The FDA has issued new information about the combined use of medication-assisted treatment (MAT) drugs with benzodiazepines or other central nervous system depressants. See the FDA Drug Safety Communication issued on 9-20-2017.
[ 8-31-2016 ] A U.S. Food and Drug Administration (FDA) review has found that the growing combined use of opioid medicines with benzodiazepines or other drugs that depress the central nervous system (CNS) has resulted in serious side effects, including slowed or difficult breathing and deaths. Opioids are used to treat pain and cough; benzodiazepines are used to treat anxiety, insomnia, and seizures. In an effort to decrease the use of opioids and benzodiazepines, or opioids and other CNS depressants, together, we are adding Boxed Warnings, our strongest warnings, to the drug labeling of prescription opioid pain and prescription opioid cough medicines, and benzodiazepines.
Health care professionals should limit prescribing opioid pain medicines with benzodiazepines or other CNS depressants only to patients for whom alternative treatment options are inadequate. If these medicines are prescribed together, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Warn patients and caregivers about the risks of slowed or difficult breathing and/or sedation, and the associated signs and symptoms. Avoid prescribing prescription opioid cough medicines for patients taking benzodiazepines or other CNS depressants, including alcohol.
Patients taking opioids with benzodiazepines, other CNS depressant medicines, or alcohol, and caregivers of these patients, should seek medical attention immediately if they or someone they are caring for experiences symptoms of unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Unresponsiveness means that the person doesn’t answer or react normally or you can’t wake them up. Talk with your health care professional if you have questions or concerns about taking opioids or benzodiazepines (see List of Prescription Opioid Pain and Cough Medicines, and List of Benzodiazepines and Other CNS Depressants).
Opioids are a class of powerful narcotic medicines that are used to treat pain severe enough to warrant use of an opioid when other pain medicines cannot be taken or are not able to provide enough pain relief. They also have serious risks including misuse and abuse, addiction, overdose, and death. Opioids such as codeine and hydrocodone are also approved in combination with other medicines to reduce coughing. Benzodiazepines are a class of medicines that are widely used to treat conditions including anxiety, insomnia, and seizures.
We conducted and reviewed several studies showing that serious risks are associated with the combined use of opioids and benzodiazepines, other drugs that depress the CNS, or alcohol (see Data Summary).1-6 Based on these data, we are requiring several changes to reflect these risks in the opioid and benzodiazepine labeling, and new or revised patient Medication Guides. These changes include the new Boxed Warnings and revisions to the Warnings and Precautions, Drug Interactions, and Patient Counseling Information sections of the labeling.
We are continuing to evaluate the evidence regarding combined use of benzodiazepines or other CNS depressants with medication-assisted therapy (MAT) drugs used to treat opioid addiction and dependence. We are also evaluating whether labeling changes are needed for other CNS depressants, and will update the public when more information is available.
We urge patients and health care professionals to report side effects involving opioids, benzodiazepines, or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
|Generic Name||Found in Brand Name(s)|
|buprenorphine||Belbuca, Buprenex, Butrans|
|butorphanol||No brand name currently marketed|
|codeine||Fioricet w/ codeine, Fiorinal w/ codeine, Soma Compound w/ codeine, Tylenol w/ codeine, Prometh VC w/ codeine (cough), Triacin-C (cough), Tuzistra-XR (cough)|
|fentanyl||Abstral, Actiq, Duragesic, Fentora, Ionsys, Lazanda, Sublimaze, Subsys|
|hydrocodone||Anexsia, Hysingla ER, Lortab, Norco, Reprexain, Vicodin, Vicoprofen, Zohydro ER, Flowtuss (cough), Hycofenix (cough), Obredon (cough), Rezira (cough), Tussicaps (cough), Tussigon (cough), Tussionex Pennkinetic (cough), Vituz (cough), Zutripro (cough)|
|hydromorphone||Dilaudid, Dilaudid-HP, Exalgo|
|morphine||Astramorph PF, Duramorph PF, Embeda, Infumorph, Kadian, Morphabond, MS Contin|
|oxycodone||Oxaydo, Oxycet, Oxycontin, Percocet, Percodan, Roxicet, Roxicodone, Xartemis XR|
|oxymorphone||Opana, Opana ER|
|tapentadol||Nucynta, Nucynta ER|
|tramadol||Conzip, Ultracet, Ultram, Ultram ER|
|Generic Name||Brand Name(s)|
|alprazolam||Xanax, Xanax XR|
|diazepam||Diastat, Diastat Acudial, Valium|
|estazolam||No brand name currently marketed|
|flurazepam||No brand name currently marketed|
|oxazepam||No brand name currently marketed|
|Other Sleep Drugs and Tranquilizers|
|secobarbital sodium||Seconal sodium|
|zolpidem||Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist|
|carisoprodol||Soma, Soma Compound, Soma Compound w/ codeine|
|chlorzoxazone||No brand name currently marketed|
|dantrolene||Dantrium, Revonto, Ryanodex|
|orphenadrine||No brand name currently marketed|
|aripiprazole||Abilify, Abilify Maintena, Aristada|
|chlorpromazine||No brand name currently marketed|
|clozapine||Clozaril, Fazaclo ODT, Versacloz|
|fluphenazine||No brand name currently marketed|
|molindone||No brand name currently marketed|
|olanzapine||Symbyax, Zyprexa, Zyprexa Relprevv, Zyprexa Zydis|
|paliperidone||Invega, Invega Sustenna, Invega Trinza|
|perphenazine||No brand name currently marketed|
|quetiapine||Seroquel, Seroquel XR|
|risperidone||Risperdal, Risperdal Consta|
|thioridazine||No brand name currently marketed|
|trifluoperazine||No brand name currently marketed|
*This is not a comprehensive list.
