Propofol Pain

8/11/2019 Propofol Pain

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R E V I E W A R T I C L E

Pain on injection of propofol

C.H. TanandM.K.Onsiong

Department of Anaesthesia, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan, Hong Kong,

Peoples Republic of China

Summary

Pain on injection of propofol is a common problem, the cause of which remains unknown. The

chemical properties and preparation of propofol, proposed mechanisms for the cause of the pain

and clinical strategies to prevent pain on injection of propofol are reviewed in the hope of

shedding some light on the subject.

Keywords Anaesthetics, intravenous; propofol. Complications; pain.

......................................................................................

Correspondence to: Dr C. H. Tan

Accepted: 3 August 1997

Propofol (Diprivan, di-isopropylphenol) is a popular intra-

venous anaesthetic induction agent, especially for brief

cases, day surgery or when a laryngeal mask airway is to be

used. Propofol can also be used in a total intravenous

anaesthesia (TIVA) technique for the maintenance of

anaesthesia and sedation. It has also been used for the

prevention of emesis [1], tracheal intubation without

neuromuscular blocking drugs [2] and the treatment of

pruritus [3, 4].

Pain on injection with propofol is a common problem

and can be very distressing to the patient. The incidence of

pain varies between 28% and 90% in adults during induc-

tion of anaesthesia and may be severe [5, 6]. In children,

the incidence of pain varies between 28% and 85% [7, 8].

The younger the child, the higher is the incidence and

severity of propofol injection pain [9]. This could be due

to the smaller veins in children. There is no gender

difference in the incidence of propofol injection pain.

Propofol has a high incidence of pain on injection whencompared to other intravenous anaesthetic agents. The

incidence of pain on induction with thiopentone is about

7% [5], whereas with methohexitone it varies between

12% and 64% [10, 11]. Diazepam in the organic solvent

propylene glycol (Valium) has an incidence of pain on

injection of 37% but this becomes 0% when diazepam is

reformulated in soya bean oil (Diazemuls) [10]. Pain on

injection is infrequent with midazolam at 1% [10]. The

incidence of pain after etomidate administration varies

between 24% and 68% [12, 13].

This article reviews the chemical properties and prepara-

tions of propofol, the postulated mechanisms for causing

injection pain and methods that have been investigated to

minimise the incidence of pain.

Chemical properties and preparation o fpropofol

Propofol is a hindered phenol that is chemically dissimilar

to any other compounds used in anaesthesia. It has a

molecular weight of 178 Da and is a colourless liquid at

room temperature. The compound absorbs light in the

ultraviolet range of the electromagnetic spectrum

(lmax275 nm) and fluoresces at 310 nm with an excita-

tion wavelength of 276 nm. Fluorescence detection with

high-performance liquid chromatography forms the basis

of the blood concentration assay technique.

Propofol was initially formulated as a 2% solution in

16% polyethylated castor oil (Cremophor EL) and 8%ethanol because of its low aqueous solubility and then as a

1% solution in 16% Cremophor EL. However, it was

reformulated in a soyabean emulsion because of concerns

over the high incidence of injection pain with this pre-

paration and in order to avoid Cremophor-related reac-

tions [14]. The currently available preparation is a 1% w/v

aqueous emulsion containing 10% w/v soya bean oil (as a

solubilising agent), 1.2% w/v egg phosphatide (as an

emulsifying agent) and 2.25% w/v glycerol (to make the

preparation isotonic), sealed under nitrogen. The pH is

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468 19 98 Blackw e llScien ce Ltd


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aqueous phase, the incidence of pain associated with

propofol injection could be reduced.

Clinical strategies for the prevention of

propofol injection pain

Based on the proposed mechanisms and factors associated

with propofol injection pain, several methods for the

prevention of pain have been tried with varying degrees

of success. Published studies have produced differing results,

in part because of different methodologies.

