Carta Acesso aberto Revisado por pares

Response to “Treating patients rather than their functional neuroimages” (Br J Anaesth 2018; 121: 969–71)

2019; Elsevier BV; Volume: 123; Issue: 2 Linguagem: Inglês

10.1016/j.bja.2019.01.016

ISSN

1471-6771

Autores

Vishvarani Wanigasekera, Karolina Wartolowska, John P. Huggins, Eugene Duff, W. Vennart, Mark Whitlock, Natalie Massat, L. Pauer, Peter Rogers, B. Hoggart, Irene Tracey,

Tópico(s)

Pain Management and Opioid Use

Resumo

Editor—Thank you for giving us the opportunity to clarify further the important issues alongside various misunderstandings raised by Boissoneault and colleagues.1Boissoneault J. Letzen J. Robinson M. Treating patients rather than their functional neuroimages. Comment on Br J Anaesth 2018; 120: 299–307.Br J Anaesth. 2018; 121: 969-971Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Our paper provides evidence of objectively detecting target engagement and pharmacodynamic efficacy in the brain in a proof-of-concept (POC) study setting, similar to that encountered during analgesic drug development. This fundamental feature of the study appears to have been overlooked by Boissoneault and colleagues. Their interpretation logically then does not fit with the premise of our study, and their extrapolation of what the data mean is not aligned with the interpretation we put forward. The general aim of POC studies in all drug development is to seek objective evidence of appropriate target engagement and modulation (ideally of relevant mechanisms) by the study compound. Together with the downstream effects of target engagement, these factors form the ‘three pillars of survival’ of a compound's transition from Phase II to Phase III.2Morgan P. Van Der Graaf P.H. Arrowsmith J. et al.Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival.Drug Discov Today. 2012; 17: 419-424Crossref PubMed Scopus (489) Google Scholar The decision to progress with maximum confidence is achieved when all three factors are satisfied. With achieving two of these factors, the compound is progressed with varying degrees of confidence and caveats. Compounds that exert their effects via modulating neural activity pose an added complexity where drug plasma concentrations cannot be relied upon to represent target exposure attributable to the blood–brain barrier. At this stage of drug development, subjective pain reports as a surrogate of downstream effects can be problematic because of the well-characterised and reported influences that other factors have on pain ratings that are non-specific to the analgesic compound's mechanism of action, such as expectation of treatment outcome, mood, and contextual factors that might completely swamp or mask such genuine pharmacodynamically related analgesic effects.3Wiech K. Tracey I. The influence of negative emotions on pain: behavioral effects and neural mechanisms.Neuroimage. 2009; 47: 987-994Crossref PubMed Scopus (396) Google Scholar, 4Bingel U. Wanigasekera V. Wiech K. et al.The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.Sci Transl Med. 2011; 3 (70ra14)Crossref PubMed Scopus (498) Google Scholar, 5Wiech K. Deconstructing the sensation of pain: the influence of cognitive processes on pain perception.Science. 2016; 354: 584-587Crossref PubMed Scopus (209) Google Scholar It is difficult to see how any subjective measure that is influenced by such factors (this extends beyond the pain and analgesia field) can provide objective evidence of target modulation to fulfil the POC needs. Vice versa, one can never objectify a subjective experience—that is not what neuroimaging does, as stated many times by us and others.6Tracey I. Mantyh P.W. The cerebral signature for pain perception and its modulation.Neuron. 2007; 55: 377-391Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar Neuroimaging provides objective and ideally mechanistic information that can powerfully aid the interpretation of why a particular subject or patient reports their pain (or analgesia) as such. It aids in the dissection of the multidimensional subjective experience into constituent components, such that it is more apparent how physiological, psychological, and contextual factors contribute to the final pain report, as we have shown.3Wiech K. Tracey I. The influence of negative emotions on pain: behavioral effects and neural mechanisms.Neuroimage. 2009; 47: 987-994Crossref PubMed Scopus (396) Google Scholar,4Bingel U. Wanigasekera V. Wiech K. et al.The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.Sci Transl Med. 2011; 3 (70ra14)Crossref PubMed Scopus (498) Google Scholar,7Ploghaus A. Tracey I. Gati J.S. et al.Dissociating pain from its anticipation in the human brain.Science. 