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by FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning
Concomitant use of opioids and benzodiazepines
FDA conducted two studies that showed an increasing trend in concomitant dispensing of opioid analgesics and benzodiazepines, and an increasing frequency of combined benzodiazepine and prescription opioid misuse, abuse, and overdose, as measured by national emergency department (ED) visit and overdose death rates (from prescribed or greater than prescribed doses).1, 2
The first study examined concomitant use patterns of opioid analgesics and benzodiazepines. Between 2002 and 2014, the annual number of patients dispensed an opioid analgesic increased 8 percent, from 75 million to 81 million, and the annual number of patients dispensed a benzodiazepine increased 31 percent, from 23 million to 30 million. During this period, the proportion of opioid analgesic recipients receiving an overlapping benzodiazepine prescription increased by 41 percent, which translates to an increase of more than 2.5 million opioid analgesic users receiving concomitant benzodiazepines in 2014, compared to 2002. The subgroups with the highest probability of receiving concomitant prescriptions were women, patients older than 65, and chronic users of opioid analgesics. However, in absolute numbers, concomitancy occurred most commonly in nonchronic opioid analgesic users, because they greatly outnumber chronic users.1
The second study2 used the Drug Abuse Warning Network (DAWN) to analyze ED visits due to nonmedical use of both prescription opioid analgesics and benzodiazepines, and the National Vital Statistics System Multiple Cause-of-Death file to analyze drug overdose deaths involving both prescription opioid analgesics and benzodiazepines. Between 2004 and 2011, the rate of nonmedical use-related ED visits involving both opioid analgesics and benzodiazepines increased from 11 to 34.2 per 100,000 population (p-trend <0.0001). During this same time period, drug overdose deaths, from taking prescribed or greater than prescribed doses and involving both opioid analgesics and benzodiazepines, increased from 0.6 to 1.7 per 100,000 (p-trend <0.0001). The proportion of prescription opioid analgesic overdose deaths in which benzodiazepines were also implicated increased from 18 percent to 31 percent during this time period (p-trend <0.0001).
Two additional studies published in the medical literature show more direct evidence of increased risk of adverse events occurring in patients dispensed both opioid analgesics and benzodiazepines. A prospective observational cohort study conducted in North Carolina found the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher (7.0 per 10,000 person-years; 95% confidence interval (CI): 6.3-7.8 ) than among patients dispensed opioid analgesics alone (0.7 per 10,000 person-years; 95% CI: 0.6-0.9).3 A case-cohort study examined the Veterans Health Administration data from 2004-2009 and found the risk of death from drug overdose increased among those with concomitant opioid analgesic and benzodiazepine prescriptions. Compared to patients taking opioid analgesics with no history of a benzodiazepine prescription, patients taking opioid analgesics with a history of a benzodiazepine prescription had an increased risk of fatal overdose (hazard ratio (HR)=2.33 (95% CI: 2.05-2.64)), and those with a current benzodiazepine prescription had a similarly increased risk (HR=3.86 (95% CI: 3.49-4.26)) for fatal overdose. In addition, the risk of drug overdose death increased as the daily benzodiazepine dose increased.4
Based on the trends of increased concomitant use of opioid analgesics and benzodiazepines as well as increased harms associated with concomitant use described in these four studies, we are requiring a new Boxed Warning to be added to the labeling of opioid analgesic and opioid cough medications and benzodiazepines. Related revisions will also be made to the Warnings and Precautions, Drug Interactions, and Patient Counseling Information sections of the labeling.
Concomitant use of opioids and other central nervous system (CNS) depressants
Recent studies in the literature show that concomitant use of opioid analgesics and CNS depressants other than benzodiazepines, including alcohol, is also associated with serious adverse events. One study reported that opioid analgesics contributed to 77 percent of deaths where benzodiazepines were determined to be a cause of death, and benzodiazepines contributed to 30 percent of deaths where opioid analgesics were determined to be a cause of death. This study also analyzed the involvement of other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) in these deaths and found that these CNS depressants were contributory to death in many cases where opioid analgesics were also implicated.5 A second study analyzed 2010 DAWN data and found that alcohol was involved in 18.5 percent of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.6
All of the studies were based on opioid analgesics; however, because of similar pharmacologic properties, it is reasonable to expect similar risks with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Based on these studies, the Boxed Warning for opioid analgesics and opioid cough medications will also highlight the risk of concomitant use with other CNS depressants.
Due to the unique medical needs and benefit/risk considerations for patients taking medication-assisted therapy (MAT) to treat opioid addiction and dependence, we are continuing to examine available evidence regarding the concomitant use of benzodiazepines and MAT drugs.
