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1.  The effect of an educational intervention on meperidine use in Nova Scotia, Canada: a time series analysis 
Purpose
To evaluate the impact of a prescriber focused individual educational and audit–feedback intervention undertaken by the Nova Scotia Prescription Monitoring Program (NSPMP) in March/April 2007 to reduce meperidine use.
Method
The NSPMP records all prescriptions for controlled substances dispensed in community pharmacies in Nova Scotia, Canada. Oral meperidine use from 1 July 2005 to 31 December 2009 was examined using NSPMP data. Monthly totals for the following were obtained: number of individual patients who filled at least one meperidine prescription, number of prescriptions, and number of tablets dispensed. Data were analyzed graphically to observe overall trends. The intervention effect was estimated on the logarithmic scale with autocorrelations over time modeled by an integrated autoregressive moving average model for each outcome measure.
Results
An overall trend toward decreasing use from July 2005 to December 2009 was apparent for all three outcome measures. The intervention was associated with a statistically significant reduction in meperidine use, after adjusting for the overall long-term trend. Compared with the pre-intervention period, the monthly number of patients declined by 12% (p <0.001; 95% confidence interval [CI] = 5%–18%), prescriptions by 10% (p <0.001; 95%CI = 3%–17%), and tablets by 13.5% (p <0.001, 95%CI = 6%–29%) in the post-intervention period.
Conclusion
Given the risks associated with meperidine, determining that this intervention successfully reduced meperidine use is encouraging. This study highlights the potential for using population data such as the NSPMP to evaluate the effectiveness of population-level interventions to improve medication use, including professional, organizational, financial, and regulatory initiatives.
doi:10.1002/pds.2259
PMCID: PMC3747098  PMID: 22081471 CAMSID: cams3253
educational intervention; meperidine; pethidine; time series analysis
2.  Interrupted Time-Series Analysis of Regulations to Reduce Paracetamol (Acetaminophen) Poisoning 
PLoS Medicine  2007;4(4):e105.
Background
Paracetamol (acetaminophen) poisoning is the leading cause of acute liver failure in Great Britain and the United States. Successful interventions to reduced harm from paracetamol poisoning are needed. To achieve this, the government of the United Kingdom introduced legislation in 1998 limiting the pack size of paracetamol sold in shops. Several studies have reported recent decreases in fatal poisonings involving paracetamol. We use interrupted time-series analysis to evaluate whether the recent fall in the number of paracetamol deaths is different to trends in fatal poisoning involving aspirin, paracetamol compounds, antidepressants, or nondrug poisoning suicide.
Methods and Findings
We calculated directly age-standardised mortality rates for paracetamol poisoning in England and Wales from 1993 to 2004. We used an ordinary least-squares regression model divided into pre- and postintervention segments at 1999. The model included a term for autocorrelation within the time series. We tested for changes in the level and slope between the pre- and postintervention segments. To assess whether observed changes in the time series were unique to paracetamol, we compared against poisoning deaths involving compound paracetamol (not covered by the regulations), aspirin, antidepressants, and nonpoisoning suicide deaths. We did this comparison by calculating a ratio of each comparison series with paracetamol and applying a segmented regression model to the ratios. No change in the ratio level or slope indicated no difference compared to the control series. There were about 2,200 deaths involving paracetamol. The age-standardised mortality rate rose from 8.1 per million in 1993 to 8.8 per million in 1997, subsequently falling to about 5.3 per million in 2004. After the regulations were introduced, deaths dropped by 2.69 per million (p = 0.003). Trends in the age-standardised mortality rate for paracetamol compounds, aspirin, and antidepressants were broadly similar to paracetamol, increasing until 1997 and then declining. Nondrug poisoning suicide also declined during the study period, but was highest in 1993. The segmented regression models showed that the age-standardised mortality rate for compound paracetamol dropped less after the regulations (p = 0.012) but declined more rapidly afterward (p = 0.031). However, age-standardised rates for aspirin and antidepressants fell in a similar way to paracetamol after the regulations. Nondrug poisoning suicide declined at a similar rate to paracetamol after the regulations were introduced.
Conclusions
Introduction of regulations to limit availability of paracetamol coincided with a decrease in paracetamol-poisoning mortality. However, fatal poisoning involving aspirin, antidepressants, and to a lesser degree, paracetamol compounds, also showed similar trends. This raises the question whether the decline in paracetamol deaths was due to the regulations or was part of a wider trend in decreasing drug-poisoning mortality. We found little evidence to support the hypothesis that the 1998 regulations limiting pack size resulted in a greater reduction in poisoning deaths involving paracetamol than occurred for other drugs or nondrug poisoning suicide.
Analysis of mortality rates for paracetamol poisoning in England and Wales does not support the view that regulations limiting pack size have been responsible for a reduction in deaths.
Editors' Summary
Background.
Paracetamol—known as acetaminophen in the United States—is a cheap and effective painkiller. It is widely used to relieve minor aches and pains as well as fevers and headaches. Recommended doses of paracetamol are considered safe in humans, but overdoses are toxic and can cause liver failure and death. Because this drug is very easy to get hold of, there are many overdoses each year, either accidental or deliberate. In the UK, paracetamol poisoning is the most common cause of acute liver failure. Toward the end of 1998, new laws were introduced in the UK to try to reduce the number of paracetamol overdoses. These laws said that pharmacies could not sell packs of paracetamol containing more than 32 tablets and other shops could not sell packs with more than 16 tablets. One of the reasons behind the introduction of this law was that many suicides are not preplanned and, therefore, if it was harder for people to get hold of or keep large quantities of tablets, they might be less likely to attempt suicide or accidentally overdose.
Why Was This Study Done?
Following the introduction of these new laws, the number of deaths caused by paracetamol overdose in the UK dropped. However, it is possible that the drop in deaths came about for a variety of different reasons and not just as a result of the new laws on paracetamol pack size. For example, the suicide rate might have been falling anyway due to other changes in society and the fall in death rate from paracetamol might just have been part of that trend. It is important to find out whether the legal changes that were introduced to address a public health problem did in fact bring about a change for the better. This knowledge would also be relevant to other countries that are considering similar changes.
What Did the Researchers Do and Find?
The researchers used data from the Office of National Statistics, which holds information on drug poisoning deaths in England and Wales. These data were then broken down by the type of drug that was mentioned on the death certificate. The researchers compared death rates involving the following drugs: paracetamol; paracetamol-containing compounds (which were not subject to the new pack size laws); aspirin; antidepressant drugs; and then finally non-drug poisoning suicides. The reason for comparing death rates involving paracetamol against death rates involving other drugs, or non-drug suicide, was that this method would allow the researchers to see if the drop in paracetamol deaths followed overall trends in the poisoning or suicide rates or not. If the paracetamol death rate dropped following introduction of the new laws but the rates of other types of poisoning or suicide did not, then there would be a link between the new laws and a fall in paracetamol suicides. The researchers compared these death data within specific time periods before the end of 1998 (when the new laws on paracetamol pack size were introduced) and after.
Overall, there were nearly 2,200 deaths involving paracetamol between 1993 and 2004. The number of deaths per year involving paracetamol dropped substantially when comparing the periods of time before the end of 1998 and after it. However, the number of deaths per year involving any drug, and the non-drug suicides, also fell during this period of time. When comparing the trends for paracetamol deaths with other poisoning or suicide deaths, the researchers did not find any statistical evidence that the fall in paracetamol deaths was any different to the overall trend in poisoning or suicide death rates.
