Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Placebo effects in osteoarthritis: implications for treatment and drug development

Nature Reviews Rheumatology volume 19, pages 613–626 (2023)Cite this article

Subjects

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

  • An understanding of placebo mechanisms and their role in clinical trials is important to facilitate the development of new treatments for osteoarthritis.

  • Valuable insights on study designs and potential pitfalls for future clinical trials can aid researchers in improving research methodologies across different health conditions.

  • 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.

  • 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Brain physiology that predicts placebo effects in OA trials.
Fig. 2: Observed effects involve treatment effects, extraneous factors and placebo effects.
Fig. 3: Interaction between drug and placebo effects in a hypothetical balanced (crossover) placebo OA trial.
Fig. 4: Translational research from bench to bedside.

Similar content being viewed by others

References

  1. Long, H. et al. Prevalence trends of site-specific osteoarthritis from 1990 to 2019: findings from the Global Burden of Disease Study 2019. Arthritis Rheumatol. 74, 1172–1183 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet 393, 1745–1759 (2019).

    Article  CAS  Google Scholar 

  3. Sebbag, E. et al. The world-wide burden of musculoskeletal diseases: a systematic analysis of the World Health Organization burden of diseases database. Ann. Rheum. Dis. 78, 844–848 (2019).

    Article  PubMed  Google Scholar 

  4. Singh, J. A., Yu, S., Chen, L. & Cleveland, J. D. Rates of total joint replacement in the United States: future projections to 2020–2040 using the national inpatient sample. J. Rheumatol. 46, 1134–1140 (2019).

    Article  PubMed  Google Scholar 

  5. Stokes, A., Berry, K. M., Hempstead, K., Lundberg, D. J. & Neogi, T. Trends in prescription analgesic use among adults with musculoskeletal conditions in the united states, 1999–2016. JAMA Netw. Open 2, e1917228 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hellio le Graverand, M. P. et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann. Rheum. Dis. 72, 187–195 (2013).

    Article  PubMed  Google Scholar 

  7. Bingham, C. O. III et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum. 54, 3494–3507 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Karsdal, M. A. et al. Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. Osteoarthritis Cartilage 23, 532–543 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Conaghan, P. G. et al. Disease-modifying effects of a novel cathepsin K inhibitor in osteoarthritis: a randomized controlled trial. Ann. Intern. Med. 172, 86–95 (2020).

    Article  PubMed  Google Scholar 

  10. Kraus, V. B. et al. Proposed study designs for approval based on a surrogate endpoint and a post-marketing confirmatory study under FDA’s accelerated approval regulations for disease modifying osteoarthritis drugs. Osteoarthritis Cartilage 27, 571–579 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Hochberg, M. C. et al. Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial. J. Am. Med. Assoc. 322, 1360–1370 (2019).

    Article  CAS  Google Scholar 

  12. Bannuru, R. R. et al. Effectiveness and implications of alternative placebo treatments: a systematic review and network meta-analysis of osteoarthritis trials. Ann. Intern. Med. 163, 365–372 (2015).

    Article  PubMed  Google Scholar 

  13. Zhang, W., Robertson, J., Jones, A. C., Dieppe, P. A. & Doherty, M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 67, 1716–1723 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Henriksen, M. et al. Exercise and education vs intra-articular saline for knee osteoarthritis: a 1-year follow-up of a randomized trial. Osteoarthritis Cartilage 31, 627–635 (2023).

    Article  CAS  PubMed  Google Scholar 

  15. Englund, M. & Turkiewicz, A. The emperor’s new clothes. Osteoarthritis Cartilage 31, 549–551 (2023).

    Article  CAS  PubMed  Google Scholar 

  16. Colloca, L. The placebo effect in pain therapies. Annu. Rev. Pharmacol. Toxicol. 59, 191–211 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Colloca, L. & Barsky, A. J. Placebo and nocebo effects. N. Engl. J. Med. 382, 554–561 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Benedetti, F., Frisaldi, E. & Shaibani, A. Thirty years of neuroscientific investigation of placebo and nocebo: the interesting, the good, and the bad. Annu. Rev. Pharmacol. Toxicol. 62, 323–340 (2022).