The methods which have been investigated so far

include: site of injection, use of aspirin and other non-

steroidal anti-inflammatory drugs, premedication, speed of

injection, speed of carrier intravenous fluid, the use of

local anaesthetics, dilution of propofol, different tempera-

tures, opiates, metoclopramide, glyceryl trinitrate, thio-

pentone, ketamine, different syringe material and theaspiration of blood.

Site of injection

With the Cremophor EL preparation, there was a marked

association between the site of injection and the incidence

of pain on injection. Briggs et al. [15] reported a 39%

incidence when it was injected into the dorsum of the

hand compared with a 3% incidence in the forearm or

antecubital fossa. While the pain is less with the emulsion

preparation, the relationship between pain and the site of

injection still applies. Briggs and White [25] reported that

pain on injection was rare in the antecubital fossa but was a

frequent occurrence (30%) in the dorsum of the hand.

McCulloch and Lees [26] produced similar results: the

incidence of pain was 37.5% using dorsal hand veins

compared to 2.5% when a forearm vein was used. Scott

et al. [22] pointed out that using a vein in the antecubital

fossa for the administration of propofol was the only

approach that caused no pain. Hannallah et al. [27] also

showed a low incidence of propofol injection pain in

children when using the antecubital veins. The proposed

reason for this observation is that the antecubital veins are

larger and contact between drug and endothelium is

reduced, as the drug tends to stay in the midstream of

the blood flow in a large vein.

Aspirin and other nonsteroidal anti-inflammatory

drugs

Studies on the use of nonopioid analgesics to decrease pain

on injection have been performed. Baharet al. [28] showed

that pretreatment with acetyl salicylic acid 1 g given

intravenously 15 min before propofol injection signifi-

cantly reduced the incidence of severe pain from 70% to

20% but did not reduce the overall incidence of pain.

Smith and Power [29] found a similar incidence of pain in

a group of patients given an intravenous injection of

ketorolac 10 mg immediately before intravenous injection

of propofol and in a control group not given ketorolac.

They suggested that this was because either ketorolac does

not block local vascular endothelial prostaglandin synth-

esis, because prostaglandins are not important in the

pathogenesis of the pain or because a longer time is

required for an effect to be produced.

Premedication

Nicolet al. [30] reported that the use of oral premedica-

tion made no difference to the incidence of propofol

injection pain. However, Briggs and White [25], using

pethidine and atropine as premedication, found that

although the incidence of painful injection with propofol

was not reduced, the severity of pain was less. Fragen et al.

[31] found that premedication with an opiate and a

sedative reduced the incidence of injection pain. Thismay be due to the additive effect of both drugs on

increasing the pain threshold.

Speed of injection and speed of infusion of carrier

intravenous fluid

At a slow rate of propofol injection, the contact between

the endothelium and the active component of propofol is

more prolonged. This results in mediator release, while a

high rate of injection allows the propofol to be cleared

from the vein and replaced with blood. This suggestion

was put forward by Scott et al. [22], who found that

decreasing the speed of propofol injection caused the

greatest discomfort.

When the speed of carrier intravenous fluid infusion is

slow, fewer kininogen molecules may be produced as a

result of the smaller contact area between the propofol and

the endothelium of the vein, due to the smaller volume

of carrier intravenous fluid given. In addition to this,

propofol may be buffered by the dilutional effect of

venous blood. However, when the speed of infusion of

the carrier intravenous fluid is fast, the dilutional effect

of venous blood will be decreased by the large amount

of intravenous fluid injected and the propofol is therefore

diluted mostly by the aqueous solution. The intensity of

pain associated with propofol will therefore be increased,as there is an increase in propofol concentration in the

aqueous phase. These findings were reported by Huang

et al. [32].

Lignocaine

The use of lignocaine to prevent propofol injection pain

is the most extensively studied technique and is the

commonest method used in clinical practice. Many studies

have shown the use of lignocaine to be effective. The

manufacturer of propofol now recommends this approach.

C.H. Tan andM.K.Onsiong Pain on injection of propofol A naesthesia,1998,53,pages 468 476................................................................................................................................................................................................................................................



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Two methods have been studied: pretreatment with

lignocaine and mixing it with the propofol.

