|Year : 2017 | Volume
| Issue : 2 | Page : 90-93
Effect of palonosetron pretreatment to attenuate the pain caused by propofol injection
Takhelmayum Hemjit Singh, Ningthoujam Anita Devi, Thanigai Arasu, Gojendra Rajkumar, Longjam Eshori Devi, Nongthombam Ratan Singh
Department of Anaesthesiology, Regional Institute of Medical Sciences, Imphal, Manipur, India
|Date of Web Publication||20-Apr-2017|
Takhelmayum Hemjit Singh
Department of Anaesthesiology, Regional Institute of Medical Sciences, Imphal - 795 004, Manipur
Source of Support: None, Conflict of Interest: None
Objective: Propofol is the induction agent of choice in modern anesthetic practice because of its rapid onset, short duration of action, easy titration, and favorable side effect profile. Pain on injection of anesthetic is an important source of patient dissatisfaction and is a recognized adverse effect of propofol. We compared the effects of pretreatment of palonosetron and saline (placebo) in ameliorating propofol injection pain. Materials and Methods: Sixty adult patients of either sex (18–50 years, American Society of Anesthesiologists I and II) were randomized into two equal groups (n = 30) to receive either 1.5 ml of intravenous saline (placebo) or 1.5 ml of 75 mg palonosetron to compare the pain relieving effects of the drugs during propofol injection before the patients had lost consciousness. The propofol injection pain was assessed according to McCririck and Hunter scale. Results: The palonosetron group had significantly (P < 0.05) more patients (86.67%) without propofol injection pain as compared with the saline group (56.67%). Conclusion: Pretreatment with palonosetron with venous occlusion for 1 min can effectively reduce the incidence of propofol injection pain.
Keywords: Pain, palonosetron, propofol
|How to cite this article:|
Singh TH, Devi NA, Arasu T, Rajkumar G, Devi LE, Singh NR. Effect of palonosetron pretreatment to attenuate the pain caused by propofol injection. J Med Soc 2017;31:90-3
|How to cite this URL:|
Singh TH, Devi NA, Arasu T, Rajkumar G, Devi LE, Singh NR. Effect of palonosetron pretreatment to attenuate the pain caused by propofol injection. J Med Soc [serial online] 2017 [cited 2018 Jul 16];31:90-3. Available from: http://www.jmedsoc.org/text.asp?2017/31/2/90/204817
| Introduction|| |
Propofol has gained unmatched popularity as an agent for intravenous (i.v.) induction because of its rapid onset and short duration of action, easy titration, and favorable side effect profile. It is also used for short duration of surgery, day care surgery, sedation in Intensive Care Unit, and ambulatory surgery. A major drawback of propofol is its potential to induce intense burning pain on injection when given in small veins and some patients recall the induction of anesthesia as the most painful part of the perioperative period.
The mechanism by which propofol causes pain on injection is not fully understood. However, the activation of pain mediators, such as the kinin cascade system, has been suggested as a possible cause which may be related to the release of local kininogens. Some postulated that the afferent free nerve endings between the media and intima are the sensors for this pathway. Many factors such as carrier i.v. fluid rate, temperature, concentration (0.5%–2%), site of injection, size of vein, speed of injection, and co-medication, pH, of propofol appear to affect the incidence of pain., This incidence varied between 28% and 95% in adults and 28%–85% in children. Among 33 clinical problems, propofol-induced pain ranked seventh when both clinical importance and frequency were considered.
Pharmacological methods such as pretreatment with lignocaine, ondansetron, magnesium sulfate, ephedrine, and opioids such as meperidine, fentanyl, morphine, butorphanol, dexmedetomidine, and topical nitroglycerin application with propofol diluting the propofol with 5% dextrose or 10% intralipid and using medium and small chain triglycerides have been tried.,,12] Nonpharmacological methods such as injecting propofol into large vein, cooling of propofol, injecting cold saline prior to the injection of propofol, and dilution of propofol solution have also been tried, but none has been proved absolutely perfect for attenuation of pain due to propofol injection.,,
Palonosetron, a longer acting antiemetic, is a second-generation 5-hydroxytryptamine (5-HT3) receptor antagonist, and it has a greater 5-HT3 receptor binding affinity. In addition, peripheral 5-HT3 receptors are involved in the nociceptive pathway, and this leads to the drug analgesic effect. The local anesthetic effect of palonosetron has not yet been fully described in literature, and there are few studies postulating the effectiveness of this drug on propofol injection pain. Hence, we conducted a prospective, randomized study to determine if pain of propofol injection can be attenuated by palonosetron pretreatment.
