The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study.
Eine randomisierte, doppel-blinde, Placebo-kontrollierten Studie wurde durchgeführt, um den Nutzen der Nabilon in der Schmerztherapie und der Verbesserung der Lebensqualität bei 40 Patienten mit Fibromyalgie zu bestimmen. Nach einer Beurteilung der Ausgangslage wurden die Probanden auf Nabilon titriert, von 0,5 mg PO vor dem Schlafengehen zu 1 mg zweimal täglich über 4 Wochen oder Placebo erhielten eine entsprechende. Bei den 2 - und 4-Wochen-Besuche, das primäre Endziel, visuellen Analogskala (VAS) für Schmerzen, und die sekundären Endpunkte, die Anzahl der tender points, die durchschnittliche Tenderpoint Schmerzgrenze, und die Fibromyalgie Impact Questionnaire (FIQ) , wurden bewertet. Nach einer 4-wöchigen Auswaschphase, kehrte Themen für Neubewertung der Zielparameter. Es gab keine signifikanten Unterschiede in der Bevölkerung Demographie zwischen den Gruppen zu Studienbeginn. Es gab eine signifikante Abnahme in der VAS (-2,04, p <.02), FIQ (-12,07, p <.02) und Angst (-1,67, p <.02) in der Nabilon behandelten Gruppe nach 4 Wochen. Es gab keine signifikanten Verbesserungen in der Placebo-Gruppe. Die behandelten Gruppe konnten mehr Nebenwirkungen pro Person bei 2 und 4 Wochen (1,58, p <0,02 und 1,54, p <.05) sind. Nabilon scheint ein Vorteil, gut verträgliche Behandlungsoption für Fibromyalgie-Patienten, mit erheblichen Vorteilen in der Schmerzlinderung und Funktionsverbesserung zu sein. PERSPEKTIVE: Nach unserer Kenntnis ist dies die erste randomisierte, kontrollierte Studie, um den Nutzen von Nabilon, ein synthetisches Cannabinoid beurteilen, auf Schmerzreduktion und Verbesserung der Lebensqualität bei Patienten mit Fibromyalgie. Als Nabilon Symptome verbessert und wurde gut vertragen, kann es eine sinnvolle Ergänzung für die Schmerztherapie bei Fibromyalgie sein.
OBJECTIVES: To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA).
METHODS: We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity.
RESULTS: Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group.
CONCLUSIONS: In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.
The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study.
