Rev. Bras. Anestesiol. vol.65 número5

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REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

OfficialPublicationoftheBrazilianSocietyofAnesthesiology

www.sba.com.br

SCIENTIFIC

ARTICLE

Lidocaine

alleviates

propofol

pain

much

better

than

metoprolol

and

nitroglycerin

Asutay

Goktug

a

_,

_Handan

_Gulec

b,∗

,

Suna

Akin

Takmaz

a

,

Esra

Turkyilmaz

c

,

Hulya

Basar

a

a_Department_of_{Anaesthesiology,}_Ankara_Education_and_Research_Hospital,_Ankara,_Turkey b_Department_of_{Anaesthesiology,}_Kecioren_Education_and_Research_Hospital,_Ankara,_Turkey c_Department_of_{Anaesthesiology,}_Zekai_Tahir_Burak_Education_and_Research_Hospital,_Ankara,_Turkey

Received25November2013;accepted2January2014 Availableonline13February2014

KEYWORDS

Propofolpain; Lidocaine; Nitroglycerin; Metoprolol

Abstract

Backgroundandobjectives: Injectionpain afterpropofoladministrationiscommonandmay disturbpatients’comfort.Theaimofthisstudywastocompareeffectivenessofintravenous (iv)nitroglycerin,lidocaineandmetoprololappliedthroughtheveinsonthedorsumofhandor antecubitalveinoneliminatingpropofolinjectionpain.

Method: Therewere147patientsandtheyweregroupedaccordingtotheanalgesic adminis-tered.Metoprolol(n=31,GroupM),lidocaine(n=32,GroupL)andnitroglycerin(n=29,Group N)wereappliedthroughivcatheteratdorsumhandveinorantecubitalvein.Painwas evalu-atedby4pointscale(0---nopain,1---lightpain,2---mildpain,3---severepain)in5,10,15 and20thseconds.ASA,BMI,patientdemographics,educationlevelandtheeffectofpathways forinjectionandlocationofoperationswereanalyzedfortheireffectontotalpainscore.

Results:Therewerenodifferencesbetweenthegroupsintermsoftotalpainscore(p=0.981). Therewere nodifferences intermsoftotalpain scoredepending onASA,education level, locationofoperation.However,lidocainewasmoreeffectivewhencomparedwithmetoprolol (p=0.015)andnitroglycerin(p=0.001)amonggroups.Althoughneitherlidocainenor metopro-lolhadanydifferenceonpainmanagementwhenappliedfromantecubitalordorsalhandvein (p>0.05),nitroglycerininjectionfromantecubitalveinhaddemonstratedstatisticallylower painscores(p=0.001).

Conclusion:We found lidocaine to be the most effective analgesic in decreasing propofol relatedpain.Wethereforesuggestivlidocaineforalleviatingpropofolrelatedpainat opera-tions.

∗_{Corresponding}_author.

E-mail:handandrhandan@yahoo.com.tr(H.Gulec).

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PALAVRAS-CHAVE

Dornolocalda injec¸ãodepropofol; Lidocaína;

Nitroglicerina; Metoprolol

Lidocaínaémaiseficazdoquemetoprololenitroglicerinaparaoalíviodador relacionadaàinjec¸ãodepropofol

Resumo

Justificativaeobjetivos: Adornolocaldainjeçãoapósaadministraçãodepropofolécomum epodecausardesconfortonospacientes.Oobjetivodesteestudofoicompararaeficáciade nitroglicerina,lidocaínaemetoprolol,aplicadosintravenosamenteatravésdeveiasdodorso dasmãosouantecubitais,paraeliminaradorcausadapelainjeçãodepropofol.

Métodos: Foramalocadosemgrupos147pacientesdeacordocomoanalgésicoadministrado: metoprolol(n=31,GrupoM),lidocaína(n=32,GrupoL)enitroglicerina(n=29,GrupoN).Os analgésicosforamaplicadosviacateterintravenosoemveiadodorsodamãoouantecubital.A dorfoiavaliadacomumaescaladequatropontos(0=semdor,1=dorleve,2=dormoderada, 3=dorintensa)nossegundoscinco,10,15e20.Osdadosdemográficosdospacientes,estado físicoASA,IMC,níveldeescolaridade,efeitodasviasdeinjec¸ãoelocaldascirurgiasforam analisadosquantoaseusefeitosnoescoretotaldedor.

