Enhancement of offset analgesia during sequential testing by Stuart Derbyshire | Papers by Stuart

Available online at www.sciencedirect.com European Journal of Pain 12 (2008) 980–989 www.EuropeanJournalPain.com Enhancement of offset analgesia during sequential testing S.W.G. Derbyshire *, J. Osborn University of Birmingham, School of Psychology, Edgbaston, B15 2TT, UK Received 29 August 2007; received in revised form 12 December 2007; accepted 23 January 2008 Available online 5 March 2008 Abstract Interruption of a continuous noxious heat by a relatively greater noxious heat evokes reductions in pain experience when the original noxious heat returns. The reduction is greater than that evoked by continuous delivery of noxious heat. This disproportionate reduction in pain experience, known as offset analgesia, is presumably mediated by a mechanism different to adaptation or habituation. Reduction in pain experience to an equivalent noxious stimulus, however, has also been demonstrated when applying the same stimulus over a number of days. This reduction due to repeated days of stimulation is known as attenuation. In order to distinguish further the mechanisms of offset analgesia and attenuation we applied noxious heat resulting in an experience of low, medium or high pain to the volar forearm of 16 subjects comparing pain intensity ratings for increases and decreases in temperature, repeated over 3 days. Offset analgesia was consistently demonstrated but the effects of attenuation were more complex. There was no attenuation effect for the unchanging stimuli delivered across the 3 days of testing but attenuation effects enhanced the offset analgesia resulting in a larger offset analgesia effect on days 2 and 3. It is possible that offset analgesia and attenuation are mediated by inter-related mechanisms. Further studies might investigate whether offset analgesia involves inhibitory structures such as the PAG-RVM. Ó 2008 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Nociception; Inhibition; Somatic; Attention; Chronic pain 1. Introduction Changes in noxious stimulus intensity have been documented to provide transient changes in pain experience, which are greater than changes due to continuous noxious stimulation (Grill and Coghill, 2002). For example, increasing from low noxious stimulus intensity and then returning to the same low noxious intensity has been demonstrated to produce reduced pain intensity ratings compared with continuing the same low noxious intensity. Pain intensity ratings fall by almost 100% (i.e., towards an experience of no pain) when low noxious * Corresponding author. Tel.: +44 121 414 4659; fax: +44 121 414 4897. E-mail address: s.w.derbyshire@bham.ac.uk (S.W.G. Derbyshire). intensity follows high noxious intensity. This disproportionate reduction in ratings of pain intensity has been described as offset analgesia, defined as an active analgesic process lasting for a limited period of about 15 s (Grill and Coghill, 2002). The large reduction in pain experience and short duration of effect distinguishes offset analgesia from simple stimulus adaptation (Becerra et al., 1999). Reduction in pain experience has also been reported during repeat sessions of the same noxious stimuli on subsequent days and has been described as attenuation (Gallez et al., 2005). Large reductions in pain experience have been reported on day 2 compared with day 1 with stabilisation of experience or smaller subsequent reductions on additional days. The reductions in pain intensity, however, were about 33% and so much lower than those observed due to offset analgesia. 1090-3801/$34 Ó 2008 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2008.01.008 S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 981 Gallez et al. (2005) propose that the attenuation of pain experience across sessions is due to alterations in cerebral processing, which is supported by their demonstration of the effects being ‘‘contralateral”. The effect of attenuation is stronger when stimulation is repeatedly delivered to the same side of the body thus implying that the contralateral hemisphere is attenuating its response. Presumably, areas that normally respond to noxious stimulation such as the thalamus, primary and secondary sensory cortices, anterior cingulate cortex and the insula, (Derbyshire et al., 1997; Coghill et al., 1999) have reduced response to the same stimulus on subsequent days providing for reduced pain experience. Grill and Coghill (2002) also suggest central mechanisms play a role in offset analgesia and imply that the effect is due to activation of central inhibitory mechanisms such as descending influence from the periaqueductal grey (PAG) via the rostral ventromedial medulla (RVM) (Budai et al., 1998; Fields, 