Sleepiness, sleep-disordered breathing, and accident risk factors in commercial vehicle drivers

Sleep-disordered breathing and excessive sleepiness may be more common in commercial vehicle drivers than in the general population. The relative importance of factors causing excessive sleepiness and accidents in this population remains unclear. We measured the prevalence of excessive sleepiness and sleep-disordered breathing and assessed accident risk factors in 2,342 respondents to a questionnaire distributed to a random sample of 3,268 Australian commercial vehicle drivers and another 161 drivers among 244 invited to undergo polysomnography. More than half (59.6%) of drivers had sleep-disordered breathing and 15.8% had obstructive sleep apnea syndrome. Twenty-four percent of drivers had excessive sleepiness. Increasing sleepiness was related to an increased accident risk. The sleepiest 5% of drivers on the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire had an in-creased risk of an accident (odds ratio [OR] 1.91, p = 0.02 and OR 2.23, p < 0.01, respectively) and multiple accidents (OR 2.67, p < 0.01 and OR 2.39, p = 0.01), adjusted for established risk factors. There was an increased accident risk with narcotic analgesic use (OR 2.40, p < 0.01) and antihistamine use (OR 3.44, p = 0.04). Chronic excessive sleepiness and sleep-disordered breathing are common in Australian commercial vehicle drivers. Accident risk was related to increasing chronic sleepiness and antihistamine and narcotic analgesic use.

Paracetamol [acetaminophen]-induced gastrotoxicity: Revealed by induced hyperacidity in combination with acute or chronic inflammation

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-β-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Regional differences in the in vitro penetration of hydrocortisone through equine skin

Little is known about the transdermal penetration of hydrocortisone in the horse and, although commercial formulations containing hydrocortisone are registered for topical use in the horse, there have been no studies investigating the movement of this glucocorticoid through different regions of equine skin. Skin was harvested from the thorax, groin and leg (dorsal metacarpal) regions of five Thoroughbred geldings and frozen (-20 degrees C) until required. Defrosted skin was placed in Franz-type diffusion cells and the amount of radiolabelled (H-3) hydrocortisone, in a saturated solution of unlabelled hydrocortisone in 50% ethanol (w/w), which penetrated through and remained within skin samples was measured over 24 h. Significantly higher (P < 0.001) maximum flux (J(max); mol/cm(2)/h) was measured when hydrocortisone was applied to skin from the leg, compared to thorax and groin, although significantly less hydrocortisone (P < 0.001) was retained within skin from the leg at 24 h. Topical application of hydrocortisone in a vehicle containing ethanol would penetrate faster through leg skin from the lower leg when compared with the thorax or groin, which depending on cutaneous blood flow, may result in higher systemic drug concentrations or greater efficiency in treating local inflamed tissue.

WOMAC 20, 50, 70 response levels in patients treated with Rofecoxib for osteoarthritis

Aim of study: The goal of this post-hoc analysis was to examine the difference between treatment groups when varying the target response level from at least a 20% improvement from baseline, to at least 50% and 70% improvements in Phase III studies of rofecoxib in patients with osteoarthritis. Methods: The analysis focused on results from two 6-week, placebo-controlled, ibuprofen-comparator, Phase III osteoarthritis studies. These studies employed a flare design requiring a minimum level of symptoms at entry following discontinuation of prior analgesics. Two definitions of ‘‘patient improved’’ from baseline were used: (1) WOMAC-P: a reduction in the WOMAC pain score and (2) WOMAC-PFS: a reduction in the WOMAC pain score and either a reduction in the WOMAC stiffness or function score. The improvement target was increased from 20% to 50% to 70%, relative to baseline, to investigate how the increase affects the ability to detect the differences between treatment groups. Analyses were conducted on the average and last of all measurements collected during a 6-week treatment period. Results: In the ibuprofen-comparator studies, 1545 patients were randomized to placebo, rofecoxib 12.5 mg once daily, rofecoxib 25 mg once daily, and ibuprofen 800 mg three times daily in a 1:3:3:3 ratio. The percentages of patients who met the improvement targets decrease as the target increases from 20% to 50% to 70%. There were meaningful differences between the active treatment and placebo that were inversely related to the improvement target. For example, there was a 31 (P ! 0.001), 21 (P ! 0.001), and 12 (P ! 0.001) percentage-point difference between rofecoxib 25 mg and placebo for the 20%, 50%, and 70% targets for WOMAC-P. For WOMAC-PFS, the differences between rofecoxib 25 mg and placebo were 33 (P ! 0.001), 18 (P ! 0.001), and 9 (P ! 0.01) percentage points for the 20%, 50%, and 70% improvement targets. Conclusions: Meaningful differences between active treatments and placebo were detected at all three response levels associated with the WOMAC-P and WOMAC-PFS endpoints. The differences between groups were more dramatic at the 20% and 50% response levels. The WOMAC (20,50,70)-P and WOMAC (20,50,70)-PFS endpoints further confirm, at an individual patient level, the clinical benefit of rofecoxib in the treatment of osteoarthritis that was previously reported as a difference in means.

