces every day. POPI stands seventh most important issue in daily practice of clinical anesthesia as per American anesthesiologist. [1] Although POPI may not be a serious complication, most of the patients remembers it as an unpleasant sensation without any major threats intraoperatively.

Incidence of pain following propofol injection is seen in approximately 70% of patients in the absence of other pre-treatments. During induction of anesthesia almost 28-98% in adults and 28-85% in children experiencing POPI is due to injection of drug in the smaller veins. The nature of pain in propofol injection is extremely sharp aching or burning. [2]

Various formulations and hundreds of clinical trials have failed to find its remedy with single intervention. Several methods have been tried to eliminate this complication with usage of drugs like lignocaine, ketamine, ephedrine, NSAIDS, narcotics, steroids etc. Search for better formulations in alleviating the POPI continues till today [3]

Ketamine, a potent analgesic is a phencyclidine derivative with NMDA receptor antagonism can reduce pain on propofol injection with its local anesthetic properties without causing any changes in hemodynamic properties and without increase in gastrointestinal secretions production [4]. Lignocaine is an amide local anesthetic, has been used widely for preventing pain on propofol injection in day-to-day routine practice by both local anesthetic property and central analgesic effect when the dose reaches 1.5mg/kg [5].

In our study, we have compared low dose ketamine and lignocaine pre- treatment in prevention of pain on propofol injection during general anesthesia in all elective surgeries by assessing the pain response by verbal rating scale (VRS) and also compared the hemodynamic response between them.

The primary objective of the study was to compare the effect of low dose ketamine and 2% lignocaine pre-treatment in preventing pain on propofol   injection (POPI) with verbal rating scale for pain response. The Secondary objective was to compare the hemodynamic changes by low dose ketamine and 2% lignocaine when used in preventing pain on propofol injection.

A study under the title of “Comparison of effect of low dose ketamine and lignocaine pretreatment in prevention of pain on propofol Injection during general anesthesia for elective surgeries” was undertaken at PSG Institute of Medical Sciences and Research, Coimbatore. After obtaining Institutional human ethical committee clearance, registered with clinical trial registry of india (CTRI/2021/04/032881) and the study was conducted in our institute. The sample size for the study was determined with reference to [6], using systolic blood pressure (SBP) before intubation  as reference value and we calculated the sample size using Zα-1.96 at 5% significance (95% confidence level to a significance level of α), Zβ– 0.84 for a power of  80%  as follows;

n = 23 in each group is the minimum required sample size and considering 10% adjustment for nonresponse, the adjusted sample size was n = 25.3; but we took 30 as sample size in each group, making a total of 60 sample size. This was a prospective randomized double blinded study done during January 2020 to September 2021.

Patients belonging to american society of anaesthesiologist ASA 1 and 2, age between 20 and 50 years, individuals undergoing general anesthesia using propofol as sole induction agent were included in our study. Patients who presented with allergic history to propofol, ketamine and egg, decompromised patients with cardiovascular, neurologic and respiratory diseases, and those who are undergoing emergency surgeries were excluded from our study.

Routine preanesthetic evaluation was done on the day prior to surgery. The patients were explained about the procedure and need of the study in their vernacular language.  We obtained written and informed consent from all those patients who were enrolled for the study. All patients were kept nil per oral (NPO) starvation according to standard ASA guidelines; 12 hours of fatty food, 6 to 8 hours for solids, 6 hours for milk and clear fluids recommended up to 2 hours prior to surgery. 

All patients were premedicated with tablet Pantoprazole 40 mg and Metoclopramide 10 mg on the night of surgery at 10 P.M and on morning of day of surgery at 6 A.M. We avoided sedative premedication in our study to make all patients conscious during our study. To avoid the bias of sedation and to avoid the confounding factors in the study, to see the better effects of pre-treatment pain with propofol, we chose fully awake state of the patient.

Patients were randomly assigned into two groups of 30 each using computer generated random sequence allocation as group K -ketamine and group L - lignocaine. Concealment was ensured using sequentially numbered opaque sealed envelope as group K - ketamine Group who received ketamine 100 mcg/kg intravenously (I.V) and group L - lignocaine Group who received lignocaine 0.5 mg/kg I.V

Patient’s identity and preoperative starvation status were confirmed in the preoperative room and shifted to operation theatre after confirming the patency of the 20G venflon secured in the ward. All patients were secured with fresh 20G venflon in the dorsum of the nondominant in the preoperative room.

