Analgesics · Medicine Class
Agonism at mu, kappa, and delta opioid receptors
Opioids bind to G-protein coupled opioid receptors (primarily mu receptors) distributed throughout the CNS, peripheral nervous system, and gastrointestinal tract. Receptor activation inhibits adenylyl cyclase, reduces neuronal excitability, and decreases neurotransmitter release (especially substance P and glutamate) — modulating pain transmission. Mu receptor activation also produces euphoria (mesolimbic reward pathway), respiratory depression (brainstem), constipation (enteric nervous system), and analgesia (spinal cord, PAG).
Morphine (MS Contin, MSIR)
Prototype opioid. IV/oral/IM/SC/epidural formulations. Active metabolite (M6G) accumulates in renal failure.
Oxycodone (OxyContin, Percocet)
Semi-synthetic; potent; oral. Prodrug in part (CYP2D6). OxyContin ER: 12-hour controlled release.
Hydrocodone (Vicodin, Norco)
Most prescribed opioid in the US. Combined with acetaminophen in most formulations — max daily acetaminophen must be considered.
Fentanyl (Duragesic, Sublimaze)
100× more potent than morphine. IV (anesthesia/ICU), transdermal patch (chronic cancer pain), buccal/nasal for breakthrough pain. Highly lipophilic.
Buprenorphine (Subutex, Suboxone)
Partial mu agonist / kappa antagonist. Used for OUD treatment and chronic pain. Lower overdose risk due to ceiling effect on respiratory depression.
Methadone (Dolophine)
Long-acting; also NMDA antagonist and SNRI. Used for OUD and chronic pain. QTc prolongation risk. Complex pharmacokinetics.
Benzodiazepines — synergistic respiratory depression; FDA black box warning; combination drives overdose deaths
Alcohol and CNS depressants — additive respiratory depression
MAOIs — serotonin syndrome and opioid toxicity; 14-day washout required
CYP3A4 inhibitors — increase levels of CYP3A4-metabolized opioids (oxycodone, fentanyl)
CYP2D6 inhibitors (fluoxetine, paroxetine) — reduce codeine activation; reduce oxycodone metabolism
Physical dependence (withdrawal symptoms when medicine is stopped or reduced) is an expected physiological adaptation that occurs with regular opioid use and is not the same as addiction. Opioid use disorder (addiction) involves compulsive use despite harm, inability to control use, and continued use despite social, occupational, and health consequences. A patient who takes opioids as prescribed and stops when the painful condition resolves is not addicted — even if they experience withdrawal.
Naloxone is an opioid antagonist that reverses opioid overdose — restoring breathing within 2-3 minutes. It should be administered for any suspected opioid overdose (unconsciousness, very slow/shallow breathing, pinpoint pupils). High-dose opioid prescriptions, opioid use disorder, and household fentanyl exposure are all indications to have naloxone available. Available as intranasal spray (Narcan), auto-injector (Evzio), and injectable.