Background/Purpose: Fibromyalgia Syndrome [FMS] is a common chronic pain disorder. Pregabalin (PGB) is one of three medications approved by the FDA for treatment of FMS. Substance P (SP), a neuropeptide known to facilitate pain transmission, is elevated in the cerebrospinal fluid (CSF) of FMS. The mechanism of PGB benefit in FMS is uncertain, but it is known to inhibit SP production by neurons in vitro. Our objective was to measure PGB’s effect, if any, on CSF SP in FMS.

Methods: This study was investigator-initiated, -designed, -conducted, and –analyzed. It was randomized (2:1, PGB:PBO), double-blinded, placebo (PBO)-controlled, and involved only FMS females, 18-65 years of age. Funding was provided by a research grant from Pfizer Inc., which also provided the study medications (150mg PGB capsules, identical-appearing PBO). It was not an efficacy or safety clinical trial, since the primary outcome variable was biological (mean change in CSF SP level with PGB therapy). The 1990 ACR Research Classification Criteria were required for entry. At Screening (Visit #1), informed consent was obtained, patients were examined for diagnosis, validated self-report measures were completed, a blood sample was obtained, participants began to taper-off potentially-interfering medications, and were off for 5+ half-lives. At Baseline (Visit #2), the self-report measures were repeated, CSF was collected for storage at -70°C, and patients were randomized to PGB or PBO, at bedtime. The dosage was increased over a period of 2 weeks to therapeutic (300-450 mg/24 hrs). After 6 full weeks of therapeutic dosage (Visit #4), the Patient Global Impression of Change (PGIC) was assessed, and a second CSF was stored. Numbered CSF samples were analyzed in-blind for SP and biogenic amines. Treatment groups were contrasted on the mean, using analysis of variance, and on categorical outcomes with Fisher’s Exact Test. All statistical testing was two-sided with a significance at 5%.

Results: The study was originally powered for 90 randomized subjects, but, a budget cut limited the sample size, leaving the study inadequately powered. Eighty four patients signed informed consent; 38 screen failed; 46 were randomized (PGB n=31, PBO n=15), five randomized patients later withdrew consent (PGB n=3, PBO n=2). A total of 41 completed the study (PGB n=28, PBO 13), each with 2 stored CSF samples. At Baseline, treatment groups did not differ in any respect (demographic, clinical, laboratory). At Visit #4, the PGIC distribution varied significantly (p=0.02) with treatment [PGB 60.7% (17/28) cf. PBO 30.7% (4/13) reporting being Much- to Very Much-Improved] while CSF SP had increased numerically in both groups (CSF SP, fmol/ml, PGB +15.8±56.7, PBO +10.8±60.2, p=0.94). Correlations between clinical outcomes and spinal fluid measures were noted. A statistical model was developed. The observed adverse events had been anticipated, and were generally mild. One post-spinal headache was considered serious, as it required blood patch treatment.

Conclusion: The study design produced comparable treatment groups. PGB affected clinically relevant improvement in more than half of the PGB-treated patients but the CSF SP concentration trended to rise.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-pregabalin-lyrica-on-cerebrospinal-fluid-substance-p-in-human-subjects-with-fibromyalgia-syndrome/