1999; 284: 1979-1981Crossref PubMed Scopus (911) Google Scholar, 8Wiech K. Ploner M. Tracey I. Neurocognitive aspects of pain perception.Trends Cogn Sci. 2008; 12: 306-313Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar, 9Berna C. Leknes S. Holmes E.A. Edwards R.R. Goodwin G.M. Tracey I. Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness.Biol Psychiatry. 2010; 67: 1083-1090Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 10Fairhurst M. Wiech K. Dunckley P. Tracey I. Anticipatory brainstem activity predicts neural processing of pain in humans.Pain. 2007; 128: 101-110Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar Because of the appalling lack of success in analgesic drug development, there is currently a concerted effort to do things differently. The problems posed by large between- and within-subject variabilities of subjective pain reports and their subsequent use for quantification of analgesia in small-scale studies in early phase drug development have been recognised since the past decade.11Chizh B.A. Greenspan J.D. Casey K.L. Nemenov M.I. Treede R.D. Identifying biological markers of activity in human nociceptive pathways to facilitate analgesic drug development.Pain. 2008; 140: 249-253Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar As a consequence, there are several initiatives to improve assay sensitivity, including innovative clinical trial designs to minimise the placebo response and training of subjects in pain reporting to minimise variability.12Dworkin R.H. Turk D.C. Peirce-Sandner S. et al.Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.Pain. 2012; 153: 1148-1158Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar There are also significant efforts towards developing validated and standardised objective measures to aid analgesic drug development,13Smith S.M. Dworkin R.H. Turk D.C. et al.The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations.J Pain. 2017; 18: 757-777Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar such as the recent Innovative Medicines Initiative's PainCare–BioPain project launched this year (https://www.imi-paincare.eu/PROJECT/BIOPAIN/). Our pharmacological imaging studies,14Rogers R. Wise R.G. Painter D.J. Longe S.E. Tracey I. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging.Anesthesiology. 2004; 100: 292-301Crossref PubMed Scopus (102) Google Scholar, 15Wise R.G. Williams P. Tracey I. Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain.Neuropsychopharmacology. 2004; 29: 626-635Crossref PubMed Scopus (100) Google Scholar, 16Iannetti G.D. Zambreanu L. Wise R.G. et al.Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.Proc Natl Acad Sci U S A. 2005; 102: 18195-18200Crossref PubMed Scopus (225) Google Scholar, 17Wanigasekera V. Lee M.C. Rogers R. Hu P. Tracey I. Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans.J Neurosci. 2011; 31: 2835-2842Crossref PubMed Scopus (28) Google Scholar, 18Lee M.C. Ploner M. Wiech K. et al.Amygdala activity contributes to the dissociative effect of cannabis on pain perception.Pain. 2013; 154: 124-134Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 19Wise R.G. Rogers R. Painter D. et al.Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil.Neuroimage. 2002; 16: 999-1014Crossref PubMed Scopus (157) Google Scholar, 20Wanigasekera V. Mezue M. Andersson J. Kong Y. Tracey I. Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: implications for analgesic drug development.Anesthesiology. 2016; 124: 159-168Crossref PubMed Scopus (36) Google Scholar including this study, were designed to contribute to this effort and interpreted as such in our paper. We do not agree with the alternative interpretation put forward by Boissoneault and colleagues1Boissoneault J. Letzen J. Robinson M. Treating patients rather than their functional neuroimages. Comment on Br J Anaesth 2018; 120: 299–307.Br J Anaesth. 2018; 121: 969-971Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar as clarified here:(i)(a) As we set out to show the utility of functional MRI (fMRI) in detecting objectively pharmacodynamic effects related to analgesia, we chose pregabalin, an analgesic with known clinical efficacy and used as first-line therapy in the target patient population recruited.21Dworkin R.H. O’Connor A.B. Audette J. et al.Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.Mayo Clin Proc. 2010; 85: S3-S14Abstract Full Text Full Text PDF PubMed Scopus (1018) Google Scholar Therefore, it is meaningless to conclude that pregabalin is ineffective merely because of a lack of a statistically significant reduction in pain reports in a cohort of 16 patients after a week of treatment. Indeed, this precise lack of measurable subjective analgesia was the whole point of the study design and the challenge set for the imaging metrics to overcome. Let us imagine this small POC study was done (without imaging) during the development of pregabalin. The developer might conclude that the drug was ineffective based solely on the subjective pain reports, and they would then be presented with a dilemma: stop the development, depriving future patients of an effective analgesic; or continue development, performing studies with ever-increasing sample sizes, higher doses, repeat dosing regimens, longer periods of dosing, and in multiple patient cohorts before realising that the compound is likely, or worse unlikely, to be effective. The development of the neurokinin-1 antagonist, aprepitant, which had strong preclinical evidence of efficacy, is just one classic example.22Borsook D. Upadhyay J. Klimas M. et al.Decision-making using fMRI in clinical drug development: revisiting NK-1 receptor antagonists for pain.Drug Discov Today. 2012; 17: 964-973Crossref PubMed Scopus (46) Google Scholar It took several years before the development programme was terminated, and this was only after the exposure of numerous patient cohorts to different dosing regimens using different sample sizes and different pain conditions.22Borsook D. Upadhyay J. Klimas M. et al.Decision-making using fMRI in clinical drug development: revisiting NK-1 receptor antagonists for pain.Drug Discov Today. 2012; 17: 964-973Crossref PubMed Scopus (46) Google Scholar, 23Goldstein D.J. Wang O. Saper J.R. Stoltz R. Silberstein S.D. Mathew N.T. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study.Cephalalgia. 1997; 17: 785-790Crossref PubMed Scopus (187) Google Scholar, 24Goldstein D.J. Wang O. Todd L.E. Gitter B.D. DeBrota D.J. Iyengar S. Study of the analgesic effect of lanepitant in patients with osteoarthritis pain.Clin Pharmacol Ther. 2000; 67: 419-426Crossref PubMed Scopus (49) Google Scholar, 25Goldstein D.J. Wang O. Gitter B.D. Iyengar S. Dose-response study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy.Clin Neuropharmacol. 2001; 24: 16-22Crossref PubMed Scopus (44) Google Scholar, 26Sindrup S.H. Graf A. Sfikas N. The NK1-receptor antagonist TKA731 in painful diabetic neuropathy: a randomised, controlled trial.Eur J Pain. 2006; 10: 567-571Crossref PubMed Scopus (48) Google Scholar Subsequently, using neuroimaging, aprepitant was shown not to suppress neural activity evoked by painful stimuli in humans.27Upadhyay J. Anderson J. Schwarz A.J. et al.Imaging drugs with and without clinical analgesic efficacy.Neuropsychopharmacology. 2011; 36: 2659-2673Crossref PubMed Scopus (55) Google Scholar Had there been objective evidence of this nature, the developers might have had the necessary confidence to make a more informed decision earlier.(b) We agree entirely with Boissoneault and colleagues1Boissoneault J. Letzen J. Robinson M. Treating patients rather than their functional neuroimages. Comment on Br J Anaesth 2018; 120: 299–307.Br J Anaesth. 2018; 121: 969-971Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar that the relationship between pain intensity and neural activity is non-linear, but not for the objections they put forward. Different brain regions encode for different features of the multidimensional pain experience. It would be non-sensical for every brain region to track slavishly one dimension of pain—20 yr of neuroimaging pain has taught us that fact. In fact, we would go a step further to remind readers that fMRI is not a surrogate of pain ratings at all; this is a common mistake made by non-imaging researchers. Neuroimaging provides a far deeper understanding of the mechanisms involved in generating the pain and analgesia experience.28Tracey I. “Seeing” how our drugs work brings translational added value.Anesthesiology. 2013; 119: 1247-1248Crossref PubMed Google Scholar, 29Woo C.W. Wager T.D. What reliability can and cannot tell us about pain report and pain neuroimaging.Pain. 2016; 157: 511-513Crossref PubMed Scopus (20) Google Scholar Therefore, in our study, we used neuroimaging to detect the pharmacodynamic effects of a known analgesic on the neural activity evoked by a clinically relevant painful stimulus rather than make a statement about neural effects related to subjective pain ratings that emerge as a consequence of the evoked painful stimulus.(c) We agree with Boissoneault and colleagues1Boissoneault J. Letzen J. Robinson M. Treating patients rather than their functional neuroimages. Comment on Br J Anaesth 2018; 120: 299–307.Br J Anaesth. 