What are examples of hazardous pharmacological combinations?

From the Guidelines

Dangerous drug combinations can lead to severe health risks or even death, and it is crucial to avoid them to prevent morbidity, mortality, and reduce the impact on quality of life. Mixing opioids like oxycodone or fentanyl with benzodiazepines such as Xanax or Valium is particularly hazardous, as both depress the central nervous system, potentially causing respiratory failure 1. Similarly, combining alcohol with any sedative medication amplifies sedation effects and can be fatal. Monoamine oxidase inhibitors (MAOIs) like phenelzine should never be taken with serotonergic drugs such as SSRIs (like fluoxetine) or certain pain medications (like tramadol), as this can trigger potentially fatal serotonin syndrome.

Some key combinations to avoid include:

• Warfarin, a blood thinner, with NSAIDs like ibuprofen, which increases bleeding risk significantly 1
• Certain antibiotics, particularly macrolides like erythromycin, with statins like simvastatin, which can cause severe muscle damage
• Concomitant use of renin-angiotensin system (RAS) blockers, such as ACE inhibitors and ARBs, which can increase cardiovascular and renal risk 1
• Combining antiplatelet drugs with anticoagulants without an adequate indication, which can lead to bleeding events 1

It is essential to inform all healthcare providers about all medications being taken, including over-the-counter drugs and supplements, to avoid dangerous interactions. These combinations are dangerous because they either compete for the same metabolic pathways, enhance each other's effects to dangerous levels, or create entirely new toxic effects when combined. Always prioritize caution and consult with a healthcare professional before taking any new medication or supplement.

From the FDA Drug Label

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with oxycodone hydrochloride tablets Clinically Significant Drug Interactions with Oxycodone Hydrochloride Tablets: Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects These effects could be more pronounced with concomitant use of oxycodone hydrochloride tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride tablets is achieved Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact:The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome Examples:Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact:MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) Examples:phenelzine, tranylcypromine, linezolid

• Dangerous drug combinations include:
  • CYP3A4 inhibitors (e.g., macrolide antibiotics, azole-antifungal agents, protease inhibitors) with oxycodone, which can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects 2
  • Benzodiazepines or other CNS depressants (e.g., alcohol, sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids) with oxycodone, which can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death 2
  • Serotonergic drugs (e.g., SSRIs, SNRIs, TCAs, triptans, 5-HT3 receptor antagonists, MAO inhibitors) with oxycodone, which can result in serotonin syndrome 2
  • MAO inhibitors (e.g., phenelzine, tranylcypromine, linezolid) with oxycodone, which can manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) 2
  • Serotoninergic agents (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine) with phenelzine, which can result in serious, sometimes fatal, reactions 3

From the Research

Dangerous Drug Combinations

• The combination of monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) can increase the risk of serotonin toxicity, a potentially life-threatening condition 4.
• Certain opioid analgesics, such as tramadol, meperidine, and methadone, can also contribute to serotonin toxicity when combined with MAOIs or SSRIs 4, 5.
• The phenylpiperidine series opioids, including pethidine, tramadol, methadone, and dextromethorphan, appear to be weak serotonin re-uptake inhibitors and have been involved in serotonin toxicity reactions with MAOIs 4.
• Some newer antidepressants, such as duloxetine and bupropion, can inhibit specific cytochrome P450 (CYP) isoenzymes, potentially leading to harmful drug interactions when coadministered with substrates of these isoforms 6.
• The combination of monoamine oxidase B (MAO-B) inhibitors and SSRIs can result in increased serotonergic effects, leading to serotonin syndrome, although this occurs rarely and the combination is generally well-tolerated 7.

Specific Drug Interactions

• MAOIs and SSRIs: increased risk of serotonin toxicity 4.
• Opioid analgesics (e.g., tramadol, meperidine, methadone) and MAOIs or SSRIs: increased risk of serotonin toxicity 4, 5.
• Duloxetine and bupropion with substrates of CYP2D6: potentially harmful drug interactions 6.
• MAO-B inhibitors and SSRIs: increased serotonergic effects, leading to serotonin syndrome (rare) 7.