Lignocaine pretreatment

The use of lignocaine as a pretreatment to decrease

propofol injection pain is based on its presumed local

anaesthetic effect on the vein. Due to the different

methodologies used in the studies, different reductions

in the incidence of pain associated with propofol injection

have been reported. McCulloch and Lees [26] showed that

the administration of lignocaine 10 mg immediately before

propofol injection reduces the incidence of pain from

37.5% to 17.5% when using the veins in the back of the

hand. This result was not statistically significant. However,

Ganta and Fee [33] reported that the incidence of pain

using lignocaine 10 mg immediately before propofol

injection was significantly reduced from 49.4% to 21.1%.

The difference between the two studies could be due tothe premedication used and the different speeds of propo-

fol injection. McCulloch and Lees did not use premedica-

tion and administered propofol over 20 s, whereas Ganta

and Fee used diazepam 10 mg as premedication and

administered the propofol over 30 40 s. Lyons et al. [34]

reported that pretreatment with lignocaine 10 mg 10 s

before propofol injection could significantly reduce the

incidence of injection pain from 64% to 44%. Nicol et al.

[30] reported that lignocaine 10 mg 15 s before propofol

administration into veins in the back of the hand could

significantly reduce the incidence of pain from 51% to

35%. Mangar and Holak [6] found that administering

lignocaine 100 mg 1 min before propofol injection

reduced the severity but not the incidence of pain, whereas

lignocaine 100 mg administered after an arm tourniquet

was inflated to 50 mmHg for 1 min (a modified Biers

block) virtually abolished the pain associated with propofol

injection. Ewart and Whitwam [35] found that the inci-

dence of pain increased with an increased time interval

between the injection of the two drugs. Lignocaine 20 mg

was injected into a dorsal hand vein with a tourniquet

placed on the proximal part of the forearm in order to

produce a mini-Bier block. The tourniquet was released

after varying time intervals and propofol was then injected.

Pain was significantly reduced in the groups given ligno-caine 10 or 30 s before propofol. Their study showed that

lignocaine was effective at reducing pain when given

before propofol.

Lignocaine mixed with propofol

The rationale behind the use of lignocaine mixed with

propofol is based on the premise that lignocaine may act as

a stabiliser for the kinin cascade, as proposed by Scott et al.

[22]. Recently, another mechanism was proposed by

Eriksson et al. [36]. They showed that lignocaine mixed

with propofol decreased its pH, resulting in a lower

concentration of propofol in the aqueous phase and there-

fore less pain. Several studies using different doses of

lignocaine have shown that the technique is effective in

decreasing the incidence of pain associated with propofol

injection. Brookeret al.[37] found that lignocaine 7.5 mg

mixed with propofol 142.5 mg before injection was associ-

ated with a decrease in the incidence of pain from 57%

to 7%. However, this was only a pilot study and there was

no randomisation, variable premedication and the admin-

istration of different opiate drugs before propofol injec-

tion. Helbo-Hansen et al. [38], in their double-blind

randomised trial, found that the addition of lignocaine

10 mg to propofol 190 mg could significantly reduce the

incidence of pain from 32.5% to 5%. The severity of pain

was also reduced.

Similar results have been found in other double-blind

randomised studies. Newcombe [39] reported that mixinglignocaine 10 mg with propofol could significantly reduce

the severity and incidence (from 86.9% to 48.9%) of pro-

pofol injection pain. Nathanson et al. [40] also reported

that the incidence of propofol injection pain could be

reduced significantly from 67% to 13% using lignocaine

40 mg mixed with propofol before injection. King et al.

[41], in their study on different doses of lignocaine mixed

with propofol, found that lignocaine 20 mg significantly

reduced the incidence of injection pain from 73% to 32%.

There was an inverse relationship between the amount of

lignocaine used and the incidence of pain.