RESOURCE: http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm
Concomitant use of opioids and benzodiazepines
FDA conducted two studies that showed an increasing trend in concomitant dispensing of opioid analgesics and benzodiazepines, and an increasing frequency of combined benzodiazepine and prescription opioid misuse, abuse, and overdose, as measured by national emergency department (ED) visit and overdose death rates (from prescribed or greater than prescribed doses).1, 2
The first study examined concomitant use patterns of opioid analgesics and benzodiazepines. Between 2002 and 2014, the annual number of patients dispensed an opioid analgesic increased 8 percent, from 75 million to 81 million, and the annual number of patients dispensed a benzodiazepine increased 31 percent, from 23 million to 30 million. During this period, the proportion of opioid analgesic recipients receiving an overlapping benzodiazepine prescription increased by 41 percent, which translates to an increase of more than 2.5 million opioid analgesic users receiving concomitant benzodiazepines in 2014, compared to 2002. The subgroups with the highest probability of receiving concomitant prescriptions were women, patients older than 65, and chronic users of opioid analgesics. However, in absolute numbers, concomitancy occurred most commonly in nonchronic opioid analgesic users, because they greatly outnumber chronic users.1
The second study2 used the Drug Abuse Warning Network (DAWN) to analyze ED visits due to nonmedical use of both prescription opioid analgesics and benzodiazepines, and the National Vital Statistics System Multiple Cause-of-Death file to analyze drug overdose deaths involving both prescription opioid analgesics and benzodiazepines. Between 2004 and 2011, the rate of nonmedical use-related ED visits involving both opioid analgesics and benzodiazepines increased from 11 to 34.2 per 100,000 population (p-trend <0.0001). During this same time period, drug overdose deaths, from taking prescribed or greater than prescribed doses and involving both opioid analgesics and benzodiazepines, increased from 0.6 to 1.7 per 100,000 (p-trend <0.0001). The proportion of prescription opioid analgesic overdose deaths in which benzodiazepines were also implicated increased from 18 percent to 31 percent during this time period (p-trend <0.0001).
Two additional studies published in the medical literature show more direct evidence of increased risk of adverse events occurring in patients dispensed both opioid analgesics and benzodiazepines. A prospective observational cohort study conducted in North Carolina found the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher (7.0 per 10,000 person-years; 95% confidence interval (CI): 6.3-7.8 ) than among patients dispensed opioid analgesics alone (0.7 per 10,000 person-years; 95% CI: 0.6-0.9).3 A case-cohort study examined the Veterans Health Administration data from 2004-2009 and found the risk of death from drug overdose increased among those with concomitant opioid analgesic and benzodiazepine prescriptions. Compared to patients taking opioid analgesics with no history of a benzodiazepine prescription, patients taking opioid analgesics with a history of a benzodiazepine prescription had an increased risk of fatal overdose (hazard ratio (HR)=2.33 (95% CI: 2.05-2.64)), and those with a current benzodiazepine prescription had a similarly increased risk (HR=3.86 (95% CI: 3.49-4.26)) for fatal overdose. In addition, the risk of drug overdose death increased as the daily benzodiazepine dose increased.4
Based on the trends of increased concomitant use of opioid analgesics and benzodiazepines as well as increased harms associated with concomitant use described in these four studies, we are requiring a new Boxed Warning to be added to the labeling of opioid analgesic and opioid cough medications and benzodiazepines. Related revisions will also be made to the Warnings and Precautions, Drug Interactions, and Patient Counseling Information sections of the labeling.
Concomitant use of opioids and other central nervous system (CNS) depressants
Recent studies in the literature show that concomitant use of opioid analgesics and CNS depressants other than benzodiazepines, including alcohol, is also associated with serious adverse events. One study reported that opioid analgesics contributed to 77 percent of deaths where benzodiazepines were determined to be a cause of death, and benzodiazepines contributed to 30 percent of deaths where opioid analgesics were determined to be a cause of death. This study also analyzed the involvement of other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) in these deaths and found that these CNS depressants were contributory to death in many cases where opioid analgesics were also implicated.5 A second study analyzed 2010 DAWN data and found that alcohol was involved in 18.5 percent of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.6
All of the studies were based on opioid analgesics; however, because of similar pharmacologic properties, it is reasonable to expect similar risks with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Based on these studies, the Boxed Warning for opioid analgesics and opioid cough medications will also highlight the risk of concomitant use with other CNS depressants.
Due to the unique medical needs and benefit/risk considerations for patients taking medication-assisted therapy (MAT) to treat opioid addiction and dependence, we are continuing to examine available evidence regarding the concomitant use of benzodiazepines and MAT drugs.
RESOURCE: http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm
