Evaluating opioid analgesic prescribing limits: A narrative review.

PURPOSE: In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research. METHODS: We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization). RESULTS: Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms. CONCLUSIONS: We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies.

Keeping the Pharmacology in Pharmacoepidemiology.

The treatment of many medical conditions requires the use of multiple drugs. A study published recently in this journal nicely illustrates the need to consider the pharmacology of potentially interacting drugs when conducting pharmacoepidemiologic studies of patient safety outcomes associated with such interactions. By examining multiple streams of data, we can piece together the risks and the mechanisms of action underlying those risks, and provide useful information for clinicians and patients to use multiple pharmacotherapies safely.

Patterns of opioid analgesic use in the U.S., 2009 to 2018.

ABSTRACT: Although overall outpatient dispensing of opioid analgesic prescriptions has declined, there may still be overprescribing. Understanding how many opioid analgesic units, primarily tablets, are dispensed with the intention of shorter-vs longer-term use can inform public health interventions. We used pharmacy prescription data to estimate the number of opioid analgesic tablets dispensed annually in the U.S. We studied patterns of new use of opioid analgesics by evaluating how many opioid analgesic prescriptions and tablets were dispensed to patients with no opioid analgesic prescriptions in the previous year. Estimated opioid analgesic tablets dispensed declined from a peak of 17.8 billion in 2012 to 11.1 billion in 2018. Patients newly starting opioid analgesics declined from 47.4 million patients in 2011 to 37.1 million patients in 2017. Approximately 40% fewer tablets were dispensed within a year to patients starting in 2017 (2.4 billion) compared with 2011 (4.0 billion). In 2011, patients with ≥5 opioid analgesic prescriptions within a year were dispensed 2.2 billion tablets (55% of all tablets in our study). This declined by 52% to 1.1 billion tablets (44% of all tablets) in 2017. Tablets dispensed within a year to patients with <5 opioid analgesic prescriptions declined by 26% from 2011 to 2017. Patients with ≥5 prescriptions comprised a small and decreasing proportion of all patients newly starting therapy. However, these patients received almost half of all tablets dispensed within a year to patients in our study, despite a larger decline than tablets dispensed to patients with <5 prescriptions within a year.

Concomitant Filled Prescriptions of Oxymorphone or Oxycodone with CYP3A Inhibitors and Inducers.

BACKGROUND: Oxymorphone's metabolism does not involve the hepatic cytochrome P450 (CYP) system. The effect of this pharmacokinetic feature of oxymorphone on opioid prescribing is unknown. OBJECTIVE: To assess the relative frequency with which oxymorphone and oxycodone (a CYP3A-metabolized opioid analgesic) were each prescribed to patients concomitantly receiving CYP3A-modifying drugs (i.e., inducers and inhibitors) to characterize opioid-prescribing patterns in patients at risk for CYP3A-related drug interactions. METHODS: We analyzed the Sentinel Distributed Database from January 1, 2013, to December 31, 2016, to identify the proportion of patients with concomitant dispensing of selected CYP3A modifiers among initiators of oxymorphone. We then repeated the analysis using oxycodone instead of oxymorphone. We conducted sensitivity analyses that varied the washout periods for each opioid to account for potential opioid switching. RESULTS: In the primary analysis, the proportion of patients with concomitant incident dispensings of oxymorphone and selected CYP3A modifiers was 3.26% (95% CI = 3.09%-3.43%), and the proportion of patients with incident dispensings of oxycodone and selected CYP3A modifiers was 2.82% (95% CI = 2.79%-2.85%). The difference between proportions was 0.43% (95% CI = 0.26%-0.60%). Sensitivity analyses that varied the washout periods for each opioid with respect to the other opioid to account for switching yielded similar results. CONCLUSIONS: We observed similar proportions of patients using selected CYP3A modifiers concomitantly with both oxymorphone and oxycodone. While the CIs of the point estimates did not overlap, the absolute differences between the proportions were small. DISCLOSURES: This project was supported by Task Order HHSF22301001T under Master Agreement HHSF223201400030I from the U.S. Food and Drug Administration (FDA). The FDA approved the study protocol, including the statistical analysis plan, and reviewed and approved the manuscript. Coauthors from the FDA participated in the results interpretation and in the preparation and decision to submit the manuscript for publication. Coyle, Money, Staffa, Meyer, and Woods are employed by the FDA. The other authors have no financial conflicts of interest to report. The views expressed are those of the authors and not necessarily those of the U.S. Department of Health and Human Services, U.S. Food and Drug Administration.

Days' Supply of Initial Opioid Analgesic Prescriptions and Additional Fills for Acute Pain Conditions Treated in the Primary Care Setting - United States, 2014.

During 2017, opioids were associated with 47,600 deaths in the United States, approximately one third of which involved a prescription opioid (1). Amid concerns that overprescribing to patients with acute pain remains an essential factor underlying misuse, abuse, diversion, and unintentional overdose, several states have restricted opioid analgesic prescribing (2,3). To characterize patterns of opioid analgesic use for acute pain in primary care settings before the widespread implementation of limits on opioid prescribing (2,3), patients filling an opioid analgesic prescription for acute pain were identified from a 2014 database of commercial claims. Using a logistic generalized additive model, the probability of obtaining a refill was estimated as a function of the initial number of days supplied. Among 176,607 patients with a primary care visit associated with an acute pain complaint, 7.6% filled an opioid analgesic prescription. Among patients who received an initial 7-day supply, the probability of obtaining an opioid analgesic prescription refill for nine of 10 conditions was <25%. These results suggest that a ≤7-day opioid analgesic prescription might be sufficient for most, but not all, patients seen in primary care settings with acute pain who appear to need opioid analgesics. However, treatment strategies should account for patient and condition characteristics, which might alternatively reduce or extend the anticipated duration of benefit from opioid analgesic therapy.

Concomitant use of buprenorphine for medication-assisted treatment of opioid use disorder and benzodiazepines: Using the prescription behavior surveillance system.

BACKGROUND: Despite clinical guidelines discouraging the practice, it is well-documented that the concomitant use of benzodiazepines and opioid analgesics occurs regularly. Information on concomitant use of buprenorphine for medication-assisted treatment (MAT) of opioid use disorder (OUD) and benzodiazepines, however, is limited. Thus, we aimed to describe real-world drug dispensing patterns for the concomitant use of buprenorphine products approved for MAT and benzodiazepines. METHODS: We examined concomitant use of buprenorphine for MAT and benzodiazepines using the 2013 Prescription Behavior Surveillance System data from eight states. For prescription-level analysis, we estimated the proportion of concomitant buprenorphine and benzodiazepine prescriptions and the proportions of concomitant prescriptions prescribed by the same provider (co-prescribing) and dispensed by the same pharmacy (co-dispensing) for each state. For patient-level analysis, we calculated the proportion of patients with ≥1 buprenorphine therapy episode overlapping with a benzodiazepine episode, i.e., concomitant users, and the proportion of concomitant users who experienced co-prescribing or co-dispensing. RESULTS: In 2013, 1,925,072 prescriptions of buprenorphine products for MAT were dispensed to 190,907 patients in eight states. Approximately 1 in 8 buprenorphine prescriptions was used concomitantly with ≥1 benzodiazepine prescription(s). Co-prescribing proportions ranged from 22.2 to 64.6% across states, while co-dispensing proportions ranged from 54.7 to 91.0%. Approximately 17.7% of patients had >1 buprenorphine episode overlapping a benzodiazepine episode for ≥7 cumulative days' supply. Among these patients, 33.1-65.2% experienced co-prescribing, and 65.1-93.3% experienced co-dispensing. CONCLUSIONS: The concomitant use of buprenorphine for MAT and benzodiazepines occurs frequently, with variations by state in co-prescribing and co-dispensing.

Patterns of Immediate-Release and Extended-Release Opioid Analgesic Use in the Management of Chronic Pain, 2003-2014.