| Materials and Methods|| |
The study was a prospective, randomized, double-blinded, placebo-controlled trial conducted in Department of Anaesthesiology, at a Tertiary Care Centre, from September 2013 to September 2015. After obtaining Institutional Ethics Committee approval and written informed consents from sixty patients with American Society of Anesthesiologists (ASA) I and II, aged 18–50 years, who were to undergo operation under general anesthesia were randomly assigned into two groups of thirty patients each by computer-generated randomization to receive either i.v. palonosetron pretreatment 0.075 mg in 1.5 ml (n = 30) or 1.5 ml of 0.9% normal saline pretreatment as a placebo (n = 30). Patients with neurological deficit, history of allergy to study drugs and propofol, taking any analgesic before surgery, history of diabetes, hypertension, cardiovascular and respiratory disease, morbid obesity, and emergency surgery were excluded from the study.
The sample size was calculated based on the study conducted by Singh and Singh  on the amelioration of propofol injection pain by palonosetron and taking into consideration of α value of 0.05 and beta (power) at 90%, the size of the study was calculated at 19 patients in each group. With considerations of any dropout, which may arise during the study period, the sample size was set at thirty patients in each group.
The patients enrolled were asked to report their pain according to the verval rating scale provided to them in the form of none(Score 0 or no response to questioning), mild(Score 1 or pain reported in response to questioning only without any behavioural signs), moderate(Score 2 or pain reported in response to questioning and accompanied by behavioural signs, or pain reported without any questioning) and severe(Score 3 or Strong vocal response or response accompanied by facial grimacing, arm withdrawal or tear).
In the operation room, a 20-gauge cannula was inserted on the dorsum of both hands-one for i.v. saline and another for drug injection. Standard monitors, namely electrocardiogram, pulse oximeter, and automatic noninvasive arterial blood pressure, were instituted. All the patients were premedicated with injection ranitidine 50 mg i.v. and glycopyrrolate 0.005 mg/kg intramuscular at least 1 h before the surgery. The study drug kept at room temperature was prepared by an independent anesthesiologist not involved in the study into 1.5 ml of equal volume. The patients received either palonosetron pretreatment 0.075 mg in 1.5 ml (n = 30) or 1.5 ml of 0.9% normal saline intravenously.
Venous occlusion was done by compressing the forearm with a tourniquet. The study drug was injected over 10 s, and the occlusion was removed after 1 min, and then first 25% of the calculated dose (2.5 mg/kg) of propofol was injected over 20 s. Then, the patients were asked to tell to the observer about the severity of pain 15 s later, and their response was assessed according to the four-point verbal rating score. Induction of anesthesia was achieved with injection propofol, and the study will be taken as complete at this point, and further anesthetic techniques were not be influenced by this study. An anesthetic procedure was continued according to the standard protocol.
The data collected were tabulated and analyzed by the Statistical Package for Social Sciences (SPSS) version 21 (IBM Corp, Chicago, IL, USA). Continuous data were analyzed by Student's t-test, Chi-square test was used for comparison of categorical data, and P < 0.05 was deemed to be significant.
| Results and Observation|| |
All the enrolled sixty patients completed the study protocol. The patients' demographic characters such as age, weight, height, sex, and ASA classification were comparable (P > 0.05) in both the groups as shown in [Table 1].
The palonosetron group, as shown in [Table 2], had more patient (26 and 86.67%) who did not experience pain as compared with the saline group (13 and 43.33%) and this difference was highly significant (P < 0.001). Among the patients who experienced pain, palonosetron group had got four (13.33%) patients who experienced mild pain only, while the saline group had got 14 (46.7%) and 3 (10%) patients with mild and moderate pain, respectively. This distribution of patients with pain in the two groups was statistically significant (P = 0.002). There were no patients in both groups who experienced severe pain in our study.
|Table 2: The distribution and comparison of pain scores in the two groups|
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| Discussion|| |
The incidence of pain with i.v. propofol varies between 28% and 90% in adults and 28% and 85% in children. Pain on injection of propofol can be immediate or delayed. The immediate pain could be the result of a direct irritant effect, but the kinin cascade is probably the cause of delayed pain which will occur within half minute. The lipid solvent for propofol activates the plasma kallikrein–kinin system which results in bradykinin production that increases local vein permeability and dilation. The aqueous-phase propofol diffuses into more free nerve endings outside the endothelial layer of the vessel, which are more permeable and dilated because of bradykinin effect, thereby intensifying pain on injection. Moreover, a recent study of Ando and Watanabehas shown that propofol characteristically causes vascular pain that occurs in response to prostanoids, particularly PG E2. According to Faerber et al., serotonin (5-HT3) receptors are located in the nerve terminals and sensory nerve endings of neurons releasing pain mediators such as substance P.
