BACKGROUND ANDAIMPropofol injection pain is distressing to patientswhich interfere with smooth induction. Several pharmacological and non-pharmacological methods have been used to prevent this pain. 5-HT3 antagonistsare commonly used antiemetics have also been used to prevent Propofol injectionpain.
This study was conducted to evaluate and compare efficacy of Ondansetronand Palonosetron in alleviating Propofol injection pain. METHODOLOGYIn this randomised double blind study 100 patientsscheduled for elective laparoscopic surgery were allocated to two groups O& P receiving Ondansetron 4mg and Palonosetron 0.075mg respectively aspretreatment with venous occlusion for 1min. Initially one fourth of calculateddose of Propofol administered over 5s, patients were assessed for pain usingMcCrirrick and Hunter scale. Postoperatively patients were observed for nausea,vomiting and other side effects 24hours.
Intravenous Metaclopramide 10mg wasgiven as rescue antiemetic. RESULTSOverall incidence of pain in groupO and groupP was32% and 26% respectively. Severe pain was complained by 4% and 2% patients in groupOand groupP respectively. No patient in either group experienced pain during theinjection of pretreatment solution. Incidence of post operative nausea andvomiting (PONV) was 20% in groupP and 38% in groupO. CONCLUSIONBoth Ondansetron and Palonosetron are equally effectivein reducing Propofol injection pain, whereas Palonosetron was more effective thanOndansetron in reducing PONV, hence Palonosetron is a better choice in reducingboth Propofol injection pain and PONV Keywords:Propofol; Injection pain; Ondansetron; Palonosetron.
INTRODUCTIONPain on injection with variousintravenous induction agents in clinical practise like Thiopentone,Methohexitone, Etomidate, Propofol, Diazepam, etc is an important cause ofpatient dissatisfaction. Incidence and intensity of pain varies with individualagent. 1 Propofol is an induction agent preferred by manyanaesthesiologists due to its fastest onset and shortest duration. The incidence of pain varies from 28% to 90%in adults.
1 Compared to other intravenous anaesthetic agentsPropofol has higher incidence of pain on injection, considering as the seventhmost important clinical drawback by the American anaesthesiologists. 2Propofol is known to cause severe, sharp, aching or burning pain on injectionthat can be distressing to the patient. 3 This pain is consideredto be clinically unacceptable as it can cause agitation and interfere withsmooth induction of anaesthesia. The pain on injection of Propofol can beimmediate or delayed in nature. The immediate pain probably results from directirritant effect whereas delayed pain results from indirect effect via the kinincascade, and has a latency of 10-20seconds. 1 Variousinterventions have been made to alleviate the pain due to Propofol injection,which include both non-pharmacological and pharmacological methods. Non-pharmacologicalmethods include use of antecubital vein as the injection site, different infusionrates of Propofol, controlling the speed of intravenous carrier fluid and cold Propofolinjection. 4 Pharmacological interventions include pretreatmentwith Lidocaine with venous occlusion, Magnesium sulphate, Meperidine, Fentanyl,Morphine, Butorphanol, Dexamedetomedine, topical Nitroglycerine application,etc.
5 However none of thesemethods are effective in completely eliminating the pain on injection. 5-HT3receptor antagonists are commonly used for prevention and treatment of postoperativenausea and vomiting. Ondansetron has been shown to exhibit the property oflocal anaesthetic when injected under the skin due to blockade of sodiumchannels and 5-HT3 receptor antagonism.6 Ondansetron also showsagonist activity at the opioid ? receptors in humans.
Based on these propertiesvarious 5-HT3 antagonists like Ondansetron, Granisetron, Ramosetron andPalonosetron have been used to reduce the pain due to Propofol injection withadded advantage of preventing postoperative nausea and vomiting. Ondansetron a prototype of 5-HT3receptor antagonist has been used in various studies to reduce Propofolinjection pain. Ondansetron was found to be as effective as Lignocaine inreducing pain on Propofol injection. Palonosetron is a novel, highly potent andselective second generation 5-HT3 receptor antagonist that has a strongreceptor binding affinity and a long plasma elimination half-life. Palonosetronhas been shown to be effective in reducing the Propofol injection pain. 6Among the pretreatment drugs for reducing Propofol injection pain 5HT3antagonists can be preferred over other drugs due to their dual antiemetic andanalgesic properties. Various authors have successfully used different 5-HT3 receptorantagonist in reducing the incidence of Propofol injection pain, but inliterature studies comparing the efficacy of two 5-HT3 antagonists are minimal.