Importance: Many stakeholders are working to improve the safe use of immediate-release (IR) and extended-release/long-acting (ER/LA) opioid analgesics. However, little information exists regarding the relative use of these 2 formulations in chronic pain management. Objectives: To describe the distribution of IR and ER/LA opioid analgesic therapy duration and examine adding and switching patterns among patients receiving long-term IR opioid analgesic therapy, defined as at least 90 consecutive days of IR formulation use. Design, Setting, and Participants: A retrospective cohort study of 169 million individuals receiving opioid analgesics from across 90% of outpatient retail pharmacies in the United States from January 1, 2003, to December 31, 2014, using the IQVIA Health Vector One: Data Extract Tool. Analyses were conducted from March 2015 to June 2017. Exposures: Receipt of dispensed IR or ER/LA opioid analgesic prescription. Main Outcomes and Measures: Distribution of therapy frequency and duration of IR and ER/LA opioid analgesic use, and annual proportions of patients receiving long-term IR opioid analgesic therapy who added an ER/LA formulation while continuing to use an IR formulation, switched to an ER/LA formulation, or continued receiving IR opioid analgesic therapy only. Results: Among the 169 280 456 patients included in this analysis, 168 315 458 patients filled IR formulations and 10 216 570 patients filled ER/LA formulations. A similar percentage of women received ER/LA (55%) and IR (56%) formulations, although those receiving ER/LA formulations (72%) were more likely to be aged 45 years or older compared with those receiving IR formulations (46%). The longest opioid analgesic episode duration was 90 days or longer for 11 563 089 patients (7%) filling IR formulations and 3 103 777 patients (30%) filling ER/LA formulations. The median episode duration was 5 days (interquartile range, 3-10 days) for patients using IR formulations and 30 days (interquartile range, 21-74 days) for patients using ER/LA formulations. From January 1, 2003, to December 31, 2014, a small and decreasing proportion of patients with long-term IR opioid analgesic therapy added (3.8% in 2003 to 1.8% in 2014) or switched to (1.0% in 2003 to 0.5% in 2014) an ER/LA formulation. Conclusions and Relevance: Most patients receiving opioid analgesics, whether for short or extended periods, use IR formulations. Once receiving long-term IR opioid analgesic therapy, patients are unlikely to add or switch to an ER/LA formulation.

Opioid analgesic dose and the risk of misuse, overdose, and death: A narrative review.

PURPOSE: Despite the rise in serious adverse events paralleling increased prescription opioid analgesic use in the United States over the past 2 decades, the association between opioid analgesic dose and the risk of serious adverse health outcomes is incompletely characterized. We sought to synthesize the medical literature for observational studies examining the association between opioid analgesic dose and the risk of serious adverse health outcomes, with particular attention to the outcomes of misuse, abuse, addiction, overdose, and death. METHODS: Searching MEDLINE using PubMed and bibliography review, we identified 22 observational studies published between 2000 and 2015 that assessed the association between opioid analgesic dose and the risk of serious adverse health outcomes. Some of these studies had significant methodological limitations. Twelve reviewed studies examined the outcomes of misuse, overdose, or death; no studies examining the risk of addiction or abuse met our criteria for inclusion. RESULTS: The results of multiple studies clearly indicate an increasing risk of serious adverse health outcomes associated with increasing opioid analgesic dose. In particular, the risk of misuse, overdose, and death increases with increasing opioid analgesic dose. However, there is no opioid dose inflection point beyond which the risk of these adverse health outcomes increases. No opioid analgesic dose is without risk. CONCLUSIONS: The reviewed studies show an increasing risk of serious adverse health outcomes-including misuse, overdose, and death-associated with increasing opioid analgesic dose. Further research is needed to characterize the relationship between opioid analgesic dose and the risk of addiction and abuse. This analysis could inform policy actions for regulators and clinical decision making for providers.

Trends in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.