Resultados: Nãohouvediferençaentreosgruposemrelaçãoaoescoretotaldedor(p=0,981). NãohouvediferençanoescoretotaldedoremrelaçãoaoestadofísicoASA,escolaridadeelocal dacirurgia.Noentanto,lidocaínafoimaiseficazemcomparaçãocommetoprolol(p=0,015)e nitroglicerina(p=0,001),nacomparaçãoentreosgrupos.Emboralidocaínaemetoprololnão tenhamapresentadodiferençanotratamentodadorquandoaplicadosemveiaantecubitalou dodorsodamão(p>0,05),ainjeçãodenitroglicerinaemveiaantecubitalapresentouescores dedorestatisticamentemenores(p=0,001).

Conclusão:Lidocaínamostrou-secomoanalgésicomaiseficazparadiminuiradorrelacionadaà injeçãodepropofol.Sugerimos,portanto,lidocaínaIVparaaliviaradorrelacionadaàinjeção depropofolemoperações.

Introduction

Propofol is an intravenous agent which is often preferred forsamedaysurgeryandhasshortperiodeffects.Injection painisthemostcommonpainandoneoftheadverseeffects disturbingpatients’comfort.Injectionpainincidencerateis 28---90%foradultsinthecourseofinduction.1,2_Various

meth-odsanddrugsaretestedandsuggestedinordertoeliminate

injectionpaincaused by Propofol.Forthis purpose,some

studiesabout injectionspeed ofpropofol,temperatureof

propofol and the vein immensity have been carried

out-fordecreasingpain.Beforepropofolinjection,somedrugs

suchasalfentanyl,tramadol,ketamine,fentanyl,morphine,

meperidine,metoprololandlidocainehave beenusedand

the effectiveness of these drugs on eliminating injection

painhasbeentested.3---10

Althoughtherearemanyresearchesonanalgesiceffects

oftransdermalnitroglycerin,researchesabouteffectiveness

ofnitroglycerin oneliminating propofolinjectionpainare

limited.2_The_aim_of_this_study_was_to_compare_{effectiveness}

ofintravenous (iv)nitroglycerin,lidocaineandmetoprolol

appliedthroughtheveinsonthedorsumofhandon

elimi-natingpropofolinjectionpainandthemainpurposeofthis

studywastoensuresatisfactionofpatients.

Methods

Aftertheapprovalofpatientsandhospitalethics

commit-tee,92patientsattheagesbetween19and70yearshave

been involved intherandomizeddoubleblind methodfor

theresearchplannedinelective conditionsat HM(Health

Ministry) Ankara Training and Research Hospital in

accor-dancewithclassificationgroupIandIIofAmericanSocietyof

Anesthesiologist.Hypertensivepatients,diabeticpatientsor

patientswithanotherneuropathy,patientswhosebodymass

indexis 35kgm−2 _or_above,_patients_with_allergy_to_these

drugsand withParkinson’sdisease,withthrombophlebitis

storyhavebeenexcludedfromthisresearch.

Routine monitorization including ECG, pulse oximeter

and non-invasive blood pressure have been applied to

patients who have undergone intramuscular (im)

preme-dicationwith50mg meperidine and0.5mg atropineafter

intravenousline(iv) hasbeen openedat thedorsumhand

veinwith20G catheter.Drugs that hadtobeusedin the

researchhavebeenpreparedas2mlintotalandnumbered

byaresearcherindependentfromapplicator.Aftervenous

discharge,tourniquetwereappliedtoarmmanuallyfor45s

and2mgmetoprololto31patientsinGroupM,20mg

lido-caineto32patientsinGroupL,0.25mgnitroglycerinto29

patients in Group N were applied through iv catheter at

dorsumhand vein. Aftertourniquet was loosened up, for

anesthesiainduction2mg/kg propofolwasinjectedwitha

flowof2mlin4s.Theadministrationpathwayswereused

forcomparisonofdifferentanalgesics.

