| Contraindicated | MAO inhibitors (phenelzine, tranylcypromine, linezolid, methylene blue) | Monoamine oxidase inhibitor | Hydromorphone with MAO inhibitors is contraindicated |
| Contraindicated | MAO inhibitors (phenelzine, tranylcypromine, linezolid, methylene blue) | Monoamine oxidase inhibitor | Opioid with MAO inhibitors is contraindicated |
| Major | Alcohol (ethanol) | CNS depressant | Hydromorphone with alcohol: additive respiratory depression |
| Major | Alcohol (ethanol) | CNS depressant | Opioid with alcohol: additive respiratory depression |
| Major | Other benzodiazepines (diazepam, clonazepam, lorazepam, alprazolam, temazepam) | Benzodiazepine | Hydromorphone with benzodiazepine: risk of profound sedation, respiratory depression, coma, and death |
| Major | Other benzodiazepines (diazepam, clonazepam, lorazepam, alprazolam, temazepam) | Benzodiazepine | Opioid with benzodiazepine: risk of profound sedation, respiratory depression, coma, and death |
| Major | Other CNS depressants (opioids, benzodiazepines, sleep aids, sedating antihistamines, gabapentinoids, muscle relaxants) | CNS depressant | Opioid with other CNS depressants: additive respiratory depression |
| Major | Other gabapentinoids (gabapentin, pregabalin) | Gabapentinoid | Opioid with gabapentinoid: serious breathing difficulties |