key: cord-1035775-smkoii0v authors: Bernstein, Michael H.; Blease, Charlotte; Vase, Lene title: Editorial: Placebo Effect in Pain and Pain Treatment date: 2022-03-29 journal: Front Pain Res (Lausanne) DOI: 10.3389/fpain.2022.884055 sha: 57389e69a8430916d64c23d8e7cc0d76b8af190c doc_id: 1035775 cord_uid: smkoii0v nan A wide and tantalizing body of research dating back to the mid-1950s has suggested that placebo may play an important role in pain treatment (11, 12) . In randomized trials, patients improve on placebo for a variety of pain conditions (13) . Although controversial (14, 15) , this finding indirectly suggests placebo effects administered via placebos promote analgesia. Disentangling the placebo effect from other factors (e.g., assessment reactivity, passage of time) is critical to how we interpret Randomized Clinical Trials (RCTs) (16, 17) . The placebo effect also features prominently in studies investigating analgesia from pain induced in the laboratory (18) . Painkillers such as morphine are more effective when a patient is aware, vs. unaware, they are receiving the drug (19) , which demonstrates the psychological nature of placebo analgesia. But the placebo effect is physiological as well. The endogenous opioid, endoconnabinoid, and dopaminergic systems are all implicated in placebo pain-relief (20) . The articles that follow show the diversity of topics related to the placebo effect and pain. Wampold and Smith et al. remind us that the placebo effect is often conceptualized broadly to include interpersonal factors (21) [see (22) for a lengthy discussion of placebo definitions]. Wampold situates the placebo effect within a healing context and argues for the importance of evolutionary considerations in how humans (and non-humans) improve through interpersonal contact. Smith et al. leverage the importance of empathy and optimism by describing a training program for primary care physicians, called Empathico, to enhance communication skills and ultimately reduce patient suffering. Two experimental studies are published in this Special Topic. Wagner et al. observe that neither a dog nor a placebo increases pain tolerance among healthy volunteers in the lab. This paper serves as an important reminder about the need to publish non-significant results to mitigate the chance that we see a replication crisis within placebo studies, as has been observed across other scientific disciplines including the adjacent field of psychology (23) . The paper by Lunde et al. further illustrates the importance of developing adequate placebo control conditions for non-pharmacological interventions like music analgesia. By introducing a placebo control to music analgesia, it is specified that the analgesic effect of music primarily steams from patients expectations rather than music per se. With respect to placebo control arms in drug treatment trials, Koechlin et al. examined the placebo response to anti-depressant medication for Fibromyalgia in a meta-analysis of randomized trials. Pain, functional disability, and depression were all reported to have improved among patients taking a placebo. Again, disentangling the placebo effect from other confounding factors would be an invaluable follow-up should a no-treatment arm be deemed ethical. Turning away from double-blind placebo, a growing number of studies suggest placebos can be effective even when given openly (24) (so-called Open-Label Placebo [OLP]), though some have raised methodological limitations with this line of research (15, 25) . Four studies explore the topic of OLP. Estudillo-Guerra et al. report an interesting case study from a prior pilot OLP study (26) where a patient was successfully able to taper off oxycodone using a placebo conditioning paradigm without experiencing an increase in pain. Leveraging placebos to reduce opioid use is one of the most important translational aspects of placebo research (27) with some initial evidence of efficacy (26, 28) . Sezer et al. report a pre-registration of another such trial where patients are randomized to Treatment as Usual (TAU) or TAU plus four OLP injections for post-operative pain. This will be the first randomized trial of OLP we are aware of to examine the efficacy of an honest placebo delivered intravenously. Heiss et al. argue that we re-examine the rationale provided in OLP studies by suggesting two new rationales that may be more effective than the standard rationale (29) for some patients. Finally, Wang et al., building off of the finding that there is a placebo genome [named the "placebome" (30) ] show that there are genetic markers which can predict the placebo to honest placebo, namely being homozygous for rs4680, which is a single nucleotide polymorphism in catechol-O-methyltransferase. With the ongoing opioid crisis and COVID-19 pandemic, chronic pain has become an especially serious public health concern. As the articles in this special issue demonstrate, understanding and leveraging the placebo effect may play an important role in addressing pain. MB wrote the initial draft. All authors make corrections and edited the manuscript. All authors contributed to the article and approved the submitted version. Management of post-acute covid-19 in primary care Sequelae in adults at 6 months after COVID-19 infection Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey Opioid abuse in chronic painmisconceptions and mitigation strategies Increases in drug and opioid-involved overdose deaths -United States Provisional Drug Overdose Death Counts. National Center for Health Statistics The powerful placebo Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice To the editor of the journal of pain research Placebos in clinical care: a suggestion beyond the evidence The role of placebos in family medicine:'Implications of evidence and ethics for general practitioners' Implications of placebo and nocebo effects for clinical practice: expert consensus The placebo analgesic effect in healthy individuals and patients: a meta-analysis Response variability to analgesics: a role for non-specific activation of endogenous opioids Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data The Placebo Effect in Clinical Practice Overcoming disagreement: a roadmap for placebo studies Estimating the reproducibility of psychological science Effects of openlabel placebos in clinical trials: a systematic review and meta-analysis Open-label placebo clinical trials: is it the rationale, the interaction or the pill? Conditioning open-label placebo: a pilot pharmacobehavioral approach for opioid dose reduction and pain control Harnessing the placebo effect: a promising method for curbing the opioid crisis? Conditioned open-label placebo for opioid reduction following spine surgery: a randomized, controlled trial Placebos without deception: a randomized controlled trial in irritable bowel syndrome Genetics and the placebo effect: the placebome The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.