    Article  PubMed  Google Scholar 

  19. Benedetti, F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron 84, 623–637 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Benedetti, F., Mayberg, H. S., Wager, T. D., Stohler, C. S. & Zubieta, J. K. Neurobiological mechanisms of the placebo effect. J. Neurosci. 25, 10390–10402 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wendt, L., Albring, A. & Schedlowski, M. Learned placebo responses in neuroendocrine and immune functions. Handb. Exp. Pharmacol. 225, 159–181 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Hadamitzky, M., Sondermann, W., Benson, S. & Schedlowski, M. Placebo effects in the immune system. Int. Rev. Neurobiol. 138, 39–59 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Luckemann, L., Stangl, H., Straub, R. H., Schedlowski, M. & Hadamitzky, M. Learned immunosuppressive placebo response attenuates disease progression in a rodent model of rheumatoid arthritis. Arthritis Rheumatol. 72, 588–597 (2020).

    Article  PubMed  Google Scholar 

  24. Ader, R. & Cohen, N. Behaviorally conditioned immunosuppression. Psychosom. Med. 37, 333–340 (1975).

    Article  CAS  PubMed  Google Scholar 

  25. Olness, K. & Ader, R. Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J. Dev. Behav. Pediatr. 13, 124–125 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Giang, D. W. et al. Conditioning of cyclophosphamide-induced leukopenia in humans. J. Neuropsychiatry Clin. Neurosci. 8, 194–201 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Goebel, M. U. et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 16, 1869–1873 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Colloca, L. Placebo, nocebo, and learning mechanisms. Handb. Exp. Pharmacol. 225, 17–35 (2014).

    Article  PubMed  Google Scholar 

  29. Colloca, L. & Miller, F. G. How placebo responses are formed: a learning perspective. Phil. Trans. R. Soc. B 366, 1859–1869 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Colloca, L. & Miller, F. G. Role of expectations in health. Curr. Opin. Psychiatry 24, 149–155 (2011).

    Article  PubMed  Google Scholar 

  31. Langford, D. J. et al. Expectations for improvement: a neglected but potentially important covariate or moderator for chronic pain clinical trials. J. Pain 24, 575–581 (2022).

    Article  PubMed  Google Scholar 

  32. Gil, M., Menzel, R. & De Marco, R. J. Does an insect’s unconditioned response to sucrose reveal expectations of reward? PLoS ONE 3, e2810 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Colloca, L. et al. Prior therapeutic experiences, not expectation ratings, predict placebo effects: an experimental study in chronic pain and healthy participants. Psychother. Psychosom. 89, 371–378 (2020).

    Article  PubMed  Google Scholar 

  34. Colloca, L., Lopiano, L., Lanotte, M. & Benedetti, F. Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. Lancet Neurol. 3, 679–684 (2004).

    Article  PubMed  Google Scholar 

  35. Suarez-Almazor, M. et al. A randomized controlled trial of acupuncture for osteoarthritis of the knee: effects of provider communication style. Arthritis Rheum. 56, S315 (2007).

    Google Scholar 

  36. Gollub, R. L. et al. A functional neuroimaging study of expectancy effects on pain response in patients with knee osteoarthritis. J. Pain 19, 515–527 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kong, J. et al. Enhancing treatment of osteoarthritis knee pain by boosting expectancy: a functional neuroimaging study. Neuroimage Clin. 18, 325–334 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rosenkjaer, S., Lunde, S. J., Kirsch, I. & Vase, L. Expectations: how and when do they contribute to placebo analgesia. Front. Psychiatry 13, 817179 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Younger, J., Gandhi, V., Hubbard, E. & Mackey, S. Development of the Stanford Expectations of Treatment Scale (SETS): a tool for measuring patient outcome expectancy in clinical trials. Clin. Trials 9, 767–776 (2012).

