Placebo effects in osteoarthritis: implications for treatment and drug development

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.

Fig. 1 |. Brain physiology that predicts placebo effects in OA trials.

a, Functional connectivity of the dorsolateral prefrontal cortex with the precentral gyrus is associated with placebo responses in patients with chronic low back pain and osteoarthritis (OA). b, Functional connectivity of the nucleus accumbens with the medial prefrontal cortex/rostral anterior cingulate cortex and the dorsolateral prefrontal cortex is associated with expectation effects in these patients. Higher expectations are associated with lower post-treatment OA pain and higher activation in the nucleus accumbens.

Fig. 2 |. Observed effects involve treatment effects, extraneous factors and placebo effects.

Placebo responses are the combination of placebo effects and extraneous factors, such as the nature of the illness, bias, co-interventions and the characteristics of the treatment itself. Placebo effects are linked to physiological and biological changes that can occur in concomitance with expectancies. Understanding what comprises the observed effects in the active intervention group requires understanding of treatment effects, extraneous effects and placebo effects.

Fig. 3 |. Interaction between drug and placebo effects in a hypothetical balanced (crossover) placebo OA trial.

The model examines the effects of a treatment and a placebo, as well as their interaction in a hypothetical osteoarthritis (OA)trial. The total effect is determined by comparing the treatment under investigation with a placebo. The balanced-placebo design predicts two types of placebo effects. Placebo 1, which includes both the placebo effect and the interaction effect, is determined by comparing the treatment described as the treatment with the treatment described as a placebo. Placebo 2, which includes only the placebo effect, is determined by comparing a placebo described as the treatment with a placebo described as a placebo.

Fig. 4 |. Translational research from bench to bedside.

This conceptual model illustrates how predictive approaches can guide clinical-care decisions. By incorporating various participant characteristics via predictive modelling (using traditional statistical analysis, machine learning or artificial intelligence) it is possible to identify key features that can phenotype individuals (and investigators) as likely to be treatment responders, placebo responders, or both. This knowledge can be incorporated into decision-making about adjunct placebo-related treatment options such as open-label placebo or dose-extending placebo (or both), or simply harnessing placebo effects without any placebo treatments.