OPIOID ANALGESICS Roy Krishna, PhD, FCP.

Opioids Narcotic – a drug with addictive properties that can produce analgesic and sedative effects. Opiate – a drug naturally derived from opium (morphine and codeine) Opioid – a drug, natural or synthetic, with morphine- like qualities Collectively called Opioid Analgesics

Classification of Opioids Agonist Strong Moderate Weak Antagonist Agonist / Antagonist Other

Indications for Opioids Analgesic Anesthetic Antitussive Antidiarrheal

Strong Opioid Agonists Fentanyl (Sublimaze, Duragesic) Alfentanil, Remifentanil, Sufentanil related to Fentanyl but use for anesthesia Hydromorphone (Dilaudid) Meperidine (Demerol) Methadone (Methadose, Dolophine) Morphine sulfate (MS Contin) Oxycodone (Oxycontin) Heroin

Moderate Opioid Agonists Codeine (Robitussin AC) Hydrocodone Combination Meds Tylenol #2, 3, 4 (acetaminophen/codeine) Vicodin, Lortab (acetaminophen/hydrocodone) Vicoprofen (ibuprofen/hydrocodone) Percocet (acetaminophen/oxycodone) class II schedule

Weak Opioid Agonists Other Loperamide (Imodium) Diphenoxylate – (Lomotil) Combined with atropine Propoxyphene (Darvon) Combined with acetaminophen-marketed as Darvocet (acetaminophen/propoxyphene) Dextromethorphan (Delsym, Robitussin DM) Other Tramodol (Ultram) Tapentadol (Nucynta)

Opioid Agonist / Antagonist (Mixed-Acting) Pentazocine (Talwin) Nalbuphine (Nubain) Butorphanol (Stadol) Opioid Antagonist Naloxone (Narcan) Naltrexone (Revia)

Schedule of Controlled Substances Criteria Examples I No medical use; high addiction potential heroin II Medical use; high addiction potential strong and moderate opioid agonists III Medical use; moderate potential for dependence Lortab, Tylenol #3 IV Medical use; low abuse potential weak opioid agonists

Opioid Receptors mu “REAP” kappa “SAM” delta (epsilon) (sigma) Respiratory depression Euphoria Analgesia Physical dependence kappa “SAM” Sedation Miosis delta (epsilon) (sigma)

Endogenous Opioids Endorphins Dynorphins Enkephalins neurohormones (ACTH) mediates pain memory mood appetite (thirst, hunger, sex) Dynorphins neurotransmitters Enkephalins Adrenocorticotropic hormone

Opioid Receptor locations in the CNS (highest to lowest concentration) 1. cerebral cortex 2. amygdala 3. septum 4. thalamus 5. hypothalamus 6. midbrain 7. spinal cord

CNS pain pathways Opioids have 3 primary sites of action for their analgesic effects: Spinal cord - opioids inhibit release of neurotransmitters from the afferents Thalamus and limbic system – opioids block the perception of pain and reaction to pain Brainstem – opioids activate descending inhibitory systems to modulate pain

Mechanism of Action of Opioids Inhibitory G-Protein (Gi) signaling→ ↓ cAMP ↓ Inhibition of presynaptic firing in the spinal cord and postsynaptic firing in the brain ↓ Hyperpolarization of neurons Diminished or blocked pain perception

Morphine Contraindications Adverse Effects PAIN severe chronic used in acute pulmonary edema Palliative measures Contraindications respiratory compromise asthma intracranial injuries (increased intracranial pressure) paralytic ileus Adverse Effects euphoria and dysphoria, respiratory depression, nausea, constipation, sedation, pruritus, urticaria, bronchospasms, urinary retention, anxiety, hypotension, miosis

Peripheral effects of morphine Cardiovascular – vasodilation, decreases blood pressure, some negative inotropic response Skin – histamine release to cause itchiness Pulmonary – bronchospasm GI – decreases secretions and motility of gut.

