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Fluoroquinolone antibiotics are associated with rare, but severe adverse events. They are frequently used for the treatment of acute exacerbations of COPD (AECOPD). While their effectiveness in severe exacerbations requiring hospitalisation has been well documented, the potential benefit in the ambulatory setting is less clear, especially in uncomplicated patients with COPD. We carried out a retrospective cohort study using health care databases from six Canadian provinces in subjects visiting their physician for uncomplicated COPD. Subjects dispensed either a quinolone or other antibiotics were compared using inverse probability of treatment weights with high dimensional propensity scores on 30-day outcomes, including repeat visits, hospitalisation for AECOPD and subsequent antibiotic prescription. Results from each province were combined by random effects meta-analysis. We identified 286,866 AECOPD events among 203,642 unique individuals. The frequency of fluoroquinolone use, mostly levofloxacin and moxifloxacin, varied by province and ranged from 8% to 32% of AECOPD antibiotic prescriptions. The risk of a repeat ambulatory care visit was increased among patients who were dispensed a fluoroquinolone compared with other antibiotics (OR 1.32, 95% CI 1.27-1.36). The risk of a hospitalisation for AECOPD was also higher with fluoroquinolones (OR 1.52, 95% CI 1.33-1.74). There was no difference in subsequent antibiotic prescriptions (OR 1.00, 95% CI 0.94-1.07). There is no apparent benefit in short-term outcomes with fluoroquinolones as compared to other antibiotics for the ambulatory treatment of AECOPD in uncomplicated patients. These findings support current recommendations that fluoroquinolones be reserved for AECOPD in patients with recurrent exacerbations, significant co-morbidity or requiring hospitalisation.

Isotretinoin, a teratogen, is widely used to treat cystic acne. Although the risks of pregnancy during isotretinoin therapy are well recognized, there are doubts about the level of adherence with the pregnancy prevention program in Canada. Our objective was to evaluate the effectiveness of the Canadian pregnancy prevention program in 4 provinces: British Columbia, Saskatchewan, Manitoba and Ontario. Using administrative data, we identified 4 historical cohorts of female users of isotretinoin (aged 12–48 yr) for the period 1996 to 2011. We defined pregnancy using International Statistical Classification of Diseases and billing codes. One definition included only cases with documented pregnancy outcomes (high-specificity definition); the other definition also included individuals recorded as receiving prenatal care (high-sensitivity definition). We studied new courses of isotretinoin and detected pregnancies in 2 time windows: during isotretinoin treatment only and up to 42 weeks after treatment. Live births were followed for 1 year to identify congenital malformations. A total of 59 271 female patients received 102 308 courses of isotretinoin. Between 24.3% and 32.9% of participants received prescriptions for oral contraceptives while they were taking isotretinoin, compared with 28.3% to 35.9% in the 12 months before isotretinoin was started. According to the high-specificity definition of pregnancy, there were 186 pregnancies during isotretinoin treatment (3.1/1000 isotretinoin users), compared with 367 (6.2/1000 users) according to the high-sensitivity definition. By 42 weeks after treatment, there were 1473 pregnancies (24.9/1000 users), according to the high-specificity definition. Of these, 1331 (90.4%) terminated spontaneously or were terminated by medical intervention. Among the 118 live births were 11 (9.3%) cases of congenital malformation. Pregnancy rates during isotretinoin treatment remained constant between 1996 and 2011. Adherence to the isotretinoin pregnancy prevention program in Canada was poor during the 15-year period of this study.