- Opioids are powerful prescription medicines that can help manage pain when other treatments and medicines cannot be taken or are not able to provide enough pain relief. Opioids such as codeine and hydrocodone are also available in combination with other medicines to treat coughing (see List of Prescription Opioid Pain and Cough Medicines).
- Common side effects of opioids include drowsiness, dizziness, nausea, vomiting, constipation, and slowed or difficult breathing. Opioids also carry serious risks, including misuse and abuse, addiction, overdose, and death.
- Benzodiazepines are a class of medicines that are widely used to treat conditions including anxiety, insomnia, and seizures (see List of Benzodiazepines and Other CNS Depressants).
- Common side effects of benzodiazepines include drowsiness, dizziness, weakness, and physical dependence.
- Both opioids and benzodiazepines depress the central nervous system (CNS).
- Both opioids and benzodiazepines are commonly prescribed drugs. In 2014 in the U.S., 81 million patients were dispensed an opioid, and 30 million patients were dispensed a benzodiazepine.1
- Combining opioid pain or prescription opioid cough medicines with medicines called benzodiazepines, which are used for anxiety, insomnia, and seizures, can result in extreme sleepiness, slowed or difficult breathing, coma, or death. These serious side effects result because both opioids and benzodiazepines impact (depress) the central nervous system (CNS). The CNS controls most of the functions of the brain and body.
- These serious side effects can also occur when opioids are combined with other medicines that depress the CNS or alcohol (see List of Prescription Opioid Pain and Cough Medicines, and List of Benzodiazepines and Other CNS Depressants).
- Do not drink alcohol with any of these medicines. Alcohol also depresses the CNS and can increase the risk for these serious and life-threatening side effects.
- Given the serious side effects that may occur, if you are already taking both opioids and benzodiazepines or other medicines that depress the CNS, talk to your health care professional to see if continued combined use is needed.
- Do not take opioid pain medicines with benzodiazepines or other medicines that depress the CNS without discussing it with your health care professional. Do not take opioid cough medicines with benzodiazepines or other medicines that depress the CNS.
- Always inform all your health care professionals about all the medicines you are taking, including prescription and over-the-counter (OTC) medicines. It is helpful to keep a list of all your current medicines in your wallet or another location where it is easily retrieved. You can fill out and print a copy of My Medicine Record.
- If you are taking an opioid pain or cough medicine or a benzodiazepine and don’t know if you are also receiving other medicines that may interact, contact your pharmacist or other health care professional.
- If you are taking both an opioid pain medicine and a benzodiazepine or other medicine that depresses the CNS, avoid driving or operating heavy machinery until you know how the medicines affect you.
- Opioids are powerful medicines that can help manage pain when other treatments and medicines are not able to provide enough pain relief. However, even when used properly, opioids also carry serious risks, and they can be misused and abused, causing addiction, overdose, and death. Benzodiazepines also carry the risk of dependence.
- It is important to lock up opioids and benzodiazepines and to dispose of them properly to keep them from being taken accidentally by children or falling into the wrong hands.
- Talk to your health care professional if you have any questions or concerns about opioids, benzodiazepines, or other medicines you are taking.
- Read the patient Medication Guide or patient information leaflet that comes with your filled prescription(s).
- Report side effects from opioids, benzodiazepines, or other medicines to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of this page.
- Concomitant use of opioid pain or cough medicines and benzodiazepines, other central nervous system (CNS) depressants, or alcohol may result in profound sedation, respiratory depression, coma, and/or death.
- Reserve concomitant prescribing of opioid analgesics with benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Avoid use of prescription opioid cough medications in patients on benzodiazepines or other CNS depressants.
- If the decision is made to concomitantly prescribe a benzodiazepine or other CNS depressant for an indication other than epilepsy with an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.
- If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid, and titrate based on clinical response.
- Monitor patients closely for respiratory depression and sedation.
- Advise both patients and caregivers about the risks of respiratory depression and sedation if opioids are used with benzodiazepines, alcohol, or other CNS depressants (including illicit or recreational drugs).
- Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid and benzodiazepine or other CNS depressant have been determined.
- Screen patients for risk of substance-use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants, including alcohol and illicit or recreational drugs.
- Encourage patients to read the Medication Guides or patient information leaflets that come with their filled prescription(s).
- Report adverse events involving opioids, benzodiazepines, or other medicines to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of this page.
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).><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.
- Hwang CS, Kang EM, Kornegay CJ, Staffa JA, Jones CM, McAninch JK. Trends in the concomitant prescribing of opioids and benzodiazepines, 2002-2014. Am J Prev Med 2016;51:151-60.
- Jones CM, McAninch JK. Emergency department visits and overdose deaths from combined use of opioids and benzodiazepines. Am J Prev Med 2015;49:493-501.
- Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S. Cohort Study of the Impact of High-dose Opioid Analgesics on Overdose Mortality. Pain Med 2016;17:85-98.
- Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ 2015;350:h2698.
- Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA 2013;309:657-9.
- Jones CM, Paulozzi LJ, Mack KA; Centers for Disease Control and Prevention (CDC). Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep 2014;63:881-5.
Drug Safety Communication (PDF - 74KB)