What Do These Findings Mean?
Although the paracetamol death rate fell immediately following the new laws on pack size, this study suggests the link might just be coincidence. The researchers could not find any data supporting the idea that the new laws caused a drop in paracetamol deaths. However, this was an observational study, not a true experimental one: the researchers here were clearly not able to set up equivalent “experimental” and “control” groups for comparison. It is very difficult to prove or disprove conclusively that new laws such as this are, or are not, effective.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040105
Information is available from Medline Plus about suicide
Wikipedia has an entry on paracetamol (note that Wikipedia is an internet encyclopedia anyone can edit)
Information about regulation of drugs in the UK is available from the Medicines and Healthcare Regulatory Agency
The Office for National Statistics provides key economic and social data about the UK, and is involved in many other important projects
doi:10.1371/journal.pmed.0040105
PMCID: PMC1845154  PMID: 17407385
3.  Confusion 
Drugs in R&d  2012;12(2):45-48.
Acetaminophen (paracetamol) plays a vital role in American health care, with in excess of 25 billion doses being used annually as a nonprescription medication. Over 200 million acetaminophen-containing prescriptions, usually in combination with an opioid, are dispensed annually. While acetaminophen is recognized as a safe and effective analgesic and antipyretic, it is also associated with significant morbidity and mortality (hepatotoxicity) if doses in excess of the therapeutic amount are ingested inappropriately. The maximum daily therapeutic dose of 3900–4000 mg was established in separate actions in 1977 and 1988, respectively, via the Food and Drug Administration (FDA) monograph process for nonprescription medications. The FDA has conducted multiple advisory committee meetings to evaluate acetaminophen and its safety profile, and has suggested (but not mandated) a reduction in the maximum daily dosage from 3900–4000 mg to 3000–3250 mg. In 2011, McNeil, the producer of the Tylenol® brand of acetaminophen, voluntarily reduced the maximum daily dose of its 500 mg tablet product to 3000 mg/day, and it has pledged to change the labeling of its 325 mg/tablet product to reflect a maximum of 3250 mg/day. Generic manufacturers have not changed their dosing regimens and they have remained consistent with the established monograph dose. Therefore, confusion will be inevitable as both consumers and health care professionals try to determine the proper therapeutic dose of acetaminophen. Which is the correct dose of acetaminophen: 3000 mg if 500 mg tablets are used, 3250 mg with 325 mg tablets, or 3900 mg when 650 mg arthritis-strength products are used?
doi:10.2165/11633010-000000000-00000
PMCID: PMC3585765  PMID: 22530736
4.  Confusion 
Drugs in R&D  2012;12(2):45-48.
Acetaminophen (paracetamol) plays a vital role in American health care, with in excess of 25 billion doses being used annually as a nonprescription medication. Over 200 million acetaminophen-containing prescriptions, usually in combination with an opioid, are dispensed annually. While acetaminophen is recognized as a safe and effective analgesic and antipyretic, it is also associated with significant morbidity and mortality (hepatotoxicity) if doses in excess of the therapeutic amount are ingested inappropriately. The maximum daily therapeutic dose of 3900–4000 mg was established in separate actions in 1977 and 1988, respectively, via the Food and Drug Administration (FDA) monograph process for nonprescription medications. The FDA has conducted multiple advisory committee meetings to evaluate acetaminophen and its safety profile, and has suggested (but not mandated) a reduction in the maximum daily dosage from 3900–4000 mg to 3000–3250 mg. In 2011, McNeil, the producer of the Tylenol® brand of acetaminophen, voluntarily reduced the maximum daily dose of its 500 mg tablet product to 3000 mg/day, and it has pledged to change the labeling of its 325 mg/tablet product to reflect a maximum of 3250 mg/day. Generic manufacturers have not changed their dosing regimens and they have remained consistent with the established monograph dose. Therefore, confusion will be inevitable as both consumers and health care professionals try to determine the proper therapeutic dose of acetaminophen. Which is the correct dose of acetaminophen: 3000 mg if 500 mg tablets are used, 3250 mg with 325 mg tablets, or 3900 mg when 650 mg arthritis-strength products are used?
doi:10.2165/11633010-000000000-00000
PMCID: PMC3585765  PMID: 22530736
5.  Single dose oral paracetamol (acetaminophen) for postoperative pain in adults 
Background
This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way.
Objectives
To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008.
Selection criteria
Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected.
Main results
Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome.
About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms.
Authors’ conclusions
A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.
doi:10.1002/14651858.CD004602.pub2
PMCID: PMC4163965  PMID: 18843665
Acetaminophen [*administration & dosage; adverse effects]; Analgesics, Non-Narcotic [*administration & dosage; adverse effects]; Pain, Postoperative [*drug therapy]; Randomized Controlled Trials as Topic; Adult; Humans
6.  Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults 
Background
This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly.
Objectives
Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events.
Search methods
We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update.
Selection criteria
Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults.
Data collection and analysis
Two authors assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected.
Main results
Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo.
Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups.
Authors’ conclusions
This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information.
doi:10.1002/14651858.CD001547.pub2
PMCID: PMC4171965  PMID: 19160199
Acetaminophen [*administration & dosage; adverse effects]; Administration, Oral; Analgesics, Non-Narcotic [*administration & dosage; adverse effects]; Analgesics, Opioid [*administration & dosage; adverse effects]; Codeine [*administration & dosage]; Drug Therapy, Combination; Pain, Postoperative [*drug therapy]; Adult; Humans
7.  Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults 
Background
Oxycodone is a strong opioid agonist used to treat severe pain. It is commonly combined with milder analgesics such as paracetamol. This review updates a previous review that concluded, based on limited data, that all doses of oxycodone exceeding 5 mg, with or without paracetamol, provided analgesia in postoperative pain, but with increased incidence of adverse events compared with placebo. Additional new studies provide more reliable estimates of efficacy and harm.
Objectives
To assess efficacy, duration of action, and associated adverse events of single dose oral oxycodone, with or without paracetamol, in acute postoperative pain in adults.
Search methods
Cochrane CENTRAL, MEDLINE, EMBASE and Oxford Pain Relief Database, searched in May 2009.
Selection criteria
Randomised, double blind, placebo-controlled trials of single dose orally administered oxycodone, with or without paracetamol, in adults with moderate to severe acute postoperative pain.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants remedicating over specified time periods, and time-to-use of rescue medication, were sought as additional measures of efficacy. Adverse events and withdrawals information was collected.
Main results
This updated review includes 20 studies, with 2641 participants. For oxycodone 15 mg alone compared with placebo, the NNT for at least 50% pain relief was 4.6 (95% Confidence Interval 2.9 to 11). For oxycodone 10 mg plus paracetamol 650 mg, the NNT was 2.7 (2.4 to 3.1). A dose response was demonstrated for this outcome with combination therapy. Duration of effect was 10 hours with oxycodone 10 mg plus paracetamol 650 mg, and 4 hours with half that dose. Fewer participants needed rescue medication over 6 hours at the higher dose. Adverse events occurred more frequently with combination therapy than placebo, but were generally described as mild to moderate in severity and rarely led to withdrawal.
