Analgesic Effects of Low-dose Intravenous Orphenadrine in the State of Capsaicin Hyperalgesia

Abstract

The present investigation aimed to elucidate the analgesic efficacy of 30 mg of intravenous orphenadrine citrate (CAS 4682-36-4) in a human pain model. Eighteen healthy female and male subjects were enrolled and received single infusions of 30 mg orphenadrine citrate and matching placebo in two periods which were separated by a 1 week washout period. The study was designed as a randomised, double-blind, placebo-controlled, two-period, cross-over trial. The intended neurogenic inflammation and hyperalgesia were induced by topical, occlusive application of 1% capsaicin solution (INCI: Capsicum frutescens, containing capsaicinoides from Capsicum annuum annuum, CAS 84603-55-4) for 30 min on defined skin areas of the back. The pain response to CO2 laser pulses applied to the capsaicin pre-treated skin was measured by event related Vertex-EEG recordings. This technique allowed studying the influence of orphenadrine citrate on the (central) P2-component and the (peripheral) Ni-component of the pain response (LSEP). Both, orphenadrine citrate and placebo were given as intravenous infusions over 60 min. Orphenadrine citrate exerted a significant reduction in central and peripheral components of the pain response when compared to placebo. The effect on the central component was highly significant and more pronounced than the peripheral effect of the drug. The analgesic effect developed fast, was already present during infusion, was ongoing, and exceeded the observational period of 4 h after start of infusion. In summary, orphenadrine citrate was able to exert an analgesic/anti-hyperalgesic effect in a low-dose paradigm (30 mg dose) which was predominantly due to central/spinal mechanisms in this capsaicin model with laser somatosensory evoked potentials.

A Phase I, Randomized, Double-Blind, Laser-Evoked Potential Study to Evaluate the Analgesic/Antihyperalgesic Effect of ASP9226, a State-Dependent N-Type Voltage-Gated Calcium Channel Inhibitor, in Healthy Male Subjects

“…Compared with a typical PoC phase II study, the LEP model is sensitive in a small cohort of healthy subjects, is relatively inexpensive, and is swift to conduct and may prevent exposing a larger number of patients with PNP to an ineffective compound over longer treatment periods (including treatment wash-outs). The LEP model has successfully been used for early clinical development of pain medications [ 16 , 20 ], and a reduction in PtP amplitude has been reported as a reliable measure of the magnitude of antinociceptive/antihyperalgesic drug effects [ 19 , 21 , 22 ]. Given the success of the LEP model and the study design used here in identifying compounds with analgesic effects, combined with the confirmed effect of pregabalin in this study, the LEP results with ASP9226, at the dose levels tested, predict that a clinically relevant benefit in pain relief would not be demonstrated if a phase II PoC study with ASP9226 in patients with PNP were to be conducted.…”

Validated Stability-Indicating Reversed-Phase-HPLC Method for Simultaneous Determination of Orphenadrine Citrate, Caffeine and Aspirin

“…6) It may be possible for its antihistaminergic properties and NMDA-receptor inhibition activity, however, the hypothesis of inhibiting the voltage-gated sodium channels has become recently solidified as a strong contributor to the analgesic action of orphenadrine. 7) A thorough literature survey revealed ORPH, CAF and ASP were reported by pharmacopeial and non-pharmacopeial methods.…”