2004; Tracey and Mantyh, 2007). Consequently there may be different but related mechanisms accounting for the reduced pain experience mediated by attenuation and offset analgesia. This speculation is supported by the large difference in the magnitude of pain experience that can be modulated by attenuation and offset analgesia. Here we propose to replicate and extend the studies of Grill and Coghill (2002) and Gallez et al. (2005) in order to investigate offset analgesia over repeated experimental sessions. Constant temperature trials were compared with variable temperature trials to produce offset analgesia and the procedure was repeated on three separate days to produce attenuation. If offset analgesia and attenuation work via separate mechanisms then it is expected that the effects of both will be additive with reduced pain experience due to offset analgesia consistently greater than the effects of attenuation. On the other hand, if offset analgesia and attenuation work via inter-related mechanisms then there is the possibility of interactions producing disproportionately greater or smaller changes in pain experience. sessions, with 1–4 days separating each subsequent session. 2.2. Apparatus Thermal stimuli was administered to the volar surface of both forearms using a 27 mm diameter peltier thermode with rise and fall rates of 30 °C/s using the CHEPS system (Medoc Advanced Medical systems; Ramat Yishia, Israel). The probe was attached to the forearm using a Velcro strap and set to a baseline temperature of 35 °C. The Gracely pain intensity scale (GPS) was used to assess pain experience (Gracely and Kwilosz, 1988; Gracely, 1992). The GPS is a 0–20 point scale anchored with verbal descriptors (e.g., faint, mild, intense, extremely intense) with lower scores indicating lower pain intensity. 2.3. Procedure All subjects were seated in a quiet, dimly lit room for obtaining the temperatures corresponding to low, medium and high pain and for each heat trial session. The method of ascending limits was used to provide temperatures corresponding to low (5/20 on the Gracely intensity scale), medium (10/20) and high (15/20) pain. The probe was attached to the right or left volar forearm and the temperature slowly (0.2 °C/s) increased from a baseline of 35 °C. Subjects pressed a button when the temperature reached 5/20 on the Gracely intensity scale, 10/20 and 15/20, after which the trial was terminated. The subject then rested for 2 min and the procedure was repeated a further 5 times and then the entire procedure repeated for the other arm. Beginning with the left or right arm was counterbalanced across subjects. The low, medium and high rating temperatures for the last 3 trials for both arms were recorded and the average used for the further trials described below. All subjects were subsequently tested using three different sets of heat trials: offset, constant and baseline (illustrated in Fig. 1). Each trial consisted of 3 different temperatures corresponding to a low, medium or high pain experience assessed using the method of ascending limits already described. 2.4. Offset trials Offset trials compared pain intensity ratings at set intervals following changes in stimulus intensity. For each trial, there was an initial 5 s baseline stimulus of 35 °C and then a painful stimulus (T1, 5 s), followed by a 1 °C increase (T2, 5 s) and then a 1 °C decrease (T3, 5 s) to the original T1 temperature. Subjects were prompted for pain intensity measurements just before the completion of T1, T2 and T3 (see Fig. 1). 2. Method 2.1. Subjects Sixteen healthy volunteers (3 males) aged between 19 and 31 (mean 22) participated in this study. Each subject received a brief demonstration of the thermal probe prior to testing to familiarise them with the sensation and to allay any initial anxiety. Subjects were informed that the heat induced pain would not cause tissue damage and that they were free to withdraw from the experiment at any time. Ethical approval was provided by the local ethics committee and all subjects provided written consent. Each subject took part in three experimental 982 S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 Fig. 1. The time course of the offset, constant and baseline trials. Each trial consisted of three contiguous phases: T1, an initial noxious heat stimulus; T2 a second noxious heat stimulus 1 °C greater than T1 (offset trials) or equal to T1 (constant trials); and T3, a 3rd heat stimulus equivalent to T1 (offset and constant trials) or 35 °C for baseline trials. Pain intensity ratings (;) were obtained just before the termination of T1, T2 and T3. 2.5. Baseline trials For baseline trials, temperatures at T1 and T2 were the same as for the offset trials, however at T3 the temperature returned to the innocuous baseline temperature of 35 °C. Pain ratings were recorded as before. 