Similar results have been obtained in children. Valtonen

et al.[8] found that lignocaine 10 mg mixed with propofol

2.02.5 mg.kg1 significantly decreased the incidence of

pain caused by propofol as compared to a control group

(from 85% to 20%). Hiller and Saarnivaara [42] found that

mixing lignocaine 10 mg with propofol significantly

reduced the incidence (from 40% to 4%) of injection

pain in children when compared to pretreatment with

alfentanil 10mg.kg1.

The efficacy of lignocaine mixed with propofol may

be weight-related. Gehan et al. [43] showed that the

optimum dose for preventing propofol injection pain

was 0.1 mg.kg1 in adults and that there was no improve-

ment when the dose was increased above this. Tham andKhoo [44] found that the optimum minimum dose

required for the effective reduction of propofol injection

pain was a propofol emulsion containing 0.05% ligno-

caine. Gajraj and Nathanson [45] reported that the opti-

mum lignocaine dose mixed with propofol 160 mg in

adult females was 30 mg. However, the optimum dose of

lignocaine needed to prevent propofol injection pain

appears to be higher in children. Cameron et al. [9], in

their study on the minimum effective dose of lignocaine to

prevent propofol injection pain in children, found that

A naesthesia,1 99 8,53,pages 468 476 C.H.TanandM.K.Onsiong P ain on injection of propo fol................................................................................................................................................................................................................................................

471 19 98 Blackw ellScien ce Ltd


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0.2 mg.kg1 was needed. This is twice the adult value and

may be related to the higher volumes of distribution in

children compared to adults.

Lignocaine comparisons between pretreatment and mixing

Studies have been performed to compare the effectiveness

of lignocaine pretreatment and lignocaine mixed with

propofol. Scott et al. [22] found that lignocaine mixed

with propofol was more effective than pretreatment with

lignocaine in decreasing propofol injection pain. They

reported a significant decrease in the incidence of pain

from 46.7% to 13.5% by mixing lignocaine 10 mg with

propofol as compared to pretreatment with lignocaine

10 mg 30 s before propofol injection (from 46.7% to

40%). However, there was no mention of observer blind-

ing. Scott proposed that lignocaine may act as a stabiliser

for the kinin cascade when mixed with propofol whereas

lignocaine injected before propofol may be washed awayin the blood before the arrival of the propofol bolus,

making less lignocaine available. Johnson et al. [46] found

no significant difference between a group of patients that

received lignocaine pretreatment and a group that received

propofol mixed with lignocaine. Pain was significantly

reduced in all groups in which lignocaine was used and a

40 mg dose was more effective than 20 mg. A factor which

may have given rise to this result is that venous occlusion

was used before injection in the pretreatment group. This

may have enhanced the local anaesthetic effect.

Procaine

Nicol et al. [30] found that procaine was comparable to

lignocaine in significantly reducing propofol injection pain

from 51% to 34% when procaine 10 mg was injected 15 s

before propofol.

Prilocaine

Eriksson [47] found that prilocaine mixed with propofol

was comparable to lignocaine in significantly reducing the

incidence of pain caused by propofol injection.

Eutectic mixture of local anaesthetics (EMLA)

Valtonen et al. [7] found that the use of topical EMLA

cream in children did not significantly reduce pain oninjection with propofol.

Dilution

Dilution of propofol with either glucose or intralipid

decreases the concentration of propofol, which results in

a decrease in the incidence of pain. This is based on the

findings by Stokeset al. [48], Klement and Arndt [23] and

Doenicke et al. [24]. They proposed that pain associated

with propofol injection is directly related to propofol

concentration in the free aqueous phase. Stokes et al.

[48] found that dilution of propofol with 5% dextrose

was able to reduce significantly the incidence of severe

pain from 32% to 10% and all pain from 50% to 24%.

Klement and Arndt [23] reported that the dilution of pro-

pofol with 10% intralipid was more effective than dilution

with 5% glucose in decreasing propofol injection pain,

while Doenickeet al. [24] showed that propofol injection

pain could be reduced further when a higher concentra-

tion of fat emulsion was used in the propofol formulation.

