Propofol at conscious sedation doses produces mild analgesia to cold pressor-induced pain in healthy volunteers

ELSEVIER

Propofol at Conscious Sedation Doses Produces Mild Analgesia to Cold Pressor-Induced Pain in Healthy Volunteers James P. Zacny, PhD, * Dennis W. Coalson, MD,-/Christopher J. Young, MD,? Jerome M. Klafta, MD,-/J. Lance Lichtor, MD,1 Gita Rupani, MD,? Pankaj Thapar, MD,5 Jeffrey L. Apfelbaum, MD$ Department

of Anesthesia

and Critical

Care, University

of Chicago,

Chicago,

IL.

objective: To determine whether subanesthetic doses of firopofol have analgesic effects in healthy volunteers. Design: Prospective, double-blind, placebo-controlled, randomized, crossover trial. Setting: Human psychomotor perfbrmance laboratory within our anesthesia and critical care department. Subjects: 12, non-drug abusing volunteers, aged 22 to 38 years. Interventions: Five drug conditions were used in which a loading injection was followed by a 20-minute infusion period: placebo [saline (Intralipid)] injection, Intralipid infusion; propofolO.125 mg/kg i?v’ection, propofol 12.5 mcg/kg/min infusion; propofol 0.25 mg/kg injection, propofol25 mcg/kg/ min infusion; propofo10.5 mg/kg injection, propofol 50 mcg/kg/min infusion; fentaxyl 1.4 mcg/kg injection (positive control), Intralipid infusion. Five minutes into the infusion period and 115 minutes after the infusion period was terminated, subjects immersed their forearms in ice-cold water for three minutes while pain assessments were recorded. Measurements and Main Results: Propofol at the two higher doses during part of the first immersion produced a signi&ant reduction (p c 0.05) in pain intensity and bothersomenessratings. However, relative to fentanyl, the analgesia was mild. Propofol did not affect any ra.tings on the 15-item short-form McGill Pain Questionnaire, whereas fentanyl reduced 10 of the ratings. Conclusion: Our laboratory results are consistent with the commonly accepted clinical practice of supplementing propofol with an opioid in conscious sedation procedures to provide a satisfactory level of pain relief: Study

*Assistant Professor of Anesthesia and Critical Care, and Assistant Professor of Psychiatry tAssistant Professor of Anesthesia and Critical Care TAssociate Professor of Anesthesia and Critical Care §Fellow in Anesthesia and Critical Care Address correspondence and reprint requests to Dr. Zacny at the Department of iinesthesia and Critical Care, MC4028, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA. Supported in part by a grant from the Clinical Practice Endowment and Anesthesia Research Foundation, University of Chicago, Chicago, IL. Received for publication August 15, 1995; revised manuscript accepted for publication November 20, 1995.

Keywords:

Analgesia,

intravenous:

fentanyl;

propofol;

mood; pain.

Introduction Propofol is an intravenous (IV) anesthetic, which, at subanesthetic doses, is often used to provide conscious sedation for surgical procedures. It is an advantageous drug in that it causes sedation that is readily tirratable by the anesthesiologist, has amnestic properties,’ and is associated with a rapid recovery profile. While propofol is not typically thought of as an analgesic, several recent

Journal of Clinical Anesthesia 8:469-474, 1996 0 1996 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

