Why We Need Pain Research: Chronic Pain, COVID-19, and the Opioid Crisis
Research into the biology, treatment, and prevention of pain has blossomed over the past decade. Recent data from the US suggest the nationwide prevalence of chronic pain is 20–21% (1, 2). Chronic pain appears more prevalent among women and older adults (3). A meta-analysis indicates that the prevalence of chronic pain in the UK is 35–51%. Cohen et al. (4) argue “It is difficult to over-estimate the burden of chronic pain,” (p. 2082) given the considerable price we pay in terms of economic cost, disability, and mortality.
Unfortunately, the public health burden of chronic pain will likely increase with the COVID-19 pandemic. Research suggests that 10–30% of people who contract COVID-19 develop Long Covid (5, 6). Pain is a common Long COVID symptom; in one study of 616 adults who self-reported a prior COVID-19 diagnosis, 30.7% met criteria for Fibromyalgia (7). As of 22 February 2022, ~428 million people world-wide have had COVID-19 (according to https://www.kff.org/coronavirus-covid-19/issue-brief/global-covid-19-tracker/). Using conservative projections based on the above statistics, if 10% of COVID-19 patients have long COVID, and 15% of long COVID patients develop chronic pain, then COVID has thus far coincided with an increase of 6.4 million chronic pain patients. This number will continue to grow with future infections.
The crisis of opioid misuse and death intersects heavily with pain management (8). In 2015–2016 ~50,000 people died annually in the U.S. from a drug overdose (9). This figure has since almost doubled (10). A November 17 front-page story in The New York Times reads: “Overdose Deaths Reached Record High as the Pandemic Spread.” It is imperative that we invest in research to understand the etiology of pain and develop effective pain treatments.
Pain and the Placebo Effect
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).
Special Issue Articles
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 incatechol-O-methyltransferase.
Conclusion
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.
Funding
MB was supported by K01DA048087.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Statements
Author contributions
MB wrote the initial draft. All authors make corrections and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of interest
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.
References
1.
YongRJMullinsPMBhattacharyyaN. Prevalence of chronic pain among adults in the United States. Pain. (2021) 163:e328–32. 10.1097/j.pain.0000000000002291
2.
DahlhamerJLucasJZelayaCNahinRMackeySDeBarLet al. Prevalence of chronic pain and high-impact chronic pain among adults-United States, 2016. Morb. Mortal. Weekly Rep. (2018) 67:1001–6. 10.15585/mmwr.mm6736a2
3.
AndrewsPSteultjensMRiskowskiJ. Chronic widespread pain prevalence in the general population: a systematic review. Eur J Pain. (2018) 22:5–18. 10.1002/ejp.1090
4.
CohenSPVaseLHootenWM. Chronic pain: an update on burden, best practices, new advances. Lancet. (2021) 397:2082–97. 10.1016/S0140-6736(21)00393-7
5.
GreenhalghTKnightMBuxtonMHusainL. Management of post-acute covid-19 in primary care. BMJ. (2020) 370:m3026. 10.1136/bmj.m3026
6.
LogueJKFrankoNMMcCullochDJMcDonaldDMagedsonAWolfCRet al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Network Open. (2021) 4:e210830. 10.1001/jamanetworkopen.2021.0830
7.
UrsiniFCiaffiJMancarellaLLisiLBrusiVCavallariCet al. Fibromyalgia: a new facet of the post-COVID-19 syndrome spectrum? Results from a web-based survey. RMD Open. (2021) 7:e001735. 10.1136/rmdopen-2021-001735
8.
VolkowNDMcLellanAT. Opioid abuse in chronic pain-misconceptions and mitigation strategies. N Engl J Med. (2016). 374:1253–63. 10.1056/NEJMra1507771
9.
RuddRASethPDavidF. Increases in drug and opioid-involved overdose deaths - United States, 2010-2015. MMWR Morb Mortal Wkly Rep. (2016) 65:1445–52. 10.15585/mmwr.mm655051e1
10.
AhmadFBRossenLMSuttonP. Provisional Drug Overdose Death Counts. National Center for Health Statistics.Atlanta, GA (2021).
11.
BeecherHK. The powerful placebo. J Am Med Assoc. (1955) 159:1602–6. 10.1001/jama.1955.02960340022006
12.
BenedettiF. Placebo Effects. Oxford: Oxford University Press (2014). 10.1093/acprof:oso/9780198705086.001.0001
13.
