Individualized dosing of a novel oral DELTA9-THC formulation improves subjective spasticity and pain in patients with progressive multiple sclerosis

BACKGROUND: Cannabinoids have been shown to improve symptoms of Multiple Sclerosis (MS) including muscle spasticity and pain through modulation of neuronal excitability via presynaptic cannabinoid receptors. Previous formulations of Δ9-THC are notorious for variable pharmacokinetic profiles, thereby demanding cumbersome uptitration. The current formulation was developed to overcome this and improve clinical application of Δ9-THC in the treatment of spasticity and pain in MS. OBJECTIVES: The aim of the present study was to evaluate the efficacy of a novel oral formulation of Δ9-THC (ECP002A) to treat spasticity, pain and improve functional outcome measures in 24 patients with primary or secondary progressive MS. METHODS: This was a two-phase study consisting of a dose-finding phase utilizing pharmacokinetic- pharmacodynamic (PK-PD) modeling and a treatment phase. In the dose-finding phase, the effect of an escalating oral dose of ECP002A on pharmacodynamic outcome variables was assessed in a randomized placebo-controlled, two-way cross-over trial design. Patients visited the outpatient clinic on two occasions and received an escalating oral dose of ECP002A or placebo. Plasma concentrations of Δ9-THC and metabolites were measured to generate an individual treatment regimen based on PK and PD. In the 4-week treatment phase, the individual dose was administered three times daily in a randomized placebo-controlled, parallel fashion. During the treatment phase muscle spasticity (Ashworth and subjective spasticity), pain and clinical outcomes (e.g. EDSS, 25Ft Timed walk, GNDS) were measured at baseline, week 2 and 4. RESULTS: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic, but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated there was no decline in cognition after 2 or 4 weeks of treatment due to ECP002A compared to placebo. CONCLUSIONS: ECP002A appears to be effective in reducing subjective symptoms including muscle spasticity and pain in patients suffering from MS when measured immediately after dosing in the clinic. This effect could not be shown when measured retrospectively using a diary.