Propofol is the most widely used intravenous anaesthetic agent for induction and maintenance of anaesthesia as well as for sedation inside and outside operation theatre because of its rapid onset and short duration of action. Pain at propofol injection site remain a frequent problem. It varies between 28-90% of adult patients [1]. Although pain is not considered as serious complication but it can be distressing to some patients. Various methods and agents has been used to alleviate this pain. One of the agents is ketamine, which is an NMDA receptor antagonist agent. It is an anaesthetic agent that has analgesic and local anaesthetic properties. It is a phencyclidine derivative that produces dissociative anaesthesia in clinical doses of 1-2 mg/kg intravenously. In the sub-anaesthetic doses, it reduces the propofol injection pain by virtue of its local anaesthetic property [2]. Internationally, ketamine has been used with different doses like 0.2mg/kg, 0.4mg/kg and 0.5mg/kg in comparison with different agents to reduce propofol injection pain [2,3,4]. In this prospective, randomised study, our aim was to evaluate the effectiveness of 0.05mg/kg and 0.1mg/kg ketamine in alleviating the pain of propofol injection. No similar study has been done locally in the Omani population.

Ethical approval for this study was obtained vide order MOH/DGPS/CSR/PROPOSAL-APPROVED/92/2021. This study was conducted in the main operating theatre of Khoula hospital which is a tertiary care institution receiving patients from all around Oman. A total of 48 consenting patients going for different elective surgeries under general anaesthesia in Khoula hospital from May 2019 to May 2021 were included. All patients belonged to ASA I or II of either gender aged between 18-65 years. Patient receiving any analgesic medication were excluded from the study. Patients were randomized into 3 groups using computer-generated random number tables. Group A patients received 2ml ketamine (0.05 mg/kg), group B patients received 2ml ketamine (0.1mg/kg), while group C patients were administered 2ml 0.9% normal saline intravenously as placebo control. None of the patients included in the study received any premedication before induction of anesthesias. Injection propofol (2.5 mg/kg) was kept loaded in a syringe. Just prior to administering propofol, the venous drainage of the selected upper limb was occluded manually by rubber tourniquet at mid-arm. Study drug (ketamine in two doses) was now administered as per group allocation. After 1 min of injection of the pre-treatment ketamine, 25% of the calculated dose of propofol was administered over 5 s. The level of pain was assessed at 0, 1 and 2 min after administration of 25% of the calculated dose of the propofol by the second observer who was unaware of the group to which the patient had been allocated. Assessment tool used in this study was VAS where 0 = no pain, 10= maximum pain. After assessing the pain of propofol injection, the general anaesthetic technique was continued as per standard technique of induction of general anaesthesia including the administration of remaining 75% propofol, narcotic agent and muscle relaxants. Our primary objective was to study two different low doses of ketamine to find the better effective dose that can be used to alleviate propofol injection pain. Secondary objective was to study if the patient demonstrated any fluctuations in HR and BP to the injection of ketamine in the two doses and postoperative hallucinations, if any.

Sample Size and Statistical Analysis

The sample size was calculated in consultation with the bio-statistician. The estimated sample size was 48 (16 in each group). The estimation was based on the anticipated effect size 0.25, alpha error 0.05 and power 90%. The number of groups were 3, number of measurements were 3 (0, 1 and 2 minutes).

Comparison of means between the three groups were assessed using the repeated measures ANOVA. Pre-post comparison of means was assessed using the paired t-test. Association between two categorical variables was assessed using an appropriate Chi-square test (Likelihood ratio test or Fisher’s exact test). A P-value less than 0.05 has been considered statistically significant. All the analysis has been carried out in the IBM SPSS statistics version 26.0. The software used for the calculation was G*Power 3.1.9.2.

As can be seen from Table 1, the mean age and weight of the patients was uniformly distributed in the 3 groups with no statistical differences between them.

ASA grading of the patients did not show any significant difference in the 3 groups (p value 0.45) (Table 2).

Table 1: Showing Demographic Data of the Patients in the 3 Groups

Table 2: Showing the Distribution of the Patients in the 3 Groups in Relation to ASA Grading 

Table 3: Showing Systolic Blood Pressure Changes at 1 and 2 minutes following Administration of Ketamine and Propofol (25% of Induction Dose) as Compared to Baseline Values

*p-value = VAS 1 and 2 compared to VAS at 0 minute, p-value = comparison between the groups

Table 4: Showing Diastolic Blood Pressure Changes at 1 and 2 Minutes Following Administration of Ketamine and Propofol (25% of Induction dose) as Compared to Baseline Values 

*p-value = VAS 1 and 2 compared to VAS at 0 minute, p-value = comparison between the groups

Table 5:  Showing Heart Rate Fluctuations in the 3 Groups During the Study Period Following Administration of 25% of Induction dose of Propofol

*p-value = VAS 1 and 2 compared to VAS at 0 minute, p-value = comparison between the groups

Table 6: Showing VAS Score for Changes in Pain Perception in the 3 Groups

*p–value = VAS 1 and 2 compared to VAS at 0 minute, p-value = comparison between the groups

A significant fall in systolic blood pressure was noted at 2 minutes after administering 25% of the propofol induction dose in groups A and B (p<0.001) but the fall was insignificant in group C (p = 0.446). In contrast, no significant changes were noted at one minute when compared to baseline in all the 3 groups (Table 3).

The diastolic blood pressure showed a fall from the basal values at 1 and 2 minutes in group A and B. However, there was a slight rise in the diastolic blood pressure at 1 minute following administration of propofol in group C, though by 2 minutes it had fallen below the baseline (Table 4).