Morphine’s effect on smooth muscle biliary tract 10 fold increase over normal pressure (normal is 20 mm H20 pressure) increase due to contraction of Sphincter of Odi urinary bladder tone of detrusor muscle increased feel urinary urgency have urinary retention due to increased muscle tone where sphincter closed off bronchial muscle bronchoconstriction uterus Reduced uterine tone- can prolong labor

Primarily renal excretion-dosage adjustment in renal dysfunction. Morphine Undergoes conjugation to active metabolites: morphine 6β glucoronide and morphine 3β glucoronide . Primarily renal excretion-dosage adjustment in renal dysfunction. PO-10-30mg q4h, IV 2.5-15mg q4h IM/SC- 5-20mg q4h

Fentanyl (Sublimaze, Duragesic) 80 to 100 times more potent than morphine rapid onset of action (peaks in 5 min) short acting (30 min) IV form used as preoperative medication Also commonly used for epidurals Transdermal form excellent in chronic patients Onset of action is 12 hours replace patch every 72 hours

Meperidine (Demerol) Synthesized to normeperidine – excess accumulation can cause seizures Normeperidine inhibits reuptake of serotonin- serotonin syndrome. Avoid in renal dysfunction patients PO/SC/IM/IV- 50-150mg q4h, prn

Methadone (Methadose, Dolophine) pharmacological activity and potency similar to morphine powerful pain reliever long duration of activity, half life of up to 24 hours absorbed well orally less addiction liability used in maintenance program for narcotic dependence treatment PO/SC/IM 2.5-10mg q 3-4h

Heroin the diacetyl derivative of morphine Most lipophilic and thus enhanced capability to enter the brain 3 times more potent than morphine No medicinal value recreational drug that is commonly injected, snorted, or smoked

Moderate Opioid Agonists Codeine (Robitussin AC) Hydrocodone Combination Meds Tylenol #1, 2, 3, 4 (acetaminophen/codeine) Vicodin, Lortab (acetaminophen/hydrocodone) Vicoprofen (ibuprofen/hydrocodone) Percocet (acetaminophen/oxycodone) class II schedule

Codeine 1/10th the potency of morphine excellent antitussive good analgesic low potential for abuse and rarely produces dependence usually combined with acetaminophen PO/IM/SC 15-60mg bid

Weak Opioid Agonists Other Propoxyphene (Darvon) Tramodol (Ultram) (acetaminophen/propoxyphene) Other Tramodol (Ultram) Loperamide (Imodium) Diphenoxylate – (Lomotil) Combined with atropine Dextromethorphan (Delsym, Robitussin DM)

Propoxyphene a derivative of methadone 1/20th the potency of morphine Given alone, analgesic effect similar to aspirin Usually combined with acetaminophen (Darvocet) PO-65mg q4h

Dextromethorphan mu, kappa, sigma receptor activity used as an antitussive (Delsym, Robitussin DM) Opioids with indications for the treatment of cough: codeine hydrocodone hydromorphone

Antidiarrheals Loperamide (Imodium)-GI effects only Diphenoxylate – (Lomotil) Combined with atropine- GI and CNS effects has very little analgesic properties at therapeutic dose no antitussive effect causes respiratory depression and euphoria at high doses Loperamide: PO 4mg, followed by 2mg

Opioid Agonist / Antagonist Pentazocine (Talwin) Nalbuphine (Nubain) Butorphanol (Stadol) Does not cause serious respiratory depression Partial Agonist Buprenorphine (Subutex ) used for outpatient opioid detoxification

Opioid Antagonists Naloxone (narcan) Naltrexone (Revia) Binds with high affinity to opioid receptors Displaces opioids from receptor site Completely and dramatically reverses the effects of opioids

Naloxone (Narcan) Administered via IV push Rapidly displaces all bound opioid molecules Binds to mu, kappa, and delta receptors But has a 10 fold affinity to the mu receptor. Respiratory depression and sedation are reversed in less than 30 seconds Short duration of 1-2 hours. Repeat doses may have to be given because of the longer durations of action of the opioid agonists IV -0.4-2mg

Naltrexone (Revia) Same pharmacodynamics as naloxone Slightly different pharmacokinetics Naltrexone comes in an oral form Unlike naloxone, it has a long half life One single 100mg dose can block the effects of injected heroin for up to 48 hours. Patient gets no euphoric effect from heroin so person gets off heroin (negative reinforcement) Approved for use by the FDA Also used for treatment of alcoholism  Highly hepatotoxic PO 25mg

Opioid Dependence Tolerance with repeated administration Cellular tolerance/receptor desensitization Abstinent withdrawal-drug seeking behavior, autonomic hyperexcitability-goose bumps, CNS originating pain, lacrimation, yawning, irritability Pered withdrawal is recommended. Precipitated withdrawal-induced by administration of opioid antagonist

Opioids-Drug Interactions Side effects exacerbated-CNS depression, respiratory depression, sedation, dizziness First generation antihistamines Barbiturates Alcohol TCA’s MAO’s Antiepileptics