STEPTRACKERPHARMACOLOGY | NEUROLOGY | HIGH-YIELD REVIEW

Opioids & Analgesics

Opioids act on μ, κ and δ receptors to block pain transmission; the testable details are which ones are partial, mixed or special, and how overdose and withdrawal look.

FOCUS ON
μ agonists (morphine, fentanyl, hydromorphone, oxycodone, methadone, meperidine, codeine, heroin): Gi → ↓ presynaptic Ca²⁺ entry, ↑ postsynaptic K⁺ efflux. Effects: analgesia, euphoria, respiratory depression, miosis, constipation (no tolerance to miosis or constipation), nausea, urinary retention, pruritus (histamine), sedation. Overdose: coma, pinpoint pupils, bradypnea → naloxone. Withdrawal: mydriasis, yawning, lacrimation, rhinorrhea, piloerection, diarrhea, cramps — not life-threatening in adults; treat with methadone, buprenorphine, clonidine/lofexidine. Special: meperidine (normeperidine seizures; serotonin syndrome with MAOI), methadone (long t½, QT), tramadol (↓ seizure threshold, SNRI → serotonin syndrome), codeine (CYP2D6), buprenorphine (partial μ; precipitates withdrawal), butorphanol, nalbuphine (κ agonist, μ partial), loperamide, dextromethorphan. Antagonists: naloxone (IV/nasal), naltrexone (oral/IM; alcohol and opioid use disorder). Other: acetaminophen, NSAIDs, gabapentinoids, duloxetine, TCAs, capsaicin, lidocaine patch.
DRUG
RECEPTOR · PROPERTY
USE
NOTES
Morphine
Full μ agonist; active metabolite M6G (renal)
Severe pain, dyspnea in palliative care
Accumulates in renal failure; histamine release
Fentanyl
Potent lipophilic μ agonist
Anesthesia, transdermal for chronic pain
Chest-wall rigidity (rapid IV), overdose deaths
Hydromorphone · oxycodone
Full μ agonists
Severe pain
Preferred over morphine in renal impairment (hydromorphone)
Methadone
Long-acting μ agonist + NMDA antagonist
Opioid use disorder maintenance, chronic pain
QT prolongation, accumulation, CYP interactions
Meperidine
μ agonist with anticholinergic effects
Postoperative shivering
Normeperidine seizures (renal failure), serotonin syndrome with MAOI, mydriasis
Codeine · tramadol
Prodrugs via CYP2D6; tramadol also SNRI
Mild–moderate pain, cough (codeine)
Ultrarapid metabolizers → overdose; tramadol seizures, serotonin syndrome
Buprenorphine
Partial μ agonist, κ antagonist; very high affinity
Opioid use disorder (with naloxone), pain
Precipitated withdrawal; ceiling on respiratory depression
Butorphanol · nalbuphine · pentazocine
κ agonist, μ partial agonist/antagonist
Labor pain, migraine (butorphanol)
Less respiratory depression; dysphoria; precipitate withdrawal
Naloxone
Competitive μ antagonist, short-acting
Opioid overdose
Repeat doses for long-acting opioids; precipitates withdrawal
Naltrexone
Long-acting oral/IM antagonist
Alcohol use disorder, opioid relapse prevention
Must be opioid-free 7–10 days; hepatotoxicity (high dose)
Opioid adverse effects
Tolerance to analgesia, euphoria, respiratory depression — not to miosis or constipation
—
Always co-prescribe a bowel regimen
Opioid withdrawal
Sympathetic and GI overactivity
Mydriasis, yawning, rhinorrhea, piloerection, diarrhea, myalgia
Neonatal abstinence syndrome — can be serious
Nonopioid adjuncts
Gabapentin, pregabalin, duloxetine, amitriptyline, topical lidocaine, capsaicin (TRPV1)
Neuropathic pain
Opioid-sparing

Mechanism — how opioids silence pain synapses

μ receptor (Gi)
→
Presynaptic: ↓ Ca²⁺ entryLess glutamate, substance P
→
Postsynaptic: ↑ K⁺ effluxHyperpolarization
→
Pain signal blocked in dorsal horn

Overdose vs withdrawal

SIGN
OVERDOSE
WITHDRAWAL
Pupils
Pinpoint
Dilated
Breathing
Slow, shallow
Normal / fast
Bowel
Constipated
Diarrhea
Mental state
Sedated, coma
Anxious, craving

How it's tested

COMMON CONFUSIONMeperidine causes mydriasis, not miosis (anticholinergic), and its toxic metabolite causes seizures.
THE TRAPNaloxone wears off in ~1 hour — patients overdosed on methadone or extended-release opioids can re-sedate; observe and redose.
YOUR APPROACHFull vs partial vs mixed → special toxicity (seizure, QT, serotonin) → reversal or maintenance plan.

If you see… think…

Coma, pinpoint pupils, RR 6 → opioid overdose → naloxone
Seizure in renal failure on a postoperative opioid → meperidine (normeperidine)
Torsades in a patient on opioid maintenance → methadone
Agitation, diarrhea, yawning after buprenorphine dose → precipitated withdrawal
Seizure and hyperthermia on tramadol + SSRI → serotonin syndrome
Opioid effect with no tolerance → constipation, miosis
Alcohol use disorder, decreases craving → naltrexone
Rigid chest wall during induction → rapid IV fentanyl
Analgesic acting as κ agonist for labor → butorphanol, nalbuphine
Antidiarrheal opioid with little CNS effect → loperamide