Hence in this study we compared the efficacy of Ondansetron and Palonosetron inreducing the incidence of pain on injection of Propofol and in PONV in patientsundergoing laparoscopic surgery under general anaesthesia METHODSA randomizeddouble blind clinical study on 100 adults of either sex in the age group of18-60 years of ASA physical status one and two posted for elective laparoscopicsurgeries under general anaesthesia. Patients with infection on dorsum ofnon-dominant hand, thin dorsal veins, hypersensitive to study drugs, history ofepilepsy, pregnant/ lactating women were excluded from the study. Hundredpatients were randomised into two groups of 50 each by computer generatedclosed envelop technique. Group O received Ondansetron 4mg diluted to 4ml withsaline and group P received Palonosetron 0.075mg diluted to 4ml with saline as IVpretreatment drugs. Pretreatment drug was prepared in the patient receivingroom by an anaesthesiologist who did not participate further in the study. Bothpatient and investigator were blinded for the composition of pretreatment studydrugs.
Onadmission a thorough pre-operative evaluation was done and written informedconsent was taken after explaining the procedure. All the patients werepre-medicated with tablet Alprazolam 0.5 mg overnight and the morning ofsurgery. Patients were kept nil orally for at least 8h. On arrival of the patient to operating room, basalvital parameters were recorded then a 20 gauge IV cannula was inserted into thelargest vein on the dorsum of non-dominant hand. No analgesics or sedativeswere given before induction. A pneumatic tourniquet was placed on the sameupper arm and inflated to 70 mmHg to produce venous occlusion and the test drugwas injected.
After the injection of the study drug the patient was assessedfor any pain at the injection site and tourniquet was released after oneminute.Initially one fourth of the total calculated dose ofPropofol (Profol 1%, Claris Injectables Limited) was administered over a periodof 5s and patients were assessed for pain using McCrirrick and Hunter scale.All patients were followed up after the surgery for the first 6h to assesspain, swelling or allergic reaction at the site of injection of Propofol.Patients complaining of nausea and/or vomiting and requirement of rescue antiemeticswas noted for 24h postoperatively. Rescueantiemetic Injection Metoclopramide 10mg was given. Table1: McCrirrick and Hunter scale of evaluation of Propofol injection pain Pain score Degree of Pain Response 0 None Negative response to questioning 1 Mild Pain reported in response to questioning only, without any behavioural signs. 2 Moderate Pain reported in response to questioning and accompanied by a behavioural sign, or pain reported spontaneously without questioning. 3 Severe Strong vocal response or response accompanied by facial grimacing, arm withdrawal or tears.
Descriptive and inferential statistical analysis hasbeen carried out in the present study. Results on continuous measurements arepresented on Mean ± StandardDeviation (Min-Max) and results on categorical measurements are presented inNumber (%). Significance is assessed at 5% level of significance. Independent Studentt test has been used to find the significance of study parameters on continuousscale between two groups (Inter group analysis) on metric parameters. Chi-square/Fisher Exact test has been used to find the significance of study parameters oncategorical scale between two groups, Non-parametric setting for Qualitativedata analysis.
The Statistical software namely SAS 9.2, SPSS 15.0, Stata 10.1,MedCalc 9.0.1, Systat 12.0 and R environment ver.
2.11.1 were used for the analysisof the data and Microsoft word and Excel have been used to generate graphs, tablesetc.
Power calculation indicated that recruitment of 40patients in each group would be significant to demonstrate a reduction of painscore of one at a level of significance of P<0.05and power of 99.3%. Considering the dropouts we have taken a 50 in each groups.
RESULTSAll patients in both group belong to ASA I and IIwere undergone Laparoscopic surgeries. Both the groups were comparable withrespect to age, weight and gender distribution. Table2: Demographic DataCharacteristics Group O(Mean±SD) Group P(Mean±SD)Age (in years) 34.02±10.36 37.92±11.90Weight (in kg) 63.14±13.
