Up-to-date : recent findings on pain modulation research

Luana COLLOCA,

MD, PhD, MS

To the readers of Somatosens Pain Rehab and to those who will read this article by reference, I am delighted to share some recent results related to placebo and pain modulation research with a focus on chronic pain. I started my independent academic career at the National Institutes of Health and more recently I moved to the University of Maryland where I established my lab showing sustained and consistent productivity in research activities through work as a principal investigator of new, peer-reviewed, competitively funded federal grants. We have been consistently publishing both data-based publications and conceptual or methodological research articles on mechanisms and applications of pain modulation induced by placebo effects, nocebo effects, social observation and virtual reality. The last few years mark a significant, well-funded expansion of my research portfolio from placebo analgesia to observation and virtual reality and I am delighted to provide you with a synopsis of the most recent findings.

Mechanisms of placebo effects in chronic orofacial pain
Patients with TemporoMandibular Disorders (TMD) are a common yet underserved faction of chronic pain patients (National Academies of Sciences & Medicine, 2020). TMD involves dysfunction of the jaw joint and/or muscles of mastication with a prevalence of 5-12% in the general population (National Academies of Sciences & Medicine, 2020), disproportionately affecting women (female-to-male ratio of 9:1 (Scrivani et al., 2008; Shaefer et al., 2018), and it is a difficult pain disorder to treat.(Binderman & Singer, 1997; Clark et al., 2016; Colloca & Grillon, 2014; Eliassen et al., 2019; Hall et al., 2015; Litt & Porto, 2013; Mogil et al., 1996; Pecina & Zubieta, 2015a, 2015b; Tchivileva et al., 2020). One promising strategy to reduce chronic pain patients’ needs for pharmacological therapeutics is to include non-pharmacological adjuvants, and low-cost interventions in the arsenal of pain management therapeutics (Colloca et al., 2016a; Colloca & Miller, 2011a). Unfortunately, access to non-pharmacological pain treatment among TMD patients is often limited, in part due to a lack of consensus on both the standard of care and the benefits of biobehavioral therapies for TMD and associated symptoms. Furthermore, patients’ ability to access non-pharmacological treatment is further obstructed by a shortage of healthcare providers with experience treating the condition (National Academies of Sciences & Medicine, 2020).

It has been shown that placebo effects depend on the release of substances such as endogenous opioids (Benedetti et al., 2007a), endocannabinoids (Benedetti et al., 2011), oxytocin (Kessner et al., 2013), and vasopressin (Colloca et al., 2016b) in descending pain modulation systems. Placebo effects can be powerful and commonly encountered in clinical practice in the form of mind-body interventions. Through an understanding placebo mechanisms, strategies promoting placebo effects can optimize therapeutic outcomes in clinical practice as we recently outlined in an article for New England Journal of Medicine (Colloca & Barsky, 2020).

We have been among the first teams to discover critical aspects of TMD phenotypes and placebo effects. We demonstrated that placebo effects observed in TMD population are of large magnitude with a Number Needed to Treat (NNT) similar to healthy controls (HC) (i.e. TMD, NNT=1.88 and HC, NNT=1.47) (Colloca et al., 2020a). We used new approaches including computational modeling and mediation analyses in one of the largest datasets for placebo effects including healthy and TMD participants. We found that placebo effects in TMD participants do not extinguish over time and depend on prior therapeutic experience (Colloca et al., 2020a). Moreover, placebo effects in TMD participants are predicted by learning patterns (Wang et al., 2020), affected by race (Okusogu et al., 2020), and sex (Olson et al., 2020).

Mechanisms of observation induced hypoalgesia[2]
The brain has the ability to modulate pain experience by releasing endogenous substances. The chain of modulatory events can be triggered by drug marketing features (Faasse et al., 2016; Kam-Hansen et al., 2014; Waber et al., 2008), color and number of pills (Blackwell et al., 1972; de Craen et al., 1999), administration route (de Craen et al., 2000; Meissner et al., 2013) and the context in which a drug is delivered (Colloca et al, 2004). Conditioning (direct exposure to pain reduction) and verbal suggestions (verbal anticipations of analgesia) have been the best studied manipulations to investigate placebo analgesia in laboratory contexts. Observing others, which begins at birth, is a powerful way to gain information.(Bandura, 1989) It influences a variety of behaviors (Koban et al., 2017) including pain and social threat (Haaker et al., 2017; Koban & Wager, 2016). We and others showed that social learning (changes in behaviors/outcomes related to observation of others) (Colloca & Miller, 2011b) elicits placebo analgesic effects (Colloca & Benedetti, 2009; Hunter et al., 2014) comparable in magnitude to those induced by direct experiences (Egorova et al., 2015; Hunter et al., 2014; Swider & Babel, 2013, 2016; Vogtle et al., 2013).