Temperature

McCrirrick and Hunter [49] studied the effect of injectate

temperature on propofol injection pain. They found that

when giving propofol at 4 C, the incidence of injection

pain could be significantly reduced from 46% to 23%. The

efficacy of propofol was not affected. They postulated that

a temperature of 4 C might decrease the speed of the

kinin cascade. Cold saline was used by Barkeret al.[50] todecrease the incidence of propofol injection pain. They

found that pretreatment with 0.9% saline 10 ml at 4 C

before propofol injection was comparable to cold propofol

(4 C) and room temperature propofol mixed with 0.05%

lignocaine in significantly reducing the incidence of pro-

pofol injection pain. There was no significant difference

between the treatment groups.

Fletcher et al. [51] found that warming propofol to

37 C significantly decreased the incidence of propofol

injection pain from 59% to 22%. They suggested

two mechanisms: that the temperature may have affected

mediator release and that the high temperature may affect

the partition coefficient and therefore the concentration of

propofol in the aqueous phase. However, extreme care is

needed to avoid contamination of the propofol with water

from the water bath used to warm the injection. Bennett

et al. [52] have recently reported an analysis of multiple

outbreaks of postoperative infection related to the use of

extrinsically contaminated propofol.

Alfentanil and fentanyl

The use of opioids, especially short-acting drugs such as

alfentanil and fentanyl, was observed to decrease the

incidence of pain on injection of propofol. Several studies

have confirmed these observations. Helmers et al. [53]found that using alfentanil 0.5 mg as a pretreatment before

propofol injection was effective in significantly reducing

the incidence of propofol injection pain from 40% to 16%,

while studies by Fletcher et al. [54] and Nathanson et al.

[40] showed that pretreatment with alfentanil 1 mg 15 and

30 s before propofol injection in adults could significantly

reduce propofol injection pain from 84% to 36% and 67%

to 24%, respectively. Hiller and Saarnivaara [42] found that

the optimum dosage of alfentanil in children to reduce

propofol injection pain was 15mg.kg1.




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Opioids may work by either a central or a peripheral

effect. Wrench et al.[55] suggested that it is unlikely that

alfentanil has an effect on peripheral opioid receptors

because alfentanil, when limited to the forearm for 30 s

before propofol injection, did not decrease the incidence

of pain associated with propofol injection. However, it is

difficult to explain how alfentanil could act so quickly on

central opioid receptors when given only 15 30 s before

propofol.

Different results have been reported with the use of fen-

tanyl. Baharet al.[28] found that fentanyl 0.1 mg 3 5 min

before propofol injection reduced the severity of pain but

not its overall incidence. However, Helmers et al. [53]

reported a significant reduction in the incidence of pro-

pofol injection pain from 40% to 16% with the use of

fentanyl. The difference between Bahar and Helmers

study could be due to the different formulations of pro-

pofol and the number of patients studied. Bahar usedpropofol in Cremorphor EL whereas Helmers used the

soyabean propofol emulsion. Bahars study group com-

prised only 10 patients while Helmers studied 50 patients.

Pethidine

Lyons et al. [34] showed that pethidine 25 mg given 10 s

before propofol reduced the severity and incidence (from

64% to 35%) of propofol injection pain and that it was

more effective in women. This could be due to the higher

dose of pethidine per kilogram in women compared to

men. They also proposed that pethidine, besides having

local anaesthetic and analgesic effects, may have a different

pharmacodynamic effect in the two sexes.

Metoclopramide

Metoclopramide is an anti-emetic with a weak local

anaesthetic action. Ganta and Fee [33] noted its ability to

decrease the incidence of pain associated with propofol

injection. They showed that metoclopramide 5 mg, given

immediately before propofol into a dorsal hand vein, when

compared to lignocaine 10 mg and normal saline was

equally effective as lignocaine in reducing propofol injec-

tion pain (pain in metoclopramide group: 23.5%, lignocaine

group: 21.1%, control group: 49.4%). They postulated that

metoclopramide may act by reducing spasm in the veins.Mecklem [56] compared metoclopramide 20 mg mixed

with propofol 200 mg and lignocaine 10 mg mixed with

propofol 200 mg in the prevention of propofol injection

pain. He found that both groups had a similar incidence of

injection pain, with less nausea occurring in the metoclo-

pramide group.