ASA gold standard monitors pulse oximetry, non-invasive blood pressure (NIBP) and 5 lead ECG were connected and baseline readings recorded. 20G venflon is flushed with 5 ml of normal saline and normal saline infusion was started @2ml/kg/hr.

Tidal volume preoxygenation was done with 100% oxygen at 6L/Min flow for 3 minutes. Premedicated with injection glycopyrrolate 0.2mg I.V and pre-treatment with either group K drug (ketamine) 100mcg/kg I.V or group L drug (lignocaine) 0.5 mg/kg I.V was supplemented.  Saline infusion was stopped and after 15 seconds 1% propofol injected at 2mg/kg I.V which is stored at room temperature over 30 seconds. The assessment of intensity of acute pain can be done using various other scales like Visual analogue scale (VAS), Verbal rating scale (VRS) and Numerical rating scale (NRS). After administering the fixed dose of propofol, blinded anaesthesiologist will ask the patient to rate the sensation of pain using McCrirrick and Hunter verbal rating scale (0-3) as follows,

Table 1: Mc Crirrick and Hunter [7].

The patient was not given any external surgical stimulus from the time of   preoxygenation till 10 minutes following the induction of anaesthesia. After propofol induction, patient will be given injection fentanyl I.V at 2mcg/kg, followed by muscle relaxation with atracurium 0.5mg/kg and ventilated for 4 minutes. After tracheal intubation with appropriate sized cuffed endotracheal tube using conventional Macintosh laryngoscope; tube position was checked for bilateral air entry by 5-point auscultation; confirmed by quantitative waveform capnography and secured in position with adhesive tapes.

Figure 1: Numerical Rating Scale and Visual Analogue Scale.

Figure 2: Interrelationship of Numerical Rating Scale and Verbal Rating  Scale.

Anesthesia was maintained with 66% nitrous oxide : 33% oxygen; sevoflurane achieving minimum alveolar concentration (MAC) around 1.2 and heart rate, blood pressure (SBP, DBP, MAP) and oxygen saturation percentage recorded post premedication, before intubation, after 1, 3 and 5 minutes of intubation were recorded.

Patient was maintained anesthesia with volatile anesthetics and intermittent doses of muscles relaxants and towards the end of the surgery, the neuromuscular blockade was reversed with injection Neostigmine 0.05mg/kg I.V and injection glycopyrrolate 0.01mg/kg IV and patient was extubated according to extubation criteria.

All the readings were noted in proforma and patient was observed in post anaesthesia care unit for any emergence reactions and adverse events or untoward side effects along with routine hemodynamic monitoring.

Data were statistically analyzed with statistical package for social sciences (SPSS) version 26.0 software 2018. Baseline characteristics were presented as mean+SD. Two-sided unpaired t-test and chi-square test was applied to analyze the data and p-value less than 0.05 was considered as significant.

Table 2: Demographic details between Group K and Group L.

Table 3: Verbal rating scale distribution between groups.

Table 4: Hemodynamic variables between two groups.

SBP – Systolic Blood Pressure; DBP – Diastolic Blood Pressure; MAP – Mean Arterial Pressure

John J Bonica, the father of pain medicine, in 1953, stated “pain in its late phases, when it becomes intractable, it no longer serves a useful purpose and then becomes, through its mental and physical effects, a destructive  force”.[8]

Propofol (2,6 diisopropylphenol) is a popular intravenous anaesthetic agent widely used by an anesthesiologist, both inside and outside the operating room for sedation because of its rapid onset, short duration of action, anti-emetic property, obtundation of airway reflexes, and faster recovery. Propofol being phenol derivative causes pain on injection is either immediate or delayed (10 – 20seconds). There is no difference in incidence of pain on propofol injection between male and female gender predisposition. [3] The immediate pain is due to direct irritation of venous endothelium, whereas delayed pain is due to irritation of venous adventitia which leads to release of kininogen from kinin cascade.

Figure 3: Mechanism of propofol pain on injection.