Authors’ conclusions
Single dose oxycodone is an effective analgesic in acute postoperative pain at doses over 5 mg; oxycodone is two to three times stronger than codeine. Efficacy increases when combined with paracetamol. Oxycodone 10 mg plus paracetamol 650 mg provides good analgesia to half of those treated, comparable to commonly used non-steroidal anti-inflammatory drugs, with the benefit of longer duration of action.
doi:10.1002/14651858.CD002763.pub2
PMCID: PMC4170904  PMID: 19588335
Acetaminophen [*administration & dosage; adverse effects]; Acute Disease; Analgesics, Non-Narcotic [*administration & dosage; adverse effects]; Analgesics, Opioid [*administration & dosage; adverse effects]; Drug Synergism; Drug Therapy, Combination; Oxycodone [*administration & dosage; adverse effects]; Pain, Postoperative [*drug therapy]; Randomized Controlled Trials as Topic; Adult; Humans
8.  Descriptive Study of Prescriptions for Opioids from a Suburban Academic Emergency Department Before New York’s I-STOP Act 
Introduction
Controlled prescription opioid use is perceived as a national problem attributed to all specialties. Our objective was to provide a descriptive analysis of prescriptions written for controlled opioids from a database of emergency department (ED) visits prior to the enactment of the I-STOP law, which requires New York prescribers to consult the Prescription Monitoring Program (PMP) prior to prescribing Schedule II, III, and IV controlled substances for prescriptions of greater than five days duration.
Methods
We conducted a retrospective medical record review of patients 21 years of age and older, who presented to the ED between July 1, 2011 – June 30, 2012 and were given a prescription for a controlled opioid. Our primary purpose was to characterize each prescription as to the type of controlled substance, the quantity dispensed, and the duration of the prescription. We also looked at outliers, those patients who received prescriptions for longer than five days.
Results
A total of 9,502 prescriptions were written for opioids out of a total 63,143 prescriptions for 69,500 adult patients. Twenty-six (0.27%) of the prescriptions for controlled opioids were written for greater than five days. Most prescriptions were for five days or less (99.7%, 95% CI [99.6 to 99.8%]).
Conclusion
The vast majority of opioid prescriptions in our ED prior to the I-STOP legislature were limited to a five-day or less supply. These new regulations were meant to reduce the ED’s contribution to the rise of opioid related morbidity. This study suggests that the emergency physicians’ usual prescribing practices were negligibly limited by the new restrictive regulations. The ED may not be primarily contributing to the increase in opioid-related overdoses and death. The effect of the I-STOP regulation on future prescribing patterns in the ED remains to be determined.
doi:10.5811/westjem.2014.12.22669
PMCID: PMC4307728
9.  Adverse Selection? A Multi-Dimensional Profile of People Dispensed Opioid Analgesics for Persistent Non-Cancer Pain 
PLoS ONE  2013;8(12):e80095.
Objectives
This study investigates utilisation patterns for prescription opioid analgesics in the Australian community and how these are associated with a framework of individual-level factors related to healthcare use.
Methods
Self-reported demographic and health information from participants in the 45 and Up Study cohort were linked to pharmaceutical claims from 2006–2009. Participants comprised 19,816 people with ≥1 opioid analgesic dispensing in the 12-months after recruitment to the cohort and 79,882 people not dispensed opioid analgesics. All participants were aged ≥45 years, were social security pharmaceutical beneficiaries, with no history of cancer. People dispensed opioid analgesics were classified as having acute (dispensing period <90 days), episodic (≥90 days and <3 ‘authority’ prescriptions for increased quantity supply) or long-term treatment (≥90 days and ≥3 authority prescriptions).
Results
Of participants dispensed opioid analgesic 52% received acute treatment, 25% episodic treatment and 23% long-term treatment. People dispensed opioid analgesics long-term had an average of 14.9 opioid analgesic prescriptions/year from 2.0 doctors compared with 1.5 prescriptions from 1.1 doctors for people receiving acute treatment. People dispensed opioid analgesics reported more need-related factors such as poorer physical functioning and higher psychological distress. Long-term users were more likely to have access-related factors such as low-income and living outside major cities. After simultaneous adjustment, association with predisposing health factors and access diminished, but indicators of need such as osteoarthritis treatment, paracetamol use, and poor physical function were the strongest predictors for all opioid analgesic users.
Conclusions
People dispensed opioid analgesics were in poorer health, reported higher levels of distress and poorer functioning than people not receiving opioid analgesics. Varying dispensing profiles were evident among people dispensed opioid analgesics for persistent pain, with those receiving episodic and long-term treatment dispensed the strongest opioid analgesics. The findings highlight the broad range of factors associated with longer term opioid analgesics use.
doi:10.1371/journal.pone.0080095
PMCID: PMC3846564  PMID: 24312456
10.  Effect of a centralized prescription network on inappropriate prescriptions for opioid analgesics and benzodiazepines 
Background:
Opioid analgesics and benzodiazepines are often misused in clinical practice. We determined whether implementation of a centralized prescription network offering real-time access to patient-level data on filled prescriptions (PharmaNet) reduced the number of potentially inappropriate prescriptions for opioids and benzodiazepines.
Methods:
We conducted a time series analysis using prescription records between Jan. 1, 1993, and Dec. 31, 1997, for residents of the province of British Columbia who were receiving social assistance or were 65 years or older. We calculated monthly percentages of filled prescriptions for an opioid or a benzodiazepine that were deemed inappropriate (those issued by a different physician and dispensed at a different pharmacy within 7 days after a filled prescription of at least 30 tablets of the same drug).
Results:
Within 6 months after implementation of PharmaNet in July 1995, we observed a relative reduction in inappropriate filled prescriptions for opioids of 32.8% (95% confidence interval [CI] 31.0%–34.7%) among patients receiving social assistance; inappropriate filled prescriptions for benzodiazepines decreased by 48.6% (95% CI 43.2%–53.1%). Similar and statistically significant reductions were observed among residents 65 years or older.
Interpretation:
The implementation of a centralized prescription network was associated with a dramatic reduction in inappropriate filled prescriptions for opioids and benzodiazepines.
doi:10.1503/cmaj.120465
PMCID: PMC3494359  PMID: 22949563
11.  Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted Time Series Analysis 
Background
Oxycodone controlled release (CR) and oxymorphone extended release (ER) are frequently prescribed long-acting opioids, which are approved for twice-daily dosing. The US Food and Drug Administration approved a reformulated crush-resistant version of oxycodone CR in April 2010.
Objective
To compare the daily average consumption (DACON) for oxycodone CR and for oxymorphone ER before and after the introduction of the reformulated, crush-resistant version of oxycodone CR.
Methods
This was a retrospective claims database analysis using pharmacy claims from the MarketScan database for the period from January 2010 through March 2011. The interrupted time series analysis was used to evaluate the impact of the introduction of reformulated oxycodone CR on the DACON of the 2 drugs—oxycodone CR and oxymorphone ER. The source of the databases included private-sector health data from more than 150 medium and large employers. All prescription claims containing oxycodone CR and oxymorphone ER dispensed to members from January 1, 2010, to March 31, 2011, were included in the analysis. Prescription claims containing duplicate National Drug Codes, missing member identification, invalid quantities or inaccurate days supply of either drug, and DACON values of <1 and >500 were removed.