The aim of this study was to evaluate the first initiation, sequence of addition, and appropriate prescribing of COPD medications in Manitoba, Canada. A population-based cohort study of COPD medication use was conducted using administrative health care data (1997-2012). Those aged ≥35 years with COPD based on three or more COPD-related outpatient visits over a rolling 24-month window or at least one COPD-related hospitalization were included. The first medication(s) dispensed on or after the date of COPD diagnosis were determined based on pharmacy claims. The next medication(s) in sequence were determined to be additions or switches to the previous regimen. Evaluation of guideline-based appropriateness to receive inhaled corticosteroids (ICS) was based on exacerbation history and past medication use. Of 13,369 patients dispensed COPD medications after diagnosis, 66.0% were dispensed short-acting bronchodilators as first medications. Although long-acting bronchodilators alone were uncommonly used as first or subsequent medications, ICS were dispensed as first medications in 28.2% of patients. Over the study period, use of short-acting bronchodilators as first medications declined from 70.6% to 59.4% ( <0.0001), whereas the use of ICS as a first medication increased from 23.5% to 34.4% ( <0.0001). Dispensation of an ICS plus a long-acting β-agonist increased dramatically from 1.2% to 27.3% ( <0.0001). By the end of the study period, the majority of patients (53.3%) were being initiated on two or more medications. Of 5,823 patients dispensed an ICS, 52.4% met Canadian guideline criteria for initiating an ICS, whereas 0.3% met Global Initiative for Chronic Obstructive Lung Disease guideline criteria. The use of first-line medications has declined over time, replaced primarily by combination inhalers prescribed early without prior trials of appropriate next step medications. This, along with an increasingly predominant use of multiple first medications, indicates a significant degree of medication burden in this already complex patient population.

Pain is a main symptom of herpes zoster (HZ), and postherpetic neuralgia (PHN) is a frequent complication occurring in 5% to 15% of cases, causing moderate to severe neuropathic pain. A population-based observational study was conducted to evaluate the treatment patterns and economic burden of prescription drug treatment of HZ and PHN pain in the province of Manitoba (Canada) over a period of 15 years. Administrative health care data, including medical and hospital separation records, were examined to identify episodes of HZ using International Classification of Diseases-9/10 codes between April 1, 1997 and March 31, 2014. Episodes of PHN were identified using medical and prescription claims. Incident use of analgesic, antidepressant, or anticonvulsant drugs was used to determine prescription pain costs. The age-adjusted incidence of HZ increased from 4.7 episodes/1,000 person-years in 1997/98 to 5.7/1,000 person-years in 2013/14. PHN occurred in 9.2% of HZ cases, a rate that did not change over the study period (P=0.57). The annual cost to treat HZ pain rose by 174% from 1997/98, reaching CAD $332,981 in 2011/12, 82.8% (95% confidence interval [CI] 81.2%, 84.3%) of which was related to PHN. The per episode cost of HZ rose by 111% from $31.59 (95% CI $25.35, $37.84) to $66.81 (95% CI $56.84, $76.78) and by 94% for PHN from $292 (95% CI $225, $358) to $566 (95% CI $478, $655). These increases were driven by increasing use of anticonvulsants, primarily gabapentin, which accounted for 57% of the increase in cost. There has been an increase in the incidence of HZ and PHN and in the average cost associated with the prescription treatment of their resultant neuropathic pain. The primary driver of the increased episodic cost is the increased use of gabapentin. These changes have resulted in a substantial increase in the economic burden associated with HZ and PHN.

Kevin J Friesen,1 Jamie Falk,1 Silvia Alessi-Severini,1 Dan Chateau,2 Shawn Bugden1 1College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; 2Department of Community Health Sciences, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB,Canada Background: Pain is a main symptom of herpes zoster (HZ), and postherpetic neuralgia (PHN) is a frequent complication occurring in 5% to 15% of cases, causing moderate to severe neuropathic pain. A population-based observational study was conducted to evaluate the treatment patterns and economic burden of prescription drug treatment of HZ and PHN pain in the province of Manitoba (Canada) over a period of 15 years. Methods: Administrative health care data, including medical and hospital separation records, were examined to identify episodes of HZ using International Classification of Diseases-9/10 codes between April 1, 1997 and March 31, 2014. Episodes of PHN were identified using medical and prescription claims. Incident use of analgesic, antidepressant, or anticonvulsant drugs was used to determine prescription pain costs. Results: The age-adjusted incidence of HZ increased from 4.7 episodes/1,000 person-years in 1997/98 to 5.7/1,000 person-years in 2013/14. PHN occurred in 9.2% of HZ cases, a rate that did not change over the study period (P=0.57). The annual cost to treat HZ pain rose by 174% from 1997/98, reaching CAD332,981 in 2011/12, 82.8% (95% confidence interval [CI] 81.2%, 84.3%) of which was related to PHN. The per episode cost of HZ rose by 111% from 31.59 (95% CI25.35, 37.84) to66.81 (95% CI 56.84,76.78) and by 94% for PHN from 292 (95% CI225, 358) to566 (95% CI 478, 655). These increases were driven by increasing use of anticonvulsants, primarily gabapentin, which accounted for 57% of the increase in cost. Conclusion: There has been an increase in the incidence of HZ and PHN and in the average cost associated with the prescription treatment of their resultant neuropathic pain. The primary driver of the increased episodic cost is the increased use of gabapentin. These changes have resulted in a substantial increase in the economic burden associated with HZ and PHN. Keywords: shingles, cost, economics, neuropathic pain, gabapentin