Prevalence of patient with low intensity pain symptom severity states during treatment with Rofecoxib and Ibuprofen for osteoarthritis

Aim of study: To examine the prevalence of low intensity symptom severity states in patients taking placebo, rofecoxib 12.5 mg once daily, rofecoxib 25 mg once daily, or ibuprofen 800 mg three times daily using a post-hoc definition of low pain intensity states (BLISS Index) based on the WOMAC Index. Methods: Two 6-week, double-blind, parallel-group, placebocontrolled, ibuprofen-comparator studies were conducted to measure the efficacy of rofecoxib in patients with knee or hip osteoarthritis. These studies employed a flare design requiring a minimum level of symptoms at entry following discontinuation of prior analgesics. The WOMAC Pain subscale (100 mm visual analog scale) was used as the pain measure. In separate analyses, WOMAC pain subscale scores from each patient were compared to five thresholds of pain:%5 mm, %10 mm, %15 mm, %20 mm, and %25 mm. The percent of patients with BLISS states (1) on average over 6 weeks, (2) at any time during the study, and (3) at week 6 was computed for each treatment group and threshold. The treatment group percentages were compared using Fisher’s exact test. Results: During the study, patients received placebo (N Z 143), rofecoxib 12.5 mg (N Z 461), rofecoxib 25 mg (N Z 459), or ibuprofen (N Z 465). For each pain threshold and treatment group, the percent of patients with BLISS states at any time (e.g., 50% for rofecoxib 25 mg) exceeded the percentage at week 6 (e.g., 40% for rofecoxib 25 mg) which, in turn, exceeded the percentage with BLISS states on average (e.g., 32% for rofecoxib 25 mg). The percentages of patients in the active treatment groups with BLISS states on average were significantly different than observed in the placebo group at the%15 mm threshold (8–11% points vs placebo, P ! 0.01), %20 mm level (10–15% points, P ! 0.01), and %25 mm level (14–17% points, P ! 0.001). Significant differences between the active treatments and placebo were also observed at the %10 mm threshold (8–9% points, P ! 0.05) for measurements at week 6 and at the%10 (12–14% points, P !0.001) and%5 mm thresholds (5–7% points, P ! 0.05) for patients with BLISS states at any time. Conclusion: These measures of BLISS states differentiate all three active treatment groups from placebo and further confirm, at an individual patient level, the clinical benefit of rofecoxib in the treatment of osteoarthritis. Furthermore, they provide information on the prevalence of patients achieving low (%15 mm, %20 mm, %25 mm), and very low (%5 mm, %10 mm) pain severity states.

Opioids and NMDA receptors: Neuro-excitation and abnormal pain behaviours

In the clinical setting, chronic administration of high doses of systemic morphine may result in neuro-excitatory behaviours such as myoclonus and allodynia in some patients. Additionally, high doses of m-opioid agonists such as morphine administered chronically by the intrathecal route in both rats and humans, as well as DAMGO in rats, have been reported to produce neuro-excitatory behaviours. However, more recently, it has begun to be appreciated that even at normal analgesic doses, opioids such as morphine are capable not only of activating pain inhibitory systems (analgesia/antinociception), but they also activate pain facilitatory systems such that post-opioid allodynia/hyperalgesia may be evident after cessation of opioid treatment. Whilst it is well documented that opioid receptors mediate the inhibitory effects of opioid analgesics, the excitatory and pro-nociceptive effects of opioids appear to involve indirect activation of N-methyl-D-aspartate (NMDA) receptors, such that the extent of pain relief produced may be the net effect of these two opposing actions. Apart from the NMDA-nitric oxide (NO) pro-nociceptive signaling cascade, considerable evidence also implicates dynorphin A as well as the endogenous anti-opioid peptides cholecystokinin (CCK), neuropeptide FF (NPFF) and orphanin FQ/nociceptin, in mediating opioid-induced neuro-excitation and abnormal pain behaviours. Apart from the neuro-excitatory effects that may be produced by the parent opioid, systemic administration of some opioid analgesics such as morphine and hydromorphone in rats and humans results in their rapid conversion to 3-glucuronide metabolites that also contribute significantly to the neuro-excitatory and abnormal pain behaviours produced