19 61.84±10.61 Gender (M/F) 18/36 12/38ASA (I/II) 43/7 41/9 Original; Valuesexpressed as mean±SD; SD- Standard deviation; ASA- American Society ofAnaesthesiologist; Theincidence and severity of pain in both the groups were comparable and nostatistical significant difference was noted in respect to pain on Propofol injection(P 0.502). Thirty four (68%) patientsin Group O and 37 (74%) patients in Group P were free from propofol injectionpain. Over all incidence of propofol injection pain was 32% and 26% in Group Oand P respectively. Only one patient in group P and two patients in group O hadsevere pain on injection.
Incidenceand severity of Propofol injection painP 0.502,Not significant, student t test Patients vital parameters were well maintainedthroughout the procedure and no significant hemodynamic variations were notedin both the study groups. We observed a statistically significant differencebetween the two groups in relation to PONV. Thirty eight percent of patients inGroupO and 20% of patients in GroupP had PONV.
P value being 0.047. No other side effects were noted in both thestudy groups. Incidenceof PONV in two groups of patients studiedP 0.047,significant, Chi-Square testDISCUSSIONPropofol a 2,6- diisoprophylphenol is a sedativehypnotic with additional antiemetic property is widely using intravenousinducing agent especially for short surgical procedures, day care surgeries, inTIVA and ICU sedation. 1 The common worrying problem that has beenmost extensively studied is pain on injection of Propofol. 1 The injectionpain is sharp, stinging or burning in nature which can be either immediate ordelayed.
3 Contributing factor for pain on injection are Vesselsize, Composition of propofol, temperature of the injection, pH, volume andspeed of injection etc, Incidence of propofol injection pain is comparativelyless when forearm veins are used for induction than dorsal hand veins.7 Theformulation of Propofol used by different authors were different. Some used LCTpropofol where as some used LCT/MCT Propofol, which is proved to cause lesserinjection pain. Ji-Yeon sim et al demonstrated that microemulsion Profofol(clear) is more painful than lipid emulsion Propofol.8 Theprobable mechanism reported to cause pain on injection of Propofol are directendothelial irritation, difference in osmolarity, non-physiologic pH of the drugand activation of pain mediators. Immediate pain may be due to stimulation ofnociception and free nerve endings where as delayed pain occurring within halfa minute is promoted by local vasodilation and hyperpermiability with themediation of neurotransmitter such as bradykinine and prostaglandins. 9Pretreatment with drugs like Ketamine, Lidocaine,fentanyl, Ramifentanyl, 5HT3 receptor antagonist, etc.
, have been tried byvarious authors to reduce the incidence and severity of pain.Ondensetron and Palenosetron are selective 5HT3receptor antagonists basically used as antiemetics in the prevention andtreatment of nausea and vomiting, they suppress nausea and vomiting byinhibiting the serotonin binding to 5HT3 receptors located peripherally atvagus afferent and centrally at CTZ. These 5HT3 antagonists bind to opoid µreceptor and exhibit agonistic activity.In our study both the study groups were comparablewith respect to age, weight and gender distribution. Though different authorshave used different scale to assess the Propofol injection pain, one proposedby McCrirrick and Hunter is the most commonly used scale because it is simpleand easy to perform, where patient’s verbal, behavioural response for simplequestion will be taken into consideration to assess the degree of pain. Mariyaet al used VAS to assess the Propofol injection pain.
10 Hand eyecoordination to VAS might not be proper in all patients during the rapidlychanging state of consciousness after Propofol injection, hence we adoptedMcCrirrick and Hunter scale for assessment of Propofol injection pain.The overall incidence of pain was 32% in Ondensetrongroup and 26% in Palonosetron group, where as 4% and 2% of our patientscomplained of severe pain respectively in Ondensetron and Palonosetron group.In our study though both the study drugs failed in relieving pain in all thepatients studied, 68% of patients who received Ondensetron pre-treatment and74% of patients who received Palonosetron pre-treatment before Propofolinjection experienced no pain.Incontrast to our results, Ansari M Umar et al showed the incidence of Propofolpain was only 15% and the incidence of severe pain was 2.