Ye et al. in their study stated that peripheral 5-HT3 receptors are involved in nociceptive pathways, so ondansetron having dual effects as a 5-HT3 receptor antagonist and a sodium channel blocker could make it effective as an i.v. regional anesthetic in the treatment of chronic pain. In addition, ondansetron binds to the opioid μ receptors in humans and exhibits agonist activity. As a result of its multifaceted actions as a Na channel blocker, a 5-HT3 receptor antagonist, and μ opioid receptor agonist, ondansetron may potentially be used to alleviate pain produced by a drug similar to propofol. Other 5-HT3 receptor antagonists such as granisetron, dolasetron, ramosetron,, and palonosetron  are also successfully used for preventing the propofol pain injection. Moreover, cooling of propofol to 4° C appears to lessen propofol injection pain through suppressing the activation of plasma kallikrein–kinin system that in turn initiates enzymatic cascade. Injecting into a large forearm vein also reduces the pain, probably by reducing contact between drug and endothelium.
The patients' demographics such as age, weight, height, sex, and ASA classification were comparable (P > 0.05) in both the groups and would not affect the outcome of our study.
In the study conducted by Ambesh et al., only 20% of the patients had pain who were pretreated with ondansetron. They concluded that pretreatment with ondansetron was successful in relieving the pain of propofol injection without any adverse effect in a significant number of patients. Our study had only 13.33% of the patients with pain in the injection palonosetron group, which is better than the above study.
In a study by Piper et al., severity but not the incidence of pain on injection was significantly reduced by dolasetron (50%) compared with placebo and there was no significant difference between dolasetron and lidocaine. According to a study conducted by Dubey and Prasad, lidocaine and granisetron significantly reduced the incidence and severity of propofol injection pain more than placebo (P < 0.001). The efficacy of granisetron in alleviating the pain on injection of propofol was no different from lidocaine. In fact, lidocaine pretreatment is the most popular method and can be described as the gold standard. However, the addition of lidocaine may destabilize the propofol emulsion with an attendant potential risk of pulmonary fat embolism if droplet size exceeds 5 μ m. Hence, 5-HT3 receptor antagonist has been found to be an effective alternative.
Ramosetron is a recently developed 5-HT3 receptor antagonist. Lee et al. reported the incidence of pain in the groups pretreated with ramosetron 0.3 mg or combination with ramosetron and lidocaine 20 mg was 60% and 38%, respectively. In another study conducted by Singh et al., the incidence of pain was 65%, 35%, and 30% in the placebo(saline), lidocaine 40 mg, and ramosetron 0.3 mg, respectively. These results show an effective reduction in propofol injection pain by pretreatment with ramosetron alone or with combined pretreatment of ramosetron and lidocaine.
However, in our study, the incidence of pain in saline group was 56.67%, and only 13.33% of the patients had pain in palonosetron group. This showed that palonosetron effectively reduced the propofol injection pain compared to ramosetron. This discrepancy in the incidence of propofol injection pain between ramosetron (30%) versus palonosetron (13.33%) might be due to varying manual occlusion pressure at mid-forearm from person to person and effectiveness of the palonosetron over ramosetron.
In a study conducted by Ryu and Kim, 60% patients experienced propofol-induced pain in the normal saline group compared to 27.5% in the palonosetron group (P < 0.05), whereas 56.67% and 13.13% of the patients experienced propofol injection pain in the normal saline and the palonosetron groups, respectively, in our study (P < 0.05). The higher incidence of propofol pain in their study may be due to the manual mid-arm occlusion technique as against tourniquet in our study. However, in the study conducted by Singh and Singh  using a tourniquet, a significant reduction in propofol pain in the palonosetron group was noted which is concurrent with our study.
Our study was not without any limitation. Pain assessment would have been more accurate if it was combined with other nonsubjective technique. Further comparative studies with lignocaine, which is a gold standard agent for alleviating propofol pain, need to be undertaken.
| Conclusion|| |
It can be concluded that pretreatment with palonosetron 75 mcg along with venous occlusion for 1 min reduced the incidence of propofol-induced pain significantly. Moreover, prevention of postoperative nausea and vomiting may be achieved along with alleviation of propofol-induced pain with a single agent.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, et al.