INTRODUCTION: Although many clinical guidelines caution against the combined use of opioids and benzodiazepines, overdose deaths and emergency department visits involving the co-ingestion of these drugs are increasing. METHODS: In this ecologic time series study, the IMS Health Total Patient Tracker was used to describe nationally projected trends of patients receiving opioids and benzodiazepines in the U.S. outpatient retail setting between January 2002 and December 2014. The IMS Health Data Extract Tool was used to examine trends in the concomitant prescribing of these two medication classes among 177 million individuals receiving opioids during this period. The annual proportion of opioid recipients who were prescribed benzodiazepines concomitantly was calculated and stratified by gender, age, duration of opioid use, immediate-release versus extended-release/long-acting opioids, and benzodiazepine molecule. The proportion of patients with concomitancy receiving opioids and benzodiazepines from the same prescriber was also analyzed. Analyses were conducted from April to June 2015. RESULTS: The nationally projected number of patients receiving opioids and benzodiazepines increased by 8% and 31%, respectively, from 2002 to 2014. During this period, the annual proportion of opioid recipients dispensed a benzodiazepine concomitantly increased from 6.8% to 9.6%, which corresponded to a relative increase of 41%. Approximately half of these patients received both prescriptions from the same prescriber on the same day. Concomitancy was more common in patients receiving opioids for ≥90 days, women, and the elderly. CONCLUSIONS: Concomitant prescribing of opioids and benzodiazepines is increasing and may play a growing role in adverse patient outcomes related to these medications.

Trends in rates of acetaminophen-related adverse events in the United States.

PURPOSE: The goal of this study is to summarize trends in rates of adverse events attributable to acetaminophen use, including hepatotoxicity and mortality. METHODS: A comprehensive analysis of data from three national surveillance systems estimated rates of acetaminophen-related events identified in different settings, including calls to poison centers (2008-2012), emergency department visits (2004-2012), and inpatient hospitalizations (1998-2011). Rates of acetaminophen-related events were calculated per setting, census population, and distributed drug units. RESULTS: Rates of poison center calls with acetaminophen-related exposures decreased from 49.5/1000 calls in 2009 to 43.5/1000 calls in 2012. Rates of emergency department visits for unintentional acetaminophen-related adverse events decreased from 58.0/1000 emergency department visits for adverse drug events in 2009 to 50.2/1000 emergency department visits in 2012. Rates of hospital inpatient discharges with acetaminophen-related poisoning decreased from 119.8/100 000 hospitalizations in 2009 to 108.6/100 000 hospitalizations in 2011. After 2009, population rates of acetaminophen-related events per 1 million census population decreased for poison center calls and hospitalizations, while emergency department visit rates remained stable. However, when accounting for drug sales, the rate of acetaminophen-related events (per 1 million distributed drug units) increased after 2009. Prior to 2009, the rates of acetaminophen-related hospitalizations had been slowly increasing (p-trend = 0.001). CONCLUSIONS: Acetaminophen-related adverse events continue to be a public health burden. Future studies with additional time points are necessary to confirm trends and determine whether recent risk mitigation efforts had a beneficial impact on acetaminophen-related adverse events. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Measures to quantify the abuse of prescription opioids: a review of data sources and metrics.

PURPOSE: The abuse and nonmedical use of prescription opioids and its subsequent consequences are an important public health concern. This phenomenon has paralleled the increase in the therapeutic use of opioids for pain management. There is thus a need to measure prescription opioid abuse to understand trends over time and to compare abuse of one product to another. The purpose of this review is to provide an overview of the strengths and weaknesses of frequently used numerators and denominators in "abuse ratios" (ARs). METHODS: For this review, we critically evaluated the various measures to quantify drug availability and the available data sources to measure prescription opioid abuse. RESULTS: There are currently no commonly adopted metrics for measuring either the prevalence of opioid abuse, or abuse relative to drug availability. Because the settings, manifestations, and severity of abuse can vary from one person to the next, no one measure of abuse, abuse-related outcome, or drug exposure is ideal. Each measure of abuse captures a specific facet of abuse, but not the whole spectrum. Reliable estimation of population-adjusted or utilization-adjusted rates of abuse can be accomplished with a prescription opioid AR. This metric estimates the prevalence of abuse in a given population or abuse relative to how much drug is available, and, in certain cases, can be used to compare abuse among various opioid drugs. AR measurements in the literature vary in the inclusion of specific measures of abuse and availability, and there is little consensus in the field regarding which measures allow for the most appropriate approximation of the extent of abuse, and for comparisons among opioids. Crude numbers of outcomes related to abuse (e.g., emergency department visits, treatment admissions, and overdoses) cannot be properly understood without context as these may overestimate or underestimate the true scope and severity of prescription opioid abuse. They can, however, serve as numerators in properly constructed ARs. The denominator of the AR provides the necessary context by accounting for populations at risk or drug availability (e.g., prescriptions or tablets dispensed, unique recipients of dispensed drug, total patient days of therapy, or kilograms sold), and each comes with its own set of assumptions to consider. CONCLUSIONS: Moving forward, it is important that there be a common understanding in the scientific community regarding how to select appropriate measures to serve as numerators and denominators in AR calculations, and how to interpret the resultant findings. There is no single best measure of abuse for use as a numerator in an AR, and each must be chosen and interpreted in the context of what it measures. For public health considerations, one must always look at both absolute numbers and adjusted numbers. When conducting multiple analyses using different measures of exposure as denominators, differences in ARs are not unexpected, but one should explore why there are differences and assess the appropriateness of each of the denominators.

