Controlled-release codeine is equivalent to acetaminophen plus codeine for post-cholecystectomy analgesia

PURPOSE: Following ambulatory surgery, long-acting analgesics may provide advantages over short-acting analgesics. This study compared controlled-release codeine (CC) and acetaminophen plus codeine (A/C; 300 mg/30 mg) for pain control in the 48-hr period following laparoscopic cholecystectomy. METHODS: Eligible patients were randomized to CC or A/C in a double-blind, double-dummy parallel group study. Unrelieved pain in hospital was treated with fentanyl i.v. bolus. Pain [100 mm visual analogue scale (VAS)] was assessed before the first dose of medication; at 0.5, one, two, three, and four hours post-dose; at discharge; and three times a day for 48 hr. Adverse events were recorded and measures of patient satisfaction were assessed at the end of the study. RESULTS: Eighty-four patients were enrolled in the study; 42 patients in each group. There were no statistically significant differences between CC and A/C treatment. Mean VAS baseline pain was similar in both groups (P = 0.49) and there was no significant difference in the time to onset of analgesia (P = 0.17). At 0.5 hr, the mean VAS pain score was significantly reduced from baseline in both groups (P = 0.0001). The VAS pain scores at discharge were reduced 59% and 56% from baseline, respectively (P = 0.61). There was no difference between treatments in the incidence of adverse events and patients reported similar levels of satisfaction. CONCLUSIONS: Controlled-release codeine provides an equivalent onset of analgesia, reduction in postoperative pain, and level of patient satisfaction, to acetaminophen plus codeine, over 48 hr following cholecystectomy, with the advantage of less frequent dosing.     

Therapeutic option for managing lung injury induced by infrarenal aortic cross-clamping

Background

Operations on the infrarenal aorta can cause ischemic-reperfusion (IR) injury in local tissues, which could result in remote organ (e.g., lung) damage. Treatment of such injuries remains an unresolved problem.

Objectives

Our aim was to reduce remote lung damage after lower limb IR by means of postconditioning.

Materials and methods

Male Wistar rats were divided into three groups: Sham-operated, IR, and Postconditioned (PostC). In the latter two groups rats underwent 180 min of exclusion of the infrarenal aorta. The reperfusion time was 4 h. Serum-free radical levels, tumor necrosis factor-α and interleukin-6 concentrations, histologic changes in the lung, wet/dry-ratio, myeloperoxidase activity, heat shock protein 72 level and blood gas changes were investigated.

Results

Postconditioning reduced histological damage in the lung (P < 0.05). Free radical levels and tumor necrosis factor-α concentrations were significantly lower in the PostC group than in the IR group (P < 0.05 and P < 0.01, respectively). Interleukin-6 concentrations did not significantly differ in the PostC group. Compared with the IR group, lung myeloperoxidase activity was lower in the PostC group. Decreased pulmonary heat shock protein 72 level was observed in the PostC group compared with the IR group and the wet/dry-ratio was also significantly lower in the PostC group (P < 0.05). A noticeably higher arterial pO₂ level was manifest in the PostC group after 2 and 4 h of reperfusion (P < 0.05).

Conclusions

Postconditioning reduced lung damage under experimental conditions, in the early period of reperfusion after lower limb IR injury.     

Cytotoxic effects of dihydroorotase inhibitors upon human CCRF-CEM leukemia

6-L-Thiodihydroorotate (TDHO) and 2-oxo-1,2,3,6-tetrahydropyrimidine-4,6-dicarboxylate (HDDP) are potent inhibitors of mammalian dihydroorotase in vitro (R. I. Christopherson, K. J. Schmalzl, E. Szabados, R. J. Goodridge, M. C. Harsanyi, M. E. Sant, E. M. Algar, J. E. Anderson, A. Armstrong, S. C. Sharma, W. A. Bubb, and S. D. Lyons, Biochemistry, 28: 463-470, 1989). Using human CCRF-CEM leukemia cells growing in culture, TDHO and HDDP as the free acids have 50% inhibitory concentration (IC50) values of 32 microM and greater than 1000 microM, respectively, whereas for TDHO methyl ester, the IC50 value is 25 microM, and for HDDP dimethyl ester, the IC50 value is 21 microM. These IC50 values were not affected by addition of dihydroorotate, uridine, or deoxycytidine to the culture medium. TDHO methyl ester (25 microM) had only slight inhibitory effects upon the dihydroorotase reaction of de novo pyrimidine biosynthesis in growing leukemia cells, cells arrested in G2 + M phases of the cell cycle. At 250 microM TDHO methyl ester, analysis of cell extracts by high-performance liquid chromatography showed that after 4 h carbamyl aspartate had accumulated from undetectable levels to 760 microM, whereas UTP decreased from 580 to 110 microM and CTP from 350 to 86 microM, indicating inhibition of dihydroorotase in growing leukemia cells. IMP accumulated from 63 to 350 microM, total guanylates increased while adenylates decreased, and the adenylate energy charge decreased from 0.91 to 0.69 after 4 h. The cellular concentration of 5-phosphoribosyl 1-pyrophosphate increased from 180 to 290 microM due to sparing from pyrimidine nucleotide biosynthesis resulting in complementary stimulation of the de novo purine pathway. HDDP dimethyl ester at concentrations of up to 250 microM had no discernable effect upon pyrimidine or purine nucleotide biosynthesis. At 25 microM HDDP-dimethyl ester, cells arrested in G2 + M phases initially, with accumulation of cells in G1/G0 at later times. These data suggest that the primary mechanisms of growth inhibition for TDHO and HDDP involve inhibition of cell cycle progression from late G2 or M phase to G1 phase and that blockade of the pyrimidine pathway by TDHO is a secondary effect found at higher concentrations.     

Randomized evaluation of controlled-release codeine and placebo in chronic cancer pain

Codeine is widely used in combination with acetaminophen and aspirin for the management of mild to moderate pain. However, there are few controlled clinical trials of single-entity codeine in chronic cancer pain. The purpose of this study was to evaluate the clinical efficacy and safety of controlled-release codeine given every 12 hr in patients with cancer pain. Thirty-five patients with chronic cancer pain were randomized in a double-blind crossover study to controlled-release (CR) codeine or placebo, for 7 days each. Pain intensity was assessed at 0800 hr and 2000 hr using a visual analogue scale (VAS) and a five-point categorical scale, and the use of “rescue” acetaminophen-plus-codeine (300 mg/30 mg every 4 hr as needed) was recorded. Thirty patients completed the study (17 male, 13 female; mean age, 64.4 ± 9.8 years) with a mean daily CR codeine dose of 277 ± 77 mg (range, 200–400 mg). CR codeine treatment resulted in significantly lower overall VAS pain intensity scores (22 ± 0.8 mm versus 36 ± 20 mm, P = 0.0001), categorical pain intensity scores (1.2 ± 0.8 versus 1.8 ± 0.8, P = 0.0001), and pain scores when assessed by day of treatment and by time of day. Daily “rescue” analgesic consumption was significantly lower on CR codeine, compared to placebo treatment (2.2 ± 2.3 versus 4.6 ± 2.8 tablets per day, P = 0.0001). Both patients and investigators preferred CR codeine to placebo (80% versus 3%, P = 0.0014 and 73% versus 7%, P = 0.0160, respectively). These data indicate that CR codeine, given every 12 hr results in significant reductions in pain intensity and the use of “rescue” acetaminophen-plus-codeine in patients with cancer pain. CR codeine provides the benefits of a flexible single entity codeine formulation and the convenience of 12-hr duration of action, which allows patients uninterrupted sleep and improved compliance.