Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies.

BACKGROUND: The efficacy of tapentadol extended release (ER) for managing chronic pain has been demonstrated in large-scale, randomized, controlled, phase 3 studies (N=318-1,030) in patients with chronic osteoarthritis (OA) pain, low back pain (LBP), and pain related to diabetic peripheral neuropathy (DPN), which led to registration in many regions, including the United States and Europe. 2 pilot 12-week, randomized, double-blind, placebo-controlled phase 2 studies of tapentadol ER for chronic pain (OA knee pain or LBP, n=91; DPN or peripheral herpetic neuralgia [PHN] pain; n=91) were conducted in Japan. These small exploratory studies were substantially underpowered compared with the registration trials. METHODS: Patients in both studies were randomized (2:1) to tapentadol ER (25-250 mg) or placebo for 12 weeks (≤6-week titration plus maintenance periods). RESULTS: For the primary efficacy endpoint (change in pain intensity from baseline to last week of treatment; last observation carried forward), both studies failed to differentiate between tapentadol ER and placebo; least-squares mean differences (95% confidence intervals) for tapentadol ER vs. placebo were -0.1 (-1.04, 0.80) in the OA/LBP study and -0.1 (-1.10, 0.99) in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Tapentadol was well tolerated. CONCLUSIONS: Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

[New application of ultrasound imaging using contrast agent].

Recently, various ultrasound contrast agent have been developed all over the world. This paper reviewed recent development of some contrast agent and clinical application of new imaging using contrast agent (Enhanced color Doppler Imaging, Harmonic Imaging, Flash Echo Imaging and Loss of Correlation Imaging). These new methods are easily feasible with a clinical ultrasound diagnosis machine for evaluating further information, for example, slow or deeply located lesion's blood flow, furthermore tissue perfusion. Contrast enhanced ultrasound imaging such as Harmonic imaging is enable to evaluate tissue function.

Bioavailability of a film-coated tablet of valproate in nonfasting volunteers.

The bioavailability of a film-coated tablet of valproate (VPA) in nonfasting volunteers was studied. Ten healthy adults received a single 200 mg (mean 3.55 mg/kg) film-coated tablet, 15 minutes after breakfast. Venous blood was then taken at regular intervals of up to 4 or 7 hours after the dosage, and the serum VPA concentrations were determined by means of a fluorescence polarization immunoassay. VPA was slowly absorbed with the peak concentrations occurring 1.5 to 4 hours after the administration. The mean concentration (Cmax) and extent of absorption (area under the concentration-time curve) between 1 and 4 hours were 22.2 micrograms/ml and 59.3 micrograms.h/ml, respectively. It was concluded that Cmax with a film-coated tablet of VPA can be detected if blood is taken at around 3 hours after the dosage under nonfasting conditions.