Results
The database yielded 483,063 prescription claims for oxycodone CR and oxymorphone ER from January 1, 2010, to March 31, 2011. The final sample consisted of 411,404 oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and 62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Before the introduction of reformulated oxycodone CR, DACON values for the highest strength available for each of the 2 drugs were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with mean DACON values of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001). The differences of mean DACON between the 2 drugs for all lower strengths were 0.46 tablets, with mean DACON values of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001). After the introduction of the new formulation, the difference in mean DACON between the 2 drugs was slightly lower: 0.45 tablets for the highest-strength and 0.40 tablets for the lower-strength pairs. Regression analyses showed that the immediate and overall impact of the reformulation of oxycodone CR on the DACON of oxycodone CR was minimal, whereas no changes were seen in the DACON of oxymorphone ER. The estimated DACON for oxycodone CR decreased by 0.1 tablets, or 3.7% (P <.001), 6 months after the new formulation was introduced.
Conclusion
The mean DACON was 0.4 tablets per day higher for oxycodone CR compared with oxymorphone ER for all dosage strengths for the entire study period. After the introduction of the reformulated oxycodone CR, the DACON for this drug was slightly mitigated; however, there was a minimal impact on the mean differences between oxycodone CR and oxymorphone ER.
PMCID: PMC4046462  PMID: 24991311
12.  Six-Year Follow-Up of Impact of Co-proxamol Withdrawal in England and Wales on Prescribing and Deaths: Time-Series Study 
PLoS Medicine  2012;9(5):e1001213.
A time-series study conducted by Keith Hawton and colleagues reports on the links between withdrawal of the analgesic co-proxamol and subsequent prescribing and deaths associated with analgesic poisoning.
Background
The analgesic co-proxamol (paracetamol/dextropropoxyphene combination) has been widely involved in fatal poisoning. Concerns about its safety/effectiveness profile and widespread use for suicidal poisoning prompted its withdrawal in the UK in 2005, with partial withdrawal between 2005 and 2007, and full withdrawal in 2008. Our objective in this study was to assess the association between co-proxamol withdrawal and prescribing and deaths in England and Wales in 2005–2010 compared with 1998–2004, including estimation of possible substitution effects by other analgesics.
Methods and Findings
We obtained prescribing data from the NHS Health and Social Care Information Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru (Wales), and mortality data from the Office for National Statistics. We carried out an interrupted time-series analysis of prescribing and deaths (suicide, open verdicts, accidental poisonings) involving single analgesics. The reduction in prescribing of co-proxamol following its withdrawal in 2005 was accompanied by increases in prescribing of several other analgesics (co-codamol, paracetamol, codeine, co-dydramol, tramadol, oxycodone, and morphine) during 2005–2010 compared with 1998–2004. These changes were associated with major reductions in deaths due to poisoning with co-proxamol receiving verdicts of suicide and undetermined cause of −21 deaths (95% CI −34 to −8) per quarter, equating to approximately 500 fewer suicide deaths (−61%) over the 6 years 2005–2010, and −25 deaths (95% CI −38 to −12) per quarter, equating to 600 fewer deaths (−62%) when accidental poisoning deaths were included. There was little observed change in deaths involving other analgesics, apart from an increase in oxycodone poisonings, but numbers were small. Limitations were that the study was based on deaths involving single drugs alone and changes in deaths involving prescribed morphine could not be assessed.
Conclusions
During the 6 years following the withdrawal of co-proxamol in the UK, there was a major reduction in poisoning deaths involving this drug, without apparent significant increase in deaths involving other analgesics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about a million people worldwide die by suicide. Most people who take their own life are mentally ill. For some, stressful events have made life seem worthless or too painful to bear. Suicide rates can be reduced by improving the treatment of mental illness and of stress and by limiting access to common suicide methods. These methods differ from place to place. For example, in England and Wales, where 4,528 suicides were recorded in 2010, drug-related poisoning is responsible for about a fifth of all suicides. Notably, between 1997 and 1999, the prescription analgesic (pain killer) co-proxamol, which contains paracetamol and the opioid dextropropoxyphene, was implicated in a fifth of drug-poisoning suicides in England and Wales. In response to concerns about co-proxamol's widespread use for suicidal poisoning and its safety/effectiveness profile, the UK Committee on Safety of Medicines announced on January 31, 2005 that the drug would be withdrawn completely from use in the UK by December 31, 2007, and that between 2005 and 2007, doctors should not prescribe co-proxamol to any new patients and should try to move patients already taking the drug onto other medications.
Why Was This Study Done?
Public health experts need to quantify the impact of co-proxamol withdrawal on analgesic prescribing in England and Wales and on suicide rates. In particular, they need to know whether its withdrawal has increased the use of other analgesics in suicide (substitution). Reassuringly, between 2005 and 2007, there was a reduction in both co-proxamol prescribing and in co-proxamol–related suicides in England and Wales but no evidence of increased poisoning deaths involving other prescription analgesics. But what about the longer-term effects of co-proxamol withdrawal? In this interrupted time-series study, the researchers assess the impact of co-proxamol withdrawal in England and Wales by comparing data on analgesic prescribing and suicide rates collected between 1998 and 2004 and between 2005 and 2010. An interrupted time-series study uses serial measurements of events in a population before and after an intervention to look for changes in response to the intervention.
What Did the Researchers Do and Find?
The researchers obtained prescribing data from 1998 to 2010 for co-proxamol and several other analgesics from government sources in England and Wales, and data on suicides, open verdicts (poisoning of undetermined intent), and accidental poisonings involving single analgesics from the UK Office for National Statistics. They then estimated changes in levels and trends in prescribing and deaths following the 2005 announcement of co-proxamol withdrawal using interrupted time-series analysis. There was a marked reduction in co-proxamol prescribing that was accompanied by increased prescribing of several other analgesics after co-proxamol withdrawal. These changes were associated with a major reduction in suicide deaths due to poisoning that equated to 500 fewer deaths occurring between 2005 and 2010 than would have occurred had co-proxamol not been withdrawn. On average, there were 20 co-proxamol-related deaths (suicides and accidental poisonings) per year during 2008–2010 compared to more than 250 per year in the 1990s. Finally, there was little evidence of a change in the number of deaths involving other analgesics after co-proxamol withdrawal except for a small increase in the number of deaths involving the opioid oxycodone.
What Do These Findings Mean?
These findings show that, during the six years that followed the beginning of the phased withdrawal of co-proxamol in the UK, there has been a major reduction in poisoning deaths involving this drug in England and Wales. The findings provide little evidence for an increase in deaths involving other analgesics. However, because the Office of National Statistics does not distinguish between deaths due to oral and intravenous morphine or between deaths due to morphine and heroin, the researchers did not assess whether there have been any changes in deaths involving morphine since 2005. Moreover, this study did not assess suicides related to the use of multiple drugs or investigate whether suicides involving methods other than drug-related poisoning have increased since co-proxamol withdrawal. Despite these limitations, these findings suggest that the withdrawal of co-proxamol in the UK and possibly elsewhere should have major beneficial effects on suicide rates, at least in the relatively short term.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001213.