Postulated theoretically by Bootzin and Caspi (Bootzin & Caspi, 2002), we were the first to demonstrate that observation led to placebo analgesia (Colloca & Benedetti, 2009). Observation generates placebo effects that are as large as those created via conditioning (pain reduction in the observational learning vs conditioning group: 39.18% vs 43.35%). Observation was strong enough to boost analgesia and pain relief along with a change at the level of autonomic responses (Colloca & Benedetti, 2009). Moreover, observing video or a live demonstrator generates the same magnitude of pain reductions that were significantly different from a control group (e.g., watching colored light stimulations). After this pioneering study (Colloca & Benedetti, 2009), other studies have replicated and extended these findings, confirming that the placebo effect of observational learning is comparable in size to the effect of directly experienced conditioning (Egorova et al., 2015; Hunter et al., 2014; Swider & Babel, 2013, 2016; Vogtle et al., 2013). Comparable pain reduction was induced by conditioning and observation in a rigorous counterbalanced within-subject design experiment that included alternating sessions of directly experienced conditioning and observational learning (Egorova et al., 2015).

The psychological and neural mechanisms behind observation-induced pain reduction are important to translate this knowledge into clinical applications.

Resting state Peak Alpha Frequency (PAF), which has maximal power within 7.4–12 Hz, has been considered to reflect shifts in the cortical excitability and information-processing rate (Angelakis et al., 2004; Furman et al., 2018; Posthuma et al., 2001). Recently, resting state PAF has also been linked to pain reports (Furman et al., 2018; Nir et al., 2010) and identified as an objective measurement of pain sensitivity and pain components (Kim et al., 2019; Kisler et al., 2020). Recorded via high-resolution electroencephalogram, PAF will be used to determine the neurophysiological changes associated with experimental pain (Nickel et al., 2017; Ploner et al., 2006a; Ploner et al., 2006b) tracking long-term clinical and neural placebo-induced effects (Raghuraman et al., 2019). We demonstrated distinct patterns of PAF changes with 1) pain sensitivity and 2) placebo responsiveness (Raghuraman et al., 2019). In particular, we demonstrated that higher resting-state PAF is associated with lower selfreported pain intensity and higher placebo effects. This is in line with the pain literature reporting that resting state PAF is a marker of cortical excitability and expresses how neural information is processed for prediction of individual pain (Samaha et al., 2015). We were the first to show that observing someone else receiving a beneficial treatment induces first-hand pain relief that is associated with neurophysiological changes at the level of the temporoparietal junction areas of the brain and modulation of the anticipatory neural P2 component of the electroencephalography.

Immersive Virtual Reality (VR)
Forms of non-pharmacological adjuvant interventions are relevant in the management of chronic pain (Honzel et al., 2019). We conducted a careful assessment of the rigor of the prior research for VR and pain. We identified weaknesses and/or gaps in the line of research. We recently published a systematic review of the literature for VR and experimental, acute, and chronic pain in PAIN® journal (Honzel et al., 2019) in which we found 288 VR articles and identified 58 data-based articles (Honzel et al., 2019) directly investigating the relationship between VR and pain in both healthy and pain-afflicted populations, using objective and subjective measures of pain as the primary outcomes. Throughout 2020, more than 58 new studies with VR and pain have been published. As Trost et al noted in their Topical Review for the journal PAIN: “Given that rapid technological progress can both facilitate and frustrate research progress within the field, systematic, theoretically-informed inquiry into factors comprising and driving the effects of VR pain applications, combined with more rigorous theoretically-informed methodology, is a critical challenge.” (Trost et al., 2020)

VR consists of immersion in artificial environments through the use of real-time rendering technologies and the latest generation devices. As part of a pain management plan, nonpharmacological and low-cost interventions might optimize clinical pain management (Colloca et al., 2016a; Colloca & Miller, 2011a). Therefore, mechanistic research that explains how VR influences both nociception and clinical pain is of paramount importance to help translate VR approaches to the bedside.

We demonstrated for the first time that immersive VR is not merely engaging attentive processes. We designed and conducted a well-controlled, fully-powered, within-subjects design study in healthy participants (Colloca et al., 2020b). More specifically, we measured changes for the objective assessment of pain tolerance limits (Fruhstorfer et al., 1976; Nielsen et al., 2005) as well as affective and evaluative processes associated with experiencing acute VR-induced pain related outcomes including mood, situational anxiety, and pain unpleasantness (Colloca et al., 2020b). Rather, virtual Reality contexts that are perceived as enjoyable increase pain tolerance, improve mood, reduce anxiety and importantly, reset vagal balance. Therefore, immersive VR is a multi-sensorial stimuli approach that activates the parasympathetic nervous system has the potential to pave the way for a new mechanisticbased intervention for acute and chronic pain. This new line of research in my lab has been broadly appreciated and the findings with immersive virtual reality have been recently featured by National Geographic in the 2020 January Special Issue on Pain.

Nocebo effects
Converging evidence suggests that the occurrence of nocebo effects - adverse events related to negative expectations and anticipations - is a critical determinant in creating poor patient outcomes and distress (Barsky et al., 2002; Colloca, 2017; Colloca & Finniss, 2012; Colloca & Miller, 2011c). A large proportion of adverse effects reported by patients in clinical trials and daily practice are not caused by the medication, because such adverse effects occur to a comparable degree in the placebo arm of studies (Amanzio et al., 2009). For decades, these nocebo effects have been dismissed as purely psychological effects without any serious consideration—this is likely due to the lack of rigorous research in the area. However, studies by our group and others illustrate that nocebo effects produce behavioral, functional, and biological effects (Benedetti et al., 2007b; Schedlowski et al., 2015). Indeed, nocebo effects can also affect the therapeutic efficacy of a drug. A recent pharmacological study using functional magnetic resonance imaging showed that negative expectancy not only abolished the subjective analgesic effect of a potent painkiller, i.e. the µ-opioid remifentanil, but also induced neural hyperalgesic activation in the brain regions known to influence the encoding of pain intensity (Bingel et al., 2011). In laboratory settings with healthy research participants, nocebo effects have produced worsening of somatosensorial perception (Colloca et al., 2008), pain (Colloca et al., 2008; van Laarhoven et al., 2011), itch (van Laarhoven et al., 2011), and motor performance (Pollo et al., 2012). Furthermore, a recent study of acute migraine treatment revealed that labeling the 5HT1B/1D agonist rizatriptan as placebo significantly reduced its efficacy (Kam-Hansen et al., 2014). Similarly, a switch from brand to generic name drugs with identical compounds is associated with an increase in adverse effects (Colloca et al., 2019; Faasse et al., 2009). Communicating potential side effects led to subsequent withdrawal from a randomized, double-blind, placebo-controlled trial examining the benefit of aspirin, sulfinpyrazone, or both drugs, for unstable angina pectoris. Specifically, the inclusion of potential gastrointestinal side effects in the consent form resulted in a remarkable increase (sixfold) of both gastrointestinal symptoms and consequent patientinitiated cessation of therapy (Myers et al., 1987). These examples highlight that patients’ expectations regarding adverse effects are important determinants of poor outcomes and increased incidence of non-specific adverse events on top of treatment side effects. The results strongly suggest that the methods by which patient-doctor communication is framed and practiced could have a significant and direct impact on improving patient outcomes via the nocebo effect (Barsky et al., 2002; Colloca & Barsky, 2020; Colloca & Finniss, 2012; Miller & Colloca, 2011).

REFERENCES

Amanzio, M., Corazzini, L. L., Vase, L., & Benedetti, F. (2009). A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain, 146(3), 261-269. doi: 10.1016/j.pain.2009.07.010

Angelakis, E., Lubar, J. F., Stathopoulou, S., & Kounios, J. (2004). Peak alpha frequency: an electroencephalographic measure of cognitive preparedness. Clin Neurophysiol, 115(4), 887-897. doi:10.1016/j.clinph.2003.11.034

Bandura, A. (1989). Human agency in social cognitive theory. Am Psychol, 44(9), 1175-1184.