Glyceryl trinitrate

Wilkinson et al. [57] showed that by applying a glyceryl

trinitrate 5 mg patch to the dorsum of the hand 20 min

before propofol injection, the incidence and severity of

propofol injection pain could be significantly reduced

from 67% to 33%. No headache or postural hypotension

was reported. They postulated that vein size, vasospasm

and blood flow are important factors in determining the

pain associated with propofol injections. Glyceryl trini-

trate causes venodilation, which increases venous flow,

dilutes the drug and reduces the contact between the

propofol and the vessel wall.

Thiopentone

Leeet al.[58], in their study comparing the effect of prior

administration of thiopentone 100 mg with lignocaine

20 mg and saline before propofol injection, found that

thiopentone was significantly more effective than ligno-

caine in reducing propofol injection pain (control: 50%,

thiopentone: 12% and lignocaine: 28%). The mechanism

is unknown but they suggested that it could either be acentral or a peripheral action. Its central action could be a

synergism between subhypnotic doses of thiopentone and

propofol. Its peripheral action could be a local mechanism

affecting the release of kinins, changes in pH or the effect

of thiopentone on the lipid solubility and free aqueous

concentration of propofol. Haugen et al. [59] found that

pretreatment with thiopentone 50 mg did not reduce the

incidence but did reduce the severity of the pain. The dif-

ference between the two studies could be due to the

different doses of thiopentone and lignocaine being used

and the speed of injection of propofol. Lee used 100 mg of

thiopentone, which could impair adequate pain assess-

ment, while Haugen used only 50 mg of thiopentone. Lee

studied a group given lignocaine 20 mg and Haugen

studied a group given lignocaine 40 mg. Lee administered

propofol 4 ml over 48 s while Haugen administered

propofol at 1 mg.kg1.min1.

Ketamine

Tan et al. [60] found that pretreatment with ketamine

10 mg in normal saline 1 ml 30 s before propofol signifi-

cantly reduced the incidence of pain during propofol

injection from 84% to 26%. They postulated that the

mechanism is the result of a peripheral local anaesthetic

action that attenuated the afferent pain pathway, ratherthan a central analgesic effect because of the low dose used

( 0.2 mg.kg1).

Syringe material

The manufacturer of propofol has shown that it strips off

the silicone lubricant in disposable plastic syringes. Lomax

[61] suggested that propofol injection pain is due to the

production of irritant substances produced when propofol

comes into contact with plastic disposable syringes. He

went on to show that the incidence of pain due to propofol




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injection could be significantly reduced from 33% to 16%

when glass syringes were used instead of plastic syringes.

Aspiration of blood

A study of the buffering effect of blood in reducing the

pain associated with propofol injection was undertaken byMcDonald and Jameson [62]. They found that the aspira-

tion of 2 ml of the patients blood into a syringe of propofol

immediately before injection was significantly more effec-

tive in reducing pain than the addition of saline 2 ml to the

propofol, and that the technique was not significantly

more effective than the addition of lignocaine 20 mg to

propofol (saline: 58%, blood: 13%, lignocaine: 18%). They

suggested that blood may alter the free aqueous concen-

tration of propofol or that the initial release of kinins by

propofol may be reduced by the initial injection of blood

back into the patient.

Conclusions

The cause of pain on intravenous administration of various

drugs including propofol is not known. Although several

mechanisms for propofol injection pain have been pro-

posed, they are not based on any hard physiological data.

Many methods have been tried, with varying success, to

reduce the incidence and severity of propofol injection

pain. This may suggest the involvement of multiple mech-

anisms, receptors or factors. Further research in this field

is required.

Currently, a wise choice would be to use a combination

of techniques, such as alfentanil pretreatment, mixinglignocaine with the propofol and injecting into a large

vein with no carrier fluid in order to decrease the

incidence and severity of propofol injection pain.

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Propofol Pain