0952-8180,‘96/$15.00 PI1 SO952-8180(96)00126-2

Original Contributions

animal and human studies have examined the potential of this drug to induce analgesia. The results have been somewhat mixed, but overall lend credence to the notion that this drug in some situations may induce analgesia. We undertook this study to determine if propofol, when administered at doses commonly used during conscious sedation procedures, produces analgesia. In isolated neonatal rat spinal cord, propofol in a doserelated manner depressed the slow ventral root potential (the activity of which increases nociception) and increased amplitude of the dorsal root potential (the activity of which decreases nociception). In addition, propofol depressed the ventral root potential when the cord was exposed to substance P, which is a peptide neurotransmitter thought to be involved in nociception.’ In another study, subhypnotic and non-sedating doses of propofol in a dosedependent fashion retarded tail withdrawal latencies on the tail flick test and decreased acetic-acid induced writhbut ing in mice.3 In a third animal study, pentobarbital, not propofol, produced preemptive analgesia in rats4 Studies examining the effects of propofol on the pain response in humans have been conducted in both patients and healthy volunteers. In one patient study, propofol 0.25 mg/kg and 0.5 mg/kg decreased the amount of pain (as measured by pain threshold and tolerance) induced by tibia1 pressure algesimetry.5 In a second patient study, propofol in an 0.5 mg/kg bolus and an 83.3 mcg/kg/min infusion did not alter thermal pain detection thresholds (relative to baseline levels) .6 In volunteers, acute pain evoked by argon laser stimulation to the hand, and measured by pain threshold and pain-evoked potentials, was reduced by propofol 0.25 mg/kg, relative to saline.’ In another volunteer study, pain induced by thermal stimulation was increased by low steady-state infusions of propofol16.6 mcg/kg/min, but decreased by a higher steadystate infusion (83.3 mcg/kg/min) .* The majority of animal and human studies reviewed above suggest that propofol has analgesic effects, but other studies cited have provided inconsistent results. In the present study, we examined different doses of propofol up to doses that are typically used in ambulatory anesthesia, to determine its effects on cold pressor-induced pain. We used pain measurement assays that assessed the sensory and/or the affective components of pain. In addition, we also examined the subjective effects of propofol, both during and in the absence of the cold water immersion, to determine if a painful stimulus modulates the mood-altering effects of this drug.

Table

1.

1.

3. 4.

5.

470

and Methods

Subjects Five non-pregnant females and seven males participated in our study, which was approved by the University of Chicago Institutional Review Board. The mean (*SD) age was 27.3 f 5.5 years. They had been previously screened by a member of our research staff to ensure they had no psychiatric (including drug abuse disorders) or medical contraindications to participating in the study. In addition, prior to entry into the study, participants underwent a physical examination and resting electrocardiogram, and they reported no prior adverse reactions to general anesthesia. Written informed consent was obtained during a practice session. Subjects were paid for their participation on completion of the study.

Exfxrimental

Design

A randomized, placebo-controlled, double-blind, crossover trial was conducted. In all five sessions, subjects who were randomized via an incomplete Latin Square Design, received two immediately-successive injections (each delivered over a 15-second interval) followed by a 20-minute infusion. Conditions are listed in Table 1 and included a placebo (Intralipid, Pharmacia, Clayton, NC) control, a positive control, fentanyl, and three doses of propofol. The doses of propofol and fentanyl tested are within the range of clinical doses given for conscious sedation and/ or pain relief. To minimize drug carryover effects, a minimum of 72 hours separated one session from another. Time line of events and assessments are listed in Table 2.

Experimental Sessions On arrival in the laboratory for each session, an IV catheter was inserted into a vein in the subject’s dominant upper extremity. Noninvasive monitoring equipment intermittently measured and recorded heart rate, blood pressure, and arterial oxygen saturation during the session. To assess the subjective effects of propofol, the subject then was given a locally-developed visual analog scale (VAS), which consisted of twenty 100 mm lines, each labeled with an adjective (eg, high, anxious, sedated, dizzy). Subjects were instructed to place a mark on each line indicating how they felt at the moment, ranging from the two endpoints “not at all” (0) to “extremely” (100). The

Drug Conditions Injection

2.

Materials

1

saline saline saline saline fentanyl 1.4 mcg/kg

J. Clin. Anesth., vol. 8, September 1996

Injection

placebo propofol propofol propofol Intralipid

2

(Intralipid) 0.125 mg/kg 0.25 mg/kg 0.50 mg/kg

Infusion

Intralipid propofol 12.5 mcg/kg/min propofol 25 mcg/kg/min propofol 50 mcg/kg/min Intralipid

Propof Table 2.

and pa&: Zacny et al.

Time Line of Events

Event or Measurement

BL

0

2

5

15

30

60

90

120

135

150

180

X

X

X X

injections Infusion* Immersiont Pain ratings

X X

X X

VAS

X

BP/HR

X

X

X

X

X

X

X

X

X

X

X

BL = baseline; VAS = visual analog scale; BP = blood pressure; HR = heart rate. *Infusion was 20 minutes in duration, which followed the two successive injections. i-Immersion periods were 3 minutes in duration (5 to 8 minutes and 135 to 138 minutes).

