|Year : 2020 | Volume
| Issue : 3 | Page : 138-143
Comparison of pain on injection of newer formulation propofol and standard propofol with added lignocaine: A randomised double-blind prospective study
Settipalli Suneela1, Radhapuram Sri Devi2, Mangu Hanumantha Rao2, Goduguchintha Dharaniprasad2
1 Department of Anaesthesiology, Medcare Women and Children Hospital, Dubai, United Arab Emirates
2 Department of Anaesthesiology, Critical Care, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
|Date of Submission||24-Jan-2019|
|Date of Decision||14-Jul-2020|
|Date of Acceptance||17-Jul-2020|
|Date of Web Publication||27-Oct-2020|
Mangu Hanumantha Rao
Senior Professor and Principal, Department of Anaesthesiology, Critical Care, Sri Venkateswara Institute of Medical Sciences 517507, Tirupati, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: The aim of the present prospective randomised double-blind clinical study was to compare the incidence of pain-free injection following the use of this new formulation (propofol with medium-chain triglycerides [MCT] and long-chain triglycerides [LCT]) with propofol dissolved in LCT with added 2% lignocaine in patients undergoing various surgical procedures under general anaesthesia.
Methods: Sixty adult patients (age range 18–50 years) were randomised to receive either 20 mL propofol dissolved in a mixture of MCT–LCT [Group L (n = 30)] or 18 mL propofol dissolved in LCT with added 2 mL 2% lignocaine [Group S (n = 30)]. A specially trained clinical research investigator assessed the occurrence of injection pain using a four-graded pain scale.
Results: There was no significant difference in propofol injection pain among patients who received either LCT propofol with added lidocaine, (Group S) (33.3%) or new formulation propofol (Group L) (30.0%) (P = 0.993).
Conclusions: The newer formulation, MCT–LCT propofol, is equally effective vis-à-vis the conventional propofol with added lignocaine to reduce the incidence of pain, thereby eliminating the need for addition of another drug, lignocaine.
Keywords: Anaesthesia, anaesthetic, injection pain, intravenous, lignocaine, propofol
|How to cite this article:|
Suneela S, Devi RS, Rao MH, Dharaniprasad G. Comparison of pain on injection of newer formulation propofol and standard propofol with added lignocaine: A randomised double-blind prospective study. J Clin Sci Res 2020;9:138-43
|How to cite this URL:|
Suneela S, Devi RS, Rao MH, Dharaniprasad G. Comparison of pain on injection of newer formulation propofol and standard propofol with added lignocaine: A randomised double-blind prospective study. J Clin Sci Res [serial online] 2020 [cited 2020 Nov 25];9:138-43. Available from: https://www.jcsr.co.in/text.asp?2020/9/3/138/298952
| Introduction|| |
Propofol (Diprivan, di-isopropyl phenol) is a popular intravenous (iv) anaesthetic induction agent used, especially for brief duration surgery cases, day-care surgery or when a laryngeal mask airway is in use. With the decrease in morbid adverse events following surgery, patient satisfaction with perioperative care is assuming more importance, and the quality of an anaesthetic is judged by any recall of discomfort or pain at the time of anaesthetic induction. Propofol is an iv sedative and hypnotic agent commonly used for anaesthesia induction. The rapidity and reliability in causing loss of consciousness and quick, smooth recovery are its salient features. However, pain on injection when given intravenously is a common problem with propofol, the incidence of which is between 28% and 90%.
Propofol belongs to the group of sterically hindered phenols that can irritate the skin and mucous membrane. The pain on injection of propofol could be due to the osmolality of the solvent used for the preparation, the pH of solution and the concentration of propofol in the aqueous phase of emulsion. Propofol, by an indirect action on the endothelium, activates the plasma kallikrein-kinin system and releases bradykinin, thereby producing venous dilation and hyperpermeability, which increases the contact between the aqueous phase of propofol and free nerve endings, resulting in pain on injection.
To attenuate this pain, several adjuvants have been used, such as addition of lignocaine,, cooling or warming of the drug, diluting propofol solution and pre-treatment with ondansetron, metoclopramide, opioids and thiopentone. Lignocaine pre-treatment is commonly used method to decrease the injection-related pain. Unfortunately, the failure rate is between 13% and 32%.
Injection pain has been attributed to the amount of free propofol in the aqueous phase of the emulsion. Reformulated lipid emulsion of propofol has been tried to alleviate injection pain. This formulation of propofol contains both medium- and long-chain triglycerides (MCT/LCT) in equal proportions in contradiction to conventional propofol which contains only LCT formulation. The amount of free propofol in an MCT/LCT emulsion is assumed to be less when compared to propofol LCT which causes less pain on injection. Lignocaine not only works as a local anaesthetic on the venous nociceptors, but it also decreases pH which decreases the percentage of free propofol in the aqueous phase of emulsion and thus reduces pain on injection when given before propofol administration.