    Article  PubMed  Google Scholar 

  40. Ferkin, A. C. et al. A psychometric evaluation of the Stanford Expectations of Treatment Scale (SETS) in the context of a smoking cessation trial. Nicotine Tob. Res. 24, 1914–1920 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shedden-Mora, M. C. et al. The treatment expectation questionnaire (TEX-Q): validation of a generic multidimensional scale measuring patients’ treatment expectations. PLoS ONE 18, e0280472 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alberts, J. et al. Development of the generic, multidimensional treatment expectation questionnaire (TEX-Q) through systematic literature review, expert surveys and qualitative interviews. BMJ Open 10, e036169 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Spisak, T., Bingel, U. & Wager, T. D. Multivariate BWAS can be replicable with moderate sample sizes. Nature 615, E4–E7 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tetreault, P. et al. Brain connectivity predicts placebo response across chronic pain clinical trials. PLoS Biol. 14, e1002570 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Vachon-Presseau, E. et al. Validating a biosignature-predicting placebo pill response in chronic pain in the settings of a randomized controlled trial. Pain 163, 910–922 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Davis, K. D. et al. Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations. Nat. Rev. Neurol. 13, 624–638 (2017).

    Article  PubMed  Google Scholar 

  47. Colagiuri, B., Schenk, L. A., Kessler, M. D., Dorsey, S. G. & Colloca, L. The placebo effect: from concepts to genes. Neuroscience 307, 171–190 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Hall, K. T., Loscalzo, J. & Kaptchuk, T. J. Genetics and the placebo effect: the placebome. Trends Mol. Med. 21, 285–294 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Eippert, F., Finsterbusch, J., Bingel, U. & Buchel, C. Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, Y. et al. Modeling learning patterns to predict placebo analgesic effects in healthy and chronic orofacial pain participants. Front. Psychiatry 11, 39 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Colloca, L., Thomas, S., Yin, M., Haycock, N. R. & Wang, Y. Pain experience and mood disorders during the lockdown of the COVID-19 pandemic in the United States: an opportunistic study. Pain Rep. 6, e958 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Shafir, R., Olson, E. & Colloca, L. The neglect of sex: a call to action for including sex as a biological variable in placebo and nocebo research. Contemp. Clin. Trials 116, 106734 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Olson, E. M. et al. Effects of sex on placebo effects in chronic pain participants: a cross-sectional study. Pain 162, 531–542 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wang, Y., Chan, E., Dorsey, S. G., Campbell, C. M. & Colloca, L. Who are the placebo responders? A cross-sectional cohort study for psychological determinants. Pain 163, 1078–1090 (2022).

    Article  PubMed  Google Scholar 

  55. Sanislow, C. A. et al. Developing constructs for psychopathology research: research domain criteria. J. Abnorm. Psychol. 119, 631–639 (2010).

    Article  PubMed  Google Scholar 

  56. Insel, T. et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167, 748–751 (2010).

    Article  PubMed  Google Scholar 

  57. Dworkin, R. H. et al. Meta-analysis of assay sensitivity and study features in clinical trials of pharmacologic treatments for osteoarthritis pain. Arthritis Rheumatol. 66, 3327–3336 (2014).

    Article  PubMed  Google Scholar 

  58. Finnerup, N. B. et al. Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy. Pain 159, 2339–2346 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Farrar, J. T. et al. Effect of variability in the 7-day baseline pain diary on the assay sensitivity of neuropathic pain randomized clinical trials: an ACTTION study. Pain 155, 1622–1631 (2014).

    Article  PubMed  Google Scholar 

  60. Treister, R., Honigman, L., Lawal, O. D., Lanier, R. K. & Katz, N. P. A deeper look at pain variability and its relationship with the placebo response: results from a randomized, double-blind, placebo-controlled clinical trial of naproxen in osteoarthritis of the knee. Pain 160, 1522–1528 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Okusogu, C. et al. Placebo hypoalgesia: racial differences. Pain 161, 1872–1883 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Olson, E. M. et al. Effects of sex on placebo effects in chronic pain participants: a cross-sectional study. Pain 162, 531–542 (2020).

    Article  Google Scholar 

  63. Dworkin, R. H. & Edwards, R. R. Phenotypes and treatment response: it’s difficult to make predictions, especially about the future. Pain 158, 187–189 (2017).

