Treatment of sleep disturbance in alcohol recovery: a national survey of addiction medicine physicians

Sleep disturbance is common among patients in recovery from alcoholism and can precipitate relapse. Though sleep complaints are commonly managed with medication, little is known about their management among recovering alcoholic patients. We performed a postal survey of a self-weighted, random systematic sample of 503 members of the American Society of Addiction Medicine (ASAM) to examine addiction medicine physicians' medical management of sleep disturbance among patients in early recovery from alcoholism. After 3 mailings, 311 (62%) responded. Of responents, 64% have offered pharmacological treatment to an insomniac, alcoholic patient in the first 3 months after detoxification, but only 22% offered medication to more than half of such patients. Trazodone was the preferred therapy, chosen first by 38% of respondents, followed by other sedating antidepressants (12%), and antihistamines (12%). The mean duration of therapy for trazodone and other sedating antidepressants exceeded one month. Experts in addiction medicine appear reluctant to prescribe medication to sleep-disturbed patients in early recovery from alcoholism. When they do prescribe, trazodone, other sedating antidepressants and antihistamines are favored, despite limited evidence for or against this indication. Although the treatment of disordered sleep among alcoholic patients in early recovery may have merit to prevent relapse, controlled studies of these sleep agents are needed.     

A new model for drug discovery--meeting our societal obligation

The development of new models that will enable and encourage drug discovery in disease areas that are neglected by the industry is urgently needed. Here, one model is described that has been established to find treatments for neurodegenerative diseases.     

Paroxetine in the treatment of post-traumatic stress disorder: pooled analysis of placebo-controlled studies

Post-traumatic stress disorder (PTSD) is increasingly understood to be a medical disorder characterised by particular psychobiological dysfunctions that respond to specific treatments. Paroxetine is a selective serotonin re-uptake inhibitor that has been found effective in the treatment of major depression as well as a range of anxiety disorders. This paper reviews data on the use of paroxetine for the treatment of adult PTSD. There have been three 12-week, placebo-controlled studies of paroxetine in PTSD. As these followed a partly similar design, a pooled analysis of the studies is possible and is reported here. Paroxetine is effective in the short-term treatment of PTSD, resulting in significantly better response and remission rates than placebo, improving sleep disturbance and reducing each of the symptom clusters of PTSD, as well as the disability associated with this condition. The medication is effective in both male and female PTSD patients and whether or not there are comorbid disorders such as depression.     

Population health metrics: crucial inputs to the development of evidence for health policy

Valid, reliable and comparable measures of the health states of individuals and of the health status of populations are critical components of the evidence base for health policy. We need to develop population health measurement strategies that coherently address the relationships between epidemiological measures (such as risk exposures, incidence, and mortality rates) and multi-domain measures of population health status, while ensuring validity and cross-population comparability.     

Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons

Opioids mediate their analgesic effects by activating mu-opioid receptors (MOR) not only within the central nervous system but also on peripheral sensory neurons. The peripheral analgesic effects of opioids are best described under inflammatory conditions (e.g., arthritis). The present study investigated the effects of inflammation on MOR binding and G-protein coupling of full versus partial MOR agonists in dorsal root ganglia (DRG) of primary afferent neurons. Our results show that Freund's complete adjuvant (FCA) unilateral hindpaw inflammation induces a significant up-regulation of MOR binding sites (25 to 47 fmol/mg of protein) on DRG membranes without affecting the affinity of either full or partial MOR agonists. In our immunohistochemical studies, the number of MOR-immunoreactive neurons consistently increased. This increase was mostly caused by small-diameter nociceptive DRG neurons. The full agonist DAMGO induced MOR G-protein coupling in DRG of animals without FCA inflammation (EC50 = 56 nM; relative Emax = 100%). FCA inflammation resulted in significant increases in DAMGO-induced MOR G-protein coupling (EC50 = 29 nM; relative Emax = 145%). The partial agonist buprenorphine hydrochloride (BUP) showed no detectable G-protein coupling in DRG of animals without FCA inflammation; however, partial agonist activity of BUP-induced MOR G-protein coupling was detectable in animals with FCA inflammation (EC50 = 1.6 nM; relative Emax = 82%). In behavioral studies, administration of BUP produced significant antinociception only in inflamed but not in noninflamed paws. These findings show that inflammation causes changes in MOR binding and G-protein coupling in primary afferent neurons. They further underscore the important differences in clinical studies testing peripherally active opioids in inflammatory painful conditions.     

Reboxetine and citalopram in panic disorder: a single-blind,cross-over,flexible-dose pilot study

Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder. The advent of selective serotonin (5-HT) reuptake inhibitors (SSRIs) (e.g. citalopram) and, more recently, selective noradrenergic (NA) reuptake inhibitors (NRIs) (e.g. reboxetine) has provided potentially important avenues of treatment for the disorder. To date, the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved. Nineteen patients with panic disorder were randomized in a single-blind, cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug. At week 18, seven of 13 patients (54%) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram (82%). Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy. However, citalopram demonstrated superior efficacy in treating depressive symptoms. One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram. Although SSRIs are viewed as a first-line treatment for panic disorder, these results suggest that a NA agent such as reboxetine may also have a role. These data also suggest an advantage for citalopram in treating comorbid depressive symptoms, although some patients may respond preferentially to an SSRI and other patients to an NRI.     