Painduringinjectionwasevaluatedinthe4pointscale

(0---nopain,1---lightpain,2---mildpain,3---severepain)at

5,10,15and20thseconds.Patientsweregroupedaccording

to their education levels as: 1 --- illiterate, 2 --- primary

school,3---secondaryschool,4---highschool,5---university

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scorewasdone.ASAclassificationandBMIwerecompared

withtotalpainscoreusingtheabovementionedscale.Inthe

pre-operativeperiod,after propofolinduction andshortly

afterintubation 5minlater,heartrateandbloodpressure

wererecorded.Thefifteenthsecondwasdeterminedasthe

maintimebecausepainfrequencywasobservedinthistime

atmost.Inthatcase,totalpainscoreinsteadofpainscore

measured after injection is more effective in reflecting

satisfactionofpatientsandtotallifequalityscore.Location

ofoperationwasrecordedanditwascomparedwithtotal

painscore.The locationwasnumberedas0--- head---neck

(n=65), 1 ---thorax (n=1),2 --- upperabdomen (n=23),3

--- lower abdomen and pelvis (n=57), 4 --- extremity and

paraspinal area(n=31). The operation at thorax wasnot

included into the evaluation because therewas only one

patient.

ANOVA variance analysis has been used for statistical

analysisoftheresultsanddemographicdataand2testhas

beenusedforcomparisonofgroupsintermsofpain.Because

thedistributionofgroupswasnormal,pulseoximetry,

arte-rial blood pressure and heart rate measurements among

groups were evaluatedaccording to thevariance analysis

andBonferronitest.Ap<0.05wasconsideredsignificant.

Results

The mean age of the patients was 40 years (range,

19---70 years) and the mean BMI (body mass index) was

25.34±3.94kgm−2_. _There _were ₈₁ _female _and ₆₆ _male

patients.Nodifferencewasfoundamongthegroupsinterms

ofdemographicaldatasuchasage,gender,andbodymass

index (p>0.05). Also there were no differences in terms

oftotalpainscoredependingoneducationlevel(p>0.05).

Number of patients withpain according to timeintervals

whileadministrationofanalgesicfromantecubitalareaand

dorsumofhandareshown inTables1 and2.Alsonumber

of patients withpain when lidocaine (n=60), metoprolol

Table1 Numberofpatients withpainaccordingtotime intervals while administration of analgesic from back of hand.

Patientswith painat

GroupL (n=32)

GroupM (n=31)

GroupN (n=29)

p

5thsec 1 5 9 0.052

10thsec 6 9 18 0.023

15thsec 6 11 22 0.001

20thsec 3 14 22 0.001

L,Lidocaine;M,Metoprolol;N,Nitroglycerin.

Table2 Numberofpatients withpainaccordingtotime intervalswhileadministrationofanalgesicfromantecubital area.

Patientswith painat

GroupL (n=29)

GroupM (n=27)

GroupN (n=29)

p

5thsec 0 3 3 0.095

10thsec 0 5 4 0.261

15thsec 2 6 6 0.589

20thsec 0 4 10 0.011

L,Lidocaine;M,Metoprolol;N,Nitroglycerin.

Table 3 Number of patients with pain when Lidocaine (n=60)wasinjectedfromdifferentpathways.

Patientswith painat

GroupE (n=31)

GroupA (n=29)

p

5thsec 1 1 1.0

10thsec 6 6 0.101

15thsec 6 2 0.317

20thsec 3 3 0.228

A,antecubitalarea;E,backofhand.

Table 4 Numberof patients with pain when Metoprolol (n=59)wasinjectedfromdifferentpathways.

Patientswith painat

GroupE (n=32)

GroupA (n=27)

p

5thsec 5 1 0.108

10thsec 3 2 0.463

15thsec 11 6 0.712

20thsec 14 4 0.071

A,antecubitalarea;E,backofhand.

(n=59) and nitroglycerin (n=58) were injected from dif-ferentpathwaysareshowninTables3---5.Althoughneither

lidocainenormetoprololhad anydifferenceonpain

man-agementwhenappliedfromantecubitalordorsalhandvein

(p>0.05),nitroglycerininjectionfromantecubitalveinhad

demonstratedstatisticallylowerpainscores(p=0.001).