The World Health Organization provides information on the global burden of suicide and on suicide prevention (in several languages)
The US National Institute of Mental Health provides information on suicide and suicide prevention web page
The UK National Health Service Choices website has detailed information about suicide and its prevention
The University of Oxford Centre for Suicide Research provides information about co-proxamol and suicide and links to other research on suicide
The 2005 announcement of the withdrawal of co-proxamol in the UK is available through the UK Medicines and Healthcare products Regulatory Agency, which also provides a question and answer document about the risks and benefits of co-proxamol
MedlinePlus provides links to further resources about suicide (in English and Spanish)
The charity Healthtalkonline has personal stories about dealing with suicide
Help is at Hand is a resource for people bereaved by suicide
doi:10.1371/journal.pmed.1001213
PMCID: PMC3348153  PMID: 22589703
13.  Non-steroidal anti-inflammatory drugs, Cyclooxygenase-2 inhibitors and paracetamol use in Queensland and in the whole of Australia 
Background
Cross national drug utilization studies can provide information about different influences on physician prescribing. This is important for medicines with issues around safety and quality of use, like non selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors. To enable comparison of prescription medicine use across different jurisdictions with a range of population sizes, data first need to be compared within Australia to understand whether use in a smaller sub-population may be considered as representative of the total use within Australia. The aim of this study was to compare the utilization of non selective NSAID, COX-2 inhibitors and paracetamol between Queensland and Australia.
Method
Dispensing data were obtained for concession beneficiaries for Australia for ns-NSAIDs, COX-2 inhibitors and paracetamol subsidized by the PBS over the period 1997–2003. The same data were purchased for Queensland. Data were converted to Defined Daily Dose (DDD)/1000 beneficiaries/day (World Health Organization anatomical therapeutic chemical classification, 2005).
Results
Total NSAID and paracetamol consumption were similar in Australia and Queensland. Ns-NSAID use decreased sharply with the introduction of COX-2 inhibitors (from approximately 80 to 40 DDD/1000 beneficiaries/day). Paracetamol was constant (approximately 45 DDD/1000 beneficiaries/day). COX-2 inhibitors consumption was initially higher in Queensland than in the whole of Australia.
Conclusion
Despite initial divergence in celecoxib use between Queensland and Australia, the use of ns-NSAIDs, COX-2 inhibitors and paracetamol overall, in concession beneficiaries, was comparable in Australia and Queensland.
doi:10.1186/1472-6963-8-196
PMCID: PMC2562379  PMID: 18816393
14.  Frequency and predictors of tablet splitting in statin prescriptions: a population-based analysis 
Open Medicine  2008;2(3):e74-e82.
Background
The price per milligram for most statin medications decreases at higher strengths, which provides an economic incentive to split tablets. We sought to determine the frequency with which statin tablets are split, and to evaluate factors associated with this practice.
Methods
We obtained prescription claims data for statins from the BC Ministry of Health for the period Jan. 1, 1996, to Dec. 31, 2006. We estimated the number of tablets per day, based on the ratio of the number of tablets to days-supply in each prescription, to estimate the frequency with which splitting occurred with each statin. We used multivariable logistic regression to assess patient and physician characteristics and the level of public drug plan coverage associated with tablet splitting. To estimate related cost savings, we used information on drug costs and quantities of dispensed statins reported by pharmacies.
Results
During the 11-year study period, we estimated that tablet splitting occurred in 2.6% of 7.2 million statin prescriptions. There was an increasing trend in the practice over time, to 4.5% of prescriptions in 2006. Lovastatin was the only scored tablet and was the most likely to be split, followed by rosuvastatin and atorvastatin. Fifty percent of the prescriptions in which tablet splitting occurred were prescribed by only 7.9% of the routine statin prescribers (i.e., > 10 statin prescriptions over the study period). Specialists were less likely than general practitioners to prescribe statins that were subsequently split (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.40–0.46). Statin prescriptions that were fully covered by the public drug plan were half as likely as those with no such coverage to involve tablet splitting (OR 0.48, 95% CI 0.44–0.92). Having no public drug coverage, having a low annual household income and being female were patient factors found to be positively associated with tablet splitting. In 2006, the cost savings associated with tablet splitting was $2.3 million.
Interpretation
The frequency of tablet splitting in statin prescriptions in British Columbia was low but increased over time. It varied between patients, physicians and different levels of insurance coverage. In the final study year, 94.5% of the statin prescriptions were dispensed at strengths for which a tablet of twice the strength was available and could have been split, which suggests a potentially enormous cost savings.
PMCID: PMC3091608  PMID: 21602952
15.  Changes in trends and pattern of strong opioid prescribing in primary care 
Background
This study evaluated the prescribing trends of four commonly prescribed strong opioids in primary care and explored utilization in non-cancer and cancer users.
Methods
This cross-sectional study was conducted from 2000 to 2010 using the UK Clinical Practice Research Datalink. Prescriptions of buprenorphine, fentanyl, morphine and oxycodone issued to adult patients were included in this study. Opioid prescriptions issued after patients had cancer medical codes were defined as cancer-related use; otherwise, they were considered non-cancer use. Annual number of prescriptions and patients, defined daily dose (DDD/1000 inhabitants/day) and oral morphine equivalent (OMEQ) dose were measured in repeat cross-sectional estimates.
Results
In total, there were 2,672,022 prescriptions (87.8% for non-cancer) of strong opioids for 178,692 users (59.9% female, 83.9% non-cancer, mean age 67.1 ± 17.0 years) during the study period. The mean annual (DDD/1000 inhabitants/day) was higher in the non-cancer group than in the cancer group for all four opioids; morphine (0.73 ± 0.28 vs. 0.12 ± 0.04), fentanyl (0.46 ± 0.29 vs. 0.06 ± 0.24), oxycodone (0.24 ± 0.19 vs. 0.038 ± 0.028) and buprenorphine (0.23 ± 0.15 vs. 0.008 ± 0.006). The highest proportion of patients were prescribed low opioid doses (OMEQ ≤ 50 mg/day) in both non-cancer (50.3%) and cancer (39.9%) groups, followed by the dose ranks of 51–100 mg/day (26.2% vs. 28.7%), 101–200 mg/day (15.1% vs. 19.2%) and >200 mg/day (8.25% vs. 12.1%).
Conclusions
There has been a huge increase in strong opioid prescribing in the United Kingdom, with the majority of prescriptions for non-cancer pain. Morphine was the most frequently prescribed, but the utilization of oxycodone, buprenorphine and fentanyl increased markedly over time.
doi:10.1002/j.1532-2149.2014.496.x
PMCID: PMC4238849  PMID: 24756859
16.  Prescription Medicines and the Risk of Road Traffic Crashes: A French Registry-Based Study 
PLoS Medicine  2010;7(11):e1000366.
Using three nationwide databases in France, Ludivine Orriols, Emmanuel Lagarde, and colleagues provide evidence that prescribed medicines contribute to the risk of experiencing a road traffic crash.
Background
In recent decades, increased attention has been focused on the impact of disabilities and medicinal drug use on road safety. The aim of our study was to investigate the association between prescription medicines and the risk of road traffic crashes, and estimate the attributable fraction.