    Article  PubMed  Google Scholar 

  64. Hohenschurz-Schmidt, D., Draper-Rodi, J. & Vase, L. Dissimilar control interventions in clinical trials undermine interpretability. JAMA Psychiatry 79, 271–272 (2022).

    Article  PubMed  Google Scholar 

  65. Hohenschurz-Schmidt, D. et al. Blinding and sham control methods in trials of physical, psychological, and self-management interventions for pain (article II): a meta-analysis relating methods to trial results. Pain 164, 509–533 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Colloca, L., Benedetti, F. & Porro, C. A. Experimental designs and brain mapping approaches for studying the placebo analgesic effect. Eur. J. Appl. Physiol. 102, 371–380 (2008).

    Article  PubMed  Google Scholar 

  67. Parsons, H. M. What happened at Hawthorne?: new evidence suggests the Hawthorne effect resulted from operant reinforcement contingencies. Science 183, 922–932 (1974).

    Article  CAS  PubMed  Google Scholar 

  68. Ulmer, F. C. The Hawthorne effect. Educ. Dir. Dent. Aux. 1, 28 (1976).

    CAS  PubMed  Google Scholar 

  69. Benedetti, F., Carlino, E. & Piedimonte, A. Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. 15, 736–747 (2016).

    Article  PubMed  Google Scholar 

  70. Berthelot, J. M., Le Goff, B. & Maugars, Y. The Hawthorne effect: stronger than the placebo effect. Jt. Bone Spine 78, 335–336 (2011).

    Article  Google Scholar 

  71. Colloca, L. & Benedetti, F. Placebo analgesia induced by social observational learning. Pain 144, 28–34 (2009).

    Article  PubMed  Google Scholar 

  72. Wolfe, F. & Michaud, K. The Hawthorne effect, sponsored trials, and the overestimation of treatment effectiveness. J. Rheumatol. 37, 2216–2220 (2010).

    Article  PubMed  Google Scholar 

  73. Ellingsen, D. M. et al. Brain-to-brain mechanisms underlying pain empathy and social modulation of pain in the patient-clinician interaction. Proc. Natl Acad. Sci. USA 120, e2212910120 (2023).

    Article  CAS  PubMed  Google Scholar 

  74. Ernst, E. & Resch, K. L. Concept of true and perceived placebo effects. Br. Med. J. 311, 551–553 (1995).

    Article  CAS  Google Scholar 

  75. Colloca, L. & Benedetti, F. Placebos and painkillers: is mind as real as matter? Nat. Rev. Neurosci. 6, 545–552 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Ross, S., Krugman, A. D., Lyerly, S. B., Clyde & J, D. Drugs and placebos: a model design. Psychol. Rep. 10, 383–392 (1962).

    Article  Google Scholar 

  77. Kirsch, I. & Weixel, L. J. Double-blind versus deceptive administration of a placebo. Behav. Neurosci. 102, 319–323 (1988).

    Article  CAS  PubMed  Google Scholar 

  78. Benedetti, F. et al. Open versus hidden medical treatments: the patient’s knowledge about a therapy affects the therapy outcome. Prev. Treat. 6, 1a (2003).

    Article  Google Scholar 

  79. Benedetti, F. et al. Autonomic and emotional responses to open and hidden stimulations of the human subthalamic region. Brain Res. Bull. 63, 203–211 (2004).

    Article  PubMed  Google Scholar 

  80. Park, L. C. & Covi, L. Nonblind placebo trial: an exploration of neurotic patients’ responses to placebo when its inert content is disclosed. Arch. Gen. Psychiatry 12, 36–45 (1965).

    Article  CAS  PubMed  Google Scholar 

  81. Kaptchuk, T. J. et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS ONE 5, e15591 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Colloca, L., Enck, P. & DeGrazia, D. Relieving pain using dose-extending placebos: a scoping review. Pain 157, 1590–1598 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Enck, P., Grundy, D. & Klosterhalfen, S. A novel placebo-controlled clinical study design without ethical concerns — the free choice paradigm. Med. Hypotheses 79, 880–882 (2012).

    Article  PubMed  Google Scholar 

  84. Fava, M., Evins, A. E., Dorer, D. J. & Schoenfeld, D. A. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother. Psychosom. 72, 115–127 (2003).