2.6. Constant temperature trials To assess the effects of within-session adaptation, constant temperature trials were conducted for a duration of 15 s following the 5 s 35 °C baseline. Pain ratings were recorded at the same intervals as for the offset and baseline trials. To minimize within-session adaptation, each trial was counterbalanced to a previously unused part of the left or right forearm. Both arms were used to provide sufficient surface area. The order of temperatures was also counterbalanced across subjects and days and all trials were separated by at least 2 min. Each temperature, corresponding to low, medium or high pain experience, was presented once per subject on each day and the entire procedure was repeated on three separate days. 2.7. Statistical analysis Pain ratings were initially assessed using a 3  3  3 repeated measures ANOVA to assess the effects of time of rating (T1, T2, T3), pain experience (low, medium, high) and day for the offset, baseline and constant trials separately. The T3 ratings were then directly assessed using a 3  3  3 repeated measures ANOVA to assess the effects of trial (offset, baseline, constant), pain experience (low, medium, high) and day. Smaller T3 ratings for the offset and baseline trials compared with the constant trials were expected with equal magnitude T3 ratings for offset and baseline. To assess the effects of attenuation on the offset analgesia effect, a 3  3 repeated measures ANOVA examined the effects of day and pain level on the T3 pain rating during the offset trials. For additional analyses, the change in pain intensity ratings (D) resulting from T1 to T2 (e.g., subtracting the ratings caused by the initial 42 °C (T1) from the ratings caused by the rise to 43 °C (T2)) and T2 to T3 (e.g., subtracting the ratings caused by the return to 42 °C (T3) from the T2 ratings caused by 43 °C) during the offset trials was used to summarise the experiential effects of increases and decreases in stimulus temperature for each day. If pain experience follows stimulus intensity then the subtraction of pain ratings at T1 and T3 from the ratings at T2 should yield the same result. A larger difference when subtracting T2 from T3 indexes the effect of offset analgesia and/or within-session adaptation. Similarly, the difference in pain intensity ratings (D) from T1 to T2 and T2 to T3 during the constant trials (e.g., T1, T2 and T3 all 42 °C) was used to summarise the experiential effects of within-session adaptation to each stimulus temperature on each day. In the absence of adaptation, the subtraction of pain ratings at T1 and T3 from the ratings at T2 should yield the same result. A 2  2  3 repeated measures ANOVA assessed the effects of trial (offset or constant), transition (T1 to T2 or T2 to T3) and day separately for the low, medium and high pain trials. Post hoc analysis contrasted the individual transitions for each pain trial. The D resulting from T1 to T2, T2 to T3 were compared to those changes resulting from T2 to T3 baseline (35 °C) (D) using a 3  3 repeated measures ANOVA to assess the effects of transition (from T1 to T2, T2 to T3 and T2 to T3 baseline) and day separately for the low, medium and high pain trials. Post hoc analysis contrasted the individual transitions for each pain trial. To further interrogate the separation of effects due to offset analgesia and effects due to within-session adaptation, a 2  3  3 repeated measures ANOVA was performed on the change in pain rating resulting from T1 to T3 (i.e., subtracting the ratings at T3 from those at T1) to assess the effects of trial (offset vs. constant), temperature (high, medium, low) and day. If offset analgesia is a larger effect than habituation then the difference between T1 and T3 should be larger during offset versus constant trials. Finally, to assess the effects of attenuation across the 3 days of testing, a 3  3  3 repeated measures ANOVA examined the effects of trial, day and pain level on the initial (T1) pain rating. Post hoc analyses confirmed individual effects throughout using p < 0.05 with Tukey correction. S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 983 3. Results 3.1. Temperatures for low, medium and high pain Delivery temperatures were set according to each individual’s subjective rating of the thermal stimulus as producing low pain (rated as 5/20 on the Gracely intensity scale), medium pain (10/20) or high pain (15/ 20). The average temperature for low pain was 40.3 °C (SD = 2.0), medium pain 42.4 °C (2.0) and high pain 44.2 °C (1.9). 