Opioid Drugs

• Opium = sticky brown gum made by air-drying the milky exudate from the cut, unripe seed capsule of the poppy Papaver somniferum ("sleep-bringing").
• It contains two chemical families of alkaloids:

• Three peptide families, each cut from its own precursor gene:
  • β-endorphin ← pro-opiomelanocortin (POMC; the same precursor that gives ACTH and MSH)
  • Enkephalins (met-, leu-) ← preproenkephalin
  • Dynorphins ← preprodynorphin
• All share the N-terminal "opioid motif" Tyr-Gly-Gly-Phe-(Met/Leu).
• Three classic receptors: μ (μ_1,2), κ (κ_1,2,3), δ (δ_1,2), plus the opioid-like ORL1 (ligand = orphanin / nociceptin). Opioid drugs act through μ, κ and δ, but most pharmacologic effects of opioid drugs are mediated by μ.

The dose-response picture for this lives in LO 6 (ceiling effect and precipitated withdrawal).

The μ receptor is a G_i/o-coupled GPCR. Binding splits the G protein into Gα_i/o and Gβγ, and each subunit has a job:

• μ receptor (GPCR) → inhibits adenylyl cyclase → ↓ cAMP → ↓ presynaptic Ca²⁺ channel opening → ↓ transmitter release; and stimulates postsynaptic K⁺ efflux → hyperpolarization.
• Analgesia = the G-protein arm (↓ cAMP/PKA and ↓ synaptic transmission + postsynaptic K⁺ channel stimulation).
• The μ receptor also drives β-arrestin signaling → tolerance + respiratory depression + constipation (know all three).

• Site = dorsal horn (substantia gelatinosa), the first synapse of the pain pathway:
  • μ receptors on central terminals of primary afferents → presynaptic inhibition
  • μ receptors on 2nd-order (spinothalamic) neurons → postsynaptic inhibition
  • Local enkephalin interneurons are switched on by descending fibers from the brainstem and do the same thing naturally
• Opioids preferentially inhibit C-fiber nociceptive transmission ("C more than Aδ" → better for chronic, dull pain):
  • C fibers = unmyelinated, slow → continuous, dull, aching, burning (chronic) pain → well relieved
  • Aδ fibers = thinly myelinated, fast → sharp, intermittent, well-localized pain → less sensitive
  • Continuous dull pain is relieved more effectively than sharp intermittent pain
  • At high enough doses opioids still relieve severe pain such as renal or biliary colic
• Giving morphine at spinal and supraspinal sites together is synergistic (~10-fold lower total dose for the same analgesia).

1. Excite descending inhibitory pathways: opioids activate the periaqueductal gray (PAG) → rostral ventromedial medulla (raphe) → fibers down to the dorsal horn that suppress incoming pain signals. (Opioids do this by disinhibiting PAG output neurons, i.e., silencing local GABA neurons.)
2. Reduce the emotional component: in limbic areas (the medial pain system, i.e., the medial anterolateral system) they reduce the "suffering", producing indifference to pain. Patients often say "the pain is still there, but it doesn't bother me".

• Opioids act in both brain and spinal cord: PAG activation + reduced emotional pain transmission → indifference to pain.
• Opioids produce more analgesia when combined with NSAIDs (central + peripheral action).

• Core effects to know: analgesia, euphoria, sedation, depression of respiration (death), constipation, nausea/vomiting, itch, miosis.
• β-arrestin signaling is linked to euphoria/reward, respiratory depression and constipation (and tolerance).
• Sedation/anxiolysis = ↓ NE release in the locus coeruleus.

• Euphoria: μ receptors sit on GABA interneurons in the VTA. Silencing them removes the brake on dopamine neurons → ↑ DA in the nucleus accumbens (mesolimbic reward pathway) → reinforcing quality of opioids. (Linked to β-arrestin signaling.)
• Sedation and anxiolysis: μ inhibition of norepinephrine release from the locus coeruleus → reduced anxiety, drowsiness, lethargy, "mental clouding", poor concentration, tranquility. (Morphine ← Morpheus, Greek god of dreams.)