Factors that affect pain on injection includes not only the intrinsic drug property such as emulsion composition, pH of the formulation, temperature, injection volume and osmolality, but it also involves the injecting techniques like speed of pushing, speed of intravenous carrier fluids and buffering effect of blood. Other interventions include cooling of Propofol, alkalinisation [9], rapid injection, injecting the drug in large   bore cannulas, intravenous lidocaine pre-treatment, lignocaine propofol mixture, intravenous lidocaine given with a tourniquet decreasing the concentration of the agent [10]. Apart from pain on injection, the current lipid formulation has other disadvantages such as bacterial contamination, anaphylaxis, hyperlipidaemia and propofol infusion syndrome.

Various doses of ketamine have been tried to eliminate this complication ranging from 0.1mg/kg to 1mg/kg. Ketamine can be either mixed with propofol or given as a pre-treatment in preventing pain on propofol injection. Low dose ketamine may be effective because of its local anaesthetic properties and high dose has central analgesic and sedative effect on POPI [11].

Lignocaine is most commonly used because of its low cost, fewer side effects; has central and local analgesic effects and decreases the pH of propofol when given as propofol Lignocaine mixture [12]. Lignocaine prevents POPI by its use either as pre-treatment or mixing with propofol. Different doses of lignocaine have been tried to reduce the intensity of pain while injecting propofol in dorsum of hand [11].

The demographic data showed there was no statistical significant difference among groups with respect to age, weight, body mass index, and sex or ASA status. In our study, Group K with 86.7 % (n=26) and Group L with 90% (n=27) did not experience any pain on propofol injection by giving pre-treatment with ketamine and lignocaine respectively. In our study, 13.3 % (n=4) of study participants in Group K experienced mild pain and 6.7% (n=2) of study participants in Group L experienced mild pain. On the other hand, 3.3 % (n=1) of Group L study population experienced severe pain in contrast to Group K with no experience of severe pain. In both the groups, there was no participant experiencing moderate pain by verbal rating scale published by [7]. Though there was a mild and severe pain between the two groups reported in our study, by statistical analysis the value was 0.431 and proved insignificant statistically.

Tan LH et al, compared the effects of lidocaine propofol mixture and lidocaine pre-treatment in adults on propofol injection pain and showed that there is no statistical difference between these two groups in pain response and induction response. Although lignocaine is commonly used; failure rate of lignocaine in preventing propofol injection pain is around 32%-48%. In contrast in our study we did not make mixture of the two drugs.

Picard and Tramer [13] showed that the most effective method in reducing this pain on propofol injection complication is administering 0.5mg/kg of 2% lignocaine with tourniquet being applied to forearm for 30-120 seconds which we did not use in our study. Pang et al [14] used 60mg of lidocaine and studied the incidence of pain on propofol injection was around 11%.  In our study instead of using propofol lignocaine mixture we used 2% lignocaine pre-treatment at 0.5mg/kg to prevent pain on propofol injection and found to be statistically insignificant.

M.Eriksson, S. Englesson et al [15] had studied effect of lignocaine, pH on propofol induced pain and observed there is decreased incidence of pain on injection caused by 1% Diprivan when mixed with lignocaine. It is known that the pH of 1% Diprivan solution decreases when lignocaine is added and the decrease is greater when larger doses of lignocaine are added. In our study, we did not mix propofol with the study drugs.

Hwang et al [4] compared the peripheral ketamine pre-treatment and ketamine added to propofol in preventing pain on propofol injection and concluded that mixing of ketamine with propofol has advantage over pre-treatment facilitating simpler and faster injection sequence but may increase risk of adverse drug reactions. In contrast in our study, we proved pre-treatment had advantageous effect with both ketamine and lignocaine. Sharma

[16], Ayman et al [17] had done comparative study on ketamine and lidocaine to decrease propofol injection pain during induction of anaesthesia and concluded that low dose ketamine (0.2mg/kg) is more effective in reducing incidence and severity of pain on injection of propofol in comparison to lidocaine. Better hemodynamic of ketamine with no emergence improves its efficacy. But we used ketamine at 100mcg/kg dose only.