Barsky, A. J., Saintfort, R., Rogers, M. P., & Borus, J. F. (2002). Nonspecific medication side effects and the nocebo phenomenon. JAMA, 287(5), 622-627. doi:10.1001/jama.287.5.622

Benedetti, F., Pollo, A., & Colloca, L. (2007a). Opioid-mediated placebo responses boost pain endurance and physical performance: is it doping in sport competitions? J Neurosci, 27(44), 11934-11939. doi:10.1523/JNEUROSCI.3330-07.2007

Benedetti, F., Lanotte, M., Lopiano, L., & Colloca, L. (2007b). When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience, 147(2), 260-271. doi:10.1016/j.neuroscience.2007.02.020

Benedetti, F., Amanzio, M., Rosato, R., & Blanchard, C. (2011). Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med, 17(10), 1228-1230. doi:10.1038/nm.2435

 Binderman, A. F., & Singer, M. T. (1997). Treatment of orofacial pain and temporomandibular disorders. Curr Opin Periodontol, 4, 144-150.

Bingel, U., Wanigasekera, V., Wiech, K., Ni Mhuircheartaigh, R., Lee, M. C., Ploner, M., & Tracey, I. (2011). The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med, 3(70), 70ra14. doi:10.1126/scitranslmed.3001244

Blackwell, B., Bloomfield, S. S., & Buncher, C. R. (1972). Demonstration to medical students of placebo responses and non-drug factors. Lancet, 1(7763), 1279-1282.

Bootzin, R. R., & Caspi, O. (2002). Explanatory mechanisms for placebo effects: cognition, personality and social learning. In H. A. Guess, A. Kleinman, J. W. Kusek, L. W. Engel, & (Eds.), The Science of the Placebo: Toward an Interdisciplinary Research Agenda. (pp. 108-132). 2002: London: BMJ Books.

Clark, G. T., Padilla, M., & Dionne, R. (2016). Medication Treatment Efficacy and Chronic Orofacial Pain. Oral Maxillofac Surg Clin North Am, 28(3), 409-421. doi:10.1016/j.coms.2016.03.011

Colloca, L. (2017). Nocebo effects can make you feel pain. Science, 358(6359), 44. doi:10.1126/science.aap8488  Colloca, L., & Barsky, A. J. (2020). Placebo and Nocebo Effects. N Engl J Med, 382(6), 554-561. doi:10.1056/NEJMra1907805

Colloca, L., & Benedetti, F. (2009). Placebo analgesia induced by social observational learning. Pain, 144(1- 2), 28-34. doi:10.1016/j.pain.2009.01.033

Colloca, L., & Finniss, D. (2012). Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA, 307(6), 567-568. doi:10.1001/jama.2012.115

Colloca, L., & Grillon, C. (2014). Understanding placebo and nocebo responses for pain management. Curr Pain Headache Rep, 18(6), 419. doi:10.1007/s11916-014-0419-2

Colloca, L., & Miller, F. G. (2011a). Harnessing the placebo effect: the need for translational research. Philos Trans R Soc Lond B Biol Sci, 366(1572), 1922-1930. doi:10.1098/rstb.2010.0399

Colloca, L., & Miller, F. G. (2011b). How placebo responses are formed: a learning perspective. Philos Trans R Soc Lond B Biol Sci, 366(1572), 1859-1869. doi:10.1098/rstb.2010.0398

Colloca, L., & Miller, F. G. (2011c). The nocebo effect and its relevance for clinical practice. Psychosom Med, 73(7), 598-603. doi:10.1097/PSY.0b013e3182294a50

Colloca, L., Lopiano, L., Lanotte, M., & Benedetti, F. (2004). Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol, 3(11), 679-684. doi:S1474442204009081

Colloca, L., Sigaudo, M., & Benedetti, F. (2008). The role of learning in nocebo and placebo effects. Pain, 136(1-2), 211-218. https://doi.org/10.1016/j.pain.2008.02.006 (02/11/2021)

Colloca, L., Enck, P., & DeGrazia, D. (2016a). Relieving pain using dose-extending placebos: a scoping review. Pain, 157(8), 1590-1598. doi:10.1097/j.pain.0000000000000566

Colloca, L., Pine, D. S., Ernst, M., Miller, F. G., & Grillon, C. (2016b). Vasopressin Boosts Placebo Analgesic Effects in Women: A Randomized Trial. Biol Psychiatry, 79(10), 794-802. doi:10.1016/j.biopsych.2015.07.019