Prevention of pain on injection of propofol: Systematic review and meta-analysis. BMJ 2011;342:d1110.
Scott RP, Saunders DA, Norman J. Propofol: Clinical strategies for preventing the pain of injection. Anaesthesia 1988;43:492-4.
Roehm KD, Piper SN, Maleck WH, Boldt J. Prevention of propofol-induced injection pain by remifentanil: A placebo-controlled comparison with lidocaine. Anaesthesia 2003;58:165-70.
Huang CL, Wang YP, Cheng YJ, Susetio L, Liu CC. The effect of carrier intravenous fluid speed on the injection pain of propofol. Anesth Analg 1995;81:1087-8.
Fletcher GC, Gillespie JA, Davidson JA. The effect of temperature upon pain during injection of propofol. Anaesthesia 1996;51:498-9.
Stokes DN, Robson N, Hutton P. Effect of diluting propofol on the incidence of pain on injection and venous sequelae. Br J Anaesth 1989;62:202-3.
Eriksson M, Englesson S, Niklasson F, Hartvig P. Effect of lignocaine and pH on propofol-induced pain. Br J Anaesth 1997;78:502-6.
Doenicke AW, Roizen MF, Rau J, Kellermann W, Babl J. Reducing pain during propofol injection: The role of the solvent. Anesth Analg 1996;82:472-4.
Picard P, Tramèr MR. Prevention of pain on injection with propofol: A quantitative systematic review. Anesth Analg 2000;90:963-9.
Ambesh SP, Dubey PK, Sinha PK. Ondansetron pretreatment to alleviate pain on propofol injection: A randomized, controlled, double-blinded study. Anesth Analg 1999;89:197-9.
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;86:382-6.
Singh HS, Singh LD, Singh NR, Singh TH, Thokchom RS, Manohar PS. Effects of dexmedetomidine and lignocaine in alleviating propofol injection pain: A randomized controlled trial. J Med Soc 2015;29:31-4.
Singh DK, Singh M. Comparative study of intravenous injection of palonosetron, magnesium sulfate and nitroglycerine to attenuate the pain caused by propofol. Inventi Impact- Anaesthesiology 2011;1:6-11.
McCrirrick A, Hunter S. Pain on injection of propofol: The effect of injectate temperature. Anaesthesia 1990;45:443-4.
Ohmizo H, Obara S, Iwama H. Mechanism of injection pain with long and long-medium chain triglyceride emulsive propofol. Can J Anaesth 2005;52:595-9.
Canbay O, Celebi N, Arun O, Karagöz AH, Saricaoglu F, Ozgen S. Efficacy of intravenous acetaminophen and lidocaine on propofol injection pain. Br J Anaesth 2008;100:95-8.
Ando R, Watanabe C. Characteristics of propofol-evoked vascular pain in anaesthetized rats. Br J Anaesth 2005;95:384-92.
Faerber L, Drechsler S, Ladenburger S, Gschaidmeier H, Fischer W. The neuronal 5-HT3 receptor network after 20 years of research – Evolving concepts in management of pain and inflammation. Eur J Pharmacol 2007;560:1-8.
Ye JH, Mui WC, Ren J, Hunt TE, Wu WH, Zbuzek VK. Ondansetron exhibits the properties of a local anesthetic. Anesth Analg 1997;85:1116-21.
Zahedi H, Maleki A, Rostami G. Ondansetron pretreatment reduces pain on injection of propofol. Acta Med Iran 2012;50:239-43.
Dubey PK, Prasad SS. Pain on injection of propofol: The effect of granisetron pretreatment. Clin J Pain 2003;19:121-4.
Piper SN, Röhm KD, Papsdorf M, Maleck WH, Mattinger P, Boldt J. Dolasetron reduces pain on injection of propofol. Anasthesiol Intensivmed Notfallmed Schmerzther 2002;37:528-31.
Lee HY, Kim SH, So KY. Prevention of microemulsion propofol injection pain: A comparison of a combination of lidocaine and ramosetron with lidocaine or ramosetron alone. Korean J Anesthesiol 2011;61:30-4.
Singh D, Jagannath S, Priye S, Shivaprakash, Kadli C, Reddy D. Prevention of propofol injection pain: Comparison between lidocaine and ramosetron. J Anaesthesiol Clin Pharmacol 2014;30:213-6.
Ryu HB, Kim SJ. Analgesic effects of palonosetron in the intravenous propofol injection. Korean J Anesthesiol 2014;66:99-104.
[Table 1], [Table 2]