How opioids are tested on Step 1
Expect an overdose vignette, a question about which effect never develops tolerance, a buprenorphine–withdrawal scenario, or a drug-specific toxicity such as meperidine seizures.
Opioid intoxication → pinpoint pupils (miosis), because tolerance never develops to it. Opioid withdrawal → dilated pupils (mydriasis), yawning, lacrimation, rhinorrhea, piloerection, diarrhea.
Receptors and mechanism
Opioids act at presynaptic and postsynaptic sites in the dorsal horn, periaqueductal gray, and rostral ventromedial medulla.
| Receptor | Main effects |
|---|---|
| μ (mu) | Analgesia, euphoria, respiratory depression, miosis, constipation, dependence |
| κ (kappa) | Spinal analgesia, sedation, dysphoria, diuresis |
| δ (delta) | Analgesia, mood effects |
Butorphanol and nalbuphine are κ agonist, μ partial agonist or antagonist mixtures — useful for pain with less respiratory depression, but can precipitate withdrawal.
Full agonists, partial agonists, and antagonists
Efficacy and affinity together determine how an opioid behaves.
| Drug | Distinguishing feature |
|---|---|
| Morphine | Active metabolite (M6G) accumulates in renal failure; histamine release |
| Fentanyl | Highly potent, lipophilic; transdermal patch; chest wall rigidity at high IV doses |
| Methadone | Long half-life; maintenance for opioid use disorder; QT prolongation |
| Meperidine | Normeperidine → seizures; serotonin syndrome with MAOIs |
| Tramadol | Weak μ agonist + SNRI; lowers seizure threshold; serotonin syndrome |
| Codeine | Prodrug → morphine by CYP2D6; dangerous in ultrarapid metabolizers |
| Loperamide, diphenoxylate | Act on gut μ receptors; antidiarrheal |
| Dextromethorphan | Antitussive; NMDA antagonist; serotonergic |
Naltrexone (oral or depot) is used for alcohol and opioid use disorder after detoxification.
Tolerance, overdose, and withdrawal
Tolerance from receptor desensitization and downregulation develops unevenly across effects.
| Effect | Tolerance? |
|---|---|
| Analgesia | Yes |
| Euphoria | Yes |
| Respiratory depression | Yes (but lost after abstinence → overdose risk on relapse) |
| Nausea, sedation | Yes |
| Miosis | No |
| Constipation | No — prescribe a laxative with every chronic opioid |
After detox or incarceration, lost tolerance makes a previously tolerated dose lethal.
Clinical application
Partial agonist pharmacology explains a frequently tested trap.
A man who uses heroin daily took his last dose 2 hours ago. He is given his first dose of buprenorphine in clinic. Within 30 minutes he has sweating, vomiting, dilated pupils, and severe cramps. Why?
- Buprenorphine has higher affinity for the μ receptor than heroin metabolites, so it displaces them.
- It is a partial agonist with lower intrinsic activity than a full agonist.
- Replacing a full agonist with a partial one suddenly lowers receptor activation — precipitated withdrawal.
- Waiting until mild-to-moderate withdrawal has begun before the first dose avoids this.
Answer. Buprenorphine-precipitated withdrawal from displacing a full agonist with a high-affinity partial agonist. Start buprenorphine only once objective withdrawal signs appear.