Trends of outpatient prescription drug utilization in US children, 2002-2010.

OBJECTIVE: To describe trends in outpatient prescription drug utilization in US children and the changes in major areas of pediatric therapeutic use for the years 2002 through 2010. METHODS: Large prescription databases (the IMS Vector One: National and Total Patient Tracker) were used to examine national drug utilization patterns for the US pediatric population (ages 0-17 years) from 2002 through 2010. RESULTS: In 2010, a total of 263.6 million prescriptions were dispensed to the US pediatric population, 7% lower than in 2002, while prescriptions dispensed to the adult population increased 22% during the same time. Analysis of pediatric drug utilization trends for the top 12 therapeutic areas in 2010 compared with 2002 showed decreases in systemic antibiotics (-14%), allergies (-61%), pain (-14%), depression (-5%), and cough/cold without expectorant (-42%) prescriptions, whereas asthma (14%), attention-deficit/hyperactivity disorder (46%), and contraceptive (93%) prescriptions increased. In 2010, amoxicillin was the most frequently dispensed prescription in infants (aged 0-23 months) and children (aged 2-11 years). Methylphenidate was the top prescription dispensed to adolescents (aged 12-17 years). Off-label use was identified, particularly for lansoprazole; ~358,000 prescriptions were dispensed in 2010 for infants <1 year old. CONCLUSIONS: Changes in the patterns of pediatric drug utilization were observed from 2002 to 2010. Changes include a decrease in antibiotic use and an increase in attention-deficit/hyperactivity disorder medication use during the examined time. This article provides an overview of pediatric outpatient drug utilization, which could set the stage for further in-depth analyses.

Medication Exposure in Pregnancy Risk Evaluation Program.

To describe a program to study medication safety in pregnancy, the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). MEPREP is a multi-site collaborative research program developed to enable the conduct of studies of medication use and outcomes in pregnancy. Collaborators include the U.S. Food and Drug Administration and researchers at the HMO Research Network, Kaiser Permanente Northern and Southern California, and Vanderbilt University. Datasets have been created at each site linking healthcare data for women delivering an infant between January 1, 2001 and December 31, 2008 and infants born to these women. Standardized data files include maternal and infant characteristics, medication use, and medical care at 11 health plans within 9 states; birth certificate data were obtained from the state departments of public health. MEPREP currently involves more than 20 medication safety researchers and includes data for 1,221,156 children delivered to 933,917 mothers. Current studies include evaluations of the prevalence and patterns of use of specific medications and a validation study of data elements in the administrative and birth certificate data files. MEPREP can support multiple studies by providing information on a large, ethnically and geographically diverse population. This partnership combines clinical and research expertise and data resources to enable the evaluation of outcomes associated with medication use during pregnancy.

Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure.