Colloca, L., Panaccione, R., & Murphy, T. K. (2019). The Clinical Implications of Nocebo Effects for Biosimilar Therapy. Front Pharmacol, 10, 1372. doi:10.3389/fphar.2019.01372

Colloca, L., Akintola, T., Haycock, N. R., Blasini, M., Thomas, S., Phillips, J., . . . Wang, Y. (2020a). Prior Therapeutic Experiences, Not Expectation Ratings, Predict Placebo Effects: An Experimental Study in Chronic Pain and Healthy Participants. Psychother Psychosom, 89(6), 371-378. doi:10.1159/000507400

Colloca, L., Raghuraman, N., Wang, Y., Akintola, T., Brawn-Cinani, B., Colloca, G., . . . Murthi, S. (2020b). Virtual reality: physiological and behavioral mechanisms to increase individual pain tolerance limits. Pain. doi:10.1097/j.pain.0000000000001900

de Craen, A. J., Kaptchuk, T. J., Tijssen, J. G., & Kleijnen, J. (1999). Placebos and placebo effects in medicine: historical overview. J R Soc Med, 92(10), 511-515.

de Craen, A. J., Tijssen, J. G., de Gans, J., & Kleijnen, J. (2000). Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol, 247(3), 183-188.

Egorova, N., Park, J., Orr, S. P., Kirsch, I., Gollub, R. L., & Kong, J. (2015). Not seeing or feeling is still believing: conscious and non-conscious pain modulation after direct and observational learning. Sci Rep, 5, 16809. doi:10.1038/srep16809

Eliassen, M., Hjortsjo, C., Olsen-Bergem, H., & Bjornland, T. (2019). Self-exercise programmes and occlusal splints in the treatment of TMD-related myalgia-Evidence-based medicine? J Oral Rehabil, 46(11), 1088-1094. doi:10.1111/joor.12856

Faasse, K., Cundy, T., & Petrie, K. J. (2009). Medicine and the Media. Thyroxine: anatomy of a health scare. BMJ, 339, b5613. doi:10.1136/bmj.b5613

Faasse, K., Martin, L. R., Grey, A., Gamble, G., & Petrie, K. J. (2016). Impact of brand or generic labeling on medication effectiveness and side effects. Health Psychol, 35(2), 187-190. doi:10.1037/hea0000282

Fruhstorfer, H., Lindblom, U., & Schmidt, W. C. (1976). Method for quantitative estimation of thermal thresholds in patients. J Neurol Neurosurg Psychiatry, 39(11), 1071-1075.

Furman, A. J., Meeker, T. J., Rietschel, J. C., Yoo, S., Muthulingam, J., Prokhorenko, M., . . . Seminowicz, D. A. (2018). Cerebral peak alpha frequency predicts individual differences in pain sensitivity. Neuroimage, 167, 203-210. doi:10.1016/j.neuroimage.2017.11.042

Haaker, J., Yi, J., Petrovic, P., & Olsson, A. (2017). Endogenous opioids regulate social threat learning in humans. Nat Commun, 8, 15495. doi:10.1038/ncomms15495

Hall, K. T., Loscalzo, J., & Kaptchuk, T. J. (2015). Genetics and the placebo effect: the placebome. Trends Mol Med, 21(5), 285-294. doi:10.1016/j.molmed.2015.02.009

Honzel, E., Murthi, S., Brawn-Cinani, B., Colloca, G., Kier, C., Varshney, A., & Colloca, L. (2019). Virtual reality, music, and pain: developing the premise for an interdisciplinary approach to pain management. Pain, 160(9), 1909-1919. doi:10.1097/j.pain.0000000000001539

Hunter, T., Siess, F., & Colloca, L. (2014). Socially induced placebo analgesia: a comparison of a prerecorded versus live face-to-face observation. Eur J Pain, 18(7), 914-922. doi:10.1002/j.1532- 2149.2013.00436.x

Kam-Hansen, S., Jakubowski, M., Kelley, J. M., Kirsch, I., Hoaglin, D. C., Kaptchuk, T. J., & Burstein, R. (2014). Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med, 6(218), 218ra215. doi:10.1126/scitranslmed.3006175

Kessner, S., Sprenger, C., Wrobel, N., Wiech, K., & Bingel, U. (2013). Effect of oxytocin on placebo analgesia: a randomized study. JAMA, 310(16), 1733-1735. doi:10.1001/jama.2013.277446

