Placebo-induced reductions in pain ratings & laser evoked potentials A.Watson 1, W. El-Deredy 2, D.E. Bentley 1, Y.Boyle 1, B.A.Vogt 3 and A. K. P. Jones 1 1 Human Pain Research Group, University of Manchester Rheumatic Diseases Centre, Hope Hospital, Salford, M6 8HD, UK. 2 School of Psychological Sciences, University of Manchester, Oxford Rd, Manchester M13 9PL 3 Dept of Neuroscience and Physiology, SUNY Upstate Medical University, 750E. Adams Street, Syracuse, NY USA Introduction Placebo analgesia can be achieved experimentally by conditioning, where the pain stimulus is reduced to a non- painful level in conjunction with the application of a placebo cream in the guise of an analgesic drug. Benedetti et al. (1999) have shown that site-specific instructions regarding the site of application of a placebo local anaesthetic produces site-specific placebo analgesia. We have previously demonstrated that laser pain stimuli are a suitable stimulus in placebo analgesia studies. Aims To investigate the effect of a placebo-induced reduction in pain ratings on the Laser Evoked Potential (LEP). To test the effect on the placebo response of ambiguous information regarding the application site of a placebo analgesic cream. Methods 23 subjects had their forearms randomly labelled arm A and arm B. Subjects were informed that on one arm they may receive a local anaesthetic cream, whereas on the other arm they would receive an inactive cream. In fact an inactive cream was applied to both arms. Heat pain from a CO 2 laser (pulse duration 100ms), was adjusted to a level that subjects rated as moderately painful (level 7 on a 0 to 10 pain scale, with level 4 corresponding to just painful). Subjects underwent 2 sequential sessions: a Conditioning session and a Fully Informed session. Sessions differed only in the information regarding the nature and effect of the cream. Each session consisted of 3 blocks. In blocks I & 3 the stimuli were at the painful level 7 for both arms, whereas in block 2 the pain stimuli were always turned down to the subjects’ non-painful level 3 at arm A only (Table 1). In the Fully Informed session subjects were told that an inactive cream would be applied to both arms. At the start of block 2, subjects were told that the pain stimulus may be turned down. In the Conditioning session subjects were not given any information about the painfulness of the stimuli they would receive in block 2. LEPs were recorded from 61 electrodes (bandpass: Hz, A/D rate: 500 Hz). Pain ratings & LEPs were compared between blocks using paired t-tests. BlockArm AArm B 1Painful 2Non-painfulPainful 3 Table 1. Stimuli used in each block for both the Conditioning & Fully Informed sessions. LEP results Preliminary analyses focussed on the P2 LEP peak (maximal at Cz) for the Conditioning session only. P2 mean peak latency across the group & blocks (measured at electrode Cz) was 374 ± 10 ms (SEM) for arm A and 380 ± 11 ms for arm B. There were no significant differences between blocks 1 & 3 for both arms. P2 mean peak amplitude at Cz for arm A was significantly smaller for block 3 (9.2 ± 2 µv) compared with block 1 (20.1 ± 1.5 µv), p<0.05 (Fig. 2). P2 mean peak amplitude at Cz for arm B was also significantly smaller for block 3 (9.9 ± 1 µv) compared with block 1 (17.6 ± 0.5 µv), p<0.05 (Fig. 2). Behavioural Results Pain ratings in block 3 were significantly lower than those in block 1 for both arms, indicating a significant placebo response. This effect was seen in both the Conditioning (Fig. 1a) and Fully Informed sessions (Fig. 1b), although the effect was significantly greater (p<0.001) for the Conditioning session for both arms. Results Summary & Conclusions These results show a placebo response on both arms when information regarding the application site of a placebo analgesic cream was ambiguous. This suggests that the placebo effect may not be site-specific. The reduction in pain rating in the Fully Informed session may suggest a residual effect from the Conditioning session, the placebo effect persisting even though the instructions had changed. This is the first demonstration of a placebo-induced reduction in cortical pain processing using LEPs. The effect on the P2 peak suggests that placebo affects the cognitive evaluation of pain. Further analyses will determine whether earlier LEP peaks, reflecting sensory processing, are also affected by placebo. As LEPs provide a less subjective measure of pain than pain ratings, these results suggest that the placebo response in this study is not simply due to subject compliance. Fig. 2. Significant reduction in P2 peak amplitude between blocks 3 (red) & 1 (black) for both arms. * indicates a significant difference from block 1 (p<0.05). Acknowledgments This work was supported by the Arthritis Research Campaign (UK). References Benedetti F. et al.(1999). Somatotopic activation of opioid systems by target directed expectations of analgesia. J. Neurosci, 19, Montgomery, G.H. & Kirsch, I. (1997). Classical conditioning and the placebo effect. Pain, 72, Price, D.D.et al. (1999). An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain, 84, Voudouris, N.J. et al. (1990). The role of conditioning and expectancy in the placebo response. Pain, 43, Watson, A. et al. (2005). Placebo induced reduction of pain intensity & unpleasantness ratings of a laser stimulus. J. Psychophys. 19, (1), Arm A Arm B 374 ms 380 ms Amplitude µV * * Mean & SEM Pain Rating ** Block 3 Block 1 (a) Conditioning Session Mean & SEM Pain Rating arm A arm B ** Block 3 Block 1 (b) Fully Informed Session arm A arm B Fig. 1. Comparison of pain ratings from blocks 1 & 3 for the Conditioning (a) & Fully Informed (b) sessions. * indicates a significant difference from block 1 (* p<0.01, ** p<0.001).