Intravenous retention of lidocaine with torniquet was found to be another important method in reducing pain and duration of venous occlusion is 30-120 seconds before propofol injection. But in our study, we did not use a torniquet because applying a torniquet is distressing in an awake patient and we feel that it was not practically possible to apply torniquets for all the patients. Seung

Woo [18] studied that injecting ketamine immediately before propofol provided the optimal timing in reducing pain sequence and hence we considered the similar methodology in our study.

Ketamine in larger doses was avoided in our study to eliminate the central effects of the drug. Emergence delirium is the most frequently encountered side effect related to ketamine when used as sole agent in sedation and induction at higher doses. In our study, none of the participants reported any event of emergence reactions. Hwang et al [4] suggested that propofol ketamine mixture is better than ketamine pre-treatment in prevention of pain on propofol injection. In our study, we never used ketamine propofol mixture, since we want to establish the local analgesic effect of ketamine rather than the pH change in propofol. None of the patient in group K reported emergence delirium.

Figure 4: Hemodynamic parameters between group K and group L.

Valid and reliable assessment of pain is essential for both clinical trials and effective pain management. Various scales are used to measure pain. To assess the intensity of acute pain well known visual analogue scale (VAS), numerical rating scale (NRS) and 4 point verbal categorical rating scale (VRS) are routinely used. Verbal categories representing as mild, moderate and severe pain may correspond to different values on VAS in same patient on different scenarios. But in our study we used verbal rating scale to assess the acute pain on propofol injection.

Mecklem [19] and Fee et al [20] has compared the lignocaine and metoclopramide on propofol injection pain and concluded that both drugs significantly reduced the incidence of pain.

Hemodynamic parameters like Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and saturation (SpO2) were studied in our study to see the variation. We observed that these parameters showed no salient clinical and statistical significance upto 5 minutes of intubation following fixed dose of propofol administration in both the groups. None of them required any specific intervention and no adverse events were noted in our study.

Boujan[21] did a study on lidocaine versus ketamine pretreatment on propofol injection pain and concluded intravenous ketamine and lidocaine were equally effective in preventing ache during propofol injection; which in contrast in our study both drugs does not completely diminish the pain response, hence further studies may apply to identify the correct doses of drugs needed to assess its effects in attenuating the pain response during propofol injection. We feel that pain on propofol injection can be completely attenuated by the combining various methods instead of using a single drug [22].

Figure 5: Consort flow diagram

Jibin Xing et al [5] has done a randomized control study on lignocaine alleviates propofol injection pain by both local anaesthetic and central analgesic effects and concluded that dosage of 40mg lidocaine is an appropriate to alleviate Propofol injection pain within the same vein and also it exerts central analgesic effect when dosage reaches 1.5mg/kg. Seung -Woo Koo [18] Stated that administration of ketamine 100µg/Kg immediately before propofol injection provided the optimal dose and timing to reduce the propofol induced pain on injection. [23]

Leena jalota et al [24] concluded that two most efficacious interventions to reduce pain on injection of propofol are use of antecubital veins or pre-treatment using lidocaine in conjugation with venous occlusion when hand vein was chosen. [6] Concluded that ketamine pre-treatment 200mcg/kg reduces the incidence and severity of pain very effectively.

The limitations in our study were

• Inadequate sample size
• Single subjective assessment tool may not be reliable
• Various pain monitoring scoring system of pain could have been implicated in the study for better results
• No placebo groups as both the drugs individually proved to reduce the incidence of pain on propofol injection
• The study showed that both Group K and Group L can be used in prevention of pain on propofol injection, but couldn’t comment the superiority of one group over another
• Both the drugs does not completely diminish the pain response, hence further studies needed to identify the correct doses of drugs to assess its effects in attenuating the pain response during propofol injection
• Multimodal approach could be better choice for attenuation of propofol pain

We conclude from our study that pretreatment with either 2% lignocaine 0.5 mg/kg or ketamine 100µg/kg were significantly effective in attenuating the pain response and decreasing the severity of pain during propofol injection and there was no hemodynamic variations and complications encountered with either of the drug group.

We would like to thank all the faculty members, operating theatre staffs in the department of anesthesiology and the statistician for helping us to complete our study in an appropriate manner. We also whole heartedly thank all the patients who involved in the study without which our study would not have been possible.

Conflict of interest: None declared

Financial support: None declared

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