Kim, J. A., Bosma, R. L., Hemington, K. S., Rogachov, A., Osborne, N. R., Cheng, J. C., . . . Davis, K. D. (2019). Neuropathic pain and pain interference are linked to alpha-band slowing and reduced beta-band magnetoencephalography activity within the dynamic pain connectome in patients with multiple sclerosis. Pain, 160(1), 187-197. doi:10.1097/j.pain.0000000000001391

Kisler, L. B., Kim, J. A., Hemington, K. S., Rogachov, A., Cheng, J. C., Bosma, R. L., . . . Davis, K. D. (2020). Abnormal alpha band power in the dynamic pain connectome is a marker of chronic pain with a neuropathic component. Neuroimage Clin, 26, 102241. doi:10.1016/j.nicl.2020.102241

Koban, L., & Wager, T. D. (2016). Beyond conformity: Social influences on pain reports and physiology. Emotion, 16(1), 24-32. doi:10.1037/emo0000087

Koban, L., Jepma, M., Geuter, S., & Wager, T. D. (2017). What's in a word? How instructions, suggestions, and social information change pain and emotion. Neurosci Biobehav Rev, 81(Pt A), 29-42. doi:10.1016/j.neubiorev.2017.02.014

Litt, M. D., & Porto, F. B. (2013). Determinants of pain treatment response and nonresponse: identification of TMD patient subgroups. J Pain, 14(11), 1502-1513. doi:10.1016/j.jpain.2013.07.017

Meissner, K., Fassler, M., Rucker, G., Kleijnen, J., Hrobjartsson, A., Schneider, A., . . . Linde, K. (2013). Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern Med, 173(21), 1941-1951. doi:10.1001/jamainternmed.2013.10391

Miller, F. G., & Colloca, L. (2011). The placebo phenomenon and medical ethics: rethinking the relationship between informed consent and risk-benefit assessment. Theor Med Bioeth, 32(4), 229-243. doi:10.1007/s11017- 011-9179-8

Mogil, J. S., Sternberg, W. F., Marek, P., Sadowski, B., Belknap, J. K., & Liebeskind, J. C. (1996). The genetics of pain and pain inhibition. Proc Natl Acad Sci U S A, 93(7), 3048-3055.

Myers, M. G., Cairns, J. A., & Singer, J. (1987). The consent form as a possible cause of side effects. Clin Pharmacol Ther, 42(3), 250-253. https://doi.org/10.1038/clpt.1987.142 (02/11/2021)

National Academies of Sciences, E., & Medicine. (2020). Temporomandibular Disorders: Priorities for Research and Care. Washington, DC: The National Academies Press.

Nickel, M. M., May, E. S., Tiemann, L., Schmidt, P., Postorino, M., Ta Dinh, S., . . . Ploner, M. (2017). Brain oscillations differentially encode noxious stimulus intensity and pain intensity. Neuroimage, 148, 141-147. doi:10.1016/j.neuroimage.2017.01.011

Nielsen, C. S., Price, D. D., Vassend, O., Stubhaug, A., & Harris, J. R. (2005). Characterizing individual differences in heat-pain sensitivity. Pain, 119(1-3), 65-74. doi:10.1016/j.pain.2005.09.018

Nir, R.R., Sinai, A., Raz, E., Sprecher, E., & Yarnitsky, D. (2010). Pain assessment by continuous EEG: association between subjective perception of tonic pain and peak frequency of alpha oscillations during stimulation and at rest. Brain research, 1344, 77-86

Okusogu, C., Wang, Y., Akintola, T., Haycock, N. R., Raghuraman, N., Greenspan, J. D., . . . Colloca, L. (2020). Placebo hypoalgesia: racial differences. Pain. doi:10.1097/j.pain.0000000000001876

Olson, E. M., Akintola, T., Phillips, J., Blasini, M., Haycock, N. R., Martinez, P. E., . . . Colloca, L. (2020). Effects of sex on placebo effects in chronic pain participants: a cross-sectional study. Pain. doi:10.1097/j.pain.0000000000002038

Pecina, M., & Zubieta, J. K. (2015a). Molecular mechanisms of placebo responses in humans. Mol Psychiatry, 20(4), 416-423. doi:10.1038/mp.2014.164