    Article  PubMed  Google Scholar 

  85. Staud, R. & Price, D. D. Role of placebo factors in clinical trials with special focus on enrichment designs. Pain 139, 479–480 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wendler, D. & Miller, F. G. Deception in the pursuit of science. Arch. Intern. Med. 164, 597–600 (2004).

    Article  PubMed  Google Scholar 

  87. Pollo, A. et al. Response expectancies in placebo analgesia and their clinical relevance. Pain 93, 77–84 (2001).

    Article  PubMed  Google Scholar 

  88. Colloca, L. et al. Veteran engagement in opioid tapering research: a mission to optimize pain management. Pain Rep. 6, e932 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Park, L. & TRIAL, C. L. N. P. An exploration of neurotic patients’responses to placebo when its inert content is disclosed. Arch. Gen. Psychiatry 12, 36–45 (1965).

    Article  CAS  PubMed  Google Scholar 

  90. Young, N. S., Ioannidis, J. P. & Al-Ubaydli, O. Why current publication practices may distort science. PLoS Med. 5, e201 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Fanelli, D., Costas, R. & Ioannidis, J. P. Meta-assessment of bias in science. Proc. Natl Acad. Sci. USA 114, 3714–3719 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Schooler, J. Unpublished results hide the decline effect. Nature 470, 437–437 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Harrison, R. K. Phase II and phase III failures: 2013–2015. Nat. Rev. Drug Discov. 15, 817–818 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Scott, A. J., Sharpe, L., Quinn, V. & Colagiuri, B. Association of single-blind placebo run-in periods with the placebo response in randomized clinical trials of antidepressants: a systematic review and meta-analysis. JAMA Psychiatry 79, 42–49 (2022).

    Article  PubMed  Google Scholar 

  95. Coleshill, M. J., Sharpe, L., Colloca, L., Zachariae, R. & Colagiuri, B. Placebo and active treatment additivity in placebo analgesia: research to date and future directions. Int. Rev. Neurobiol. 139, 407–441 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Colagiuri, B. Participant expectancies in double-blind randomized placebo-controlled trials: potential limitations to trial validity. Clin. Trials 7, 246–255 (2010).

    Article  PubMed  Google Scholar 

  97. Vollert, J. et al. Assessment of placebo response in objective and subjective outcome measures in rheumatoid arthritis clinical trials. JAMA Netw. Open 3, e2013196 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Wechsler, M. E. et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N. Engl. J. Med. 365, 119–126 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kent, D. M. et al. The predictive approaches to treatment effect heterogeneity (PATH) statement. Ann. Intern. Med. 172, 35–45 (2020).

    Article  PubMed  Google Scholar 

  100. Schnitzer, T. J. et al. Effect of tanezumab on joint pain, physical function, and patient global assessment of osteoarthritis among patients with osteoarthritis of the hip or knee: a randomized clinical trial. J. Am. Med. Assoc. 322, 37–48 (2019).

    Article  CAS  Google Scholar 

  101. Berenbaum, F. et al. Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period. Ann. Rheum. Dis. 79, 800–810 (2020).

    Article  CAS  PubMed  Google Scholar 

  102. Vase, L., Amanzio, M. & Price, D. D. Nocebo vs. placebo: the challenges of trial design in analgesia research. Clin. Pharmacol. Ther. 97, 143–150 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Morton, D. L., Watson, A., El-Deredy, W. & Jones, A. K. Reproducibility of placebo analgesia: effect of dispositional optimism. Pain 146, 194–198 (2009).

    Article  PubMed  Google Scholar 

  104. Vase, L. et al. Predictors of the placebo analgesia response in randomized controlled trials of chronic pain: a meta-analysis of the individual data from nine industrially sponsored trials. Pain 156, 1795–1802 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Lang, T. A. & Stroup, D. F. Who knew? The misleading specificity of “double-blind” and what to do about it. Trials 21, 697 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wood, L. et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. Br. Med. J. 336, 601–605 (2008).