VAS took approximately 1 minute to complete. Following this baseline testing, two syringes containing either drug or placebo were each administered intravenously over I5 seconds, and then the infusion was started using a Baxter Infusion Pump Model AS20GH-2 (Baxter Health Care Corp, Deerfield, IL). During the injection and infusion period, the vital signs of the subject were intermittently recorded. Two minutes after the infusion pump was activated, the VAS was again administered, as well as 15, 30, 60, 90, 120, 150, and 180 minutes after pump activation. Five minutes after pump activation, the cold pressor test was initiated. The cold pressor test is a well accepted pain assay that reliably produces pain of a tonic as opposed to phasic nature.g The cold pressor apparatus consisted of a standard ice chest divided into two compartments by a wire screen. The tank was filled with water, and ice was added to one side of the screen. A cradle for the subject’s forearm was positioned in the side of the chest with no ice and allowed the subject to rest the nondominant forearm for 180 seconds while immersing it into the cold water. The water in the ice chest was constantly circulated by an aquarium pump and was maintained at 2.0” + 1.0%. At 30 seconds, 70 seconds, 110 seconds, and 170 seconds after onset of the cold-water immersion, the subject verbally reported how much pain he or she felt on a scale of 0 (not at all painful) to 10 (extremely painful) and how much the pain was bothersome on a scale of 0 (not at all bothersome) to 10 (extremely bothersome). The subject completed the short-form McGill Pain Questionnaire (SFMPQ)r’ 80 seconds after the onset of immersion, and the VAS was done beginning at 120 seconds after the onset of immersion. The SF-MPQ consists of 15 descriptors (eg, throbbing, shooting, stabbing) that represent the sensory and affective dimensions of the pain experience. Each descriptor is ranked on an intensity scale from 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). The descriptors, which represented the affective dimensions of the pain experience, were tiring-exhausting, sickening, fearful, and punishing-cruel. The cold pressor test was repeated at 135 minutes post-pump activation to determine if propofol had residual analgesic effects after its infusion had been terminated. Repeated measures analysis of variance (ANOVA) was used for statistical treatment of the data. Propofol was compared with placebo, and this served as the primary

data analyses. In the pain intensity and bothersomeness analyses, factors were propofol dose (four levels), trial (7 minutes and 137 minutes postinjection), and time (30, 70, 110, 170 seconds intra-immersion). In the SF-MPQ rating analyses, factors were dose and trial. In addition, using pain reports as the dependent measures, fentanyl was compared with placebo in separate analyses. In the other analyses (ie, mood, physiologic measures), factors were propofol dose and time ( 2 to 9 levels). In addition, VAS ratings during the first immersion (while propofol was being administered) were subjected to a separate analysis to determine the effects of propofol in the presence of a painful stimulus. F-values were considered significant for a p-value less than or equal to 0.05, with adjustments of within-factors degrees of freedom (Huynh-Feldt) to protect against violations of symmetry. When significant (p < 0.05), dose, dose x trial, or dose x time interactions were obtained, Tukey post hoc comparison tests were done.

Results When examining propofol’s effects on the pain response, a significant dose x trial x time interaction was obtained on both pain intensity [F(Q,QQ) = 2.0, p < 0.051 and pain bothersomeness [F(Q,QQ) = 2.1, p < 0.051 ratings. During the first time point of the first immersion, pain ratings did not differ across conditions. However, during one or more of the later three time points of the first immersion (ie, during the infusion period), ratings were significantly lower with the two higher propofol doses than with placebo (Figure 1). Pain intensity and bothersomeness ratings were significantly lower in the fentanyl condition than placebo ratings during the first cold-water immersion, and this was observed during all four time points of the immersion [pain intensity, dose x trial: F(l,ll) = 39.1, p < 0.001; pain bothersomeness, dose x trial: F(l,ll) = 23.5, p < O.OOl]. The degree of pain reduction by fentanyl was nearly twice that of the high dose of propofol (Figure 1). By the second cold-water immersion, neither propofol nor fentanyl pain ratings were different from that of placebo. Propofol did not affect any of the pain adjective ratings from the SF-MPQ. In contrast, ten adjective ratings (ie, aching, cruel, gnawing, hot-burning, sharp, shooting, splitting, stabbing, tender, throbbing) were significantly reduced by fentanyl, relative to placebo. J. Clin. Anesth., vol. 8, September 1996