Antibiotic prophylaxis in total hip arthroplasty: effects of antibiotic prophylaxis systemically and in bone cement on the revision rate of 22,170 primary hip replacements followed 0-14 years in the Norwegian Arthroplasty Register

We studied the effects of antibiotic prophylaxis, systemically and in bone cement, on the revision rate of cemented total hip arthroplasties (THAs) in data from the Norwegian Arthroplasty Register during the period 1987-2001. To have comparable groups, only THAs performed because of primary osteoarthritis, using cemented implants with documented good results, and high-viscosity cement were included. If systemic antibiotic prophylaxis had been given, only operations with cephalosporin or penicillin were selected. Cox-estimated survival relative revision risks (RR) are presented with adjustment for differences among groups in gender, age, cement brand, type of systemic antibiotic prophylaxis, type of prosthesis, type of operating room, and duration of the operation. Of 22,170 THAs studied, 696 THAs (3.1%) were revised, 440 (2.0%) for aseptic loosening and 102 (0.5%) for deep infection. We found the lowest risk of revision when the antibiotic prophylaxis was given both systemically and in the cement (15,676 THAs). Compared to this combined regime, patients who received antibiotic prophylaxis only systemically (5,960 THAs) had a 1.4 times higher revision rate with all reasons for revision as endpoint (p = 0.001), 1.3 times higher with aseptic loosening (p = 0.02) and 1.8 times higher with infection as the endpoint (p = 0.01). With the combined antibiotic regime, the results were better if antibiotics were given 4 times on the day of surgery (2,194 THAs), as compared to once (1,424 THAs) (p < 0.001), twice (2,680 THAs) (p < 0.001), or 3 times (5,522 THAs) (p = 0.02). Those who received systemic prophylaxis a single day 1, 2 or 3 times, as compared to 4 times, had a revision rate 1.8-3.5 times higher with all reasons for revision as endpoint, 1.5-3.1 times higher with aseptic loosening, and 2.7-6.8 times higher with infection. When we compared systemic prophylaxis 4 times in 1 day, no further improvement resulted in those given systemic prophylaxis for 2 days (1,928 THAs) or 3 days (717 THAs). In a subset of data including only the Charnley prosthesis, we obtained similar results. This observational study shows that the best results were recorded when antibiotic prophylaxis was given both systemically and in the bone cement, and if the systemic antibiotic was given 4 times on the day of surgery.     

Heparin-coated circuits and reduced systemic anticoagulation applied to 2500 consecutive first-time coronary artery bypass grafting procedures

BACKGROUND: In contrast to the widespread popularity of off-pump techniques for coronary artery bypass grafting, our institution has chosen a different strategy, emphasizing improvements in the technology for extracorporeal circulation, as well as simplifying surgical and clinical management. The clinical short-term results of this approach were analyzed. METHODS: The on-pump strategy includes routine use of heparin-coated circuits combined with low systemic heparinization (activated coagulation time of more than 250 seconds), intention of total revascularization within limited ischemic times and pump times, minimal use of blood transfusions, early extubation, and rapid postoperative recovery. The data from the first 2,500 consecutive first-time coronary artery bypass grafting patients (January 1998 to February 2002) treated with this protocol were retrospectively analyzed. RESULTS: There were 487 female (median age 68 years) and 2013 male (median age 64 years) patients. A median of four (one to nine) (mean 4.5 +/- 1.2) distal anastomoses were created, and the median aortic cross-clamp time and pump time were 34 and 54 minutes, respectively. At least one internal mammary artery was used in 99.7% of the patients. Blood or bank blood products were given to 118 patients (4.7%). Median extubation time was 1.5 hours. The stroke rate was 0.8%, transient neurologic deficits occurred in 0.6% of the patients, and the incidence of perioperative myocardial infarction was 1.1%. By the fifth day, 91% of the patients were ready for discharge. Seven patients (0.28%) died during their hospital stay. CONCLUSIONS: Coronary artery bypass grafting with heparin-coated cardiopulmonary bypass circuits and reduced systemic anticoagulation resulted in excellent clinical results, with minimal blood transfusions and rapid postoperative mobilization. The high number of grafted coronary arteries indicates complete revascularization in most patients, which is known to be a significant predictor of long-term event-free survival.     

Metabolic evaluation of 94 patients 5 to 16 years after ileocecal pouch (Mainz pouch 1) continent urinary diversion

PURPOSE In continent urinary diversion metabolic disturbances may be encountered in long-term followup. We evaluated metabolic consequences in patients with a minimum followup of 5 years after Mainz pouch 1 urinary diversion. MATERIALS AND METHODS: At our institution continent urinary diversion using the ileocecal segment was performed between 1983 and 1995 in 458 patients. A total of 94 patients with an ileocecal pouch for a minimum of 5 years were reevaluated for metabolic changes. Median followup was 9.0 years. Routine laboratory parameters, blood gas analysis, vitamin B12, vitamin D25, cross-laps, bone specific alkaline phosphatase, osteocalcin and propeptide of type I collagen were obtained. Bone density was measured in 18 patients. Vitamin B12 changes could be followed longitudinally in 24 patients. RESULTS: Medians of all parameters were in normal ranges. Clinical examinations revealed no signs of megaloblastic anemia, funicular myelosis or osteoporosis. There was no significant decrease of vitamin B12 in the long run. After followup examination we recommended vitamin B12 supplementation in 32% of patients because levels were in the lower normal range or below. A total of 37% of patients continue to take Na+/K+-citrate for prevention of metabolic acidosis. CONCLUSIONS: Patients with an ileocecal pouch and a followup of more than 5 years did not present with clinical symptoms caused by metabolic disturbances. Nevertheless, systematic followup of blood gases in particular and alkali supplementation may have prevented bone demineralization. Followup of vitamin B12 is of concern because about a third of these patients need supplementation.