Meperidine (pethidine) offers little to no therapeutic advantage over other opioids, may be more prone to abuse, and produces a neurotoxic metabolite with a long half-life. The Institute for Safe Medication Practices (ISMP) issued warnings in 2004 and 2005 suggesting that meperidine be avoided, and when used, it should be in limited doses (<600 mg/24 h) and for a limited duration (<48 hours). Hospitals have responded to these warnings, but much less is known about meperidine prescribing in the community setting. This study examined the potential impact of ISMP warnings on the prescribing of meperidine using time series analysis. A population-based longitudinal cross-sectional study was conducted to examine oral meperidine utilization among persons 16 years of age and older in Manitoba, Canada, between April 1, 2001 and March 31, 2014. Amounts of meperidine were expressed using defined daily doses (DDDs), the equivalent of 400 mg of meperidine per day. The number of meperidine prescriptions and users per quarter were determined and analyzed using regression analysis. There were 49,063 prescriptions for 442,641 DDDs of meperidine dispensed to 9,374 distinct users. The number of DDDs of meperidine per 1,000 persons peaked in the second quarter of 2003 at 11.75, and then dropped to a low of 5.36 by 2014. This represented a marked decline in the numbers of users and prescriptions over the study period. The piecewise regression model revealed a significant breakpoint in the last quarter of 2004 (F (3, 48)=337.00, P<0.0001). In contrast to these findings, among the remaining users, there was an increase in the amount of meperidine per prescription (increase of 0.34 DDDs/prescription/year; F(1, 50)=434, P<0.0001, R (2)=0.89) and the amount of meperidine per user (increase of 1.17 DDDs/user/year; F(1, 50)=653.5, P<0.0001, R (2)=0.93). Following the ISMP warnings, meperidine use dramatically declined. Unfortunately, the remaining users of meperidine are using more meperidine and receiving more meperidine in each prescription. This pattern of results suggests that there may be limits to voluntary safety warnings. Policy action such as removal of medication insurance coverage may represent a logical next step to reverse or de-adopt meperidine and further enhance patient safety.

Herpes zoster (HZ) is a common viral disease that produces a painful vesicular rash. Early use of antiviral medications is recommended, as it reduces pain and speeds healing. A population-based observational study was conducted to evaluate the changing burden of HZ in the province of Manitoba (Canada) over a period of 17 years. Administrative health care data including medical and hospital records were examined, and International Classification of Diseases, Ninth Revision, Clinical Modification and International Classification of Diseases, Tenth Revision, Clinical Modification codes were used to identify episodes of HZ between April 1, 1997 and March 31, 2014 in persons aged 20 or over. Annual age-adjusted incidence and hospitalization rates were calculated. Prescription records of HZ-diagnosed persons for acyclovir, valacyclovir, and famciclovir were used to calculate the rates and costs of antiviral treatment. There were 73,893 identified cases of HZ and 1,245 HZ-related hospitalizations between 1997 and 2013. Of these episodes, 42,270 (57.2%) were treated with antiviral medications at a total cost of $4,708,065 (CAD). The age-adjusted incidence of HZ rose from 4.67/1,000 person years in 1997/1998 to 5.67/1,000 person years in 2013/2014, a 21.9% increase. Antiviral treatment rates increased from 41.7% to 66.2% of all diagnosed episodes. Mean treatment costs per episode dropped from $127.29 in 1997/1998 to $56.06 in 2013/2014, primarily due to the introduction of generic antiviral medications. The total cost of antiviral treatment peaked in 2005/2006 at $329,935 and dropped steadily thereafter to $223,973 in 2013/2014. HZ-related hospitalization rates decreased from 3.1% to 0.9%. While both the incidence of HZ and the rates of antiviral treatment have risen substantially, the economic burden from antiviral treatment has been decreasing since a peak in 2005/2006 and was only 3.2% higher in 2013/2014 than in 1997/1998. This drop in cost is attributed to the introduction of generic antiviral drugs.

