Opioids bind to opioid receptors (mu, kappa, delta) in the brain, spinal cord, and gut. Most clinical effects — good and bad — come from the mu receptor. Binding reduces release of pain-signaling transmitters in the spinal cord and changes how the brain perceives pain.

Classes by receptor activity

• Full agonists (morphine, hydromorphone, oxycodone, fentanyl, methadone, hydrocodone, codeine) — no ceiling to analgesia or to respiratory depression.
• Partial agonist (buprenorphine) — high receptor affinity with a ceiling effect on respiratory depression; can displace full agonists and precipitate withdrawal.
• Mixed agonist-antagonists (butorphanol, nalbuphine) — kappa agonists, mu antagonists; they precipitate withdrawal in opioid-dependent clients.
• Antagonists (naloxone, nalmefene, naltrexone) — occupy mu receptors without activating them and reverse opioid effects. Peripherally acting mu antagonists (methylnaltrexone, naloxegol) treat opioid-induced constipation without reversing analgesia.

Tolerance, dependence, and addiction: tolerance and physical dependence are expected with regular use; opioid use disorder is compulsive use despite harm. Fear of addiction should not lead to undertreated pain.

Indications: moderate to severe acute pain, cancer and end-of-life pain, dyspnea at the end of life, cough (codeine), anesthesia adjunct (fentanyl), and opioid use disorder (methadone, buprenorphine).

"Opioid-tolerant" means taking at least about 60 mg oral morphine per day (or an equivalent) for 1 week or longer. Extended-release products and fentanyl patches are for opioid-tolerant clients only.

• Respiratory depression (slow, shallow breathing, hypercapnia) — greatest in opioid-naive, older, obese, sleep apnea, and postoperative clients and in the first 24 hours
• Sedation, confusion, delirium (older adults), dizziness, falls
• Constipation (the most common and persistent effect), nausea and vomiting, urinary retention, pruritus
• Orthostatic hypotension, bradycardia
• Opioid-induced hyperalgesia — increasing pain sensitivity with rising doses
• Hormonal effects with long-term use (low sex hormones), immune effects
• Fentanyl: chest-wall rigidity with fast IV dosing; methadone: QT prolongation and torsades de pointes
• Neonatal opioid withdrawal syndrome after prolonged use in pregnancy

US boxed warnings (class): addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion (fatal in children); neonatal opioid withdrawal syndrome; risks with benzodiazepines or other CNS depressants; CYP3A4 interactions (fentanyl, oxycodone, methadone). July 2025 FDA labeling updates also stress the higher risks of long-term and high-dose use, add gabapentinoids to the CNS-depressant interaction warning, and describe toxic leukoencephalopathy after overdose and opioid-induced esophageal dysfunction.

• Contraindicated: significant respiratory depression without monitoring and resuscitation equipment; acute severe asthma in an unmonitored setting; known or suspected GI obstruction or paralytic ileus; hypersensitivity.
• Caution: sleep apnea, COPD, head injury (masks neurologic signs; retained CO₂ raises intracranial pressure), older adults (start low, go slow), kidney or liver impairment, hypovolemia, history of substance use disorder, adrenal insufficiency.
• Children: codeine and tramadol are contraindicated under 12 and after tonsillectomy/adenoidectomy under 18.
• Pregnancy: use the lowest effective dose for the shortest time; prolonged use causes neonatal withdrawal. In opioid use disorder, do not detoxify during pregnancy — methadone or buprenorphine is recommended. Breastfeeding: avoid codeine and tramadol.
• Interactions:
  • Benzodiazepines, alcohol, gabapentin/pregabalin, sedating antihistamines, muscle relaxants, sleep aids → additive respiratory depression and death
  • CYP3A4 inhibitors (clarithromycin, azole antifungals, ritonavir, grapefruit) raise fentanyl, oxycodone, and methadone levels; stopping a CYP3A4 inducer (rifampin, carbamazepine, phenytoin) has the same effect
  • Serotonergic drugs (SSRIs, SNRIs, triptans, linezolid) with tramadol, tapentadol, meperidine, methadone, or fentanyl → serotonin syndrome
  • MAO inhibitors with meperidine or tramadol — contraindicated
  • Mixed agonist-antagonists or buprenorphine given to a client on full agonists → precipitated withdrawal
  • Methadone with other QT-prolonging drugs

Listed in priority order.