471

INTENSITY

aI--

BOTHERSOMENESS 8

7

7

rating

rating 6

6

5

3b

' 70

li0

' 170

4

r

TIME (set) 1. Effects of placebo (Intralipid) and propofol (PROP) on mean pain intensity and pain bothersomeness ratings (possible range of 0 to 10) during the first immersion trial (5 to 8 minutes post-injection). Ratings were taken at 30 seconds, 70 seconds, 110 seconds, and 170 seconds during immersion. Asterisks indicate when a propofol dose differed significantly from placebo at a given time point, as determined by Tukey post hoc testing. For comparison purposes, the mean intensity and bothersomeness ratings from the fentanyl (FENT) condition are also shown. For pain intensity ratings, standard errors of the means in the saline, low-dose propofol, moderate-dose propofol, high-dose propofol, and fentanyl conditions ranged from 0.59 to 0.63, 0.56 to 0.61, 0.60 to 0.71, 0.48 to 0.58, and 0.52 to 0.55, respectively. For pain bothersomeness ratings, standard errors of the means in the saline, low-dose propofol, moderate-dose propofol, high-dose propofol, and fentanyl conditions ranged from 0.78 to 0.84, 0.79 to 0.86, 0.80 to 0.90, 0.72 to 0.78, and 0.66 to 0.70, respectively. INF = infusion. Circles = placebo plus infusion; diamonds = 0.125 mg/kg propofol dose plus infusion; open squares = 0.25 mg/kg propofol dose plus infusion; triangles = 0.5 mg/kg propofol dose plus infusion; and close squares = 1.4 pg/kg fentanyl dose. Figure

Mood changes induced by propofol were examined in two different analyses: one examining propofol effects during baseline and the non-immersion time points, and the second analysis examining effects during the first immersion time point, while propofol (or placebo) was being administered. In nine cases, there were discrepancies between the analyses. Subjects reported increased ratings of “carefree,” “confusion,” “dizzy,” “drunk,” “elated,” “having pleasant bodily sensations,” and “sedated” during propofol infusion in the absence of the cold-water immersion; these effects of propofol were absent in the analysis that included the cold-water immersion. Conversely, subjects reported increased ratings of “having unpleasant bodily sensations” and decreased ratings of “feeling in control of body” during propofol infusion within the first cold-water immersion, but they did not report changes in these ratings in the absence of the immersion. This may indicate that pain had a modulating influence on the mood-altering effects of propofol. In both analyses, the relationship between propofol and mood was doserelated, with higher doses eliciting more extreme ratings. The cold-water immersion had a pressor effect, in that it significantly increased systolic blood pressure (SBP) and diastolic blood pressure (DBP), relative to baseline values (time effects: p < 0.05) _A significant dose x time effect was 472

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Anesth.,

vol. 8, September 1996

obtained with SBP [F(6,66) = 3.5, p < 0.011. During the first cold-water immersion, SBP was significantly lower in the high-dose propofol condition than in the placebo condition. A similar trend was noted with DBP, but the effect was not significant [dose x time: F(6,66) = 2.0, p < 0.081. Heart rate was unaffected by propofol or the cold-water immersion manipulation.

Discussion Propofol at the two higher doses tested had an analgesic effect as measured by ratings of intensity and bothersomeness of the pain. However, the reduction in pain ratings was only apparent after approximately one or two minutes into the cold-water immersion period. Further, another pain assay (SF-MPQJ did not detect the analgesic effects of propofol. In contrast, the analgesic effects of fentanyl effects were apparent at all the time points in which pain was assessed during immersion, and the degree of analgesia was at least twice as great as that of the higher doses of propofol. Further, fentanyl decreased a number of pain ratings as measured on the SF-MPQ. Thus, while propofol did show some analgesic effect on the cold pressor test, the degree of analgesia was mild at best, and it was inconsis-

Propofol and pain: Zacny et al.