The present study was undertaken to determine whether propofol in a reformulated MCT, LCT emulsion without further addition of lignocaine was more effective in preventing pain on injection compared with the frequently used standard LCT propofol with a pre-mixture of lignocaine.
| Material and Methods|| |
After obtaining approval from the Institutional Ethics Committee, the present randomised, double-blind study was conducted. The reported incidence of pain to propofol injection along with lignocaine pre-treatment has been reported to be 34%. Assuming the use of MCT, LCT propofol would reduce the pain by 85% and α of 0.05 and a power of 80%, the sample size for each group was calculated to be 30. The study population comprised 60 patients of American Society of Anaesthesiologists (ASA) physical status grade 1 and 2 aged between 18 and 50 years, scheduled to undergo various elective surgical procedures under general anaesthesia. Written informed consent was obtained from each patient. Patients not belonging to ASA physical status 1 and 2, not willing to participate in the study, pregnant and lactating women, patients with known hypersensitivity to propofol, patients with neurologic or cardiovascular disorder, patients with history of drug abuse and patients with any history of egg lecithin or soybean oil allergies.were excluded from the study Patients receiving sedatives or analgesics within 24 H preceding surgery were also excluded. Randomisation into one of the two groups was done by using computer-generated random number table and sealed opaque envelope technique. Randomisation was done before initiating the study into two groups comprising 30 patients in each group. Study participants were randomly allocated to one of the following two groups: [i] new formulation group (Group L, n = 30): 20 mL of MCT, LCT propofol without lignocaine (Fresofol 1% by Fresenius Kabi); and ii standard propofol (Group S, n = 30): 18 mL of LCT propofol with 2 mL (2%) lignocaine [Figure 1].
A standard pre-anaesthetic evaluation was done in all patients during the pre-operative visit 1 day before surgery, reassurance was given to patients and no premedication was given. All study drugs were prepared and labelled by a person not involved in the study. The level of pain intensity was assessed by a clinical research investigator who was unaware of the group to which the patient had been allocated. Injection pain assessment included verbal response and behavioural signs (such as facial grimacing, arm withdrawal or tears). Injection pain was graded using a four-point scale.
Two separate 20 mL syringes were used: one with 20 mL of MCT, LCT propofol without lignocaine and another with 18 mL LCT propofol with 2 mL (2%) lignocaine. Patients were informed that, during the injection, pain was possible and that they would be evaluated by the anaesthesia team at different time points. Upon arrival into the operating room, an iv cannula (18-gauge) was placed into the largest vein on the dorsal of the hand vein and flushed with 10 mL of normal saline over 5 Sec to ensure pain-free injection. No analgesic or sedative was administered before injection of propofol. Perioperative monitoring included electrocardiogram, non-invasive blood pressure and pulse oximetry. Each patient was pre-oxygenated through a facemask with fresh gas flow of 6 L/Min oxygen for 3 min, and anaesthesia was induced with propofol. The induction drugs were given according to the group allotment by an observer not involved in the study. Patients in Group L received MCT, LCT propofol without lignocaine, while patients in Group S received LCT propofol with lignocaine. Drugs were given at a speed of 0.4 mL/Sec (2 mL every 5 Sec). After the loss of verbal contact (consciousness) with the patient, the study was terminated and the anaesthesia was continued as necessary in relation to the planned surgical intervention. During anaesthesia induction, patients were not actively asked whether they felt any discomfort or pain, and evaluation of pain was done by four-point scale by a single observer blinded to the study drug administered.
Assessment of pain
Injection pain was assessed according to a four-point scale: (i) pain (no reaction to injection); (ii) mild pain (minor verbal/facial response or motor reaction to injection); (iii) moderate pain (clear verbal or facial response or motor response to injection); (iv) severe pain (the patient both complained of pain and withdrew the arm).
The assessment was made from the start of the injection to the point when the patient lost consciousness. Before the patient was discharged, injection site was inspected for signs of residual irritation.,
Continuous variables were compared using unpaired t-test, and four-point pain score was compared with Chi-square test with Yates correction. The relationship between age and weight and occurrence of pain for each group was studied using bivariate correlation of variance and linear regression analysis. A P < 0.05 was considered statistically significant. Statistical Package for Social Sciences, version 12 (SPSS Inc., Chicago, USA) was used for statistical analysis.
| Results|| |
Of the 60 adult patients included in the study; 30 were assigned to the MCT–LCT propofol (20 mL) group (Group L) and 30 patients (17 males) were assigned to the LCT propofol (18 mL) plus 2% lignocaine group (Group S) (19 males). Gender distribution in both groups was comparable (P = 0.32).
The mean age (years) of the patients in Group L was 40.5 ± 11.9 and the mean weight (Kg) was 57.6 ± 12.5 (SD). In Group S, the mean age (years) was 36.6 ± 12.2 and the mean weight (Kg) was 58.3 ± 10.5. There was no statistically significant difference in demographic data between the groups [Table 1].