2018; 121: 969-971Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar that, if this study was performed 20 yr ago at the inception of fMRI, we would not be able to conclude that our neuroimaging results are representative of analgesic pharmacodynamic effects in the absence of behavioural findings. However, 20 yr on, there is now a wealth of information about the neural correlates of chronic pain and its relief.30Garcia-Larrea L. Peyron R. Pain matrices and neuropathic pain matrices: a review.Pain. 2013; 154: S29-S43Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 31Friebel U. Eickhoff S.B. Lotze M. Coordinate-based meta-analysis of experimentally induced and chronic persistent neuropathic pain.Neuroimage. 2011; 58: 1070-1080Crossref PubMed Scopus (97) Google Scholar As a consequence, we are in a position to conclude that our results likely represent the neural effects related to pregabalin's analgesic efficacy on a clinically relevant stimulus [dynamic mechanical allodynia (DMA)] despite the lack of convincing behavioural effects. Again, the latter were expected, having deliberately chosen a small sample size to produce such a lack of behavioural effect in order to challenge the imaging metric.(ii)Boissoneault and colleagues1Boissoneault J. Letzen J. Robinson M. Treating patients rather than their functional neuroimages. Comment on Br J Anaesth 2018; 120: 299–307.Br J Anaesth. 2018; 121: 969-971Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar have rightly cited studies that demonstrate the reliability of self-reported measures32Rosier E.M. Iadarola M.J. Coghill R.C. Reproducibility of pain measurement and pain perception.Pain. 2002; 98: 205-216Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar and their sensitivity to treatment effects.33Campbell B.K. Fillingim R.B. Lee S. Brao R. Price D.D. Neubert J.K. Effects of high-dose capsaicin on TMD subjects: a randomized clinical study.JDR Clin Trans Res. 2017; 2: 58-65Crossref PubMed Scopus (9) Google Scholar These studies are indeed excellent albeit rare examples where special measures, as mentioned earlier, were used to improve the reliability of pain reports adopting the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for improving assay sensitivity—precisely because of the recognised problems in using self-report for drug discovery we also cite. Boissoneault and colleagues and others have shown that the test–retest reliability for fMRI metrics does not outperform self-report.34Letzen J.E. Boissoneault J. Sevel L.S. Robinson M.E. Test-retest reliability of pain-related functional brain connectivity compared with pain self-report.Pain. 2016; 157: 546-551Crossref PubMed Scopus (22) Google Scholar, 35Upadhyay J. Lemme J. Anderson J. et al.Test-retest reliability of evoked heat stimulation BOLD fMRI.J Neurosci Methods. 2015; 253: 38-46Crossref PubMed Scopus (23) Google Scholar However, there are several problems with their inclusion of this information. The first is that both studies were performed in healthy volunteers using experimental heat stimuli and assessing pain intensity in response—without it being agreed within the community which subset of brain regions should be quantified for such a comparison. Therefore, relating the imaging metrics chosen to the ratings is problematic. Also, the results of these volunteer acute pain studies cannot be extrapolated to a chronic patient cohort where both subjective pain reports and the fMRI signal are more complex because of the physiological, cognitive, and affective loads on these patients, and the chronicity of the condition. The second problem we have with the data they have included relates to its fundamental relevance for our study. The relative reproducibility in test–retest of different metrics for an individual is not the factor being explored in our study design, but rather the sensitivity of the metric to modulation (in this case by a drug). What we were assessing here relates better to an earlier study we published that highlighted the superiority of the imaging metric relative to behaviour when challenged by various drugs.20Wanigasekera V. Mezue M. Andersson J. Kong Y. Tracey I. Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: implications for analgesic drug development.Anesthesiology. 2016; 124: 159-168Crossref PubMed Scopus (36) Google Scholar Boissoneault and colleagues want to suggest replacing pain reports with fMRI signals, but that is not how we see the use of neuroimaging for drug development, as stated in many prior pharmacological imaging studies by us and indeed in this paper.14Rogers R. Wise R.G. Painter D.J. Longe S.E. Tracey I. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging.Anesthesiology. 2004; 100: 292-301Crossref PubMed Scopus (102) Google Scholar, 15Wise R.G. Williams P. Tracey I. Using fMRI to quantify the time dependence of remifentanil analgesia in the human brain.Neuropsychopharmacology. 2004; 29: 626-635Crossref PubMed Scopus (100) Google Scholar, 16Iannetti G.D. Zambreanu L. Wise R.G. et al.Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.Proc Natl Acad Sci U S A. 2005; 102: 18195-18200Crossref PubMed Scopus (225) Google Scholar, 17Wanigasekera V. Lee M.C. Rogers R. Hu P. Tracey I. Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans.J Neurosci. 2011; 31: 2835-2842Crossref PubMed Scopus (28) Google Scholar, 18Lee M.C. Ploner M. Wiech K. et al.Amygdala activity contributes to the dissociative effect of cannabis on pain perception.Pain. 2013; 154: 124-134Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 19Wise R.G. Rogers R. Painter D. et al.Combining fMRI with a pharmacokinetic model to determine which brain areas activated by painful stimulation are specifically modulated by remifentanil.Neuroimage. 2002; 16: 999-1014Crossref PubMed Scopus (157) Google Scholar, 20Wanigasekera V. Mezue M. Andersson J. Kong Y. Tracey I. Disambiguating pharmacodynamic efficacy from behavior with neuroimaging: implications for analgesic drug development.Anesthesiology. 2016; 124: 159-168Crossref PubMed Scopus (36) Google Scholar, 28Tracey I. “Seeing” how our drugs work brings translational added value.Anesthesiology. 2013; 119: 1247-1248Crossref PubMed Google Scholar, 36Wise R.G. Tracey I. The role of fMRI in drug discovery.J Magn Reson Imaging. 2006; 23: 862-876Crossref PubMed Scopus (165) Google Scholar, 37Mitsis G.D. Iannetti G.D. Smart T.S. Tracey I. Wise R.G. Regions of interest analysis in pharmacological fMRI: how do the definition criteria influence the inferred result?.Neuroimage. 2008; 40: 121-132Crossref PubMed Scopus (61) Google Scholar, 38Lee M.C. Wanigasekera V. Tracey I. Imaging opioid analgesia in the human brain and its potential relevance for understanding opioid use in chronic pain.Neuropharmacology. 2014; 84: 123-130Crossref PubMed Scopus (28) Google Scholar, 39Tracey I. Neuroimaging mechanisms in pain: from discovery to translation.Pain. 2017; 158: S115-S122Crossref PubMed Scopus (23) Google Scholar Our aim was to provide objective evidence of how the analgesic drug acts on brain regions implicated in chronic pain processing. To avoid repetition, we have addressed the comment about fMRI reflecting affective and cognitive factors under Point iv.(iii)We wholeheartedly agree with Boissoneault and colleagues1Boissoneault J. Letzen J. Robinson M. Treating patients rather than their functional neuroimages. Comment on Br J Anaesth 2018; 120: 299–307.Br J Anaesth. 2018; 121: 969-971Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar that treatment outcome expectation is integral to the management of patients in a clinical setting, and that we should harness its benefits40Finniss D.G. Kaptchuk T.J. Miller F. Benedetti F. Biological, clinical, and ethical advances of placebo effects.Lancet. 2010; 375: 686-695Abstract Full Text Full Text PDF PubMed Scopus (871) Google Scholar—hence, our prior work in this area.4Bingel U. Wanigasekera V. Wiech K. et al.The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.Sci Transl Med. 2011; 3 (70ra14)Crossref PubMed Scopus (498) Google Scholar, 41Bingel U. Tracey I. Wiech K. Neuroimaging as a tool to investigate how cognitive factors influence analgesic drug outcomes.Neurosci Lett. 2012; 520: 149-155Crossref PubMed Scopus (18) Google Scholar, 42Tracey I. Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans.Nat Med. 2010; 16: 1277-1283Crossref PubMed Scopus (365) Google Scholar However, when a compound is being developed as an analgesic, it is first necessary to demonstrate that it suppresses pain-related neural activity. We agree that a placebo is needed that ideally has all the sensory and psychoactive properties of the study drug, but not the analgesic effects, thereby allowing investigators to isolate the pure analgesic effects of the drug by providing absolute control over the magnitude of expectations for both active and placebo arms. That is not in question, but it seems a subtlety surrounding what we report and its significance has been misunderstood. As we discussed, it is well established that experimentally induced placebo analgesic responses are driven by well-characterised neural networks that can be separated from those networks modulated during drug-related analgesia.4Bingel U. Wanigasekera V. Wiech K. et al.The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.Sci Transl Med. 2011; 3 (70ra14)Crossref PubMed Scopus (498) Google Scholar, 43Wager T.D. Roy M. Separate mechanisms for placebo and opiate analgesia?.Pain. 2010; 150: 8-9Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 44Atlas L.Y. Whittington R.A. Lindquist M.A. Wielgosz J. Sonty N. Wager T.D. Dissociable influences of opiates and expectations on pain.J Neurosci. 2012; 32: 8053-8064Crossref PubMed Scopus (119) Google Scholar, 45Wanigasekera V. Mezue M. Kong Y. Tracey I. Neural correlates of pain relief expectation in a double blind placebo controlled study setting.in: Proceedings of the 8th congress of the European federation of IASP® chapters (EFIC®). 