Identification of pain categories associated with change in pain in patients receiving placebo: data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis

Abstract

Background: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC).

Methods: Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed.

Results: The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee.

Conclusions: These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted.

Trial registration: NCT00486434 (trial 1) and NCT00704847 (trial 2).

Keywords: Pain categories; Placebo-response; Radiographic progression.

Conflict of interest statement

Ethics approval and consent to participate

The conduct of both trials was approved by all applicable national regulatory authorities, independent review boards and ethical committees. All participating subjects gave a written, informed consent to participate in the trial, including consent to publish results from the trial.

Competing interests

ARB, IB, ACBJ, CC, BJR, JRA, and MAK are full-time employees in Nordic Bioscience, a company engaged in biomarker research and development of treatments for OA. ARB, ACBJ, CC, BJR, JRA and MK are shareholders of Nordic Bioscience. BJR and CC are major shareholders and board members of Nordic Bioscience. IV is a full-time employee of BioClinica. MH does not have any conflicts of interest to declare.

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Figures

Fig. 1

Target knee (n = 771) and Non-target knee (n = 256) mean pain change from baseline in % over 24 months, normalized (0–100), by pain question (a) and category; Weight-bearing pain (WOMAC questions 1, 2 and 5), and non-weight-bearing pain (WOMAC questions 3 and 4) (b). Baseline values below 10 are set to 10 to reduce noise. Non-target knees were selected to include only those meeting the pain inclusion criteria of the target knee for comparability. c depicts mean change from baseline in %, adjusted for the estimated regression to the mean as listed in Table 2. Error bars are SEM. *: p < 0.05 ***: p < 0.001

Fig. 2

Joint-space narrowing (JSN) at year 2 by baseline pain severity level of individual and total WOMAC pain scores of target (a)- and non-target (b) knees. Data on JSN are mixed-model least-square means (standard error) adjusted for KL-score, BMI, study code, and sex. Pain severity is divided into quintile subgroups of normalized maximum possible score ranging from 0 mm (least possible pain) to 100 mm (worst imaginable pain for each WOMAC pain category. The number of observations (knees) in each category are shown in the table below the figures. Sub-groups with less than 10 observations, marked with * in the table, are excluded from the figure. Target knee. NT: Non-target knee. WOMAC: Western Ontario and McMaster’s Universities Arthritis Index. Error bars are SEM

Fig. 3

Hypothetical depiction of pain category severity and progressive disease stage over time. While disease progression is likely occurring in limited periods follow by periods of inertia [35], pain trajectories appear to be progressing more steadily, although slowly [19, 32, 33]. Weight-bearing pain is the first pain category to present, followed by non-weight-bearing pain [19]. Variable radiographic disease progression rates may blur the otherwise expected hypothetical association between pain severity and risk of progression at one or very few given time points