tent (ie, not evident at all time points and not evident by the SF-MPQ) There are several caveats to our findings. First, perhaps propofol at some other time during the ZO-minute infusion period had greater pain-reducing effects. Based on the pharmacokinetics of propofol, the highest brain levels were most likely for several minutes immediately after the However, the plasma levels would be bolus injection.” decreasing during this time period due to propofol’s rapid distribution and clearance rates.” Hence, an infusion period was incorporated into the design in an attempt to achieve close to steady-state plasma levels (although this level was not measured), and pain responses were not tested until it was thought that propofol levels would be more stable in the brain (ie, 5 to 8 minutes after the offset of the bolus and the onset of the infusion). Another caveat is that if a higher dose of propofol had been tested, greater analgesia might have been detected. The 0.5 mg/kg bolus dose along with the accompanying infusion of 50 mcg/kg/min is a dosage regimen that is clinically relevant for conscious sedation procedures. However, it is possible that subjects still could have responded to the pain assessment battery during the infusion had even a higher dosage regimen been employed. Our choice of the highest dose of propofol tested was based on ensuring that subjects would be alert enough to complete the cold pressor test and pain assessment battery within the test. It is also possible that other types of pain (e.g., pressure, visceral) might not have been affected by propofol, and this certainly cannot be discounted by the present study. However, a recent study has provided clinical evidence that propofol may have efficacy in relieving pruritis and other symptoms of central pain (spinal cord injuries, facial pain), including allodynia? Our analyses characterizing the subjective effects of propofol both in the presence of a painful stimulus, as well as in its absence, provided some intriguing, albeit preliminary, results. In past studies, healthy volunteers given propofol by either a bolus or a bolus and infusion have reported a pleasant spectrum of subjective effects (including increased “drug liking” ratings) .13,14In the present study, such ratings as “carefree,” “coasting,” “elated,” and “having pleasant bodily sensations,” were significantly elevated when comparing propofol to placebo in the absence of pain, but the ratings were not elevated when tested during the cold water immersion. Whether propofol effects are modulated by a painful stimulus must be considered speculation at this point, however, because plasma levels of propofol were not measured in this study. It is conceivable that plasma levels at the time point when mood was assessed during the first immersion (5 minutes intra-infusion) may have differed from plasma propofol levels taken at other non-immersion time points during the infusion (ie, 2 and 15 minutes). Still, these results are reminiscent of that result obtained in a study in which nitrous oxide increased ratings of “elated” when subjects had their arms immersed in lukewarm water, but not when their arms were immersed in cold water.15 Future studies may want to more systematically examine drug effects (eg; cognitive, psychomotor, and subjective) when subjects are

stressed, which may more closely approximate how patients feel during the perioperative period while experiencing the effects of drugs. The results of this study stand in contrast to that recently obtained in our laboratory with the benzodiazepine midazolam. In that study, midazolam up to a dose of 3 mg per 70 kg of body weight had neither pain-increasing nor The disparate results are somepain-decreasing effectsi what difficult to reconcile because both drugs have mechanisms of action at the GABA-benzodiazepine-ionophore receptor complex. However, propofol and midazolam appear to act at different sites on the receptor complexbenzodiazepines such as midazolam bind specifically at the benzodiazepine receptor site, while propofol is thought to have its actions at the chloride ion channel.17X1s It is admittedly speculation at this point as to whether the different sites of action play a role in the degree to which analgesia is or is not obtained with these drugs. Further research is needed to directly examine potential mechanisms by which propofol exerts its pain-reducing effects. In conclusion, our results are consistent to some extent with those animal and human studies that have demonstrated an analgesic effect of propofol. An analgesic effect of propofol at higher doses was obtained on some, but not all, of our pain assessment measures. At the dosages that were used in the present study, the self-reports of pain reduction were not entirely consistent (ie, obtained with only some measures, not observed at all time points during the cold-water immersion), unlike that observed with the opioid fentanyl. This inconsistent and mild analgesia produced by propofol supports the use of opioid analgesics as an adjunct to propofol sedation for painful surgical procedures.

Acknowledgments The authors would like to thank Ronald Thisted, PhD, for his helpful comments regarding the statistical analysis of the data, and Nada Williamson, CRNA, Robert Shaughnessy, CRNA, Mary Maurer, CRNA, Mark Choi, BA, and Priya Patil, BA, for their assistance in conducting the sessions.

