Ro 15-8081, a substituted
cyclohexanol hydrochloride, inhibits the re-uptake of
norepinephrine and of
serotonin. Its antinociceptive properties have been demonstrated in animals and then confirmed in humans after single-dose administration. The objective was to determine the
analgesic efficacy and the safety of
Ro 15-8081 in
osteoarthritis of the hip and knee (femoro-tibial location) after multiple-dose application. The design for studying dosage employed 5 parallel groups in an international multicenter, double-blind, randomized trial having a duration of 2 weeks. Drugs studied were: 20 mg
Ro 15-8081 (divided into 2 doses), 50 mg
Ro 15-8081 (divided into 2 doses), 100 mg
Ro 15-8081 (divided into 2 doses), placebo twice daily or 20 mg/day
piroxicam (
piroxicam in the morning and placebo in the evening).
Piroxicam was used as a reference
drug in order to validate clinical testing. Assessment criteria were
pain (100-mm VAS) and function (Lequesne's index). A responder (main assessment criterion) was defined as a patient exhibiting a reduction of at least 30% of
pain (VAS) during the study (intention-to-treat analysis). A total of 522 patients were enrolled in the study. A clear beneficial effect of
piroxicam was observed when compared with placebo (70% and 48% of responders in
piroxicam and placebo groups respectively; P < 0.0001). Multigroup comparison showed a statistically significant difference between
Ro 15-8081 groups and the placebo group regarding mean change in
pain between D1 and Dend and the rate of VAS responders. Comparison (Dunnett's t or chi 2 tests) between each individual
Ro 15-8081 and the placebo group reached statistical significance for the 100 mg
Ro 15-8081 group (mean change in
pain between D1 and Dend: P = 0.05; percentage of responders: P = 0.0008) but no statistically significant difference for the other dosages of
Ro 15-8081. Fifty-three patients withdrew from the study because of adverse events and/or inefficacy, mainly in 50 and 100 mg
Ro 15-8081 groups and in a dose-related manner. The adverse events which appeared to be
drug related were mainly dryness of the mouth,
insomnia,
headache,
constipation,
nausea,
dizziness, nervousness, palpitation. This study suggests that 100 mg
Ro 15-8081 per day divided into 2 doses has (1) an
analgesic effect in hip or
knee osteoarthritis and (2) poor acceptability in the conditions of the study regimen application.