Totalpainscoreinwomenwas1.63±2.89andtotalpain

score in men was1.62±2.44. There were no differences

betweenthegroupsintermsoftotalpainscore(p=0.981).

WhenASAIandIIdifferencesaretakenintoconsideration,

therewerenosignificantdifferencesthatexistedamongthe

groupsintermsoftotalpainscore(ASAI=134,ASAII=42)

(p=0.661).ThemeanpainscoresatASA-IandASA-IIpatients

were1.63±2.58and1.42±2.82,respectively.

The total pain score in patients who have undergone

extremityandspinaloperationshasbeenmeasuredhasthe

lowest rate when compared with other locations. There

were no differences among other areas in terms of pain

score.Lidocainewasmore effective whencomparedwith

metoprolol(p=0.015)andnitroglycerin(p=0.001).

Further-more,metoprololwasleasteffectivewhencomparedwith

nitroglycerinintermsoftotalpainscore(p=0.002).Intotal

painscoreevaluation,injectionsinantecubitalareaswere

determinedtobemoreadvantageous(p=0.001).Totalpain

scoreforthegroupincludingpatientswithBMIlowerthan

30,withnormalBMIandhighBMIwas1.40±2.48kgm−2_._For

Table5 NumberofpatientswithpainwhenNitroglycerin (n=58)wasinjectedfromdifferentpathways.

Patientswith painat

GroupE (n=29)

GroupA (n=29)

p

5thsec 9 3 0.132

10thsec 18 4 0.001

15thsec 22 6 0.001

20thsec 22 10 0.014

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theobesegroup(n=30),thescorewas2.70±3.38kgm−2_. The total pain score for obese patients was statistically higher(p=0.016).

Discussion

Because propofol injection causes negative experiences about anesthesiaand restricts comfort of patients, some studieshavebeen carriedouttofindvariousmethods and tools.Thepropofol,whichisaphenol,causesirritationat skin,mucous membranesandintimaoftheveins.11 _Direct

endotelial irritation of nerve endings caused by propofol

causessecretionofbradykininbystimulatingkallikrein-kinin

cascadesystem.Thisstatebringsoutinjectionpainby

caus-ing increase in contact of free nerve endings and liquid

phaseofpropofolaswellasvenousdilatationandincrease

ofpermeability.Everydruggivenbeforepropofolinjection

alleviates pain by diluting liquid phaseof propofolwhich

hasanendotheliumirritanteffect.Itisthoughtthatpainis

relatedtoconcentrationofliquidphasealthoughthereisno

certaininformationaboutitsmechanism.12

Paincaused bypropofolinjectionemergesat earlyand

lateperiods.Painatearlyperiodisrelatedtodirecteffectof

propofolandpainatlateperiodisrelatedtolocalsecretion

ofkininogens.Atthepresentday,themostcommonagent

usedfor alleviating propofolinjection pain is lidocaine.10

Scott et al. stated that lidocaine alleviates pain by

sta-bilizing kinincascadewhile Erikssonstated thatthis agent

alleviatespainbydecreasingpHandconcentration.13,14

Propofol,byanindirectactionontheendothelium,

acti-vates the kallikrein-kinin system and releases bradykinin,

therebyproducingvenousdilationandhyperpermeability,

which increases the contact between the aqueous phase

of propofol and free nerve endings, resulting in pain on

injection.15_Propofol,_when_drawn_up_in_a_disposable_syringe,

mayleadtoformationofirritantsandpropofolpain.Ithas

been confirmed that propofol stripsthe siliconelubricant

from the inside barrel of plastic syringes. A reduction in

propofolpainbycoolingitto4◦_C_and_minimizing_propofol

injectionpainis animportantclinicalgoalbecauseitmay

influencethepatient’sperceptionofqualityand

acceptabil-ityofanesthesia.Inconclusion,pretreatmentwithlidocaine

40mg, thiopental 0.25mg/kg, and thiopentone 0.5mg/kg

after manual venous occlusion attenuates propofol pain.

However, pretreatment with thiopental 0.5mg/kg after

manualvenous occlusionwasthemost effective in

atten-uatingpropofol-inducedpain.Wethereforesuggestroutine

pretreatmentwiththiopental0.5mg/kgalongwithmanual

venousocclusionfor1minforpreventionofpainassociated

withpropofolinjection.

