Lessons Learned

Opioids’ Dangerous Sidekick: Benzodiazepines

Opioids were the most commonly mentioned drug class among the CHPSO database. Of all the medication incident reports submitted to CHPSO, opioids were mentioned in 62,157 reports. The second most common drug class was benzodiazepines and non-benzodiazepine hypnotics, with 23,508 reports. Although this is a large drop off from opioids, benzodiazepines/hypnotics should not be overlooked as a source of potential harm.

Within the benzodiazepine/hypnotic class, the most frequently mentioned types were diazepam (Valium), alprazolam (Xanax) and lorazepam (Ativan). In some event reports, patients were prescribed polydrug cocktails. Below is a sample:

A middle-aged male patient presented with mental confusion. Besides medications for hypertension, he was receiving diphenhydramine, morphine, theophylline, and acetaminophen/hydrocodone. Those medications were tapered then discontinued, and his mental status markedly improved.

Each year, doctors write 17 million tranquilizer prescriptions for older adults, including for benzodiazepines like Ativan, Xanax and Valium, the most widely misused drug class among that age group. Researchers hypothesize that the reason for the use of both opioids and benzodiazepines is therapeutic. Users and abusers “self-medicate anxiety, mania or insomnia” and they seek out prescriptions to add to their opioid “high.” The number of prescription medicine abusers in 2010 was 8.76 million and the most abused drugs fell under three categories:

  • painkillers – 5.1 million
  • tranquilizers – 2.2 million
  • stimulants – 1.1 million

A mini overview on these two drugs is noteworthy for those of us unfamiliar with them. In a nutshell, opioids relieve severe pain and benzodiazepines sedate. While benzodiazepines may reduce the overt manifestations of pain (e.g., reduced patient complaints due to decreased anxiety), the actual effect on pain is complex, and in many patients, benzodiazepines’ inherent antanalgesic effect (due to GABAA receptor potentiation) predominates. Paradoxically, while benzodiazepines may reduce analgesia, they simultaneously enhance respiratory depression.

Opioids and benzodiazepine/hypnotics are frequently prescribed to and often used illicitly by people of all ages. Opioids, along with alcohol, depress central nervous system (CNS) activity, as do benzodiazepines and hypnotics. Used together, they may cause severe harm and rarely, death. The Substance Abuse and Mental Health Services Administration (SAMHSA) issued Drug Abuse Warning Network reports, or DAWN Reports, through a surveillance system monitoring drug-related hospital emergency department visits that analyzed the impact of drug abuse across the United States. One DAWN report indicated that while benzodiazepines are reasonably safe when prescribed alone, they are frequently unsafe when combined with opioids. In an estimated 174,998 ED visits among patients aged 12 to 34, those who combined benzodiazepines with opioids faced a 37 percent risk of a serious outcome (hospitalization or rarely, death). The report concluded with a suggestion that prescribers may need more information about reducing the risks associated with the drug combination. For patients, they may need to be reminded of reading drug labels and not to mix them with alcohol.

A study of prescription drug users in West Virginia (Peirce, et al, table 1 below) showed significantly increased risk when prescribed both opioids and benzodiazepines. Thirty-six percent of the deaths in the opioid plus benzodiazepine group were attributable to the interaction between the two drugs.

Table 1. Odds ratio for drug-related mortality (from Peirce et al)
If person has a prescription filled for: Odds ratio
Opioids 3.4
Benzodiazepines 7.2
Opioids and Benzodiazepines 14.9

The recently-released CDC Guideline for Prescribing Opioids for Chronic Pain goes further: stating that “clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.” In the acute care setting, for patients not on ventilatory support, caution is definitely required when combining the two and the rationale for benzodiazepine use should be clearly identified.

While benzodiazepine use and overuse cannot be observed in the context of the total number of times they appeared in the CHPSO database, they can be viewed in the context of the patients’ condition and symptoms for which they are prescribed. If more patients receive prescribed benzodiazepines than suffer from mental distress, drug overuse may occur. Conversely, if mental distress occurs more often than the number of times patients are prescribed benzodiazepines, drug underuse may be a consideration.

Data source details

Table 2 below represents the drug classes that most frequently appeared in medication safety event reports. A drug may be mentioned in the safety event report because it was:

  1. related to the event,
  2. used as a rescue medication, or
  3. incidentally mentioned.

Each safety event report was scanned for words predominantly used in drug names. Drug names were then mapped to classes. Duplicate class mentions within a single report were ignored. This does not assess the severity associated with each class.

Table 2. Drug classes as they appear in medication safety event reports submitted to CHPSO for all years.
Drug Class Frequency
Opioid Agonists 62,157
Benzodiazepines and Nonbenzodiazepine Hypnotics 23,508
Insulin and Insulin Analogs 16,249
Heparin and Low-Molecular-Weight Heparins 12,970
Glycopeptides 10,906
Histamine H1 Receptor Antagonists 10,743
Corticosteroids 10,575
Vitamin K Antagonists 9,835
Cephalosporins 9,305
Penicillins 8,809
Nonsteroidal Anti-inflammatory Drugs 8,368
β-Adrenergic Blockers 5,892
Antidepressants 5,774
Opioid Antagonists 5,576
Catecholamines 5,463
Loop Diuretics 5,434
Quinolones 5,124
Antipsychotics 4,528
Anti-epileptic Agents 4,303
Calcium Channel Blockers 3,808


Dowell, D., Haegerich, T. M., & Chou, R. (2016). CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. JAMA, 315(15), 1624–1645.

Gear, R. W., Miaskowski, C., Heller, P. H., Paul, S. M., Gordon, N. C., & Levine, J. D. (1997). Benzodiazepine mediated antagonism of opioid analgesia. Pain, 71(1), 25–29.

Gudin, J. A., Mogali, S., Jones, J. D., & Comer, S. D. (2013). Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use. Postgraduate Medicine, 125(4), 115–130.

Jones, J. D., Mogali, S., & Comer, S. D. (2012, September). Polydrug abuse: A review of opioid and benzodiazepine combination use. Drug Alcohol Depend, 125(1–2), 8–18.

National Institutes of Health. National Institute on Drug Abuse. (2014, January). Popping Pills: Prescription Drug Abuse in America.

Peirce, G. L., Smith, M. J., Abate, M. A., & Halverson, J. (2012). Doctor and Pharmacy Shopping for Controlled Substances. Medical Care, 50(6), 494–500.

Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (2014, December 18). The DAWN Report: Benzodiazepines in Combination with Opioid Pain Relievers or Alcohol: Greater Risk of More Serious ED Visit Outcomes. Rockville, MD.