Once-Daily Oxycodone Prolonged-Release Tablets Are Resistant to Alcohol-Induced Dose Dumping: Results From a Randomized Trial in Healthy Volunteers.

The objective of this study was to determine the effect of concomitant alcohol intake on the bioavailability of oxycodone from an oxycodone once-daily (OOD) formulation and an oxycodone twice-daily (OTD) formulation. A phase I, open-label, randomized, crossover alcohol interaction study in 20 healthy volunteers under fasting conditions was conducted. Participants received five treatments, OOD with 240 mL of 0%, 20%, or 40% alcohol; and OTD with 240 mL of 0% or 40% alcohol. Pharmacokinetic parameters did not differ between participants taking OOD with water or with 240 mL of 20% alcohol. There was a slight increase in overall oxycodone absorption from OOD with 40% alcohol but no increase in peak absorption. Oxycodone absorption from OTD showed peak and overall increases with 40% alcohol but maintained a prolonged-release profile. Although it is recommended that alcohol be avoided while taking opioids, there was no evidence of alcohol-induced dose dumping in these oxycodone formulations.

Efficacy of a new once daily hydromorphone formulation in comparison with twice daily administration in chronic pain: a randomized, double-blind, cross-over study.

Objective Efficacy and safety of a novel multiple-unit hydromorphone once daily (HOD) was compared to an established hydromorphone twice daily (HTD) regimen in patients with moderate-to-severe chronic pain. Design and methods The results from a randomized, double-blind, multicenter, cross-over trial in patients (n = 37) with chronic malignant or non-malignant pain are reported. The primary efficacy parameter was current pain on 0-100 mm VAS assessed four times daily and prior to intake of rescue medication (immediate-release hydromorphone) throughout the last 5 days with each treatment (after an 8 day build-up period to avoid carry-over effects). Total daily dose of hydromorphone (TDD: 8-32 mg/day) was kept stable during the double-blind treatment phase. Results The difference observed in mean current pain (-0.92 mm VAS) over the 5 day assessment period between HOD and HTD (28.44 mm vs. 29.36 mm VAS) was found to lack clinical relevance, as the 95% CI (-4.10 to 2.28 mm VAS) did not exceed the prespecified limit for non-inferiority of 9 mm VAS. Results from the full analysis set were consistent with per protocol data confirming robustness, as did the data for 12 h recalled pain assessed at 08:00 h and 20:00 h, showing no significant differences between once and twice daily medication. Both treatments produced effective and stable pain control with only minor day-to-day and intra-day fluctuations. Switching between treatments was suitable, considering both efficacy and safety, as no relevant or significant differences in adverse events were seen (25.0% HOD, 24.3% HTD). Most frequently typical side-effects of opioid therapy were observed, such as nausea, vomiting and headache. Conclusion Although this study was of short duration and included a limited number of patients, the results confirm that the new HOD is as effective and safe as the established HTD.

Extended-release but not immediate-release and subcutaneous methylnaltrexone antagonizes the loperamide-induced delay of whole-gut transit time in healthy subjects.

Methylnaltrexone (MNTX) is approved for subcutaneous treatment (MNTX-SC) of opioid induced constipation. MNTX in oral immediate-release (MNTX-IR) and extended-release (MNTX-ER) dosage forms may antagonize the opioid induced delay in oro-cecal transit time (OCT) as measured by using radiolabeled lactulose. Because lactulose acts laxative by its own and efficacy of MNTX on colon transit time (CTT) was unknown, the opioid antagonistic effects MNTX-IR and MNTX-ER (both 500 mg) relative to MNTX-SC (12 mg) were evaluated in 15 healthy subjects with loperamide (LOP, 3 × 4 mg, 12 hourly) induced experimental constipation using the sulfasalazine/sulfapyridine method and radio-opaque markers to measure OCT and whole gut transit time (WGT). MNTX-ER significantly antagonized the LOP effects in 12 of our 15 subjects who responded to LOP with prolongation of WGT by 20.6-74.1 h (OCT by 0.50-10.5 h, CTT by 18.3-73.6 h). MNTX-SC and MNTX-IR were without significant influence. Compared to MNTX-SC, bioavailability of MNTX-IR and MNTX-ER was 1.53-5.49% and 0.11-1.24%, respectively. MNTX-SC and MNTX-IR achieved active serum levels only for ∼ 3-5 h. MNTX-ER antagonized the opioid-induced delay of CTT most likely by local effects on µ-opioid receptors in the colon.

Clinical evaluation of the first oxycodone once daily prolonged release tablet in moderate to severe chronic pain: a randomized, double-blind, multicenter, cross-over, non-inferiority study to investigate efficacy and safety in comparison with an established oxycodone twice daily prolonged release tablet.

OBJECTIVE: The first oxycodone once daily (OOD) has been developed and after successful pharmacokinetic characterization, therapeutic efficacy and safety were compared to an established oxycodone twice daily (OTD: Oxygesic/OxyContin, Mundipharma). DESIGN AND METHODS: A randomized, double-blind, multicenter, cross-over, non-inferiority study was conducted in patients (n = 68) with chronic malignant or non-malignant pain. The new OOD was compared to OTD at identical total daily doses (TDD: 40-120 mg/day) employing intensive, five times daily current pain (0-100 mm visual analog scale, VAS) and twice daily 12 h recalled pain assessments as well as safety parameters such as nausea and sedation (VAS) over 5 days for each treatment (after a 5 day run-in phase). RESULTS: There was no significant difference in analgesic potency detected between the two treatments based on 95% CI for difference in the daily mean current pain (-2.09 mm VAS) over 5 days, determined as -5.09 to 0.91 mm VAS. A difference ≤12 mm VAS indicated non-inferiority of OOD, i.e. lack of clinically relevant difference in analgesia. Intake of rescue medication had no effect on study results as evaluated by ANCOVA. The difference in adverse events (AEs) between the two treatments did not reach significance, as 19.1% and 23.5% of patients experienced treatment-related AEs while on OOD and OTD, respectively. Advantages for OOD regarding consistency of analgesia (i.e. use of rescue medication, current and recalled pain) and sedation did not reach statistical significance in this limited study population. CONCLUSION: Despite the small number of patients and short study duration, the results support the conclusion that new OOD is (at least) equivalent to established OTD regarding safety and efficacy.