A Phase I study of the pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxymorphone transdermal patch system.

AIM: Characterize the pharmacokinetic profile and tolerability of two tocopheryl phosphate mixture/oxymorphone patch formulations in healthy subjects, and the active metabolite (6-OH-oxymorphone). MATERIALS & METHODS: Fifteen participants received a single application of oxymorphone patches +/- capsaicin for 72 h and were crossed-over for another 72 h. RESULTS: Plasma oxymorphone was detected approximately 7 h and 6-OH-oxymorphone after approximately 18-19 h postapplication of both formulations, respectively. For oxymorphone, median tmax was 24 h, and Cmax/Cmin ratio was approximately 2.4. The most frequently reported treatment-related adverse event was application site reaction, mainly with capsaicin formulation. CONCLUSION: Tocopheryl phosphate mixture/oxymorphone transdermal patches can successfully deliver therapeutic amounts of oxymorphone in a sustained manner over 72 h and are well tolerated. ANZCTR registration number: ACTRN12614000613606.

Pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxycodone transdermal patch system: a Phase I study.

AIM: To characterize the pharmacokinetic profile and evaluate the safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM). PATIENTS & METHODS: Eleven healthy subjects received a single application of three TPM/oxycodone patches applied to the torso for 72 h. RESULTS: Oxycodone was detected 8.0 ± 2.7-h postpatch administration, reaching a mean maximum plasma concentration of 3.41 ± 1.34 ng/ml at 49.3 ± 21.2 h. The safety profile was consistent with the application method and known side-effect profile of oxycodone and naltrexone. No treatment-limiting skin irritation was observed. CONCLUSION: A 3-day application of the TPM/oxycodone patch demonstrated an acceptable safety profile and was well tolerated by healthy subjects, with limited dermal irritation following application.

MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance.

While many pre-clinical and clinical studies have suggested that the addition of N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan (DM), to opioid analgesics, such as morphine (MS), may enhance the analgesic effects and prevent the tolerance that may result from chronic opioid administration, others have not. The potential for reduced doses, enhanced opioid analgesia, and decreased analgesic tolerance associated with the MS/DM combination were evaluated in a series of three large, randomized, double-blind, parallel group, phase 3, multicenter trials each of 3 months duration in patients with chronic, non-malignant, non-neuropathic pain. To evaluate these unique endpoints, novel study designs were employed. In Study A, patients received fixed doses of MS or MS/DM, based on the stable dose of MS/DM attained during a Run-in period; changes from baseline in average daily pain intensity were compared. In Studies B and C, patients self-titrated doses of MS or MS/DM, based on stable doses of MS or other opioids attained during Run-in periods, to maintain pain relief; percentage changes from baseline in MS (or MS-equivalent) doses were compared. No statistically significant differences between treatment groups in any primary or secondary efficacy variables were demonstrated in any trial. These results suggest that adding the NMDA antagonist, dextromethorphan, to opioids does not add any clinical benefit.

Effectiveness and safety of new oxycodone/acetaminophen formulations with reduced acetaminophen for the treatment of low back pain.

OBJECTIVE: To evaluate the analgesic effectiveness/safety of the new oxycodone 7.5- and 10-mg/acetaminophen 325-mg (Percocet) formulations in patients with low back pain (LBP) suboptimally responsive to nonsteroidal anti-inflammatory drugs, muscle relaxants, tramadol, cyclo-oxygenase-2 inhibitors, and/or prn opioids. DESIGN: Prospective, open-label, nonrandomized, 4-week trial. SETTING: Multicenter. PATIENTS: Thirty-three men and women (mean age: 52.2 years) with LBP (mean duration: 10.9 years). INTERVENTIONS: All prior analgesics were discontinued, and oxycodone/acetaminophen was dosed three times a day (TID), titrated to clinically meaningful pain relief. Initial oxycodone/acetaminophen dose: 2.5/325 mg TID; maximum: 20/650 mg TID. OUTCOME MEASURES: Effectiveness: Brief Pain Inventory (BPI) and Neuropathic Pain Scale 4 score (sharp, hot, dull, and deep pain). Quality of life: BPI and North American Spine Society Lumbar Spine questionnaire. SAFETY: Adverse events, physical/neurologic examinations, vital signs, and clinical laboratory tests. RESULTS: In all, 28 of 33 patients (85%) completed the study; discontinuations were for adverse events (N=3), patient choice (N=1), and lack of effectiveness (N =1). The mean oxycodone/acetaminophen dose at the end of treatment was 8.2/325 mg TID. After 4 weeks, treatment significantly reduced BPI pain intensity and improved pain relief (P < 0.0005), improved Neuropathic Pain Scale 4 score (P =0.007), reduced pain interference with quality of life (P < 0.0004), and reduced disability (P < 0.0001). Treatment was found to be safe and well tolerated. Adverse events were those most commonly expected from an opioid, and most were of mild-to-moderate intensity. CONCLUSIONS: The primary purpose of this study was to preliminarily test the effectiveness of the new formulations of oxycodone/acetaminophen with reduced acetaminophen in the clinical practice setting. The results from this trial suggest that these formulations are effective in the treatment of moderate-to-severe chronic LBP. Most patients (67%) reported significant pain relief/tolerable side effects with a TID dosing frequency or less (mean: 3.04 doses/day), suggesting chronic pain patients can experience meaningful pain relief with around-the-clock dosing of oxycodone/acetaminophen and minimal risk of hepatotoxicity. Further long-term, controlled studies of the efficacy/safety of the new formulations of oxycodone/acetaminophen in LBP are warranted to fully characterize efficacy in this patient population and corroborate the findings from our study.

Randomized, double-blind, placebo-controlled comparison of the analgesic efficacy of oxycodone 10 mg/acetaminophen 325 mg versus controlled-release oxycodone 20 mg in postsurgical pain.

This randomized, controlled trial compared the analgesic efficacy and safety of the new oxycodone 10-mg/acetaminophen 325-mg formulation (Percocet) for the treatment of acute pain following oral surgery with double the dose of oxycodone alone (controlled-release [CR] oxycodone 20 mg [OxyContin]). A total of 150 male and female patients with > or = 2 full or partial bone-impacted mandibular molars, at least moderate persistent pain, and moderate trauma received a single dose of combination agent, CR oxycodone, or placebo following oral surgery and rated pain intensity and pain relief over the next 6 hours. The intent-to-treat population comprised 141 patients (55 on combination agent, 56 on oxycodone, and 30 on placebo). Combination agent and CR oxycodone were significantly superior to placebo for all efficacy measures. Combination agent was statistically superior to CR oxycodone in four of five outcome measures of pain intensity and pain relief (PPID, PPAR, SPID, and SPRID). It also provided a faster onset and 24% reduction in the number of patients reporting treatment-related adverse events compared with twice the dose of opioid alone. This new formulation offers the combination of two analgesic drugs with complementary mechanisms of action, which results in enhanced analgesia, an "opioid-sparing" effect, and an improved side effect and safety profile.