Interaction Between Opioids and Benzodiazepines

Nearly 14% of opioid overdoses in the United States coincided with the use of benzodiazepines (BZD) in 2021 (1). Given that benzodiazepines and opioids are both central nervous system (CNS) depressants, their concurrent use can potentially lead to higher rates of overdose. As both opioid and BZD usage has climbed over the decades, this prompts concern regarding future prescription practices and the need for robust substance abuse prevention measures (2).

How do opioids work?

Opioids are a class of medication typically prescribed to relieve pain, but can elicit other effects such as nausea, vomiting, and respiratory depression.3Commonly used opioids include morphine, diamorphine (heroin), fentanyl, and codeine. The three primary receptors exogenous opioids act on are mu (μ), which induces supraspinal analgesia; kappa (κ), responsible for spinal analgesia, and delta (δ), which can cause both supraspinal and spinal analgesia (3,4) These are G-protein coupled receptors (GCPRs) distributed throughout the CNS. Upon binding to the GPCR, adenylyl cyclase is inhibited, leading to lowered levels of the secondary messenger cyclic adenosine monophosphate. Subsequently, neuronal cells are hyperpolarized and neurotransmission is reduced (3,4).

The analgesic effects of opioid medication are largely attributed to its action on the mu receptors, which can be found concentrated in the midbrain and thalamus. When stimulated by an agonist, mu receptors trigger descending inhibitory pathways that interrupt the transmission of nociceptive information traveling from the periphery to the thalamus, resulting in its painkilling effects (3). Other complications associated with the mu receptor are sedation, euphoria, and reduced gastrointestinal motility (4).

How do BZDs work?

BZDs are characterized as antianxiolytic and amnesic drugs used to treat anxiety, insomnia, epilepsy, among other conditions associated with nervous system overactivity. Well-known BZDs include alprazolam (Xanax), clonazepam (Klonopin), and lorazepam (Ativan) (5). These compounds work by potentiating the action of gamma aminobutyric acid (GABA), the most common inhibitory neurotransmitter in the CNS. BZDs specifically bind to GABA-A receptors, which are ligand-gated ion channels that release chloride to inhibit neurotransmission (5,6) GABA-A receptors undergo conformational change when BZD is bound to increase affinity for GABA, thus reducing CNS activity and producing a calming effect. Similar to opioids, BZDs can also induce respiratory depression, drowsiness, and nausea (5,6)

Opioid-benzodiazepine interactions

BZDs are frequently used to enhance the subjective sensations induced by opioids. Over a quarter of long-term opioid treatment patients in a methadone program have used BZD for nonclinical purposes, seeking to experience sensations such as “feeling good” or “getting high.” (2). Participants also reported an amplification of euphoric feelings when combining BZDs and opioids, underscoring the potential for abuse in this concurrent usage (2).

Furthermore, some research suggests that BZDs may modulate the pharmacokinetics of opioids, generating a stronger effect. An example emerges from studies performed between the opioid methadone and BZD diazepam: when diazepam was given to mice an hour before they were administered methadone, higher levels of methadone were found in brain and hepatic tissues and lower concentrations of methadone metabolites were excreted in the urine and liver (7). This suggests that diazepam may partially inhibit the metabolism of methadone, allowing the opioid to remain in the body longer.

Considering that fatal opioid overdoses are primarily caused by respiratory depression, pairing opioids with BZDs can exaggerate this mechanism and heighten the risk of fatality. The medulla receives input via the peripheral chemoreceptors to control respiration. Inhibition from opioids with GABA upregulation from BZDs slow medulla activity, creating a relatively greater risk of overdose compared to using the drugs independently (2,7).

Significance in overdose risk

Concomitant use of BZDs and opioids poses a large risk for overdose. A retrospective analysis done in the United States revealed that there was an 80% relative increase in opioid users who have also used a BZD between 2001-2013 (8). Those who used the drugs concurrently were 40-80% more likely to be admitted to the emergency room or inpatient treatment for overdose, depending on whether they were chronic or intermittent opioid users (8). Another study conducted in North Carolina revealed that fatal overdoses were ten times more prevalent in individuals using both opioids and BZDs compared those only taking opioids (9). This emphasizes the importance of exercising caution when considering co-prescription of BZDs and opioids.

References

1. Benzodiazepines and opioids [Internet]. U.S. Department of Health and Human Services; 2022 [cited 2024 Feb 3]. Available from: https://nida.nih.gov/research-topics/opioids/benzodiazepines-opioids

2. Gudin JA, Mogali S, Jones JD, Comer SD. Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use. Postgraduate Medicine. 2013 Jul;125(4):115–30. doi:10.3810/pgm.2013.07.2684

3. Pathan H, Williams J. Basic Opioid Pharmacology: An update. British Journal of Pain. 2012 Feb;6(1):11–6. doi:10.1177/2049463712438493

4. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008 Mar 14;2s;11(3;2s). doi:10.36076/ppj.2008/11/s133

5. Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABA receptor subtypes and addiction. Trends in Neurosciences. 2011 Apr;34(4):188–97. doi:10.1016/j.tins.2011.01.004

6. Griffin CE, Kaye AD, Rivera Bueno F, Kaye AM. Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects. The Ochsner Journal. 2013 Summer;13(2):214–23.

7. Jones JD, Mogali S, Comer SD. Polydrug Abuse: A review of opioid and benzodiazepine combination use. Drug and Alcohol Dependence. 2012 Sept;125(1–2):8–18. doi:10.1016/j.drugalcdep.2012.07.004

8. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association between concurrent use of prescription opioids and benzodiazepines and overdose: Retrospective analysis. BMJ. 2017 Mar 14;356. doi:10.1136/bmj.j760

9. 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 Medicine. 2016 Jan 13;17(1):85–98. doi:10.1111/pme.12907