References I. Veselis RA, Reinsel RA, Wronski M, Marino P, Tong WP, Bedford RF’: EEG and memory effects of low-dose infusions of propofol. Br JAnaesth 1992;69:246-54. 2. Jewett BA, Gibbs LM, Tarasiuk A, Kendig.11: Propofol and barbiturate depression of spinal nociceptive neurotransmission. Anesthesiology 1992;77:1148-54, Erenmemisoglu A, Madenoglu H, Tekol Y Antinociceptive effect of propofol on somatic and visceral pain in subhypnotic doses. Cuw Ther f&s 1993;53:677-81. Goto T, MarotaJ, Crosby G: Pentobarbitone, but not propofol, produces pre-emptive analgesia in the rat formalin model. Br J Anaesth 1994;72:662-7. Briggs LP, Dundee JW, Bahar M, Clarke RS: Comparison of the effect of diisopropyl phenol (ICI 35,868) and thiopentone on response to somatic pain. Br JAnaesth 1982;54:307-11. Wilder-Smith OH, Kolletzki M, Wilder-Smith CH: Sedation with J. Clin. Anesth., vol. 8, September 1996

473

Original Contributions

7.

8. 9.

10. 11. 12. 13.

intravenous infusions of propofol or thiopentone. Effects on pain perception. Anaesthesia 1995;50:218-22. Anker-Moller E, Spangsberg N, Arendt-Nielsen L, Schultz P, Kristensen MS, Bjerring P: Subhypnotic doses of thiopentone and propofol cause analgesia to experimentally induced acute pain. Br JAnaesth 1991;66:185-8. Wilder-Smith 0, Borgeat A: Analgesia with subhypnotic doses of thiopentone and propofol [Letter]. Br JAnaesth 1991;67:226-7. Chen AC, Dworkin SF, Haug J, Gehrig J: Human pain responsivity in a tonic pain model: psychological determinants. Pain 1989; 37:143-60. Melzack R: The short-form McGill Pain Questionnaire. Pain 1987;30:191-7. Cockshott ID: Propofol (‘Diprivan’) pharmacokinetics and metabolism-an overview. Postgrad Med J 1985;61 (Suppl 3):45-50. Bradac GB, Bergui M, Canavero S: Propofol analgesia in central pain: preliminary clinical observations. J New01 1995;242:561-7. Zacny JP, Lichtor JL, Coalson DW, et al: Subjective and psycho-

14.

15.

16.

17.

18.

motor effects of subanesthetic doses of propofol in healthy volunteers. Anesthesiology 1992;76:696-702. Zacny JP, Lichtor JL, Zaragoza JG, et al: Assessing the behavioral effects and abuse potential of propofol bolus injections in healthy volunteers. Drug Alcohol Depend 1993;32:45-57. Pirec V, Coalson DW, Lichtor JL, et al: Does cold-induced pain modulate the reinforcing effects of nitrous oxide in healthy volunteers? Exp Clin Psychopharmacol1995;3:148-55. Zacny JP, Coalson D, Young C, et al: A dose-response study of the effects of intravenous midazolam on cold pressor-induced pain. An&h Analg 1995;80:521-5. Collins GG: Effects of the anaesthetic 2,6diisopropylphenol on synaptic transmission in the rat olfactory cortex slice. Br J Phurmacol1988;95:939-49. Concas A, Santoro G, Mascia MP, Serra M, Sanna E, Biggio G: The general anesthetic propofol enhances the function of gamma-aminobutyric acid-coupled chloride channel in the rat cerebral cortex. JNeurochem 1990;55:2135-8.

Subhypnotic

Doses of Thiopentone and Propofol Cause Analgesia to Experimentally Induced Acute Pain E. Anker-Moller, N. Spangsberg, L. Arendt-Nielsen, P. Schutz, M.S. Kristensen, and P. Bjerring

Abstract Subhypnotic doses of thiopentone are considered to have a hyperalgesic effect, while propofol has a hypoalgesic effect. We investigated the effect of these drugs on the nociceptive system by measuring the pain threshold to laser stimulation and the pain evoked potential (power and latency). Nineteen patients (ASA group I) participated. Twelve patients received thiopentone 0.5 mg/kg and propofol 0.25 mg/kg in random order separated by an interval of 14 h, and seven patients received saline. Immediately after the injection of both agents, the pain threshold was increased significantly (p < 0.001) and the amplitude of the evoked potential was reduced significantly (p < 0.05), while the latency of the evoked potential remained constant. It is concluded that, in subhypnotic doses, both thiopentone and propofol decrease the acute pain evoked by argon laser stimulation. Reprinted

474

with permission

J. Clin. Anesth., vol. 8, September 1996

from the Editor,

British Journal of Anaesthesia 1991;66:185-8.