    Article  Google Scholar 

  107. Moerman, D. E. Cultural variations in the placebo effect: ulcers, anxiety, and blood pressure. Med. Anthropol. Q. 14, 51–72 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Blease, C. R. et al. Sharing clinical notes, and placebo and nocebo effects: can documentation affect patient health? J. Health Psychol. 27, 135–146 (2022).

    Article  PubMed  Google Scholar 

  109. Garcia, M. K. et al. Effect of true and sham acupuncture on radiation-induced xerostomia among patients with head and neck cancer: a randomized clinical trial. JAMA Netw. Open 2, e1916910 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Karst, M. & Li, C. Acupuncture—a question of culture. JAMA Netw. Open 2, e1916929 (2019).

    Article  PubMed  Google Scholar 

  111. Waber, R. L., Shiv, B., Carmon, Z. & Ariely, D. Commercial features of placebo and therapeutic efficacy. J. Am. Med. Assoc. 299, 1016–1017 (2008).

    Article  CAS  Google Scholar 

  112. Kam-Hansen, S. et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci. Transl Med. 6, 218ra215 (2014).

    Article  Google Scholar 

  113. Faasse, K., Martin, L. R., Grey, A., Gamble, G. & Petrie, K. J. Impact of brand or generic labeling on medication effectiveness and side effects. Health Psychol. 35, 187–190 (2016).

    Article  PubMed  Google Scholar 

  114. Meissner, K. et al. Differential effectiveness of placebo treatments: a systematic review of migraine prophylaxis. JAMA Intern. Med. 173, 1941–1951 (2013).

    Article  PubMed  Google Scholar 

  115. Blease, C., Colloca, L. & Kaptchuk, T. J. Are open-label placebos ethical? Informed consent and ethical equivocations. Bioethics 30, 407–414 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Lembo, A. et al. Open-label placebo vs double-blind placebo for irritable bowel syndrome: a randomized clinical trial. Pain 162, 2428–2435 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nurko, S. et al. Effect of open-label placebo on children and adolescents with functional abdominal pain or irritable bowel syndrome: a randomized clinical trial. JAMA Pediatrics 176, 349–356 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Carvalho, C. et al. Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain 157, 2766–2772 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Carvalho, C. et al. Open-label placebo for chronic low back pain: a 5-year follow-up. Pain 162, 1521–1527 (2021).

    Article  CAS  PubMed  Google Scholar 

  120. Kelley, J. M., Kaptchuk, T. J., Cusin, C., Lipkin, S. & Fava, M. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother. Psychosom. 81, 312–314 (2012).

    Article  PubMed  Google Scholar 

  121. Schaefer, M., Harke, R. & Denke, C. Open-label placebos improve symptoms in allergic rhinitis: a randomized controlled trial. Psychother. Psychosom. 85, 373–374 (2016).

    Article  PubMed  Google Scholar 

  122. Hoenemeyer, T. W., Kaptchuk, T. J., Mehta, T. S. & Fontaine, K. R. Open-label placebo treatment for cancer-related fatigue: a randomized-controlled clinical trial. Sci. Rep. 8, 2784 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Pan, Y. et al. Open-label placebos for menopausal hot flushes: a randomized controlled trial. Sci. Rep. 10, 20090 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Olliges, E. et al. Open-label placebo administration decreases pain in elderly patients with symptomatic knee osteoarthritis — a randomized controlled trial. Front. Psychiatry 13, 853497 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Ader, R. et al. Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom. Med. 72, 192–197 (2010).

    Article  PubMed  Google Scholar 

  126. Morales-Quezada, L. et al. Conditioning open-label placebo: a pilot pharmacobehavioral approach for opioid dose reduction and pain control. Pain Rep. 5, e828 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Sandler, A. D. & Bodfish, J. W. Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Health Dev. 34, 104–110 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Perlis, M. et al. Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study. Sleep Med. 16, 1160–1168 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Goebel, M. U., Meykadeh, N., Kou, W., Schedlowski, M. & Hengge, U. R. Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother. Psychosom. 77, 227–234 (2008).