1. Respiratory and sedation assessment
   • Assess sedation level (e.g., Pasero Opioid-Induced Sedation Scale) and respiratory rate, depth, and pattern before each dose and at peak effect (IV about 15–30 minutes; oral about 1 hour).
   • Hold the dose and notify for excessive sedation (frequently drowsy, drifts off during conversation) or a respiratory rate below about 10–12/min or shallow breathing, per policy.
   • Unresponsive or minimally responsive with slow breathing → stop the opioid, stimulate, support ventilation, give naloxone, call the rapid response team.
   • Continuous pulse oximetry or capnography for high-risk clients; capnography is preferred with supplemental oxygen because SpO₂ falls late.
2. Naloxone administration
   • Clients receiving opioids for pain: dilute 0.4 mg in 10 mL and give 0.04 mg (1 mL) every 1–2 minutes until breathing improves — the goal is adequate breathing, not full reversal (full reversal causes severe pain, withdrawal, vomiting, hypertension, and pulmonary edema).
   • Overdose in the community or cardiac/respiratory arrest: 0.4–2 mg IV/IM/SC or 4 mg intranasal, repeated every 2–3 minutes as needed while supporting ventilation.
   • Monitor for recurrent sedation — naloxone lasts about 30–90 minutes, shorter than most opioids; an infusion may be needed for long-acting opioids.
3. Right drug, right dose — double-check hydromorphone versus morphine, concentrations, and pump programming; when switching opioids, reduce the calculated equianalgesic dose by about 25–50%; oral morphine is roughly 3 times the IV dose.
4. Patient-controlled analgesia — only the client presses the button; verify settings at every handoff.
5. Fentanyl patch — remove the old patch first; apply to intact, hairless skin; rotate sites; no heating pads, hot tubs, or electric blankets; report fever; fold used patches sticky sides together and dispose as policy directs.
6. Prevent adverse effects — start a stimulant laxative (with or without an osmotic laxative) with regular opioids; stool softener alone is not enough; antiemetics; fall precautions; check for urinary retention.
7. Reassess pain and function after each dose; use multimodal analgesia to reduce opioid need.

• Take exactly as prescribed; never combine with alcohol, sleeping pills, benzodiazepines, or gabapentinoids unless the prescriber approves.
• Do not drive or make important decisions until you know how the drug affects you.
• Prevent constipation: fluids, fiber, activity, and the laxative prescribed.
• Rise slowly to prevent dizziness and falls.
• Keep naloxone at home, and teach family how to use it; call emergency services after giving it.
• Do not crush, chew, or cut extended-release tablets — this can release a fatal dose.
• Store locked away from children and visitors; dispose of leftover medicine at take-back sites or by approved methods.
• After long-term use, do not stop suddenly — taper with the prescriber to avoid withdrawal.
• Report trouble breathing, extreme sleepiness, confusion, or pain that worsens despite higher doses.

Opioid overdose triad: decreased level of consciousness, pinpoint pupils, respiratory depression (plus cyanosis, bradycardia, hypotension).

• Buprenorphine overdose may need higher and repeated naloxone doses.
• Fentanyl mixed with xylazine may cause sedation that naloxone does not reverse — still give naloxone and support breathing.
• Opioid withdrawal: rhinorrhea, lacrimation, yawning, dilated pupils, piloerection, muscle aches, abdominal cramps, diarrhea, anxiety — very uncomfortable but rarely fatal in adults; neonatal withdrawal needs specialist care.
• Meperidine toxicity: tremor, myoclonus, seizures (normeperidine) — naloxone does not reverse seizures.
• Tramadol overdose: seizures and serotonin syndrome in addition to respiratory depression.

• Sedation precedes respiratory depression — assess sedation and breathing before each dose
• Hold and notify for excessive sedation or respiratory rate below about 10–12/min
• Overdose triad: coma, pinpoint pupils, respiratory depression → ventilate + naloxone
• Naloxone is shorter-acting than most opioids — watch for re-sedation
• Post-op respiratory depression: dilute and titrate naloxone (0.04 mg), not full reversal
• Constipation does not improve with tolerance — start a laxative
• Fentanyl patch: opioid-tolerant only; no heat
• Hydromorphone is 5–7 times more potent than morphine
• Morphine: avoid in kidney failure; meperidine: avoid (seizures)
• Codeine and tramadol contraindicated under 12
• Opioids + benzodiazepines/alcohol/gabapentinoids = deadly respiratory depression
• Buprenorphine and mixed agonist-antagonists precipitate withdrawal in clients on full agonists