Nocebo in Biosimilars and Generics in Neurology: A Systematic Review

Abstract

Background: Nocebo refers to adverse events related to patients’ negative expectations and previous experiences, mediated by several neurobiological pathways within the brain. It is common among neurological patients and affects adherence and treatment outcomes, representing a real clinical challenge. Methods: We conducted a systematic search based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE database, using several keywords for studies that can be processed to investigate the magnitude of nocebo in generics and biosimilars used in the most common neurological diseases. The aim was to estimate its size and suggest strategies to minimize its prevalence in clinical trials and practice. Results: Of a total of 2,606 identified articles, after criteria-based selection, 35 studies were included for analysis. Overall, there was vast heterogeneity across the studies concerning population, study design, and outcomes. Nocebo response could be estimated only in one double-blind randomized trial of generic glatiramer acetate in relapsing remitting multiple sclerosis that included a placebo arm. In this trial, no significant differences observed between the three arms (innovator, bioequivalent, and placebo) in favorable and unfavorable outcomes. In the open-label phase of the trial, an increased withdrawal rate was recorded in patients switched from placebo to bioequivalent (8.4%) that may be related to nocebo. In other open-label and real-world studies evaluating biosimilars or generics for brain disorders, a similar indirect nocebo effect is assuming by several investigators. Also, knowledge gaps between health-care providers and patients exist towards generics and biosimilars. Conclusions: Despite its presence, the true burden of the nocebo response and effect cannot be accurately estimated in existing studies with generics and biosimilars in neurological diseases. Targeted strategies for clinical trials’ design are needed in order to measure the exact nocebo’s size.

Risk factors associated with nocebo effects: A review of reviews

“… Not Applicable (NA) Contextual factors and expectations are the fundamental drivers of placebo and nocebo effects as well as clinician-patient interaction Prior Expectations and Learning Setting Communication of information and patient-physician relationship 27. Spanou, I., Mavridis, T., & Mitsikostas, D. D. (2019) To investigate the presence of the nocebo in generics and biosimilar substitution studies in some of the most common neurological diseases. The full scope of the adverse consequences of the nocebo effect and placebo effect on patients with neurological conditions using generic and biosimilar medications is not yet fully understood based on current research.…”

“…Overall, it is improbable that the nocebo effect is restricted to a particular disease or a singular pathophysiological process, but it seems that patient populations, such as those with PD, may be more susceptible to it. While the literature has shown the relevance of the nocebo effect in Parkinson's disease, a common belief among neurologists is that the nocebo effect may also be relevant in other neurological conditions, such as multiple sclerosis or epilepsy ( Spanou et al, 2019 ). Inflammatory conditions.…”

Practical Strategies for Advanced Practitioners Streamlining the Integration of Oncology Biosimilar Therapies Into Practice

“…In contrast, although biosimilars typically offer a more affordable version of the same reference product, patient skepticism can be triggered by the lower cost of biosimilars compared with reference products that are typically more expensive ( Renton et al, 2019 ). Irrational thoughts about potentially receiving an inferior product, and the negative expectations stemming from a patient's misconceptions that their medication will harm rather than improve their health (nocebo effects), can pose clinical challenges ( Janjigian et al, 2018 ; Spanou et al, 2019 ). Failing to address the potential for cost-related concerns early on could, for some patients, foster an anxiety-driven internal monologue that reduces their receptivity to the education that follows.…”

European Headache Federation recommendations for placebo and nocebo terminology

“…Appendix Table 2 Environmental factors and stimuli modifying placebo/nocebo effects Modifiable Non-modifiable Patient's expectations [13] Previous experiences [14] Pre-treatment verbal and non-verbal suggestions [15,16] Patient's personality [17] Speed of treatment titration [18] Cultural factors [19,20] Safety profile of treatment [21] Age [22] Patient-doctor relation/communication [23] Social Media and Internet information [24] Investigator/physician status [15] Gender [25] Affective and cognitive traits [26] Level of patients' education [22] Generic formulations [27,28] Genetics [29] The appearance of drugs or medical devices, e.g. packaging, color, price, drug taste, etc.…”