    Article  PubMed  Google Scholar 

  130. Kirchhof, J. et al. Learned immunosuppressive placebo responses in renal transplant patients. Proc. Natl Acad. Sci. USA 115, 4223–4227 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Colloca, L. & Miller, F. G. Harnessing the placebo effect: the need for translational research. Phil. Trans. R. Soc. B 366, 1922–1930 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Doering, B. K. & Rief, W. Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends Pharmacol. Sci. 33, 165–172 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Enck, P., Bingel, U., Schedlowski, M. & Rief, W. The placebo response in medicine: minimize, maximize or personalize? Nat. Rev. Drug Discov. 12, 191–204 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Benedetti, F., Pollo, A. & Colloca, L. Opioid-mediated placebo responses boost pain endurance and physical performance: is it doping in sport competitions. J. Neurosci. 27, 11934–11939 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Amanzio, M. & Benedetti, F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J. Neurosci. 19, 484–494 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Guo, J. Y., Wang, J. Y. & Luo, F. Dissection of placebo analgesia in mice: the conditions for activation of opioid and non-opioid systems. J. Psychopharmacol. 24, 1561–1567 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Colloca, L. & Benedetti, F. How prior experience shapes placebo analgesia. Pain 124, 126–133 (2006).

    Article  PubMed  Google Scholar 

  138. Fiorio, M. et al. Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation. Neuroscience 217, 96–104 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Fiorio, M., Recchia, S., Corra, F. & Tinazzi, M. Behavioural and neurophysiological investigation of the influence of verbal suggestion on tactile perception. Neuroscience 258, 332–339 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Klinger, R., Soost, S., Flor, H. & Worm, M. Classical conditioning and expectancy in placebo hypoalgesia: a randomized controlled study in patients with atopic dermatitis and persons with healthy skin. Pain 128, 31–39 (2007).

    Article  PubMed  Google Scholar 

  141. Adie, S., Harris, I., Chuan, A., Lewis, P. & Naylor, J. M. Selecting and optimising patients for total knee arthroplasty. Med. J. Aust. 210, 135–141 (2019).

    Article  PubMed  Google Scholar 

  142. Quinlan, J., Levy, N., Lobo, D. N. & Macintyre, P. E. Preoperative opioid use: a modifiable risk factor for poor postoperative outcomes. Br. J. Anaesth. 127, 327–331 (2021).

    Article  PubMed  Google Scholar 

  143. Ravi, B. et al. Patterns of pre-operative opioid use affect the risk for complications after total joint replacement. Sci. Rep. 11, 22124 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Shadbolt, C. et al. Opioid use and total joint replacement. Curr. Rheumatol. Rep. 22, 58 (2020).

    Article  PubMed  Google Scholar 

  145. Colloca, L. Informed consent: hints from placebo and nocebo research. Am. J. Bioeth. 15, 17–19 (2015).

    Article  PubMed  Google Scholar 

  146. Miller, F. G. & Colloca, L. The placebo phenomenon and medical ethics: rethinking the relationship between informed consent and risk-benefit assessment. Theor. Med. Bioeth. 32, 229–243 (2011).

    Article  PubMed  Google Scholar 

  147. Brody, H., Colloca, L. & Miller, F. G. The placebo phenomenon: implications for the ethics of shared decision-making. J. Gen. Intern. Med. 27, 739–742 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Barnes, K. et al. Can positive framing reduce nocebo side effects? Current evidence and recommendation for future research. Front. Pharmacol. 10, 167 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Brody, H. & Colloca, L. Patient autonomy and provider beneficence are compatible. Hastings Cent. Rep. 43, 6 (2013).

    Article  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Section of Rheumatology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Tuhina Neogi

  2. Department of Pain and Translation Symptom Science, School of Nursing, University of Maryland, Baltimore, MD, USA

    Luana Colloca

  3. Placebo Beyond Opinions Center, School of Nursing, University of Maryland, Baltimore, MD, USA

    Luana Colloca

Authors
  1. Tuhina Neogi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luana Colloca
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Luana Colloca.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Rheumatology thanks Jean-Marie Berthelot, Damien Finniss and Serge Marchand for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Active-control group

The group assigned to receive a treatment that is known to have physiological effects.

Balanced-placebo

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

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

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

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

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

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

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

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

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

Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes.

Placebo responses

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

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.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-023-01021-4

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research