The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer reviewed.
Both placebo and nocebo effects can greatly affect the interpretation of outcomes in randomized controlled trials of chronic neuropathic pain treatments.
When trials are being designed and interpreted, these effects need to be considered so that safety and efficacy can be better determined.
Why This Matters
Clinicians who are trying to determine causality vs association between an event and a medication when treating chronic neuropathic pain need to know if outcomes are related to a placebo or nocebo effect.
For future trials, the best choice of endpoints when studying chronic neuropathic pain may be determined by this study’s findings.
This was a systematic review and meta-analysis of randomized controlled trials in which drugs (topical capsaicin, tricyclic antidepressants, effexor diary ring serotonin-norepinephrine reuptake inhibitors, calcium channel alpha-2-delta ligands) used to treat chronic peripheral neuropathic pain were compared with placebo.
The trials studied individuals 18 years of age or older with chronic peripheral neuropathic pain in the following categories: chemotherapy-induced peripheral neuropathy, HIV neuropathy, painful diabetic peripheral neuropathy, postherpetic neuralgia, mixed disease, and postsurgical neuropathy.
The primary endpoints were placebo response (proportion of patients with reported pain intensity reduction ≥30% in the placebo arm) and nocebo response (proportion of patients with adverse events).
The secondary endpoints were pain intensity reduction of ≥50%, global pain assessment, discontinuations (either because of lack of efficacy or adverse events), serious adverse events, and specific adverse events.
An additional analysis of the proportion of symptoms that was not attributable to the pharmacologic action of the drugs was done by a calculation.
Meta-regressions were conducted for the primary endpoints, looking for possible confounders. To do this, the authors evaluated the impact of transdermal application, pain duration at baseline, trial duration, overall trial risk of bias, the underlying condition, percentage of female participants, median participant age, and year of publication.
The placebo response showed that 38% of patients who received placebo had a pain intensity reduction ≥30% (95% CI, 34 – 42; I2 = 86%), compared to 51% of patients who received active drugs (95% CI, 47 – 56; I2 = 89%).
The nocebo response revealed that 50% of patients receiving placebo had adverse events (95% CI, 43 – 58; I2 = 97%), compared to 67% of those who received active drugs (95% CI, 60 – 74; I2 = 97%).
The proportion of symptoms that was not attributable to the pharmacologic action of the drugs was 75% for both the placebo and nocebo responses.
Pain intensity reduction of ≥50% occurred in 23% of the patients receiving placebo (95% CI, 20 – 27; I2 = 81%). The calculated proportion of symptoms that was not attributable to the pharmacologic action of the drugs was 64%.
Global pain assessment, measured by the Patient Global Impression of Change, improved or very much improved in 26% of patients receiving placebo (95% CI, 21 – 33; I2 = 93%), with a calculated proportion of symptoms that was not attributable to the pharmacologic action of the drugs of 62%.
Of the patients receiving placebo, 4% (95% CI, 3 – 6; I2 = 77%) discontinued the drug secondary to adverse events (with a calculated proportion of symptoms that was not attributable to the pharmacologic action of the drugs of 50%), and 4% (95% CI, 3 – 6; I2 = 80%) discontinued the drug secondary to lack of efficacy.
Serious adverse events occurred in 2% of patients receiving placebo (95% CI, 2 – 3; I2 = 58%), with a calculated proportion of symptoms that was not attributable to the pharmacologic action of the drugs of 100%.
The meta-regressions showed that the publication year was positively associated with pain intensity reduction ≥30% (P = .0067) and negatively associated with adverse events (P = .0371).
The meta-regressions also showed that adverse events and the percentage of female participants had a negative association (P = .00061) and that adverse events were positively associated with the duration of a trial (P = .0447).
In addition to the placebo and nocebo effects, other factors, such as the Hawthorne Effect, may have affected the results of the studies evaluated.
Regression to the mean may lead to interpreting the normal disease fluctuations as being improving or worsening of the disease.
Both external factors and the patient’s underlying conditions causing their pain may contribute to the course of their pain and may then be interpreted as adverse effects.
Joaquim J. Ferreira received speaker and consultant fees from Novartis, AbbVie, BIAL, Merck Sharp & Dohme, Biogen, Sunovion Pharmaceuticals, and Medtronic.
Filipe B. Rodrigues received consultant fees from Roche and GLG.
The remaining authors have nothing to disclose.
There were no specific grants from any funding agencies.
This is a summary of a preprint research study, “Placebo Response in Chronic Peripheral Neuropathic Pain Trials: Systematic Review and Metaanalysis,” written by Gonçalo S. Duarte, MD, from the Laboratório de Farmacologia Clínica e Terapêutica, Universidade de Lisboa, Lisboa, Portugal, IMM, Universidade de Lisboa, and the Centro de Estudos de Medicina Baseada na Evidência, Universidade de Lisboa, Lisboa, Portugal, and colleagues, on MedRxiv, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.
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