2013Google Scholar Therefore, when a brain has a drug on board with potentially widespread binding, it is not known whether the neural networks/mechanisms required to drive a placebo response are independently influenced by the drug's presence—such that they might not function the same as if the brain was not on drug. Therefore, it is an oversimplification to assume that the neural networks required to drive the placebo response are functioning precisely the same in both the active drug and placebo arms. The existing debate on the validity of the additivity model of placebo-controlled clinical trials highlights the concerns we express and our hypothesis as to how these concerns might be realised. We have discussed this at length in our paper and provide preliminary evidence suggestive of a possible interference by drug of the placebo network (Fig. 4).46Wanigasekera V. Wartolowska K. Huggins J.P. et al.Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging.Br J Anaesth. 2018; 120: 299-307Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar A recent study corroborates our findings in reporting neuroimaging evidence of distinct brain mechanisms underlying placebo and duloxetine in a group of 19 osteoarthritis patients.47Tetreault P. Baliki M.N. Baria A.T. Bauer W.R. Schnitzer T.J. Apkarian A.V. Inferring distinct mechanisms in the absence of subjective differences: placebo and centrally acting analgesic underlie unique brain adaptations.Hum Brain Mapp. 2018; 39: 2210-2223Crossref PubMed Scopus (13) Google Scholar Similar to our study findings despite 3 months of dosing, they also failed to show a significant difference in behavioural pain reports between the drug arm and the placebo even though duloxetine is an analgesic with known clinical efficacy in osteoarthritis.48Wang Z.Y. Shi S.Y. Li S.J. et al.Efficacy and safety of duloxetine on osteoarthritis knee pain: a meta-analysis of randomized controlled trials.Pain Med. 2015; 16: 1373-1385Crossref PubMed Scopus (67) Google Scholar(iv)(a) We agree entirely with Boissoneault and colleagues1Boissoneault J. Letzen J. Robinson M. Treating patients rather than their functional neuroimages. Comment on Br J Anaesth 2018; 120: 299–307.Br J Anaesth. 2018; 121: 969-971Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar that fMRI can capture neural activity related to affect, distraction/cognition, context—indeed, that has been a major part of our research.3Wiech K. Tracey I. The influence of negative emotions on pain: behavioral effects and neural mechanisms.Neuroimage. 2009; 47: 987-994Crossref PubMed Scopus (396) Google Scholar, 4Bingel U. Wanigasekera V. Wiech K. et al.The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.Sci Transl Med. 2011; 3 (70ra14)Crossref PubMed Scopus (498) Google Scholar, 7Ploghaus A. Tracey I. Gati J.S. et al.Dissociating pain from its anticipation in the human brain.Science. 1999; 284: 1979-1981Crossref PubMed Scopus (911) Google Scholar, 8Wiech K. Ploner M. Tracey I. Neurocognitive aspects of pain perception.Trends Cogn Sci. 2008; 12: 306-313Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar, 9Berna C. Leknes S. Holmes E.A. Edwards R.R. Goodwin G.M. Tracey I. Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness.Biol Psychiatry. 2010; 67: 1083-1090Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 10Fairhurst M. Wiech K. Dunckley P. Tracey I. Anticipatory brainstem activity predicts neural processing of pain in humans.Pain. 2007; 128: 101-110Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 14Rogers R. Wise R.G. Painter D.J. Longe S.E. Tracey I. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging.Anesthesiology. 2004; 100: 292-301Crossref PubMed Scopus (102) Google Scholar, 49Ploghaus A. Narain C. Beckmann C.F. et al.Exacerbation of pain by anxiety is associated with activity in a hippocampal network.J Neurosci. 2001; 21: 9896-9903Crossref PubMed Google Scholar, 50Bantick S.J. Wise R.G. Ploghaus A. Clare S. Smith S.M. Tracey I. Imaging how attention modulates pain in humans using functional MRI.Brain. 2002; 125: 310-319Crossref PubMed Scopus (651) Google Scholar, 51Wise R.G. Lujan B.J. Schweinhardt P. Peskett G.D. Rogers R. Tracey I. The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI.Magn Reson Imaging. 2007; 25: 801-810Crossref PubMed Scopus (48) Google Scholar Although brain areas sub-serving affective and cognitive factors are co-activated with pain, they are distinguishable from nociceptive processing areas. A recent meta-analysis published by the Placebo Imaging Consortium confirms this.52Zunhammer M. Wager T.D. Bingel U. Placebo effects on the neurolog

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