• Death from opioid poisoning is nearly always respiratory arrest.
• Mechanism (brainstem):
  • ↓ responsiveness of brainstem respiratory centers to CO₂ (the main drive)
  • Depression of pontine and medullary rhythm centers
• What you see: ↓ rate (even at therapeutic doses; may fall to 3–4 breaths/min), ↓ tidal and minute volume, irregular/periodic breathing.
• Linked to β-arrestin signaling.
• Timing of peak depression after morphine: 5–10 min IV, ~30 min IM, ~90 min SC.
• Higher risk with:
  • Other CNS depressants: benzodiazepines (FDA black-box warning for the combination), alcohol, sedative-hypnotics, general anesthetics
  • ↓ respiratory reserve: COPD, asthma, frail elderly, head injury
• Clinically significant depression is uncommon at standard doses in people with normal lungs, and it is fully reversed by naloxone.

• Because they are so constipating, opioids are the most effective antidiarrheals:
  • Loperamide (Imodium): μ agonist with limited CNS entry (P-glycoprotein pumps it out of the brain) → OTC
  • Diphenoxylate (Lomotil): GI-selective opioid, formulated with atropine to deter abuse (high doses → unpleasant anticholinergic effects)
• Biliary tract: sphincter of Oddi spasm → ↑ common bile duct pressure → biliary colic-like pain.
• Urinary: ↑ sphincter tone, inhibits voiding reflex → urinary retention (sometimes needs catheter).

• Miosis: morphine and most μ and κ agonists excite the parasympathetic nerve to the pupil (Edinger-Westphal nucleus → CN III → sphincter pupillae). Some tolerance develops, but people with high circulating opioid levels keep pinpoint pupils.
• Pruritus and flushing: histamine release from mast cells (morphine > fentanyl) + changes in C-fiber activity (scratching = noxious stimulus that relieves itch; opioids alter this balance).
• Cardiovascular: peripheral vasodilation, ↓ resistance, blunted baroreceptor reflex → orthostatic hypotension when the patient sits up (histamine plays a big role; antihistamines may not reverse it, naloxone may be needed). Morphine also venodilates → ↓ preload (historic use in acute pulmonary edema).
• Neuroendocrine: ↓ GnRH and CRF → ↓ LH, FSH, ACTH → ↓ testosterone and cortisol → altered menstruation, libido, fertility; μ agonists ↑ prolactin. κ agonists ↓ ADH (diuresis); μ agonists tend to be antidiuretic.
• Convulsions: rare in humans at high doses (morphine inhibits GABA release onto hippocampal pyramidal cells → disinhibition). More relevant for meperidine (normeperidine), tramadol and morphine's M3G.
• Immune: immunosuppressive effects (mostly δ receptor, plus central sympathetic/HPA effects).

• Tolerance = functional desensitization: with continued use opioids become less potent, so a higher dose is needed for the same response.
• All effects of opioids display tolerance EXCEPT constipation and miosis. When morphine is increased gradually: constipation worsens (no tolerance), initial nausea goes away, physical dependence occurs, and respiratory depression does NOT occur.
• It can be fast: a clinical morphine dose of ~30 mg may rise to ~300 mg in as little as 10 days.
• Mechanism unclear; β-arrestin signaling (receptor desensitization and internalization) is implicated. NMDA (glutamate) signaling also contributes: NMDA antagonists block morphine tolerance in animals (one reason methadone's NMDA block is useful).

• Tolerance and dependence are physiological, seen in all patients, and are not predictors of addiction. Cancer patients on high-dose opioids become tolerant and dependent, but abuse in that setting is very unusual.
• Addiction affects ~10–15% of physicians (alcohol/drugs) over a career: stress and access are risk factors.
• Avoiding withdrawal: taper by about 10–20% per day in a dependent patient.

Withdrawal is the mirror image of the drug: whatever the opioid suppressed comes roaring back.

• Classic presentation = abdominal pain, sweating, diarrhea.
• Triggered by abruptly stopping the opioid or giving an opioid antagonist (opioid receptor blockers can cause withdrawal symptoms).
• Miserable but rarely life-threatening in adults (unlike alcohol or benzodiazepine withdrawal, which can cause seizures and death). Neonates of dependent mothers get neonatal abstinence syndrome.
• Treatment: replace with a long-acting opioid and taper (methadone or buprenorphine); clonidine / lofexidine (α2 agonists) for autonomic symptoms.

Rule of thumb running through this LO: more lipid-soluble → faster into the brain → faster onset, often more potent.