5% in their Ondensetrongroup. This difference may be attributed to the difference in the volume of thePropofol injected initially. We have given one fourth of the calculated dose ofPropofol and assessed the pain, where as they have used only 2ml of Propofol as bolus irrespective of body weightand the pain was assessed after 15s of giving the bolus.
11 Theintensity and severity of the pain also depends on the volume of Propofolinjected and the speed of carried fluid infusion. 1 Scottet al suggested that the intensity of Propofol pain is inversely proportionalto the size of the vein and also stated that rapid injection of Propofol causesless pain than slow bolus. 12Withrespect to Palanosetron free treatment in reducing the Propofol injection pain,our results are in par with the results in the study conducted by Han-Bon Ryuand Sujin Kim.9In contrast KyeHyeok Lee et al, demonstrated a very high incidence of Propofol injection painin their Palonosetron group(73%), but rate of severe pain is almost equal toour study. This high incidence of pain may be due to slow intravenous infusionof Propofol. Target controlled infusion pump(TCI pump) to achieve a 6µg effectsite concentration. 13Jae-HwaYoo et al, also showed a higher incidence of Propofol injection pain in the Palonosetrongroup that may be the dose of Propofol used before evaluating pain. They usedfull dose of Propofol where as in other studies they have used either 2ml initialbolus or one fourth of calculated dose of Propofol.
14Postoperative nausea and vomiting are distressing symptoms commonly reported bypatients after Laproscopic surgery performed under General Anaesthesia(……..
.).5HT3 receptor antagonist are widely used as prophylactic anti-emetics inreducing PONV.
Ondestronprevents emetic symptoms by acting on the 5HT3 receptor located in the CTZ andgastrointestinal tract, where as Palonostron is a second generation 5HT3antagonist with different mechanism inpreventing PONV. 15Differentstructural characteristics, lower plasma half life, inhibition of substance Pmediated delayed emesis are some of the unique features of Palonosetron inother 5HT3 receptor antagonist. 16Theincidence of post operative nausea and vomiting in our study was 38% inOndesteron group and 20 % in Palanosetron group. The difference between thegroups was statistically significant. In comparison with our study, S.K.Park etal and Y.
Y.Kim et al showed that Palanosetron was better than Ondensetron inreducing the incidence of PONV.17 18 K.Gupta et al stated that Palanosetronwas more effective than Ondensetron and Granisetron in reducing nausea andvomiting.
19Vitalparameters were well maintained in all the patients. We observed no sideeffects in respect to study drugs. Headache, dizzness ,drowsiness are some ofthe adverse effects noted with 5HT3antagonist. S.K.
Park , et al observed that the incidence of head ache and dizzinesswere comparable between Ondesetron and Palanosetron, where as J.Bhall et alstated that the incidence of the head ache was more with Ondesetron than Palanosetron.1720Inour study, baseline incidence of injection pain has not measured as we did notinclude control group or placebo group, considering not taking any preventivemeasures to reduce pain in placebo group is unethical. CONCLUSION:BothOndensetron and Palonosetron are equally effective in reducing the Propofol injectionpain, where as Palonosetron was statistically more effective in reducing theincidence of PONV than Ondensetron. Therefore considering the dual actions ofthese drugs we observed that Palonosetron pretreatment is a better choice thanOndensetron in reducing the Propofol injection pain in patients undergoinglaparoscopic surgeries. Since cause of Propofol injection pain is multifactoriala combination of non-pharmacological andpharmacological methods may be a better choice. REFERENCES:1.
Tan CH, Onsiong MK. Pain on injection ofpropofol. Anaesthesia. 1998 May 1;53(5):468-76.
2. Macario A, Weinger M, Truong P, Lee M. Whichclinical anesthesia outcomes are both common and important to avoid? The perspective of a panel ofexpert anesthesiologists. Anesthesia & Analgesia. 1999 May 1;88(5):1085-91.3.
Kang HJ, Kwon MY, Choi BM, Koo MS, Jang YJ, LeeM. Clinical factors affecting the pain on injection of propofol. Korean journalof anesthesiology. 2010 Mar 1;58(3):239-43.4.
Jalota L, Kalira V, George E, Shi YY, HornussC, Radke O, Pace NL, Apfel CC. Prevention of pain on injection of propofol:systematic review and meta-analysis. Bmj. 2011 Mar 15;342:d1110.
