Background/Purpose: Explore carryover effects and their influence on crossover and randomized withdrawal design (RWD) studies.

Methods: We examine pregabalin crossover and RWD studies in fibromyalgia (FM), painful diabetic peripheral neuropathy (pDPN), and post-herpetic neuralgia (PHN). Data visualization methods and meta-analytic summaries are used to explore the difference in carryover effects across studies and pain types. Weekly mean pain scores are compared for 4 crossover studies of similar design, 2 in FM (studies 1165 and 1275) and 2 in pDPN (1268, 1269), for patients randomized to the pregabalin to placebo treatment sequence (Pgb – Pla) or to the placebo to pregabalin (Pla – Pgb) treatment sequence (Figure 1).

Results: In fibromyalgia crossover studies, a greater return of pain occurred following pregabalin treatment than in the pDPN studies (Figure 1). There was a differential effect of period one treatment on period two outcomes. FM crossover studies returned to a common pain level regardless of period one treatment, whereas DPN crossover studies did not. Similar results hold for the pregabalin to placebo arm in the FM vs DPN RWD studies.

Figure 1. Crossover Studies in Fibromyalgia and Painful Diabetic Peripheral Neuropathy

FM: Fibromyalgia; DPN: Painful Diabetic Peripheral Neuropathy; Pain NRS: Pain Numeric Rating Scale; Pgb: Pregabalin; Pla: Placebo; Bsl: Baseline; P1: Period 1; P2: Period 2; W/O: placebo washout period

Conclusion: The type of pain under study may affect the ability of crossover or RWD studies to determine the magnitude of treatment effect; pain type should be carefully considered when choosing among study designs for pain.