Abstract
Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without any structure-modifying agents, management of OA focuses on ameliorating pain and improving function. Treatment approaches typically have modest efficacy, and many patients have contraindications to recommended pharmacological treatments. Drug development for OA is hindered by the gradual and progressive nature of the disease and the targeting of established disease in clinical trials. Additionally, new medications for OA cannot receive regulatory approval without demonstrating improvements in both structure (pathological features of OA) and symptoms (reduced pain and/or improved function). In clinical trials, people with OA show high ‘placebo responses’, which hamper the ability to identify new effective treatments. Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings. Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes. To mitigate the effects of the placebo phenomenon, we must first understand what it is, how it manifests, how to identify placebo responders in OA trials and how these insights can be used to improve clinical trials in OA. Leveraging placebo responses and effects in clinical practice might provide additional avenues to augment symptom management of OA.
Key points
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An understanding of placebo mechanisms and their role in clinical trials is important to facilitate the development of new treatments for osteoarthritis.
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Valuable insights on study designs and potential pitfalls for future clinical trials can aid researchers in improving research methodologies across different health conditions.
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Recognizing the clinical implications and potential benefits of harnessing placebo effects can lead to more effective treatment approaches in the management of diverse medical conditions.
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Examining opioid reduction in patients undergoing joint-replacement surgery for conditions other than osteoarthritis and its effect on outcomes offers important insights for optimizing postsurgical care in different health contexts.
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Acknowledgements
The authors thank Y. Shaham for his critical review of the manuscript. Part of this research is supported by the National Institutes of Health (L.C. R01AT01033, R01AT011347, 1R01DE025946 and R21DE032532; T.N. K24AR070892, P30AR072571, R01AG066010, R01AG066914, R01NS121419).
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L.C. researched data and wrote the article. Both authors contributed substantially to the discussion of content, and reviewed and edited the manuscript before submission.
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Glossary
- Active-control group
-
The group assigned to receive a treatment that is known to have physiological effects.
- Balanced-placebo
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The balanced-placebo design refers to a research methodology used in placebo-controlled studies to differentiate between the pharmacological effects of a treatment and the psychological effects of believing that one is receiving the treatment. In this design, participants are divided into groups, and each group receives a combination of active treatment, placebo and information about which they have received.
- Bias
-
Bias in research refers to an aspect of the study design, data collection or analysis of data that can lead to incorrect interpretation and/or conclusions about the results of a study.
- Control groups
-
The groups assigned to receive either no treatment or a placebo, enabling comparison to determine the effectiveness of the experimental treatment.
- Dose-extending placebo
-
A classic conditioning placebo-related procedure used to extend the effect of the active treatment. After repeated pairing of the active full-dose treatment with a conditioning stimulus, exposure to the conditioned stimulus, either alone or together with a lower dose of the active treatment, mimics the therapeutic effect of the active treatment or extends its effect.
- Double-blind versus deceptive
-
Comparison between a double-blind and a deceptive design. In the double-blind design neither the participants nor the researchers administering the treatments know who is receiving the active treatment and who is receiving the placebo. This helps to reduce bias and ensures objective evaluation of the treatment’s effects. The deceptive design in the context of clinical trials or experiments refers to intentionally misleading participants or withholding information about the nature of the treatment or intervention that they are receiving.
- Expectancy
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Implicit expectancies are those that are present without full awareness or conscious intent. As opposed to expectations, expectancies are difficult to formally measure and quantify.
- Expectations
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Expectations refer to the belief or anticipation that a certain outcome will occur, which can be both conscious and unconscious. Expectations can be measured using validated scales and questionnaires to assess how strongly participants expect a certain outcome to occur in clinical trials and other studies.
- Hawthorne effects
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Hawthorne effects refer to the phenomenon whereby individuals modify their behaviours or responses in research or clinical settings because of the awareness of being observed or studied.
- Natural history
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The natural history of a condition refers to the expected course and outcome of a particular medical condition in the absence of any intervention or treatment.
- No-treatment group
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The group randomly assigned to receive no treatment who provide information about the natural history of the condition in the absence of the intervention.
- Open–hidden treatment
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A research design where some participants are aware of the treatment they are receiving (open treatment), whereas others are unaware or are kept in the dark about the nature of their treatment or the time of administration (hidden treatment). This design enables the investigation of how participants’ knowledge or lack thereof about their treatment influences treatment outcomes and placebo responses.
- Open-label placebo
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An adjuvant treatment given along with the treatment-as-usual to elicit placebo effects. Participants and researchers are aware that the treatment being given is a placebo and not an active treatment.
- Placebo
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A substance or treatment that is physically inert and has no therapeutic effect on a person’s health condition. Non-physical placebos do not involve any tangible substances and encompass a wide range of interventions, such as sham procedures, psychological interventions and imagined treatments.
- Placebo effects
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Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes.
- Placebo responses
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Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings.
- Regression to the mean
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The phenomenon where extreme results obtained by chance after a first measurement tend to move closer to the mean on repeated measurements, often seen when patients with high-activity disease flares are enrolled in trials and experience reduction of disease activity that is falsely attributed to the treatment.
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Neogi, T., Colloca, L. Placebo effects in osteoarthritis: implications for treatment and drug development. Nat Rev Rheumatol 19, 613–626 (2023). https://doi.org/10.1038/s41584-023-01021-4
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DOI: https://doi.org/10.1038/s41584-023-01021-4
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