Methods and Findings
We extracted and matched data from three French nationwide databases: the national health care insurance database, police reports, and the national police database of injurious crashes. Drivers identified by their national health care number involved in an injurious crash in France, between July 2005 and May 2008, were included in the study. Medicines were grouped according to the four risk levels of the French classification system (from 0 [no risk] to 3 [high risk]). We included 72,685 drivers involved in injurious crashes. Users of level 2 (odds ratio [OR]  = 1.31 [1.24–1.40]) and level 3 (OR  = 1.25 [1.12–1.40]) prescription medicines were at higher risk of being responsible for a crash. The association remained after adjustment for the presence of a long-term chronic disease. The fraction of road traffic crashes attributable to levels 2 and 3 medications was 3.3% [2.7%–3.9%]. A within-person case-crossover analysis showed that drivers were more likely to be exposed to level 3 medications on the crash day than on a control day, 30 days earlier (OR  = 1.15 [1.05–1.27]).
Conclusion
The use of prescription medicines is associated with a substantial number of road traffic crashes in France. In light of the results, warning messages appear to be relevant for level 2 and 3 medications and questionable for level 1 medications. A follow-up study is needed to evaluate the impact of the warning labeling system on road traffic crash prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
About 1.3 million people die each year on the world's road. 90% of road traffic deaths occur in developing countries, with pedestrians, cyclists, and users of two-wheel vehicles (scooters, motorbikes) the most vulnerable road users. Although the use of prescribed benzodiazepines has already been documented to be associated with road traffic accidents in industrialized countries, the effects of other medicines have not been well studied or have inconsistent results (for example opioids and antidepressant medications). In the European Union, it is mandatory for pharmaceutical companies to provide data about the effect of a medicine on ability to drive. In France, a multidisciplinary group of experts was appointed to classify all medicines into four levels of risk (from level 0, no or negligible risk, to level 3, major risk), in terms of their effect on driving performances. In 2006, the International Council on Alcohol, Drugs and Traffic Safety proposed a classification list similar to the French classification system.
Why Was This Study Done? There is a pressing need to understand the association between prescribed medicines and the risk of road traffic crashes and also to have a more accurate picture of the fraction of road traffic crashes that are attributable to the use of prescribed medicines. This large French study aimed to advance knowledge in this important area.
What Did the Researchers Do and Find? The researchers used three data sources to find the information they needed: the national health care insurance database (which covers the whole French population and includes data on reimbursed prescription medicines), police reports, and the national police database of injurious road traffic crashes. Drivers involved in road traffic crashes (identified by their national healthcare number) between July 2005 and May 2008 were included in the study. The researchers used a statistical model to conduct a responsibility analysis, which determined factors associated with each driver responsible for the road traffic crash and each driver who was not responsible (controls). In addition, the researchers compared medicine exposure during a period immediately before the crash (case period) with exposure during an earlier period (control period) for each driver involved in a crash. The researchers retrieved data on reimbursed medicines, dispensed within six months of the road traffic crash, by linking included drivers to the national health care insurance database using their national ID, gender, and date of birth and grouped all prescribed medicines according to the four risk levels of the French classification system.
During the study period, 72,685 drivers involved in injurious road traffic crashes were included. The researchers found that drivers who had been prescribed level 2 and level 3 medicines were at higher risk (odds ratio 1.31 and OR 1.25, respectively) of being responsible for the road traffic crash, an association that remained after the researchers adjusted for the presence of chronic diseases. Furthermore, the researchers found that the fraction of road traffic crashes attributable to the use of (prescriptions for) level 2 and 3 medicines was 3.3% and that drivers were more likely to be exposed to level 3 medicines on the day of the road traffic crash than on a control day.
What Do These Findings Mean? This study provides strong evidence for the contribution of medicines to the risk of experiencing a road traffic crash. The French drug risk classification scheme seems accurate for medicines classified as levels 2 and 3 of risk for road traffic crashes. The effect on driving abilities of level 2 medicines depends both on the pharmacodynamics of the drug and on individual susceptibility, whereas for level 3 medicines, the pharmacodynamic effect seems to be predominant. The effects of level 1 medicines seem to be so dependent on individual susceptibility that effects on driving abilities are rare, which raises questions about the relevance of the labels for these medicines. However, some limitations with the study methodology might affect the interpretation of these findings. For example, the researchers used dispensing dates for medications as a surrogate for ingestion and were not able to check for noncompliance.
However, this study provides some of the strongest evidence to date of the need for health care workers to provide patients with proper information on the potential effect of any medicine that they are prescribed (or take) on their driving abilities.
Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000366.The World Health Organization (WHO) provides information on road traffic accidentsTwo Web sites provide information for drivers about drugs that could affect their ability to driveThe US National Institute on Drug Abuse of the National Institutes of Health has an information sheet on drugged driving
doi:10.1371/journal.pmed.1000366
PMCID: PMC2981588  PMID: 21125020
17.  Trends in opioid use and dosing among socio-economically disadvantaged patients 
Open Medicine  2011;5(1):e13-e22.
Background
Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality.
Methods
Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality.
Results
Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions.
Interpretation
Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed.
PMCID: PMC3205807  PMID: 22046214
18.  Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults 
Background
Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine.
Objectives
To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine in adults.
Search methods
We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010.
Selection criteria
We included randomised, double-blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment.
Main results
Ten studies (2769 participants, 4062 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12, 5.2 and 5.0 for 2-hour pain-free and 1- and 2-hour headache relief, respectively, when medication was taken for moderate to severe pain. Nausea, photophobia and phonophobia were reduced more with paracetamol than with placebo at 2 hours (NNTs of 7 to 11); more individuals were free of any functional disability at 2 hours with paracetamol (NNT 10); and fewer participants needed rescue medication over 6 hours (NNT 6).
Paracetamol 1000 mg plus metoclopramide 10 mg was not significantly different from oral sumatriptan 100 mg for 2-hour headache relief; there were no 2-hour pain-free data. There was no significant difference between the paracetamol plus metoclopramide combination and sumatriptan for relief of “light/noise sensitivity” at 2 hours, but slightly more individuals needed rescue medication over 24 hours with the combination therapy (NNT 17).
Adverse event rates were similar between paracetamol and placebo, and between paracetamol plus metoclopramide and sumatriptan. No serious adverse events occurred with paracetamol alone, but more “major” adverse events occurred with sumatriptan than with the combination therapy (NNH 32).
Authors’ conclusions
Paracetamol 1000 mg alone is an effective treatment for acute migraine headaches, and the addition of 10 mg metoclopramide gives short-term efficacy equivalent to oral sumatriptan 100 mg. Adverse events with paracetamol did not differ from placebo; “major” adverse events were slightly more common with sumatriptan than with paracetamol plus metoclopramide.
doi:10.1002/14651858.CD008040.pub2
PMCID: PMC4161111  PMID: 21069700
Acetaminophen [adverse effects; * therapeutic use]; Analgesics, Non-Narcotic [adverse effects; * therapeutic use]; Antiemetics [adverse effects; * therapeutic use]; Drug Therapy, Combination; Hyperacusis [drug therapy]; Metoclopramide [adverse effects; therapeutic use]; Migraine Disorders [* drug therapy]; Photophobia [drug therapy]; Randomized Controlled Trials as Topic; Sumatriptan [adverse effects; therapeutic use]; Adult; Humans
19.  Increases in the Use of Prescription Opioid Analgesics and the Lack of Improvement in Disability Metrics Among Users 
Background and Objectives
In the United States, use of oral opioid analgesics has been associated with increasing rates of addiction, abuse, and diversion. However, little is known about recent national use of non-illicit prescription opioid analgesics (those prescribed in a doctor-patient relationship), the primary source of these drugs for the general US population. Our primary objective was to examine trends in the use of prescription opioid analgesics in the United States and to identify defining characteristics of patient users of prescribed opioids from 2000 to 2010.