3.2. All ratings The pain ratings were entered into three separate analyses to assess the effects of temperature, time of rating and day during the offset, baseline and constant trials. Table 1 includes the results and demonstrates a main effect of temperature and time on the pain ratings for all trials but no main effect of day for any of the trials. No interactions with day reached significance but there were significant interactions of temperature and time, indicating that some temperatures produced greater changes in pain rating due to offset analgesia and within-session adaptation (see Fig. 5), and significant interactions of day with time for the offset trials, indicating that offset analgesia and attenuation interacted (see Fig. 8). 3.2.1. T3 ratings There was a significant main effect of trial (baseline, offset and constant) (F2,30 = 12.3, p < 0.05) on the T3 ratings. Fig. 2 illustrates significantly (p < 0.05, corrected) lower pain ratings during T3 for both the baseline and offset trials relative to the constant trials. The T3 ratings for the baseline trials were also significantly lower than those during the offset trials. T3 ratings were also significantly influenced by the temperature of the stimulus (F2,30 = 27.0, p < 0.05). The interaction of trial with temperature was significant (F4,60 = 5.2, p < 0.05) mostly due to significantly greater pain ratings during the high temperature constant trials (not shown). Summary effects are illustrated in Fig. 3. There was only a trend towards effects of day (F2,30 = 2.7, p = 0.08) and a significant interaction of day and temperature (F4,60 = 2.7, p < 0.05) due to greater T3 pain ratings for the high temperature on day 1 (not shown). No other interactions reached significance. Table 1 The ANOVA results based on the absolute pain ratings recorded for the offset, constant and baseline trials Measure Offset Constant Baseline Temperature F(2,30) = 47.3 (0.000) F(1.3,19.2) = 29.2 (0.000) F(2,30) = 32.3 (0.000) Day F(1.4,21.4) = 2.7 (0.1) F(1.4,20.5) < 1 (ns) F(2,30) < 1 (ns) Time F(1.1,16.4) = 66.6 (0.000) F(2,30) = 45.5 (0.000) F(1.2,17.6) = 57.6 (0.000) Temp  day F(4,60) = 1.5 (ns) F(4,60) = 1.0 (ns) F(4,60) < 1 (ns) Temp  time F(4,60) = 15.3 (0.000) F(2.4,35.9) = 1.5 (0.010) F(2,30) = 15.1 (0.000) Day  time F(2.5,37.9) = 3.9 (0.021) F(2.6,39.1) < 1 (ns) F(4,60) = 1.5 (ns) Temp = temperature; ns = not significant. Fig. 2. The pain intensity ratings reported during the T3 period averaged across trials and days for the baseline (T3 temperature returns to 35 °C), offset (T2 temperature 1 °C higher than T2 and T3) and constant (T1 = T2 = T3) trials. Returning to baseline produced a significantly lower pain rating than returning to the T1 temperature (offset) and a significantly lower pain rating than maintaining the same temperature (constant). Returning to the T1 temperature (offset), however, produced a significantly lower pain rating than maintaining the same temperature (constant). 984 S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 Fig. 3. The pain intensity ratings reported during the T3 period averaged across days for the baseline, offset and constant trials. 3.2.2. Offset T3 ratings The effects of day and temperature were assessed for the offset trials only using a 3  3 repeated measures ANOVA. There was a significant main effect of temperature (F2,30 = 17.1, p < 0.05) and day (F1.4,20.8 = 5.8, p < 0.05) and an interaction of temperature with day (F4,60 = 3.5, p < 0.05). Fig. 4 illustrates the interaction being due to greater T3 ratings at the higher temperature on day 1 compared with day 2 and on day 2 compared with day 3. 3.3. Changes in ratings: low stimulus temperature Changes in perceived pain intensity associated with incremental decreases in noxious heat were not significantly larger than those occurring as a consequence of within-session adaptation for the low stimulus condition (illustrated in Fig. 5). Within subjects ANOVA of the D values when transitioning from T1 to T2 and from T2 to T3 during low stimulus experimental and constant trials revealed a main effect of experimental trial (F1,15 = 12.8, p < 0.05) and transition (T1 to T2 versus T2 to T3; F1,15 = 115.2 p < 0.05) but no interaction of trial with transition (F1,15 = 2.4, p = 0.139). There was no main effect of day (F2,30 < 1) but there was a significant interaction of day with transition (F2,30 = 3.8, p < 0.05). No other interactions reached significance. A further within subjects ANOVA of the D values when transitioning from low stimulus T1 to T2, T2 to T3 experimental (T1 + 1 °C) and T2 to T3 baseline (35 °C) revealed a main effect of transition (F1,15 = 78.2, p < 0.05) but no main effect of trial (F1,15 = 2.8, p = 0.116) (see Fig. 6). Thus there was a significantly greater change in pain rating when transitioning from T2 to T3 than when transitioning from T1 to T2 but this difference was not significantly