• Structure: OH groups at C3 and C6 make it hydrophilic → slower CNS penetration than lipophilic opioids. The N-CH₃ is important for activity.
• High first-pass metabolism → oral bioavailability only ~25% (oral dose ≈ 3× the injected dose).
• Metabolism: conjugated with glucuronic acid (liver, kidney, brain):
  • Morphine-3-glucuronide (M3G) ~60%: inactive at opioid receptors but neuroexcitatory (CNS stimulant → myoclonus, seizures)
  • Morphine-6-glucuronide (M6G) ~10%: active, ~2× more potent than morphine
  • Minor: N-demethylation → normorphine (inactive)
• Elimination: morphine, M6G and M3G are all excreted by the kidneys → in renal impairment they accumulate → prolonged sedation, respiratory depression (M6G) and seizures (M3G) (chronic use → build-up of active metabolite).
  • Do NOT give morphine in renal insufficiency; choose an opioid without renally cleared active metabolites: fentanyl (no active metabolites) or hydromorphone / oxycodone (oral or IV). Methadone is an option but not first line.
  • Hepatic dysfunction → start opioids at ~50% of the usual dose.
• Routes: oral, IM, IV, SC, epidural, intrathecal. Oral onset is slower.
• Duration: 4–5 h (oral, IM, IV, SC); up to 24 h epidural/intrathecal, but being hydrophilic it lingers in CSF and spreads rostrally → delayed respiratory depression.
• Limitations summary: low oral bioavailability, poor CNS penetration, high abuse potential.

• Codeine = 3-methylmorphine: the CH₃O at C3 kills receptor activity → a prodrug with very low μ affinity.
• Analgesia comes from O-demethylation to morphine by CYP2D6 (~10% of a dose).
• Weak because of low potency at μ receptors: only 10–15% as potent as morphine (~1/12); works slower than morphine; clinically about as strong as aspirin or acetaminophen alone. Better oral bioavailability than morphine but slower onset.
• Usually combined with acetaminophen or aspirin (Tylenol #3). Strong antitussive (may involve sites that bind codeine itself).
• Pharmacogenetics:
  • ~10% of Caucasians are poor metabolizers → little or no analgesia
  • ~1–2% carry multiple gene copies (ultrarapid metabolizers) → too much morphine → toxicity
• Drug interactions: CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) block codeine analgesia. Morphine and oxycodone are unaffected by an SSRI, but the codeine effect may decrease.

• Ladder: codeine < morphine = methadone < heroin (better CNS penetration) < hydromorphone / oxymorphone (6–10× morphine) << fentanyl (100×).
• Hydrocodone and oxycodone are quoted relative to codeine (6–8× and 9–10× oral codeine) → near morphine orally, below heroin and hydromorphone.

• Buprenorphine (from thebaine): high-affinity μ partial agonist + κ antagonist (also δ antagonist).
• Analgesia similar to morphine but with a ceiling; ceiling on respiratory depression → safer in overdose and in COPD/frail patients (history of COPD → buprenorphine).
• κ antagonism → no psychotomimetic effects; abuse liability less than morphine.
• Long t½ 20–70 h; poor oral bioavailability (first pass) → sublingual tablet/film, buccal, transdermal patch, injectable.
• Uses: detoxification and maintenance for opioid use disorder (long-lasting partial agonist, vs methadone the long-lasting full agonist) (Subutex; Suboxone/Zubsolv = + naloxone), chronic pain (Butrans patch, Belbuca).
• Precipitated withdrawal: if given while a full agonist is still on the receptors, its higher affinity + lower efficacy drops net μ signaling → abrupt withdrawal. Start it only once the patient is already in mild–moderate withdrawal.
• High affinity also means naloxone reverses buprenorphine poorly (large doses needed).

• Developed hoping for less addiction and respiratory depression; in practice, for the same analgesia similar side effects occur, plus a ceiling on analgesia.
• Can precipitate withdrawal in opioid-dependent patients → use is limited.

All are competitive antagonists derived from oxymorphone (N-allyl or N-cyclopropylmethyl in place of N-methyl), much stronger at μ than at κ and δ.

Opioid receptor blockers can cause withdrawal symptoms. Naloxone given alone has little effect at usual doses and causes no tolerance or dependence. Given after an opioid, it reverses respiratory depression, sedation, euphoria, miosis, GI effects and analgesia.

They exploit route-dependent bioavailability: the antagonist is harmless when the pill is taken as intended but becomes active if the tablet is crushed and injected or snorted.