Methods
We used the nationally representative Medical Expenditure Panel Survey to examine trends in prescription oral opioid analgesic use from 2000 to 2010. We used survey design methods to make national estimates of adults (18 years and older) who reported receiving an opioid analgesic prescription (referred to as opioid users) and used logistic regression to examine predictors of opioid analgesic use. Our primary outcome measures were national estimates of total users of prescription opioid analgesics and total number of prescriptions. Our secondary outcome was that of observing changes in the disability and health of the users.
Results
The estimated total number of opioid analgesic prescriptions in the United States increased by 104%, from 43.8 million in 2000 to 89.2 million in 2010. In 2000, an estimated 7.4% (95% CI, 6.9–7.9) of adult Americans were prescription opioid users compared with 11.8% (95% CI, 11.2–12.4) in 2010. Based on estimates adjusted for changes in the general population, each year was associated with a 6% increase in the likelihood of receiving an opioid prescription from 2000 to 2010. Despite the apparent increase in use, there were no demonstrable improvements in the age- or sex-adjusted disability and health status measures of opioid users.
Conclusions
The use of prescription opioid analgesics among adult Americans has increased in recent years, and this increase does not appear to be associated with improvements in disability and health status among users. On a public health level, these data suggest that there may be an opportunity to reduce the prescribing of opioid analgesics without worsening of population health metrics.
doi:10.1097/AAP.0000000000000022
PMCID: PMC3955827  PMID: 24310049
20.  Reformulation of controlled-release oxycodone and pharmacy dispensing patterns near the US–Canada border 
Open Medicine  2012;6(4):e141-e145.
Background
In August 2010, a tamper-resistant formulation of controlled-release oxycodone (OxyContin-OP) was introduced in the United States but not in Canada. Our objective was to determine whether introduction of OxyContin-OP in the United States influenced prescription volumes for the original controlled-release oxycodone formulation (OxyContin) at Canadian pharmacies near the international border.
Methods
We conducted a population-based, serial, cross-sectional study of prescriptions dispensed from pharmacies in the 3 cities with the highest volume of US–Canada border crossings in Ontario: Niagara Falls, Windsor and Sarnia. We analyzed data on all outpatient prescriptions for OxyContin dispensed by Canadian pharmacies near each border crossing between 2010 Apr. 1 and 2012 Feb. 29. We calculated and compared monthly prescription rates, adjusted per 1000 population and stratified by tablet strength.
Results
The number of tablets dispensed near 4 border crossings in the 3 Canadian cities remained stable over the study period. However, the rate of dispensing at pharmacies near the Detroit–Windsor Tunnel increased roughly 4-fold between August 2010 and February 2011, from 505 to 1969 tablets per 1000 population. By April 2011, following warnings to prescribers and pharmacies regarding drug-seeking behaviour, the dispensing rate declined to 1683 tablets per 1000 population in this area. By November 2011, the rate had returned to levels observed in early 2010. Our analyses suggest that 242 075 excess OxyContin tablets were dispensed near the Detroit–Windsor Tunnel between August 2010 and October 2011.
Conclusions
Prescribing of the original formulation of controlled-release oxycodone rose substantially near a major international border crossing following the introduction of a tamper-resistant formulation in the United States. It is possible that the restriction of this finding to the area surrounding the Detroit–Windsor Tunnel reflects specific characteristics of this border crossing, including its high traffic volume, direct access to the downtown core and drug-trafficking patterns in the Detroit area. Our findings highlight the potential impact of cross-border differences in medication availability on drug-seeking behaviour.
PMCID: PMC3654510  PMID: 23687529
21.  Does Antimicrobial Prescription Data Improve Influenza Surveillance in VA? 
Introduction
Antimicrobial prescriptions are a new data source available to the Veterans Health Administration (VHA) biosurveillance program. Little is known about whether antiviral or antibacterial prescription data correlates with influenza ICD-9-CM coded encounters. We therefore evaluated the utility and timeliness of antiviral and antibacterial utilization for influenza surveillance.
Methods
Antiviral (oseltamivir, zanamivir) and antibacterial (azithromycin) outpatient (OP) prescriptions and OP ESSENCE coded respiratory syndrome, influenza-like-illness (ILI) or influenza-specific ICD-9-CM coded visits were analyzed covering the 2010–2011 and 2011–2012 influenza seasons (July 1, 2010–July 31, 2012) for 152 VA medical centers and 971 outpatient clinics using VA Corporate Data Warehouse and ESSENCE biosurveillance tool. Correlation analysis and peak comparisons were performed.
Results
For this time period, there were 2,880,415 respiratory, 1,578,421 ILI, and 5,158 influenza-specific coded visits. For both influenza seasons, respiratory and ILI visits peaked at weeks 1–2 whereas influenza-specific visits had two peaks between weeks 37–40 and weeks 6–11 (See Figure 1 and 2). The total number of prescriptions was 631,272 azithromycin; 8,362 oseltamivir; and 88 zanamivir (See Figure 2). Spearman rank correlation coefficients for daily antiviral prescriptions and influenza-coded visits were (0.70); ILI visits (0.64), and respiratory illness visits (0.62), respectively; and for azithromycin prescriptions 0.77, 0.98, and 0.97 respectively. Oseltamivir and zanamivir prescriptions only increased in 2010–2011 starting with week 51 and peaking week 6 and in 2011–2012 starting with week 8 and peaking week 14. However, azithromycin prescriptions tracked better across the entire influenza season (peaking at weeks 1–2 for both influenza seasons).
Conclusions
VA outpatient prescription data indicated that significantly more ILI and respiratory syndrome visits occurred compared to antiviral prescriptions dispensed with marginal temporal correlation between visits and antiviral prescriptions. Reasons for this finding require further investigation. Although we did not chart review the visit code and antimicrobial prescription in individual records, possible factors may be related to later presentation of cases, perceived lack of efficacy of antivirals, or insufficient coding of influenza. Thus, antiviral prescription data provided minimal additional information for influenza trend monitoring in VA although may still be useful a marker of more severe illness. Interestingly, azithromycin use tracked better with the onset and peaks of the influenza season. Further investigation is also needed to determine whether patients with influenza-specific coded encounters were also prescribed azithromycin and why relatively few encounters were coded with an influenza-specific code.
PMCID: PMC3692879
ESSENCE; Surveillance; Influenza; Veterans; Antimicrobials
22.  Trends in prescriptions for oxycodone and other commonly used opioids in the United States, 2000–2010 
Open Medicine  2012;6(2):e41-e47.
Background
Little information has been published on opioid prescribing practices in the United States as a whole for any year since 2005, despite increased use and increased overdoses. The objective of this study was to describe trends in prescribing rates and prescription sizes for commonly used opioids over the past decade.
Methods
We used 2 data systems. Vector One: National (VONA; data obtained for the period 2000–2009) is a service that can estimate the number of prescriptions dispensed by retail pharmacies. The Automation of Reports and Consolidated Orders System (ARCOS; data obtained for the period 2000–2010) is a mandatory reporting system that allows the US Drug Enforcement Administration to monitor certain controlled substances from the point of manufacture to the point of sale. ARCOS data represent the amount of controlled substances legitimately distributed at the retail level. We calculated crude prescription rates of various opioids from VONA data, total drug amounts distributed (as milligrams per 100 persons) from ARCOS data and morphine milligram equivalents (MME) per prescription by combining data from these 2 sources.