larger when transitioning Fig. 4. Pain intensity ratings following T3 stimulation during the offset trials for each of the 3 days of testing. There was a significant main effect of temperature and day and an interaction of temperature with day of testing. The high pain trials produced significant reductions in T3 ratings across the 3 days. S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 985 Fig. 5. The pain intensity rating changes observed during the transition from T1 to T2 and T2 to T3 collapsed across the 3 days of testing. Temperature decreases (T2 to T3) produced a significantly larger change in pain intensity ratings than equal magnitude temperature increases (T1 to T2) during the medium temperature trails and the differences approached significance during the low and high temperature trials. The equivalent time periods did not produce any significant changes during the low constant trials but within-session attenuation to the stimulus did result in significant changes during the medium and high constant temperature trials. Fig. 6. The pain intensity rating changes produced by increases and decreases in stimulus temperatures averaged across the 3 days of testing. During the medium temperature offset trials, temperature decreases (T2 to T3) produced significantly larger changes in pain intensity ratings than equal magnitude temperature increases (T1 to T2) and these effects approached significance in the low and high temperature offset trials. The much larger reduction of the heat stimulus to a clearly innocuous temperature (35 °C) did not result in significantly greater changes in pain intensity ratings than during the offset trials for any of the trial temperatures. to a non-noxious baseline at T3 compared with a return to the noxious T1 temperature. No other effects reached significance. 3.4. Changes in ratings: medium stimulus temperature Changes in perceived pain intensity associated with incremental decreases in noxious heat were also not significantly larger than those occurring as a consequence of within-session adaptation for the medium stimulus condition (illustrated in Fig. 5). Within subjects ANOVA of the D values when transitioning from T1 to T2 and from T2 to T3 during medium stimulus experimental and constant trials revealed a main effect of experimental trial (F1,15 = 37.8, p < 0.05) and transition (T1 to T2 versus T2 to T3; F1,15 = 58.2, p < 0.05) but no interaction of trial with transition (F1,15 = 2.4, p = 0.139). There was no main effect of day (F1.4,20.8 < 1) and no significant interactions. A further within subjects ANOVA of the D values when transitioning from medium stimulus T1 to T2, T2 to T3 experimental (T1 + 1 °C) and T2 to T3 baseline (35 °C) revealed a main effect of transition (F1,15 = 52.2, p < 0.05) but no main effect of trial (F1,15 = 2.5, p = 0.137) (see Fig. 6). Thus there was a significantly greater change in pain rating when transitioning from 986 S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 Table 2 The ANOVA results based on the change in pain rating from T1 to T3 during the offset and constant trials Parameter Trial Temperature Day Trial  temperature Trial  day Temperature  day Trial  temperature  day ns = not significant. Result F(1,15) = 7.5 (0.015) F(2,30) = 3.3 (0.05) F(1.4,21.5) = 4.0 (0.045) F(2,30) = 7.8 (0.002) F(2,30) < 1 (ns) F(4,60) = 1.2 (ns) F(4,60) = 2.6 (0.047) T2 to T3 than when transitioning from T1 to T2 but this difference was not significantly larger when transitioning to a non-noxious baseline at T3 compared with a return to the noxious T1 temperature. No other effects reached significance. 3.5. Changes in ratings: high stimulus temperature Changes in perceived pain intensity associated with incremental decreases in noxious heat were significantly larger than those evoked by equal magnitude increases in noxious heat and than those occurring as a consequence of within-session adaptation for the high stimulus condition (illustrated in Fig. 5). Within subjects ANOVA of the D values when transitioning from T1 to T2 and from T2 to T3 during high stimulus experimental and constant trials revealed a main effect of experimental trial (F1,15 = 41.0, p < 0.05), transition (T1 to T2 versus T2 to T3; F1,15 = 79.5, p < 0.05) and a significant interaction of trial with transition (F1,15 = 11.2, p < 0.05). There was also a significant main effect of day (F2,30 = 3.5, p < 0.05) and a significant interaction of day with transition (F2,30 = 3.4, p < 0.05). A further within subjects ANOVA of the D values when transitioning from high stimulus T1 to T2, T2 to T3 experimental (T1 + 1 °C) and T2 to T3 baseline (35 °C) revealed a main effect of transition (F1,15 = 66.1, p < 0.05) but no main effect of trial (F1,15 < 1) (see Fig. 6). Thus there was a significantly greater change in pain rating when transitioning from T2 to T3 than when transitioning from T1 to T2 but this difference was not significantly larger when transitioning to a non-noxious baseline at T3 compared with a return to the noxious T1 temperature. There was also a signif- icant trial by transition (F1,15 = 11.3, p < 0.05) and trial by transition by day (F2,30 = 3.8, p < 0.05) interaction (see Fig. 7). 