Assessment of pain was done with four-point pain score. Twenty patients from Group L and 21 patients from Group S reported no pain which was denoted with pain score of '1'. Similarly, 8 patients from Group L and 7 patients from Group S reported pain with a pain score of '2'. The pain scores '3' and '4' were reported by one patient in each group during the administration of newer formulation of propofol in Group L (MCT, LCT) and standard propofol (LCT) with lignocaine in Group S. Ten of the 30 patients in Group L complained of pain (pain scores ≥2–4), while 9 of the 30 patients in Group S complained of pain with same scores. There was no statistically significant difference between the two groups (P = 0.993) [Table 2].
| Discussion|| |
Pain on injection when given intravenously is a common problem with propofol. Injection pain has been attributed to the amount of free propofol in the aqueous phase of the emulsion. Lignocaine pre-treatment is the most used method to decrease the injection-related pain. Always, there is a trend to look for new drugs or formulations to avoid the side effects or complications of the old drugs. The amount of free propofol in newer formulation MCT, LCT emulsion is assumed to be less compared with standard propofol LCT that causes less pain on injection. Furthermore, newer formulation MCT, LCT emulsion avoids further addition of drugs which frequently lead to drug errors. The present study was undertaken to determine whether propofol in a reformulated MCT, LCT emulsion without further addition of other drug was more effective in preventing pain on injection compared with the frequently used standard LCT propofol with a pre-mixture of lignocaine.
The main finding of the present study was that the use of the new MCT, LCT propofol formulation as a plain solution was associated with the same incidence of pain as compared to LCT propofol with added 2% lignocaine. In the study, we have seen that propofol in a newer formulation with MCT, LCT without pre-mixed lignocaine is as effective as standard lipid emulsion containing LCT with premixed lignocaine (40 mg in 200 mg propofol). Reformulation of lipid emulsion using MCT, LCT in contrast to LCT alone was found to cause less pain on injection when compared to standard propofol with LCT emulsion without the addition of lignocaine. A study confirmed these findings in the clinical setting. The incidence of pain with LCT propofol was 61.3% and of pain with MCT, LCT propofol was 28%. There was already evidence that MCT, LCT propofol was superior to LCT propofol without the addition of lignocaine. Besides, we did not find it to be justified ethically using LCT propofol without any method of pain prevention to confirm already published results. Because the experience of pain is a highly subjective matter, we standardised the procedure as much as possible and assessed all patients about their pain in a non-suggestive manner.
We have pre-mixed lignocaine to propofol instead of pre-treatment because it was shown in previous studies that mixing is better than pre-treatment. We used 40 mg lignocaine in our study because it was shown to be more effective. The efficacy of 20 mg and 40 mg lignocaine mixed with propofol in a study where it was reported that 40 mg was more effective than 20 mg.
We used four-point pain score in our study rather than visual analogue scale because of the effect of anaesthesia; patients may not be able to assess the score properly. Further, because of non-uniform distribution of literacy level, there may be errors in the pain assessment. However, the patients who reported pain with the pain scores ≥2–4 were thoroughly assessed and used for the analysis [Table 3]. Similar results were reported in other studies, In a study the incidence of pain with LCT propofol with lignocaine was 40% and with plain LCT propofol was 20%. The in another study lesser incidence of pain was observed with LCT propofol with lignocaine.
|Table 3: Demographic variables of patients who reported pain and their pain perception characteristics in Group L and Group S during intravenous injection of propofol|
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Several mechanisms could explain the discrepancy in incidence of pain on injection of propofol. One is the variety of definitions and modes of evaluation of pain used by investigators. In all studies reporting the use of propofol LCT, MCT, patients were actively asked to grade pain severity while propofol was administered. We assessed the pain according to four-point score. The difference in sample size also can explain the varied results. Our observations also suggested that as age increased, a more patients were experiencing pain with LCT propofol.
Although review of literature did not provide any clue for establishing a relationship between age and pain during propofol injection, we found a mild positive correlation (r = 0.3) for age versus pain in Group L. However, as there can be a subjective variation in pain threshold, we could not comment on this trend of the increased pain intensity in the elderly people. One patient in each group had myoclonic jerk, which was one of the known adverse effects of propofol.
In the present study, we found that newer formulation was as effective as standard formulation with lignocaine in decreasing pain on injection. Both the methods were equally effective in the reduction of pain. With the use of newer formulation, inherent errors like drug-mixing errors associated with addition of lignocaine to propofol were not observed. Newer formulation propofol can be a better alternative to conventional propofol with added lignocaine. Hence, we suggest the usage of the newer formulation of propofol to reduce the incidence of propofol injection pain, which alleviates the need of addition of another drug lignocaine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]