Results
The number of opioid prescriptions per 100 persons increased by 35.2%, from 61.9 to 83.7, during the period 2000–2009. The distribution of opioids to US pharmacies, in milligrams per 100 persons, increased by at least 100% for all selected opioids during the period 2000–2010. The average size of an oxycodone prescription increased by 69.7% (from 923 MME to 1566 MME) during the same period, while the average size of a hydrocodone prescription increased by 69.4% (from 170 MME to 288 MME). The increase for fentanyl was smaller (20.9%) (from 4804 MME to 5809 MME).
Interpretation
The rate of opioid prescribing, the amount of opioids distributed and the average prescription size all increased markedly in the United States over the past decade. Rates of death from opioid overdose also have increased steadily through 2008 and have likely continued to increase in subsequent years. Effective measures to prevent prescription drug overdoses have yet to be identified and employed.
PMCID: PMC3659213  PMID: 23696768
23.  The POPPY Research Programme protocol: investigating opioid utilisation, costs and patterns of extramedical use in Australia 
BMJ Open  2015;5(1):e007030.
Introduction
Opioid prescribing is increasing in many countries. In Australia, there is limited research on patterns of prescribing and access, or the outcomes associated with this use. The aim of this research programme is to use national dispensing data to estimate opioid use and costs, including problematic or extramedical use in the Australian population.
Methods and analysis
In a cohort of persons dispensed at least one opioid in 2013, we will estimate monthly utilisation and costs of prescribed opioids, overall and according to individual opioid formulations and strengths. In a cohort of new opioid users, commencing therapy between 1 July 2009 and 31 December 2013, we will examine patterns of opioid use including initiation of therapy, duration of treatment and concomitant use of opioids and other prescribed medicines. We will also examine patterns of extramedical opioid use based on indicators including excess dosing, use of more than one opioid concomitantly, doctor/pharmacy shopping and accelerated time to prescription refill.
Ethics and dissemination
This protocol was approved by the NSW Population and Health Services Ethics Committee (March 2014) and data access approved by the Department of Human Services External Review Evaluation Committee (June 2014). This will be one of the first comprehensive Australian studies with the capability to investigate individual patterns of use and track extramedical use. In the first instance our analysis will be based on 5 years of dispensing data but will be expanded with ongoing annual data updates. This research has the capability to contribute significantly to pharmaceutical policy within Australia and globally. In particular, the trajectory of extramedical prescription-opioid use has been the subject of limited research to date. The results of this research will be published widely in general medical, pharmacoepidemiology, addiction and psychiatry journals.
doi:10.1136/bmjopen-2014-007030
PMCID: PMC4316424  PMID: 25631315
EPIDEMIOLOGY; PAIN MANAGEMENT; PUBLIC HEALTH
24.  Paracetamol (acetaminophen) poisoning 
Clinical Evidence  2007;2007:2101.
Introduction
Mortality from paracetamol overdose is now about 0.4%, although severe liver damage occurs without treatment in at least half of people with blood paracetamol levels above the UK standard treatment line. In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute paracetamol poisoning? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: activated charcoal (single or multiple dose), gastric lavage, ipecacuanha, liver transplant, methionine, N-acetylcysteine.
Key Points
Paracetamol (acetaminophen) is a common means of self-poisoning in Europe and North America, often taken as an impulsive act of self-harm in young people. Mortality from paracetamol overdose is now about 0.4%, although without treatment, severe liver damage occurs in at least half of people with blood paracetamol levels above the UK standard treatment line.In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage.
Standard treatment of paracetamol overdose is acetylcysteine, which based on animal studies and clinical experience, is widely believed to reduce liver damage and mortality, although few studies have been done. Adverse effects from acetylcysteine include rash, urticaria, vomiting, and anaphylaxis which can, rarely, be fatal.We don't know what the optimal dose, route, and duration of acetylcysteine treatment should be. However, liver damage is less likely to occur if treatment is started within 8 to 10 hours of ingestion.
It is possible that methionine reduces the risk of liver damage and mortality after paracetamol poisoning compared with supportive care, but we don't know for sure.
We don't know whether activated charcoal, gastric lavage, or ipecacuanha reduce the risks of liver damage after paracetamol poisoning. The rapid absorption of paracetamol suggests that a beneficial effect from treatments that reduce gastric absorption is unlikely in many cases.
Liver transplantation may increase survival rates in people with fulminant liver failure after paracetamol poisoning compared with waiting list controls, but long-term outcomes are unknown.
PMCID: PMC2943815  PMID: 19450343
25.  The rate of prescribing gastrointestinal prophylaxis with either a proton pump inhibitor or an H2-receptor antagonist in Nova Scotia seniors starting nonsteroidal anti-inflammatory drug therapy 
BACKGROUND:
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used agents that can cause serious gastrointestinal (GI) side effects. For patients at increased risk of NSAID-related GI complications, prophylaxis with either a nonselective NSAID plus gastroprotective agent (GPA) or, alternatively, therapy with a cyclooxygenase-2 selective inhibitor with or without a GPA such as a proton pump inhibitor (PPI), is recommended.
AIM:
To describe the rate, timing and duration of GI prophylaxis in Nova Scotia seniors receiving nonselective NSAIDs.
METHODS:
The Nova Scotia Seniors’ Pharmacare Program beneficiaries for the years 1998 to 2002 were studied. A cohort of incident NSAID and GPA users was selected from all nonselective NSAID users (no prescribed NSAID dispensed 12 months before the index month and no GPA dispensed two months before the index prescription). Monthly coprescribing rates were calculated by dividing the number of patients in the cohort using GPAs by the number of NSAID users. GI prophylactic coprescribing was defined as the coprescribing rate present at the first month (index month) of prescribing an NSAID.
RESULTS:
The cohort consisted of 12,906 patients. Seventy-five per cent of the nonselective NSAID prescriptions dispensed were for up to two months duration, with only 2.3% longer than one year. GI prophylaxis was given to only 3.8% of patients starting NSAIDs who were not on a GPA in the two months before starting NSAIDs. Of this 3.8%, 92.7% of the patients received H2-receptor antagonists (H2RAs), and 7% received PPIs. The rate of H2RA coprescribing increased with the number of consecutive months on an NSAID from 3.5% in the first month to 24.1% at 48 months. For PPIs, the coprescribing rate increased from 0.3% to 1.9% of all NSAID users in the cohort. The rate of gastroprophylaxis coprescribing for patients receiving NSAIDs did not rise with increasing age.
CONCLUSION:
In Nova Scotian seniors using nonselective NSAIDs, the rate of GI prophylaxis was low. Most patients received H2RAs as GPAs despite evidence that they offer insufficient protection.
PMCID: PMC2947001  PMID: 20711527
Cohort study; Cyclooxygenase-2 selective inhibitor; Drug utilization; Gastrointestinal prophylaxis; Histamine-2 receptor antagonist; Misoprostol; Nonsteroidal anti-inflammatory drugs; NSAIDs; Proton pump inhibitor; Prescribing; Seniors

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