Pecina, M., & Zubieta, J. K. (2015b). Over a decade of neuroimaging studies of placebo analgesia in humans: what is next? Mol Psychiatry, 20(4), 415. doi:10.1038/mp.2015.33

Ploner, M., Gross, J., Timmermann, L., Pollok, B., & Schnitzler, A. (2006a). Pain suppresses spontaneous brain rhythms. Cereb Cortex, 16(4), 537-540. doi:10.1093/cercor/bhj001  Ploner, M., Gross, J., Timmermann, L., & Schnitzler, A. (2006b). Pain processing is faster than tactile processing in the human brain. J Neurosci, 26(42), 10879-10882. doi:10.1523/JNEUROSCI.2386-06.2006

Pollo, A., Carlino, E., Vase, L., & Benedetti, F. (2012). Preventing motor training through nocebo suggestions. Eur J Appl Physiol. doi:10.1007/s00421-012-2333-9

Posthuma, D., Neale, M., Boomsma, D., & De Geus, E. (2001). Are smarter brains running faster? Heritability of alpha peak frequency, IQ, and their interrelation. Behavior genetics, 31(6), 567-579.

Raghuraman, N., Wang, Y., Schenk, L. A., Furman, A. J., Tricou, C., Seminowicz, D. A., & Colloca, L. (2019). Neural and behavioral changes driven by observationally-induced hypoalgesia. Sci Rep, 9(1), 19760. doi:10.1038/s41598-019-56188-2

Samaha, J., Bauer, P., Cimaroli, S., & Postle, B. R. (2015). Top-down control of the phase of alpha-band oscillations as a mechanism for temporal prediction. Proc Natl Acad Sci U S A, 112(27), 8439-8444. doi:10.1073/pnas.1503686112

Schedlowski, M., Enck, P., Rief, W., & Bingel, U. (2015). Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice. Pharmacol Rev, 67(3), 697-730. doi:10.1124/pr.114.009423

Scrivani, S. J., Keith, D. A., & Kaban, L. B. (2008). Temporomandibular disorders. N Engl J Med, 359(25), 2693-2705. doi:10.1056/NEJMra0802472

Shaefer, J. R., Khawaja, S. N., & Bavia, P. F. (2018). Sex, Gender, and Orofacial Pain. Dent Clin North Am, 62(4), 665-682. doi:10.1016/j.cden.2018.06.001

Swider, K., & Babel, P. (2013). The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning. Pain, 154(8), 1312-1317. doi:10.1016/j.pain.2013.04.001

Swider, K., & Babel, P. (2016). The Effect of the Type and Colour of Placebo Stimuli on Placebo Effects Induced by Observational Learning. PLoS One, 11(6), e0158363. doi:10.1371/journal.pone.0158363

Tchivileva, I. E., Hadgraft, H., Lim, P. F., Di Giosia, M., Ribeiro-Dasilva, M., Campbell, J. H., . . . Slade, G. D. (2020). Efficacy and safety of propranolol for treatment of TMD pain: a randomized, placebo-controlled clinical trial. Pain. doi:10.1097/j.pain.0000000000001882

Trost, Z., France, C., Anam, M., & Shum, C. (2020). Virtual reality approaches to pain: toward a state of the science. Pain. doi:10.1097/j.pain.0000000000002060

van Laarhoven, A. I., Vogelaar, M. L., Wilder-Smith, O. H., van Riel, P. L., van de Kerkhof, P. C., Kraaimaat, F. W., & Evers, A. W. (2011). Induction of nocebo and placebo effects on itch and pain by verbal suggestions. Pain, 152(7), 1486-1494. doi:10.1016/j.pain.2011.01.043

Vogtle, E., Barke, A., & Kroner-Herwig, B. (2013). Nocebo hyperalgesia induced by social observational learning. Pain, 154(8), 1427-1433. doi:10.1016/j.pain.2013.04.041

Waber, R. L., Shiv, B., Carmon, Z., & Ariely, D. (2008). Commercial features of placebo and therapeutic efficacy. JAMA, 299(9), 1016-1017. doi:10.1001/jama.299.9.1016

Wang, Y., Tricou, C., Raghuraman, N., Akintola, T., Haycock, N. R., Blasini, M., . . . Colloca, L. (2020). Modeling Learning Patterns to Predict Placebo Analgesic Effects in Healthy and Chronic Orofacial Pain Participants. Front Psychiatry, 11, 39. doi:10.3389/fpsyt.2020.00039