Is propofol an analgesic?

Owing to its pharmacokinetic and pharmacodynamic profile, propofol has become the intravenous anaesthetic of choice in ambulatory anaesthesia, fast track anaesthetic techniques and monitored anaesthesia care, and provides sedation for endoscopies and in the ICU.1 Like other general anaesthetics, propofol affects the central nervous system and inhibits neuronal pathways, which may be inhibitory or excitatory, producing distinct behaviour. Although predictable and rapid loss of consciousness is the common characteristic of intravenous general anaesthetics, their specific effects on the central nervous system and other systems differ. Propofol has been assessed recently for its ‘analgesic properties’ in the clinical setting and some studies suggest that the drug improves post-operative analgesia.2,3 Laboratory studies suggest an involvement of propofol in the N-methyl-D-aspartate (NMDA) receptor subunits. Propofol inhibits the phosphorylation of NMDA receptor NR1 subunits in a culture of cortical neurones obtained from rats.4 However, it is not known whether this effect is associated with the actions of propofol or whether it can be observed only at propofol concentrations much higher than those used in clinical practice. Propofol exhibits an inhibitory effect on the NMDA subtype of glutamate in neurones of the mouse hippocampus and on the nociception-specific neurones in the parafascicular nucleus of the thalamus.5,6 The last effect is associated with visceral pain originating from experimentally produced acute myocardial ischaemia in the rat.6 These studies originating from neuronal cultures or animal experimental models cannot be extrapolated to humans and do not provide solid support for an analgesic effect of propofol in the clinical setting. The ‘analgesic effects’ of propofol have been evaluated in human pain models. Anker-Moller et al.7 assessed the analgesic properties of thiopental and propofol in 12 healthy patients exposed to laser stimulation. They reported that sub-hypnotic doses of propofol increased the pain threshold to laser stimulation and decreased the amplitude of pain-evoked potentials.7 However, measurements of pain threshold and of amplitude of the pain-evoked potentials were limited to the first 15 min after injection of the anaesthetic. Sub-anaesthetic doses of propofol infused in 12 volunteers submitted to the cold pressor test were associated with a decrease in visual analogue scale (VAS) scores lasting only 1–2 min and did not alter the ratings in the short McGill Pain Questionnaire in comparison with the group of patients treated with a control infusion.8 In contrast, fentanyl injected as a positive control produced longer lasting and more intense analgesia, as assessed by the VAS and the short McGill Pain Questionnaire measurements. The investigators concluded that propofol must be supplemented by opioid analgesia when used for sedation or anaesthesia. Responses to different noxious stimuli depend not only on the intensity but also on the type of stimulus. Experimental techniques used to investigate and assess pain, and human pain models, differ in many ways. Healthy volunteers experienced decreased pain, hyperalgesia and allodynia elicited by intra-cutaneous electrical stimulation when they received a target-control infusion of propofol (2 μg ml−1) compared with controls. However, as soon as the infusion of propofol was discontinued, pain scores, hyperalgesia and allodynia did not differ between the propofol and the control groups.9 Experimental models suggest some analgesic effect of propofol which is inconsistent and which disappears on discontinuation of the drug. Two recent studies in patients undergoing general anaesthesia with propofol or isoflurane, or propofol or sevoflurane, suggest that propofol anaesthesia is associated with better post-operative analgesia when compared with the inhalational anaesthetics. In the first study,2 women scheduled for hysterectomy or myomectomy and anaesthetised with isoflurane reported higher pain intensity and consumed more morphine during the first 24 h when compared with women anaesthetised with propofol. The investigators used as the primary outcome the numerical analogue score for pain. Day stay surgery patients anaesthetised with sevoflurane experienced higher post-operative pain when compared with patients anaesthetised with propofol, but consumed similar doses of morphine.3 These data were collected only during the first 4 h post-operation. There is inconsistency between the two studies regarding the post-operative analgesic effect of propofol. As a primary end point, both studies used pain intensity at rest, which was reduced by propofol, but neither assessed pain on movement. Only the study comparing propofol with isoflurane reported less consumption of morphine. Why did patients with more pain not make use of their free access to morphine? According to the classification of McQuay et al.,10 with reference to post-operative pain scores, these studies are classified as B2 (the first) and B (the second).10 As pain scores are available only for 4 h, these studies cannot be further classified. Category A trials are considered more robust studies and adopt analgesic consumption as the primary outcome. In contrast to the above studies, Boccara et al.11 reported less analgesic requirements in the early post-operative period (first 6 h post-operatively) and lower pain scores in women in whom general anaesthesia was maintained with isoflurane than in women anaesthetised using an infusion of propofol. This study is classified also as B, according to McQuay et al.,10 because pain and analgesic requirements differed during the first 6 h. Pain was assessed only at rest. In another study,12 patients were kept deeply anaesthetised or lightly anaesthetised with sevoflurane during surgery, controlled by bispectral index (BIS) values. Post-operatively, patients with low BIS values during surgery had lower VAS scores at rest and on coughing, and fewer of these patients required rescue doses of analgesics during the first 8 h post-operatively, but not thereafter. These results may be due to patients with low BIS values during surgery being more sedated post-operatively compared with the patients with higher BIS values, and not to different intra-operative or post-operative drug treatment. The investigators did not compare the level of sedation post-operatively between the two groups. Consequently, it remains questionable whether these results relate to a post-operative analgesic effect of intra-operative anaesthetic administration. A prospective randomised trial compared morphine consumption and pain during the first 24 h post-operatively in women undergoing abdominal hysterectomy or myomectomy and anaesthetised either using a propofol infusion or with sevoflurane or desflurane.13 Neither morphine requirements nor pain scores at rest or on coughing differed among the three groups. These results are consistent with the results in human pain models in which the ‘analgesic effect’ of propofol wore off when administration of the drug was discontinued. Similarly, the ‘anti-emetic effect’ of propofol is limited to the early post-operative period.14 During general anaesthesia, the central nervous system is ‘out of order’. Propofol or other general anaesthetics might exhibit inconsistent and temporary ‘analgesia’ as part of the suppression of the central nervous system. However, after surgery, surgical patients need to be treated adequately and efficaciously with conventional analgesics, no matter what general anaesthetic agent is used intra-operatively. Propofol has changed the practice of anaesthesia for the better,1 but it does not provide the analgesia required in the clinical setting after surgery. Acknowledgements This work was supported by the Department of Anaesthesiology, Aretaieio Hospital, University of Athens, Greece. The author has no conflict of interest. This article was checked and accepted by the Editors, but was not sent for external peer-review.

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