KaptchukTJHemondCCMillerFG. Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice. BMJ. (2020) 370:m1668. 10.1136/bmj.m1668
14.
JonesCMMaherCG. To the editor of the journal of pain research. J Pain Res. (2021) 14:3649. 10.2147/JPR.S344005
15.
MaherCGTraegerACAbdel ShaheedCO'KeeffeM. Placebos in clinical care: a suggestion beyond the evidence. Med J Australia. (2021) 215:252–3. e1. 10.5694/mja2.51230
16.
BleaseCR. The role of placebos in family medicine:'Implications of evidence and ethics for general practitioners'. Austral J General Practice. (2019) 48:700. 10.31128/AJGP-05-19-4939
17.
EversACollocaLBleaseCAnnoniMAtlasLYBenedettiFet al. Implications of placebo and nocebo effects for clinical practice: expert consensus. Psychother Psychosomat. (2018) 87:204–10. 10.1159/000490354
18.
ForsbergJTMartinussenMFlatenMA. The placebo analgesic effect in healthy individuals and patients: a meta-analysis. Psychosomat Med. (2017) 79:388–94. 10.1097/PSY.0000000000000432
19.
AmanzioMPolloAMaggiGBenedettiF. Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain. (2001) 90:205–15. 10.1016/S0304-3959(00)00486-3
20.
ZunhammerMSpisákTWagerTDBingelU. Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data. Nat Commun. (2021) 12:1391. 10.1038/s41467-021-21179-3
21.
BrownWA. The Placebo Effect in Clinical Practice. New York, NY: Oxford University Press (2013).
22.
BleaseCAnnoniM. Overcoming disagreement: a roadmap for placebo studies. Biol Philos. (2019) 34:18. 10.1007/s10539-019-9671-5
23.
Open Science Collaboration. Estimating the reproducibility of psychological science. Science. (2015) 349:aac4716. 10.1126/science.aac4716
24.
von WernsdorffMLoefMTuschen-CaffierBSchmidtS. Effects of open-label placebos in clinical trials: a systematic review and meta-analysis. Sci Rep. (2021) 11:1–14. 10.1038/s41598-021-83148-6
25.
BleaseCRBernsteinMHLocherC. Open-label placebo clinical trials: is it the rationale, the interaction or the pill?BMJ Evid Based Med. (2019) 25:159–65. 10.1136/bmjebm-2019-111209
26.
Morales-QuezadaLMesia-ToledoIEstudillo-GuerraAO'ConnorKCSchneiderJCSohnDJet al. Conditioning open-label placebo: a pilot pharmacobehavioral approach for opioid dose reduction and pain control. PAIN Rep. (2020) 5:e828. 10.1097/PR9.0000000000000828
27.
BernsteinMHMagillMBeaudoinFLBeckerSJRichJDet al. Harnessing the placebo effect: a promising method for curbing the opioid crisis?Addiction. (2018) 113:2144–55. 10.1111/add.14385
28.
FlowersKMPattonMEHruschakVJFieldsKGSchwartzEZeballosJet al. Conditioned open-label placebo for opioid reduction following spine surgery: a randomized, controlled trial. Pain. (2021) 162:1828. 10.1097/j.pain.0000000000002185
29.
KaptchukTJFriedlanderEKelleyJMSanchezMNKokkotouESingerJPet al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS ONE. (2010) 5:e15591. 10.1371/journal.pone.0015591
30.
HallKTLoscalzoJKaptchukTJ. Genetics and the placebo effect: the placebome. Trends Mol Med. (2015) 21:285–94. 10.1016/j.molmed.2015.02.009
Summary
Keywords
placebo & nocebo effects, pain, pain management, analgesia, placebo response
Citation
Bernstein MH, Blease C and Vase L (2022) Editorial: Placebo Effect in Pain and Pain Treatment. Front. Pain Res. 3:884055. doi: 10.3389/fpain.2022.884055
Received
25 February 2022
Accepted
08 March 2022
Published
29 March 2022
Volume
3 - 2022
Edited and reviewed by
Cheryl L. Stucky, Medical College of Wisconsin, United States
Updates
Copyright
© 2022 Bernstein, Blease and Vase.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Michael H. Bernstein michael_bernstein@brown.edu
This article was submitted to Pharmacological Treatment of Pain, a section of the journal Frontiers in Pain Research
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.