PURPOSE: Osteonecrosis of the jaw (ONJ) is a serious complication associated with bisphosphonate therapy, but its epidemiology in the setting of oral bisphosphonate therapy is poorly understood. The present study examined the prevalence of ONJ in patients receiving chronic oral bisphosphonate therapy. MATERIALS AND METHODS: We mailed a survey to 13,946 members who had received chronic oral bisphosphonate therapy as of 2006 within a large integrated health care delivery system in Northern California. Respondents who reported ONJ, exposed bone or gingival sores, moderate periodontal disease, persistent symptoms, or complications after dental procedures were invited for examination or to have their dental records reviewed. ONJ was defined as exposed bone (of >8 weeks' duration) in the maxillofacial region in the absence of previous radiotherapy. RESULTS: Of the 8,572 survey respondents (71 +/- 9 years, 93% women), 2,159 (25%) reported pertinent dental symptoms. Of these 2,159 patients, 1,005 were examined and an additional 536 provided dental records. Nine ONJ cases were identified, representing a prevalence of 0.10% (95% confidence interval 0.05% to 0.20%) among the survey respondents. Of the 9 cases, 5 had occurred spontaneously (3 in palatal tori) and 4 occurred in previous extraction sites. An additional 3 patients had mandibular osteomyelitis (2 after extraction and 1 with implant failure) but without exposed bone. Finally, 7 other patients had bone exposure that did not fulfill the criteria for ONJ. CONCLUSIONS: ONJ occurred in 1 of 952 survey respondents with oral bisphosphonate exposure (minimum prevalence of 1 in 1,537 of the entire mailed cohort). A similar number had select features concerning for ONJ that did not meet the criteria. The results of the present study provide important data on the spectrum of jaw complications among patients with oral bisphosphonate exposure.

Emergency department visits attributed to selected analgesics, United States, 2004-2005.

PURPOSE: To estimate the rate of emergency department (ED) visits attributed to selected analgesic-containing medications. METHODS: We used a nationally representative public health surveillance system to provide estimates of adverse events identified in EDs, and a national telephone survey to provide estimates of selected analgesic-containing medication usage in the US population, 2004-2005. Analysis was restricted to products containing acetaminophen, aspirin, ibuprofen, or naproxen. Types of adverse events and outcomes were compared. Estimated numbers and rates of ED visits were calculated by analgesic groupings and patient age groups. RESULTS: The estimated overall rate of ED visits attributed to analgesic-containing medications was 1.6 visits /100,000 users per week. The very old and very young had the highest rates; there were minimal differences in rates by patient gender. Acetaminophen was the attributed drug with the most estimated ED visits and generally had the highest rates of ED visits. The highest estimated rate for a specific product group was among subjects 18-64 years of age taking narcotic-acetaminophen products (8.9 ED visits /100,000 users per week). Overall, 12% of patients presenting to EDs with analgesic-attributed events were hospitalized. CONCLUSIONS: Rates of ED visits due to analgesics vary depending on the age of the patient and the product; most do not result in hospitalization. Although the rate of emergency visits is relatively low, because of the wide use of the analgesics, public health impact is considerable.

Onset of acute myocardial infarction after use of non-steroidal anti-inflammatory drugs.

PURPOSE: To examine the association between cyclooxygenase-2 (COX-2) selective and traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and incident acute myocardial infarction (AMI), and to address unanswered questions regarding the contour of risk over time. METHODS: A cohort of new NSAID users aged 40-84 years was followed for the occurrence of first AMI. Data were collected within the General Practice Research Database (GPRD) from 1 January 1997 to 31 December 2004. RESULTS: The study population included 1185 AMI events (889 probable and 296 possible) from a cohort of 283 136 patients. After adjustment for demographic and cardiovascular risk factors, the hazard ratio (HR) for AMI was significantly increased for both coxib (2.11, 95% confidence interval (CI) 1.04-4.26) and non-coxib (2.24, 95%CI 1.13-4.42) COX-2 selective NSAIDs when compared to remote exposure to NSAIDs, but was not increased for traditional NSAIDs. Stratifying exposure into the first month of use versus use beyond 1 month, the risk of AMI was increased during the first month of COX-2 selective NSAIDs use, but not later (3.43, 95%CI 1.66-7.07 and 1.88, 95%CI 0.82-4.31, respectively p-value for interaction = 0.6). CONCLUSIONS: The results suggest that the use of coxib and non-coxib COX-2 selective NSAIDs was associated with an elevated risk of AMI within the first month of exposure. Recent past exposure to NSAID was not associated with a similar increase in risk.