5. Singh TH, Devi NA, Arasu T, Rajkumar G, DeviLE, Singh NR. Effect of palonosetron pretreatment to attenuate the pain causedby propofol injection. Journal of Medical Society. 2017 May 1;31(2):90.6. Ye JH, Mui WC, Ren J, Hunt TE, Wu WH, ZbuzekVK. Ondansetron exhibits the properties of a local anesthetic.
Anesthesia . 1997 Nov 1;85(5):1116-21.7. Zahedi H, Maleki A, Rostami G. Ondansetronpretreatment reduces pain on injection of propofol. Acta Medica Iranica. 2012Apr 1;50(4):239.
8. Sim JY, Lee SH, Park DY, Jung JA, Ki KH, LeeDH, Noh GJ. Pain on injection with microemulsion propofol. British journal ofclinical pharmacology. 2009 Mar 1;67(3):316-25.9. Ryu HB, Kim SJ. Analgesic effects ofpalonosetron in the intravenous propofol injection.
Korean journal ofanesthesiology. 2014 Feb 1;66(2):99-104.10. Mamiya H, Noma T, Fukuda K, Kasahara M,Ichinohe T, Kaneko Y. Pain following intravenous administration of sedativeagents: a comparison of propofol with three benzodiazepines. Anesthesiaprogress.
1998;45(1):18.11. Ansari.M Umar, Garg. Gangashankar, Lodha L.R, Qureshi. S.
U & Porwal. S. Pre- treatment with intravenous ondansetronto alleviate pain on propofol injection: A randomized, controlled -blind study. Journal of pharmaceutical and biomedical sciences (J Pharm Biomed Sci.) 2013, July;32(32): 1274-1278.
12. Scott RP, Saunders DA, Norman J. Propofol:clinical strategies for preventing the pain of injection. Anaesthesia. 1988 Jun1;43(6):492-4.
13. Lee KH, Rim SK, Lee JY, Lee SY, Lee SN, Lee EJ,Lee JH. Effects of pretreatment with intravenous palonosetron for propofol-remifentanil-basedanesthesia in breast and thyroid cancer surgery: a double-blind, randomized,controlled study. Korean journal of anesthesiology. 2014 Jul 1;67(1):13-9.14.
Yoo JH, Kim YI, Im Kim S, Lee SJ, Han YM.Evaluation of palonosetron for the prevention of pain on injection of LCT/MCTpropofol: Randomized controlled comparison with lidocaine. Anesthesia and PainMedicine. 2016 Jul 31;11(3):249-54.15. Moon YE, Joo J, Kim JE, Lee Y.
Anti-emeticeffect of ondansetron and palonosetron in thyroidectomy: a prospective,randomized, double-blind study. British journal of anaesthesia. 2012 Mar1;108(3):417-22.16.
Rojas C, Stathis M, Thomas AG, Massuda EB, AltJ, Zhang J, Rubenstein E, Sebastiani S, Cantoreggi S, Snyder SH, Slusher B.Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor.Anesthesia & Analgesia. 2008 Aug 1;107(2):469-78.
17. Park SK, Cho EJ. A randomized, double-blindtrial of palonosetron compared with ondansetron in preventing postoperativenausea and vomiting after gynaecological laparoscopic surgery. Journal ofInternational Medical Research. 2011 Apr;39(2):399-407.18. Kim YY, Moon SY, Song DU, Lee KH, Song JW, KwonYE.
Comparison of palonosetron with ondansetron in prevention of postoperativenausea and vomiting in patients receiving intravenous patient-controlledanalgesia after gynecological laparoscopic surgery. Korean journal ofanesthesiology. 2013 Feb 1;64(2):122-6.19. Gupta K, Singh I, Gupta PK, Chauhan H, Jain M,Rastogi B. Palonosetron, Ondansetron, and Granisetron for antiemeticprophylaxis of postoperative nausea and vomiting-a comparative evaluation.Anesthesia, essays and researches.
2014 May;8(2):197.20. Bhalla J, Baduni N, Bansal P.
Comparison ofpalanosetron with ondansetron for postoperative nausea and vomiting in patientsundergoing laparoscopic cholecystectomy under general anesthesia. Journal ofminimal access surgery. 2015 Jul;11(3):193.