Lead Investigator: Cosima Locher, University Hospital Zurich
Title of Proposal Research: Predictors of placebo response in opioid trials for patients with Chronic Primary Pain – An Individual-Patient Data (IPD) Meta-Analysis
Vivli Data Request: 6024
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
CPP – Chronic Primary Pain – Chronic Pain in one or more bodily regions, persists or recurs for more than three months and is associated with significant emotional distress and functional disability. These syndromes are for the first time combined as a separate entity in the ICD-11 classification
IPD – Individual Patient Data – Study data from individual patients participating in the respective study
RCT – Randomized Controlled Trial – Most common trial design
The project background: Systematic reviews and meta-analyses in patients suffering from chronic noncancer pain found moderate effect sizes for the efficacy of opioids compared to placebo. However, these studies also reveal that patients with Chronic Primary Pain (CPP) syndromes show a substantial and clinically relevant placebo response, with significant placebo effect sizes for pain relief in fibromyalgia, chronic low back pain, irritable bowel syndrome, migraine, and complex regional pain syndrome. It has been shown that placebo responses are especially high in opioid trials since patients have increased outcome expectations – they are informed that they may receive an opioid, a known powerful analgesic. The literature suggests that there is an interindividual variability in placebo responses. Likewise, meta-analyses that examined CPP syndromes indicate that trial- and patient-related characteristics influence the magnitude of the placebo response. Most prominent determinants include patients’ baseline pain intensity , year of study initiation, the quantity of investigator-patient relationship , age, and dosing regimen. However, conclusions are premature and further confirmations are required, especially in opioid trials where comparable investigations are lacking. For the investigation of opioids, the ‘randomized withdrawal’ design or ‘enriched enrollment randomized withdrawal’ (EERW) design has been postulated as useful because it allows to specifically examine the subgroup of people who benefit from opioids and who tolerate the adverse effects. In this design, after an initial open label period, only the responders are randomized to receive the opioid therapy and placebo, respectively.
Necessity of the research: The findings of this study will have implications for the interpretation and design of placebo-controlled clinical trials in the field of opioids. Detailed information about the placebo response and its determinants helps to interpret opioid-placebo differences (i.e., ‘assay sensitivity’) and, in turn, prevents an under- or overestimation of the specific opioid effect in comparison with nonspecific effects. This knowledge will also be of interest for clinicians and patients, enabling to design an evidence-based treatment plan.
How many patients are potentially affected: Patients already participated in the studies we aim to analyze. Thus, we will re-examine data that has been already collected. No additional effort is needed from patients’ side. However, the gained findings will be of general interest for patients with CPP being treated with opioids.
How the research will add to medical science or patient care: Future RCTs could try to minimize placebo responses and thereby limit their influence on the overall findings with different strategies: (a) to statistically control for patient characteristics shown to be related to placebo responses; and (b) to adapt the study design by considering trial characteristics associated with placebo responses. Furthermore, the findings will have implications for the clinical practice. There, the gained knowledge will allow to maximize and personalize placebo responses within an ethical framework (e.g., to foster a patient-physician relationship that is based on trust).
How the research will be conducted: We aim to conduct an individual patient data (IPD) meta-analysis. A meta-analysis combines various trials that have been already conducted, allowing to calculate an overall effect size. In a first step, the original trial data will be sought from the sponsors and / or authors of all studies fulfilling the inclusion criteria. In a second step, we will combine the study data into one master file. Then, we will calculate the placebo effect size and its determinants.
What design and methods you have chosen and why: We did choose to use an IPD. Data sharing agreements make it possible for researchers to apply IPD instead of aggregate data. IPD results in more clinically relevant results than a meta-analysis of aggregate data, going beyond the “grand mean” toward individualized medicine. Thus, the estimation of results for each covariate value allows different recommendations to be made for different subgroups of patients; personalising treatment in this way can benefit patients and ensure the cost‐effective use of health.
A Phase 2, Randomized Withdrawal Study of the Analgesic Efficacy and Safety of Hydrocodone/Acetaminophen Extended Release Compared to Placebo in Subjects With Chronic Low Back Pain
Study ID: NCT01364922
Sponsor ID: M12-807
A Phase 3, Open-Label Period Followed By a Randomized, Double-Blind, Placebo-Controlled Study of the Analgesic Efficacy and Safety of Extended Release Hydrocodone/Acetaminophen (Vicodin® CR) Compared to Placebo in Subjects With Chronic Low Back Pain
Study ID: NCT00325949
Sponsor ID: M05-790
A Phase 3, Open-Label Period Followed by a Randomized, Double-blind, Placebo-controlled Study of the Analgesic Efficacy of Extended-release Hydrocodone/Acetaminophen (Vicodin CR) Compared to Placebo in Subjects With Chronic Low Back Pain
Study ID: NCT00761150
Sponsor ID: M10-385
A Phase 3, Open-Label Period Followed by a Randomized, Double-blind Placebo-controlled Study of the Analgesic Efficacy of Extended-release Hydrocodone/Acetaminophen (Vicodin CR) Compared to Placebo in Subjects With Chronic Low Back Pain
Study ID: NCT00763321
Sponsor ID: M10-277
Update: This data request was withdrawn on 11-Jan-2022 by the researcher.