FDA Black Box Warnings for Combined Opioid and Benzodiazepine Use

by Michael Nguyen, PharmD, CPh, Director of Clinical Services
Andi Moore, PharmD

After an extensive review of the latest scientific evidence, the U.S. Food and Drug Administration announced on August 31, 2016, that class-wide changes to drug labeling, including patient information, was being required for the opioid and benzodiazepine therapeutic classes because of serious risks associated with using medications from these two classes at the same time. The FDA now requires “black box warnings” and patient-focused Medication Guides for prescription opioid analgesics, opioid-containing cough products, and benzodiazepines–affecting close to 400 different products.

Opioids and Benzodiazepines are a Dangerous Mix

Medical literature suggests that benzodiazepine users are more likely to receive prescription opioids than non-benzodiazepine users, despite the well-known additive side effects that make the combination dangerous.1, 2 Substance abuse treatment admissions resulting from co-abuse of benzodiazepines and narcotic pain relievers increased by 569.7% between 2000 and 2010, while admissions related to all other substance abuse decreased by almost 10% during this same period.3 Several studies4 – 11 suggest that benzodiazepines may play a role in as many as 80% of unintentional overdose deaths involving opioids, primarily caused by respiratory depression.12

New Black Box Warning is Part of FDA’s Opioids Action Plan

FDA WarningThe FDA black box warning added to drugs in both of these classes indicates the seriousness of taking opioids and benzodiazepines at the same time. The intent of the warning is to inform health care providers and patients of the serious risks associated with combining these drugs – risks that include extreme sleepiness, respiratory depression, coma and death. This FDA action was one of a number of steps the agency is taking as part of their Opioids Action Plan, a program focused on reversing the prescription opioid epidemic that is currently occurring in the U.S.

How the myMatrixx Alert, Review and Manage (ARM)® Program Reduces Risks

As part of its Alert, Review and Manage (ARM)® clinical intervention program, myMatrixx actively identifies claimants who are taking an opioid and benzodiazepine concurrently. A letter is faxed to the prescriber on the same day a drug in one of the two classes is prescribed when a drug from the second class is already being taken by the claimant. If both drugs are prescribed on the same day, this results in an alert to the prescriber. In the event of multiple prescribers for one claimant, all prescribers of drugs in the two classes receive letters. Our goal is to identify these claimants and reach the prescriber(s) immediately in order to prevent serious side effects.

More about Opioids and Benzodiazepines

  • 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. They are also approved in combination with other medicines to reduce coughing. Common side effects include drowsiness, dizziness, nausea, vomiting, constipation, and slowed or difficult breathing. Opioids also carry serious risks, including misuse and abuse, addiction, overdose, and death. Examples of opioids include oxycodone, hydrocodone, codeine, and morphine.
  • Benzodiazepines are drugs prescribed to treat conditions like anxiety, insomnia, and seizures. Examples of these drugs include alprazolam, clonazepam, and lorazepam. Common side effects include drowsiness, dizziness, weakness, and physical dependence.

by Andrea Moore, PharmD, VP of Clinical Strategy
Michael Nguyen, PharmD, Director of Clinical Services

1 Webster LR. Considering the risks of benzodiazepines and opioids together. Pain Med. 2010; 11(6): 801–802. [PubMed: 20624235]
2 Skurtveit S, Furu K, Bramness J, Selmer R, Tverdal A. Benzodiazepines predict use of opioids—a follow-up study of 17,074 men and women. Pain Med. 2010; 11(6):805–814. [PubMed: 20624237]
3 The TEDS Report: Substance Abuse Treatment Admissions for Abuse of Benzodiazepines. Rockville, MD: Center for Behavioral Health Statistics and Quality; 2011. Substance Abuse and Mental Health Services Administration (SAMHSA)
4 The TEDS Report: Admissions Reporting Benzodiazepine and Narcotic Pain Reliever Abuse at Treatment Entry. Rockville, MD: Center for Behavioral Health Statistics and Quality; 2012. Substance Abuse and Mental Health Services Administration (SAMHSA).
5 Kintz P. Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int. 2001; 121(1–2):65–69. [PubMed: 11516889]
6 Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I. A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine associated and 35 methadone-associated deaths. Addiction. 2004; 99(8):978–988. [PubMed:15265095]
7 Ernst E, Bartu A, Popescu A, Ileutt KF, Hansson R, Plumley N. Methadone-related deaths in Western Australia 1993–99. Aust N Z J Public Health. 2002; 26(4):364–370. [PubMed: 12233959]
8 Wolf BC, Lavezzi WA, Sullivan LM, Flannagan LM. Methadone-related deaths in Palm Beach County. J Forensic Sci. 2004; 49(2):375–378. [PubMed: 15027564]
9 Oliver P, Keen J. Concomitant drugs of misuse and drug using behaviours associated with fatal opiate-related poisonings in Sheffield, UK, 1997–2000. Addiction. 2003; 98(2):191–197. [PubMed: 12534424]
10 Jones JD, Mogali S, Comer SD. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend. 2012; 125(1–2):8–18. [PubMed: 22857878]
11 Webster LR. Considering the risks of benzodiazepines and opioids together. Pain Med. 2010; 11(6): 801–802. [PubMed: 20624235]
12 White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction. 1999; 94(7):961–972. [PubMed: 10707430]