3.6. Changes in ratings from T1 to T3 The differences between within-session adaptation and offset analgesia were assessed directly by examining the changes in pain rating from T1 to T3. Within subjects ANOVA of the D values when subtracting pain ratings at T3 from those at T1 during the experimental and constant trials revealed a main effect of experimental trial, temperature and day and interactions of trial with temperature and a three way interaction of trial, temperature and day. These results are summarised in Table 2 and Fig. 8. The three way interaction is due to greater offset effects on days 2 and 3 during the high pain trials. Separate analysis (not shown) demonstrated that the changes in pain rating from T1 to T3 due to within-session adaptation were not influenced by temperature or day of testing. Fig. 7. The pain intensity rating changes produced by increases and decreases in stimulus temperatures on each of the 3 days of testing during the high pain trials. On each day, offset temperature decreases (offset T2 to T3) produced significantly larger changes in pain intensity ratings than equal magnitude temperature increases (offset T1 to T2). The much larger reduction of the heat stimulus to a clearly innocuous temperature (35 °C) produced significantly greater changes in pain intensity than the offset decrease on day 1 only. S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 987 Fig. 8. The pain intensity rating changes observed when contrasting ratings at T1 with those at T3. Larger differences are apparent during the offset trials indicating offset effects to be larger than those due to adaptation (see Table 2). The interaction of trial type, temperature and day is due to the significantly elevated effects of offset analgesia relative to within-session adaptation on days 2 and 3. Fig. 9. Pain intensity ratings following T1 stimulation for each of the 3 days of testing. There was no significant main effect of day or interaction of T1 temperature with day of testing. 3.7. T1 ratings The effects of attenuation were assessed directly using the T1 ratings. A within subjects ANOVA revealed a main effect of temperature (F2,30 = 44.6, p < 0.05) but no effect of day (F2,30 = 1.0, p = 0.363) or temperature by day interaction (F4,60 = 1.3, p = 0.266). Fig. 9 illustrates the pain ratings for the low, medium and high stimuli on days 1–3. 4. Discussion The present study confirms that analgesia can be evoked by slight incremental decreases in noxious stimulus temperatures, a phenomenon that has been called off- set analgesia (Grill and Coghill, 2002). Offset analgesia effects were directly assessed using the T3 ratings and demonstrated lower absolute ratings following a more intense stimulus than when using constant stimulus delivery. Absolute ratings, however, were greater during the offset T3 period than when returning to the non-noxious baseline temperature of 35 °C. We also demonstrated an interaction of offset analgesia with attenuation effects. Similar to Grill and Coghill (2002), we assessed offset analgesia effects based on the change scores and demonstrated larger changes when transitioning from a higher to lower temperature than when transitioning from a lower to higher temperature. We also demonstrated, however, that change scores based on the same time periods from the constant trials also produced significant differences. These latter effects were because of 988 S.W.G. Derbyshire, J. Osborn / European Journal of Pain 12 (2008) 980–989 within-session adaptation to the stimulus, which meant that the first 5 s of the noxious stimulus (T1) were experienced as more painful than the second 5 s (T2) for the low and medium trials, and the second 5 s (T2) were experienced as more painful than the last 5 s (T3) for all trials. Consequently, when assessing the transition from T1 to T2 (ratings at T2 minus ratings at T1) there was a negative change recorded for the low and medium temperatures (because adaptation was leading to lower pain scores yielding a negative value when subtracting T1 from T2) and when assessing the transition from T2 to T3 (ratings at T2 minus ratings at T3) there was a positive change recorded for all temperatures (because adaptation lowered pain scores yielding positive values when subtracting T3 from T2). It is important to recognise that this within-session adaptation exaggerated the offset analgesia effect or, to state that differently, part of the apparent offset analgesia effect was due to withinsession adaptation. Nevertheless, offset analgesia effects were significantly larger than the effects of within-session adaptation for the high pain trials. Contrary to the findings of Gallez et al. (2005) we did not find any evidence of across session attenuation when examining the T1 ratings. It is possible that the relatively low temperatures used in the current study do not provide for large attenuation effects. Gallez et al. (2005) delivered temperatures of over 48 °C while the average temperature for our moderate pain trials averaged at 4 °C lower and the maximum temperature used for any of our subjects was 48 °C. Although our temperatures are lower than those used by Gallez et al. (2005) and by Grill and Coghill (2002), our temperatures are comparable to those used in other studies to generate mild to moderate pain. Chen et al. (2001), for example, used a temperature of 45–46 °C as their noxious heat condition for stimulating the left leg; Becerra et al., 2001) used a temperature of 46 °C as their noxious heat condition for stimulating the hand; and we have previously used temperatures 44–46 °C to generate mild to moderate pain in control subjects (Derbyshire et al., 2002). It is also possible that subjects misunderstood or misinterpreted the Gracely scales. Although it was emphasised that subjects were to rate pain and not sensation, zero on the Gracely intensity scale is labelled ‘‘no sensation” and the first anchor point (just before a rating of 1) is labelled ‘‘faint”. Subjects may have rated the strength of the stimulus as greater than zero even though it was non-painful, which may also account for why the baseline was rated above zero (Figs. 2 and 3). Another reason we may not have replicated the findings of Gallez et al. (2005) is because we applied heat to both arms, which may weaken the effects of attenuation compared to the stimulation of a single arm. Alternatively, the attenuation effects may only become apparent as the subjects more directly engage the stimulus because of the changes in temperature, which would be consis- tent with the suggestion that active involvement in a task helps to stabilize attention towards the stimulus (Gallez et al., 2005). This latter possibility may explain why the offset analgesia effects increased after day 1 of testing for the high pain trials (illustrated in Figs. 7 and 8). Attenuation may interact with the offset analgesia effects to increase or facilitate the phenomenon. The relief following reduction from the higher stimulus is easily predictable by the subjects such that future repetition of the stimulus is less threatening. Relief as the higher temperature terminates might even be rewarding, resulting in a conditioned analgesic response (Seymour et al., 2005). Furthermore, the subjects may learn that the noxious stimuli are nonthreatening because no tissue damage is observed after the first trials; future encounters with the stimuli are therefore predictable and non-threatening and, thus, less painful (Carlsson et al., 2006). In conclusion, our findings provide further evidence of an endogenous analgesic mechanism that magnifies reductions in pain experience following a 1 °C decrease in temperature (Grill and Coghill, 2002). These changes in experience interact in perhaps unexpected ways with the attenuation of pain experience that has been observed over subsequent daily sessions of noxious stimulation (Gallez et al., 2005). The complementary cognitive and brain mechanisms subserving offset analgesia and attenuation remain unknown and might be investigated using brain imaging techniques. One possibility is that the attenuation to noxious stimuli across days may be mediated by cortical structures, such as the insula and anterior cingulate cortex, while offset analgesia is mediated by subcortical structures, such as the RVMPAG (Tracey and Mantyh, 2007). Although we favour an explanation based on brain mechanisms, peripheral changes could also explain the offset analgesic response. It has been demonstrated that peripheral fibres alone can provide the information necessary to detect noxious stimuli and to make magnitude judgements of pain elicited by fluctuating noxious stimuli (Robinson et al., 1983). It is entirely possible, therefore, that the effects described here and elsewhere may be due to changes in the periphery rather than in the brain. The precise details remain for further investigation but this study confirms previous suggestions that behavioural manipulations can induce adaptive plastic changes within the nociceptive system. 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