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Opioid Analgesics and Antagonists April 15, 2010 1. Pharmacokinetics of opioids a. Distribution of natural opiates: i.

Beta-endorphin: hypothalamus and pituitary ii. Enkephalins: widely distributed in CNS and PNS, adrenal gland, and enteric nervous system iii. Dynorphins: CNS; major role in spinal analgesia b. Synthesis i. Precursors: preproopiomelanocortin (POMC), preproenkephalin, and preprodynorphin ii. Products: met-enkephalin and leu-enkephalin iii. POMC: only source of beta-endorphin iv. Preprodynorphin: only source of dyorphins c. Absorption i. Parental usually > oral absorption d. Metabolism and excretion i. Most are metabolized in the liver ii. Morphine & levorphanol are glucuronidated  excreted by kidney iii. Heroin  deacetylated to morphine iv. Codeine  partly demethylated to morphine 2. Pharmacodynamics of opioids a. Opioid receptors: i. All are G-coupled 1. Inhibit adenylate cyclase  cAMP formation 2. Presynaptic effect: reduce pain-associated excitatory NT release from afferents to dorsal horn neurons

a. Via inhibition of Ca2+ influx in the presynaptic terminal 3. Postsynaptic effect (mu receptors): reduce spinal pain transmission in the dorsal horn a. Via opening of K+ channels  hyperpolarization b. Also act at the periaqueductal gray to reduce pain transmission (supraspinal level) 4. *Mu in midbrain: increases firing rate of DA neurons a. Narcotic analgesics occupation of opioid receptors may release endogenous opioids  potentiates narcotics!! ii. Mu: most drugs act here 1. Effects: analgesia, euphoria, and respiratory depression iii. Kappa & delta: contribute to spinal analgesia

3. Effects of opioids on organ systems
Organ System Cardiovascular Effect Therapeutic doses: little/no effect on HR or BP in supine patient Orthostatic hypotension may occur in standing patient (due to release of histamine; depression of vasomotor center) Depression of renal function Elevated ADH = fluid retention (due to opioid receptors in supraoptic nuclus of hypothalamus) Decreased GI motility (anti-parasympathetic) Constipation (no tolerance) Inhibition of peristalsis due to block of ACh release from myenteric plexus neurons

Renal system Gastrointestinal

Bronchial effects

Bronchoconstriction (due to histamine) Bronchodilation (via direct administration of opioid to the lung; non-histamine-stimulating opiate = fentanyl) Respiratory depression; decreased cough reflex (antitussive) Vasodilation and flushing Itching and urticaria (due to histamine) Analgesia (dull pain blocked > than sharp pain) Sedation (esp morphine) Euphoria (activation of DA neurons) Nausea/vomiting/dizziness Respiratory depression: brainstem respiratory neurons less responsive to CO2; pontine/medullary respiratory centers may also be depressed Miosis: via mu receptors (can be blocked by sympathomimetic or muscarinic antagonist)  no tolerance Exception: meperidine Antitussive effect: suppression of cough reflex Convulsions: via high toxic doses of meperidine, codeine, propoxyphene

Skin CNS

4. Contraindications of opioid analgesics a. Avoid combining pure agonists & mixed agonists-antagonists b. Avoid in patients w/ head injuries: opiates can increase ICP c. Avoid in pregnancy: drugs can cross the placenta and immature BBB of fetus  fetus can become addicted! i. Respiratory depression during labor ii. Opiates can reduce uterine contractions  longer labor d. Avoid in patients w/ impaired lung function (e.g. asthmatics) e. Use w/ caution in patients w/ liver or kidney issues f. Use w/ caution in patients w/ adrenal insufficiency or hypothyroidism  conditions may potentiate effects of opioids! g. Avoid co-administration w/ antipsychotics or sedative/hypnotics  too much depressant effects (especially in respiration) h. Avoid co-administration w/ MAO-I: associated incidence of febrile coma 5. Table of opioid analgesics


Type of analgesic
Full agonist (mu>kappa&del ta) Full agonist (weak)

Parenteral Long duration of action Oral short duration


Therapeutic use
Severe pain

Adverse Effect
High risk of abuse/addiction High risk of abuse/addiction


Less than morphine

Often combined w/ aspirin Excellent antitussive


Full agonist

Oral; nasal

High (more than morphine)

Strong CNS effects (crosses BBB) Miosis w/ overdose high risk of abuse Useful in labor (no respiratory depression in neonate) Acute, severe pain Anticholinergic effects: no miosis (don’t use in tachycardic patients) Not useful for cough High doses: seizures

Meperidine (Demerol)

Full agonist (mu)

Oral short duration

Medium < morphine > codeine


Full agonist (mu)

Parenteral and oral Long duration


Treating opiate dependence  tx withdrawal sxs  decrease euphoria Useful in anesthesia due to fast induction/emergence also severe, chronic pain Often combined w/ aspirin Not effective against cough Good: no histamine release!

Fentanyl (Sublimaze)

Full agonist (mu)

Intrathecal, epidural, transdermal short duration


Propoxyphene (Darvon)

Full agonist


Less than codeine

High risk of abuse/addiction

Butorphanol (Stadol)


Parenteral or nasal

More than morphine

Very low abuse risk Psychotomimetic effects sometimes (kappa agonism)

Pentazocine (Talwin) Buprenorphine (Buprenex)

Mixed Mixed

Oral or parental Parenteral long duration at mu

Less than morphine High

Less psychotomimetic effect

Very low abuse risk can ↑BP Some abuse risk

Loperamide (Imodium) Dextromethorph an (Romilar)

Full agonist



Very little crosses BBB  no analgesia benefit  no abuse risk No analgesia benefit; little abuse May act like PCP in antagonizing NMDA receptor

Full delta agonist primarily: NMDA receptor antagonist


Antitussive (found in Robitussin) No respiratory depression!

a. Some more information on mixed drugs i. Kappa receptor: agonists ii. Mu receptor: partial agonists (low doses) or antagonists (high doses) 1. Reduces abuse liability 2. Reduces side effects (respiratory depression), but still has some analgesic efficacy 3. Full mu agonists CANNOT displaced mixed drugs from mu iii. Sometimes have psychotomimetic effects 6. Table of opioid receptor antagonists a. General information i. All pass BBB 1. Block respiratory depression effects of opiates ii. All metabolized by the liver iii. All are competitive inhibitors of the mu receptor

1. Silent antagonists: in absence of agonist drug, these antagonists elicit no effect 2. Will reverse effects of morphine in 1-3 minutes iv. All are inverse agonists of kappa and delta receptors v. No tolerance; no withdrawal syndrome after chronic use Drug
Naloxone (Narcan) Nalmefene (Revex) Naltrexone (ReVia)

Duration of effect
Short; may need to repeat dose Long; only need single dose Long; oral bioavailable

Mechanism of action
Antagonist at all three opioid receptors Same as naloxone Can block heroine effects for up to 2 days produces no euphoria (only motivated pts likely to succeed w/ naltrexone)

Therapeutic use
Tx of choice for acute opiate overdose Tx of acute opiate overdose Maintenance drug for opiate addicts May alleviate alcohol craving in chronic alcoholics; relapse rate ↓