Citalopram is the most commonly prescribed antidepressant in Canada. Concerns have been raised about its cardiac safety, and a dose-dependent prolongation of the QT interval has been documented. Drug interactions involving concomitant use of other medications that prolong the QT interval or increase citalopram levels by interfering with its metabolism increase the cardiac risk. Regulatory bodies (Health Canada and the US Food and Drug Administration) issued warnings and required labeling changes in 2011/2012, suggesting maximum citalopram doses (<40 mg for those <65 years; <20 mg for those ≥65 years) and avoiding drug interactions that increase cardiac risk. The purpose of this study is to assess the impact of these warnings on citalopram prescribing practices. A quasi-experimental interrupted time series analysis was conducted using all citalopram prescribing data from the population of Manitoba, Canada from 1999 to 2014. This allowed for the examination of high-dose prescribing (above regulatory warning levels) and the number of interacting medications per citalopram prescription. There was a dramatic decline in the prescribing of high doses in both age groups, with a 64.8% decline in those <65 years and 33.6% in those ≥65 years. Segmented regression models indicated significant breakpoints in the third quarter of 2011 for both age groups (P<0.0001), corresponding to the time the regulatory warnings were issued. There appeared to be no impact of the warnings on the prescribing of interacting medications. The number of interacting medications actually increased in the postwarning period (<65, 0.78-0.81 interactions per citalopram prescription; ≥65, 0.93-0.94, P<0.001). Regulatory changes appear to have produced an important reduction in the high-dose prescribing of citalopram. In contrast to this relatively simple dosage change, there was no indication that the more complex issue of resolving drug-drug interactions was impacted by regulatory warnings.

According to Trivers (1974), parent-offspring (P-O) conflict arises because offspring are selected to solicit more care than parents are selected to provide. However, should benefits fail to increase with increasing care, the offspring optimum can be reduced to the point where predicted P-O conflict vanishes. We examined offspring demand and parental care in such a benefit-limited system in herring gulls (Larus argentatus). In this species, parents typically neglect their last-hatched (C-) egg during the final hours of hatching (pipped-egg stage), allowing mean temperature to drop by about 4°C, to near 33°C. Other studies indicate that no increased offspring benefit arises from increasing pipped egg incubation temperature above that level, but embryo damage occurs if temperature drops lower. In such a system, P-O conflict over preferred incubation temperature is predicted to be minimal or absent. We assessed phenotypic manifestations of conflict by determining incubation temperature preferences of parent and offspring independently. Temperature provided solely by parental initiative was 33.9°C (artificial eggs, corrected for embryonic heat production). Preferred incubation temperature of pipped embryos was measured by exposing them to moderate chilling (20°C) punctuated by 4-min periods of rewarming when they called. Temperature of vocally thermoregulating embryos stabilized around a mean of 32.9-33.4°C, about 0.5-1.0°C below parental preference. Acting independently, parents and embryos each maintained egg temperature at or near minimum developmentally safe levels. Results provided no evidence for phenotypic conflict, as predicted by a benefit-limited version of Trivers' P-O conflict model. Benefit limitation may also be relevant to P-O conflict in other contexts such as feeding of newly-hatched young.