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Opioids

Opioids are mu-opioid receptor agonists (or partial/mixed agonists) used for moderate to severe pain, anesthesia, perioperative analgesia, and palliative care.

They act centrally and spinally to reduce pain perception and emotional response to pain.

Mechanism of Action

Opioids bind to:

μ (mu) – analgesia, respiratory depression, euphoria, dependence
κ (kappa) – analgesia, dysphoria
δ (delta) – minor analgesic contribution

Cellular effect:

↑ Potassium efflux
↓ Calcium influx
↓ Neurotransmitter release (substance P, glutamate)
Hyperpolarization of pain pathways

Core Clinical Effects

Analgesia
Sedation / euphoria
Respiratory depression
Constipation (NO tolerance develops)
Miosis (pinpoint pupils)
Nausea / vomiting
Pruritus (histamine release)

Classification & Comparison

Drug	Brand Examples	Receptor Activity	Relative Potency (vs Morphine)	Unique Clinical Pearls	Major Risks
Morphine	MS Contin	Full μ agonist	1x (reference)	Histamine release; active renally cleared metabolites	Hypotension, renal accumulation
Hydromorphone	Dilaudid	Full μ agonist	4–7x	Less histamine than morphine	Potent respiratory depression
Oxycodone	Roxicodone, OxyContin	Full μ agonist	1.5x	Good oral bioavailability	High misuse potential
Hydrocodone	Hysingla ER	Full μ agonist	1x	Often combined with acetaminophen	CYP3A4 interactions
Oxymorphone	Opana	Full μ agonist	3x	Potent oral agent	Respiratory depression
Fentanyl	Duragesic, Sublimaze	Full μ agonist	100x	No histamine; safe in renal failure	High overdose risk
Remifentanil	Ultiva	Full μ agonist	100–200x	Ultra-short acting (ester metabolism)	Requires infusion
Sufentanil	Sufenta	Full μ agonist	500x	Extremely potent (anesthesia)	Severe respiratory depression
Alfentanil	Alfenta	Full μ agonist	10–20x	Rapid onset IV	Short duration
Methadone	Dolophine	Full μ agonist + NMDA antagonist	Variable	Long half-life; neuropathic pain benefit	QT prolongation
Meperidine	Demerol	Full μ agonist	0.1x	Normeperidine metabolite (seizures)	Neurotoxicity
Codeine	—	Weak μ agonist (prodrug)	0.1x	Requires CYP2D6 activation	Variable metabolism
Tramadol	Ultram	Weak μ + SNRI	0.1x	Serotonin + NE reuptake inhibition	Seizures, serotonin syndrome
Tapentadol	Nucynta	μ agonist + NRI	0.4x	Less serotonergic than tramadol	CNS depression
Buprenorphine	Subutex, Suboxone, Butrans	Partial μ agonist	High affinity	Ceiling effect; MOUD	Precipitated withdrawal
Butorphanol	Stadol	κ agonist / μ antagonist	Moderate	Ceiling effect	Withdrawal in dependent patients
Nalbuphine	Nubain	κ agonist / μ antagonist	Moderate	Ceiling effect	Dysphoria
Pentazocine	Talwin	κ agonist / weak μ antagonist	Weak	Psychotomimetic effects	Hypertension, dysphoria

Full μ Agonists (No Ceiling Effect)

Morphine
Hydromorphone
Oxycodone
Hydrocodone
Oxymorphone
Fentanyl
Remifentanil
Sufentanil
Alfentanil
Methadone
Meperidine
Codeine (weak)

These carry full risk of respiratory depression.

Partial / Mixed Agonists

Buprenorphine (partial μ)
Butorphanol (κ agonist)
Nalbuphine (κ agonist)
Pentazocine (κ agonist)

Ceiling effect on respiratory depression. Can precipitate withdrawal in opioid-dependent patients.

High-Yield Clinical Pearls

Tolerance develops to analgesia, sedation, and respiratory depression.
Tolerance does NOT develop to constipation.
Renal failure → avoid morphine.
Methadone prolongs QT interval.
Codeine and tramadol require CYP2D6 activation.
Tramadol increases serotonin → risk of serotonin syndrome.
Avoid combining opioids with benzodiazepines or alcohol.

Classic Opioid Toxidrome

CNS depression
Respiratory depression
Miosis
Decreased bowel sounds

Treatment:

Naloxone

Withdrawal Symptoms

Yawning
Lacrimation
Rhinorrhea
Mydriasis
Diarrhea
Piloerection
Anxiety

See:

Opioid Withdrawal