Clinical Update

Complexities of Risk Assessment: Opioids, Drug Interactions, & Designer Benzodiazepines

As the number of fatal and non-fatal overdoses continues to rise, we should question why this is occurring. One frequent cause of death in drug overdose is from central nervous system (CNS) depression.1 When illicit or prescription substances cause CNS depression, there can be a decrease in oxygen that is delivered to the brain. This results in a phenomenon known as hypoxia, which can lead to debilitating short- and long-term effects, such as brain damage or putting the individual into a comatose state. CNS depression is often a consequence of an alteration in neurotransmitter activity within the brain. Most CNS depressants increase the action of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA).2 Agents commonly associated with CNS depression include opioids, gabapentinoids, benzodiazepines, barbiturates, alcohol, nonbenzodiazepines indicated for insomnia, tricyclic antidepressants, typical antipsychotics, and skeletal muscle relaxants.3,4 Ongoing monitoring for drug interactions is crucial as concomitant use of multiple CNS depressants may result in oversedation. Some symptoms to recognize when an overdose occurs include loss of concentration, confusion, reduced heart rate, reduced blood pressure and slowed breathing.2 Certain drug classes that are commonly misused, can cause CNS depression and may lead to an overdose death.

Commonly prescribed medications such as opioids and benzodiazepines can be classified as CNS depressants.3 Opioids are Mu-receptor agonists and are associated with notable nervous system effects including a depressed level of consciousness. Common prescription opioids include hydrocodone, oxycodone, morphine, hydromorphone, and fentanyl. The use of opioids with skeletal muscle relaxants may allow for opioid sparing but could enhance CNS depression.4 GABA analogs including gabapentin and pregabalin, produce CNS depression as they are structurally similar to the inhibitory neurotransmitter, GABA.3 Recent reports have found gabapentin overdoses have increased in individuals suffering from opioid use disorders.5  Benzodiazepines and barbiturates, such as phenobarbital, cause sedation by slowing action potential propagation in the central nervous system.3 Examples of commonly used benzodiazepines include alprazolam, diazepam, and lorazepam. Ethanol causes sedation via the facilitation of GABA receptors and inhibition of glutamate, an excitatory neurotransmitter. Nonbenzodiazepine sedatives, also known as “Z-drugs”, treat insomnia and cause sedation through agonist activity at GABA receptors in the brain. Z-drugs include zolpidem, eszopiclone, and zaleplon. In addition, tricyclic antidepressants and first-generation antipsychotics in particular have anticholinergic properties that contribute to CNS depression. The FDA warns that patients taking medication assisted treatment (MAT) for opioid addiction, such as methadone and buprenorphine, are also at a potential risk of CNS depression and other hazardous outcomes if the patient combines these medications with other CNS depressants.6

Benzodiazepines are commonly prescribed in the United States, for a variety of indications.7 With increased prescribing, it is important for practitioners to be aware of what other substances their patients are consuming. For instance, patients may consume prescription and designer benzodiazepines. Designer benzodiazepines are illicitly manufactured in clandestine laboratories and, as a result, there are limited clinical studies on a quantifiable potency. Unfortunately, due to the variability in illicit manufacturing, these designer benzodiazepines may possess less than or greater effects when compared to prescription benzodiazepines and may lead to increased mortality.8,9,10 Many are aware of the risks of CNS depression when opioids and benzodiazepines are co-ingested, but any medication that affects the patient’s opioid or GABA receptors may produce this effect. In particular, designer drugs can have a profound effect on the patient. Identification of any designer drug affords providers the opportunity to discuss the unpredictability of the illicit drug supply and possibly result in more effective harm reduction strategies. One recent trend observed is the cutting of xylazine in fentanyl.11 This is particularly dangerous because, while xylazine has CNS depressant activity, it is not an opioid, so it does not likely respond to naloxone reversal.

In the following patient case below, multiple potential drug-drug interactions are identified. The interaction between bupropion and oxycodone is important as bupropion inhibits the cytochrome P450 (CYP450) liver enzyme CYP2D6, which metabolizes oxycodone to oxymorphone, a more active metabolite.12 This interaction may cause the patient to not achieve expected analgesic effects, and result in taking more oxycodone than prescribed to relieve their pain. If adherence to bupropion therapy is a concern, or if the bupropion is transitioned to another therapy without CYP2D6 inhibition, there is a resultant increase in oxycodone effect despite no change in dosage. A distinct gabapentin and oxycodone interaction also may contribute to CNS depression in this patient.13 While these two pairs of drug interactions are deemed moderate risk, both can contribute to CNS depression. As seen below, the final report indicated the presence of alpha-hydroxyetizolam, a metabolite of the designer benzodiazepine etizolam. The presence of etizolam should be given further consideration as it may also contribute to CNS depression.