As can be seen from Table 5 there were an insignificant fall in the heart rate at 1 and 2 minutes following the administration of 25% propofol in group A&B. In contrast, we noted an insignificant rise in heart rate at 1 and 2 minutes in group C.

The VAS score for pain perception was minimal in group B patients at 1 and 2 minutes. In contrast, the mean VAS for pain relief was 3.88 and 5.06 at 1 and 2 minutes respectively in group C. The VAS score of patients belonging to group A was closer to that seen in group B patients. This difference in VAS score was statistically highly significant between the groups at 1 and 2 minutes (p<0.001) (Table 6).

Several studies have been reported in literature where ketamine has been used to attenuate pain of propofol injection. But in most of these studies comparison has been made between ketamine and different agents like meperidine, thiopental, paracetamol, lidocaine and dexmedetomidine [3,4,5].

We noted 3 studies by Aly et al. [1], Tan et al. [6] and Kad et al. [7], who studied the attenuating effect of ketamine in doses of 0.2 mg/kg, 10 mg (fixed dose) and 0.2 mg/kg respectively. In Aly et al.’s [1] trial, ketamine in the dose of 0.2 mg/kg was used to study its effect on attenuation of propofol induced pain on injection as compared to normal saline. In their study, ketamine was found to reduce the incidence of propofol injection pain from 93.2% in saline group to 55% in ketamine group. Their incidence of severe pain was completely abolished with the use of ketamine in 0.2 mg/kg dose though mild to moderate pain was still encountered in few patients [1]. About 84% of the saline control patients in Tan et al. [6], study experienced pain compared to 26% of those who were given 10 mg fixed dose of ketamine pre-treatment (p<0.05). In 2008, a study by Kad et al. [7] used ketamine pre-treatment with 0.2 mg/kg in comparison to 0.9% saline and it showed that pain was reduced significantly in the ketamine group (p<0.001).

However, in the present study the incidence of propofol induced pain as assessed by VAS score at 1 and 2 minutes in group A (0.05 mg/kg of ketamine) was a mean of 1.25 and 1.69 respectively while it was 0.56 and 1.06 in group B patients who received 0.1 mg/kg of ketamine. These differences in group A and B patients were highly significant as compared to placebo group (p<0.001). Pain relief was maximum with 0.1 mg/kg of ketamine.

All our patients remained conscious after receiving 25% of the calculated dose of propofol for answering their VAS score. 

It is therefore evident from all the above studies [1,6] including ours, that ketamine in doses ranging from 0.05 to 0.2 mg/kg is effective in attenuating the pain of propofol induced injection pain. Our study showed that 0.1 mg/kg of ketamine is superior to 0.05 mg/kg when administered 1 minute prior to propofol injection.

Aly et al. [1], studied only middle aged patients in their study whereas Kad et al. [7] studied patients with age ranges between 18-50 years. In contrast, the patients age ranged between 18-65 years in our study. In addition, Kad et al. [7] included males and females in their study like ours whereas Aly et al. [1] studied only female patients. M: F ratio was almost equal between the 3 groups in the present study. Neither of these three studies attempted to compare the pain relief difference between different age groups nor gender of the patients.

In Aly et al. [1] and Kad et al.’s [7] 2008 studies, no attempt was made to observe the effect of ketamine on haemodynamics (heart rate, systolic and diastolic blood pressure) during the study period. However, in the present study, patients who received ketamine showed greater degree of fall in systolic and diastolic blood pressure after injection of 25% of calculated dose of propofol as compared to the patients who received saline placebo. This may be attributed to the effect of pain felt by placebo group patients which restricted fall in blood pressure. Likewise, patients receiving placebo prior to injection of propofol showed significant rise in heart rate as compared to patients receiving ketamine where heart rate remained fairly stable.

We did not observe any side effects of ketamine such as hallucination at emergence from anaesthesia. This is in agreement to the findings of Kad et al. [7] who reported no side effects such as hallucination or delayed recovery. 

In this study, several limitations maybe noted such as a smaller sample size, being single centric, using only two small doses of ketamine and non-inclusion of paediatric age group patients.

In conclusion, the results of this study demonstrate that 0.01 mg/kg of ketamine administered one minute prior to propofol injection is superior to 0.05 mg/kg of ketamine without any side effects.

1. Aly, N.M. et al. "Low dose ketamine in prevention of propofol injection pain." The Egyptian Journal of Hospital Medicine, vol. 72, 2018, pp. 4189–4193.

2. Mehra, N. et al. "Ketamine pre-treatment to alleviate the pain of propofol injection-a prospective, double-blind, randomized, placebo, controlled study." International Journal of Scientific Study, vol. 5, 2017, pp. 257–263.

3. Saadawy, I. et al. "Painless injection of propofol: pretreatment with ketamine vs thiopental, meperidine and lidocaine." Middle East Journal of Anaesthesiology, vol. 19, 2007, pp. 631–644.

4. Elsayed, A.A. and Rayan, A.A. "A comparative study between a small dose of ketamine, lidocaine 1% and acetominophen infusion to decrease propofol injection pain." Ains Shams Journal of Anesthesiology, vol. 8, 2015, pp. 437–442.

5. Thukral, S. et al. "Dexmedetomidine versus ketamine infusion to alleviate propofol injection pain: a prospective randomized and double-blind study." Indian Journal of Anaesthesia, vol. 8, 2015, pp. 488–492.

6. Tan, C.H. et al. "The effect of ketamine pretreatment on propofol injection pain in 100 women." Anaesthesia, vol. 53, 1998, pp. 302–305.

7. Kad, N. et al. "Ketamine pretreatment to alleviate the pain of propofol injection: A randomized, double blind study." The Internet Journal of Anesthesiology, vol. 20, no. 2, 2008.