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.

Fluxes of peptide and of free AA in plasma and blood cells were quantified across the gastrointestinal tract and liver of six growing Holstein steers (136 kg). Calves were fed hourly, and blood was obtained simultaneously from the aorta, protal vein, and hepatic vein cannulas on 1 d between d 9 and 12 postsurgery and again following 72 h without feed. Blood flow was determined by p-aminohippuric acid infusion. Peptide AA accounted for the greatest concentration of AA in arterial blood of all calves. There was a net flux of free AA in plasma across the tract, and lack of feed reduced the magnitude of the flux. Glutamine and glutamate were the only free AA in plasma with a negative flux across the tract in fed calves. Alanine accounted for over 14% of the total tract flux of free AA in plasma of fed calves. Hepatic removal of free AA in plasma increased after feed deprivation. Flux of free AA in blood cells was negative across the tract of fed calves but to a lesser extent in unfed calves. The hepatic flux of free AA in blood cells offset the negative tract flux, thus resulting in no net splanchnic output of free AA in blood cells by calves. Peptide AA flux across the tract was 2.5 times (fed) to 7.2 times (unfed) greater than free AA flux. Net splanchnic output of peptide AA was 7 times the magnitude (738 vs. 92 g/d) of the net splanchnic output of free AA in plasma. Peptides with molecular mass from 500 to 1500 Da accounted for the largest flux of peptide AA across the tract. Quantitatively, peptides appeared to be involved extensively in interorgan transport and may be a substantial form of absorbed AA in calves.

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.

Ninety normal healthy adults were given 0, 8, 20 or 32 g/d olestra for 8 wk as part of a diet that provided 1 +/- 0.2 of the recommended dietary allowance (RDA) of vitamins A, D, E and K, folate zinc, calcium and iron. In addition, a 20 microg/d supplement of vitamin D was supplied. The diet provided 15% of energy from protein, 35% from fat and 55% from carbohydrate. The purpose of the study was to determine the dose response of olestra on vitamins D, E and K, carotenoids, vitamin B12, folate and zinc. Circulating concentrations of retinol, carotenoids, tocopherols, 25-hydroxy- and 1,25-dihydroxyvitamin D metabolites, phylloquinone, des-gamma-carboxyprothrombin, prothrombin, folate and hematological parameters were measured biweekly, as were urine concentrations of zinc and gamma-carboxyglutamic acid (Gla). Clinical chemistry, urinalysis and vitamin B12 absorption were measured at wk 0 and 8. Olestra reduced serum concentrations of carotenoids, alpha-tocopherol, 25-hydroxyergocalciferol and phylloquinone in a dose-responsive manner. Olestra did not affect Gla excretion, plasma des-gamma-carboxyprothrombin or prothrombin concentrations, prothrombin time, vitamin B12 absorption, overall vitamin D status or the status of folate or zinc. Laboratory evaluations showed no health-related effects of olestra. Subjects in all groups reported common gastrointestinal symptoms such as loose stools, fecal urgency and flatulence, which were transient and generally mild to moderate in severity. These symptoms did not affect protocol compliance or the ability to measure the potential for olestra to affect nutrient availability.

A B S T R A C TObjective. 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.