Nitroglycerinisacommonlyusedagentintreatmentof

ischemic heart disease.16 _{Nitroglycerin,}_a _strong

vasodila-tor,ismetabolizedasnitricoxide(NO)incells.NOcauses

intracellular concentration of cylicguanosine

monophos-phate(cGMP)whichleadstopainmodulationincentraland

peripheral nervous system.17 _NO,_applied _topically, _shows

anti-inflammatoryandanalgesic effectby blocking

neuro-geniccomponentofinflammatoryedemaandhyperallergy

and inhibits adhesion of neutrophils to endothelium

sur-face. The fact that transdermal nitroglycerin is effective

in paintreatment hasbeen provenwithvariousstudies.18

Transdermal nitroglycerin shows vasodilation effect and

analgesic effectby increasing diffusion of local

anesthet-icsandarrivaltonervetrunk.19_{Nitroglycerin}_pomade_shows

analgesiceffectandvasodilatoreffectinveinsizes.20

Nitroglycerinis metabolizedtonitric oxide(NO)inthe

cell.17,21 _NO _causes _increase _in _the _{intracellular}

concen-trationof, whichproduces painmodulationin thecentral

andperipheralnervoussystem.NOgeneratorsalsoinduce

anti-inflammatoryeffectsandanalgesiabyblocking

hyper-algesia and the neurogenic component of inflammatory

edema by topical application.22 _Another _possible

mech-anism includes an analgesic effect through the direct

stimulation of peripheral fibers mimicking the actions

of locally appliedacetylcholine.23 _Mechanisms _mentioned

above, or their combinations, might contribute to the

analgesic effects of nitroglycerin added to lidocaine in

intravenous regional anesthesia. The clinical efficacy of

transdermal nitroglycerin for acute pain relief has been

documentedin several studies.23 _{Nitroglycerin} _was _found

to be useful for the treatment of shoulder pain and

thrombophlebitis and for enhancing the effect of spinal

sufentanilorneostigmine.22_Lauretti_et_al._also_showed_that

deliveryofNOdonors(transdermalnitroglycerin)together

with.24

Opioidsmaybeofsignificantbenefitincancerpain

man-agement,delayingmorphinetolerance anddecreasingthe

frequencyofadverseeffectsrelatedtolargedosesofopioid.

Ithasbeenconcludedthat0.25nitroglycerinislesseffective

inalleviatingpropofolinjectionpaincomparedtolidocaine

andmetroprolol.Wehaveconcludedthathigherpainrates

inobesepatientsstemsfromstandardamountof

premedi-cation.Inotherwords,amountofdrugsperkiloislowerin

obesepatients

Nitroglycerinis metabolizedtonitric oxide(NO)inthe

cell.17,21_NO_causes_an_increase_in_the_{intracellular}

concen-trationofcyclicguanosinemonophosphate,whichproduces

pain modulation in the central and peripheral nervous

system.24,17 _NO _generators _also _induce _{anti-inflammatory}

effects and analgesia by blocking hyperalgesia and the

neurogenic component of inflammatory edema by

top-ical application.22 _Another _possible _mechanism _includes

an analgesic effect through the direct stimulation of

peripheral fibers mimicking the actions of locally applied

acetylcholine.17,23_As¸ık_et_al._have_stated_that_{pre-treatment}

with(iv)metoprololisaseffectiveaslidocaineinalleviating

propofolinjectionpain.10

In conclusion, we found Lidocaine to be the most

effective analgesic in decreasing propofol related pain.

Wetherefore suggest iv Lidocaine for alleviatingpropofol

relatedpainatoperations.However,nitroglycerininjection

intoantecubitalveinshasyieldedlowerlevelsofpropofol

relatedpain. Also we have confirmed that injection pain

isnotrelatedtogenderandeducationlevel.Furthermore,

wefoundthatinjectionpainisrelatedtoobesityandtotal

pain score in obese patients was statistically higher. For

evaluation of total pain score, antecubital area is more

advantageousthanthedorsumofthehand.

Conflict

of

interest

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Acknowledgements

The authors thank Ismail Demirkale, MD, for hisvaluable

guidanceandsupportoncompletionofthisarticle.

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