Opioids: Pharmacology and Abuse Routes of Administration and Pharmacokinetics PDF

# Opioids: Pharmacology and Abuse ## Introduction Opioids are well-established analgesics used to treat moderate to severe pain. They can be used for acute or chronic pain, and are increasingly used in the treatment of opioid addiction. ## Opioid Pharmacokinetics ### Absorption - Opioids are base...

# Opioids: Pharmacology and Abuse ## Introduction Opioids are well-established analgesics used to treat moderate to severe pain. They can be used for acute or chronic pain, and are increasingly used in the treatment of opioid addiction. ## Opioid Pharmacokinetics ### Absorption - Opioids are bases, and are less effective when administered orally than parenterally (i.m., s.c. or i.v.). - Morphine (pKa 8.2) is quickly ionized in the acidic environment of the digestive tract and is not lipid soluble. - Oral bioavailability of morphine and heroin is low due to significant enzymatic destruction within the stomach, intestine and liver during first-pass metabolism. - Extended-release formulations have multiple layers or matrixes that break down at different rates to release the active ingredient as the medication passes through the digestive tract. - Some opioids are less impacted by enzymes during first-pass metabolism and are lipid soluble, allowing for better absorption from the gastrointestinal tract. - Fentanyl is highly lipophilic and is best absorbed through buccal membranes. ### Distribution - After absorption, opioids become concentrated in the heart, lungs, kidney, liver, spleen, muscles and brain. - Highly lipophilic opioids (buprenorphine, fentanyl, methadone) are prone to protein binding and have long half-lives. - Opioids are slowly redistributed to muscles and fat. - Codeine, morphine, and hydromorphone exhibit lower protein binding and have shorter durations of action. - Oxycodone exhibits a 700% higher permeability across the blood-brain barrier compared to morphine. - Heroin is highly lipophilic and has 0% protein binding, allowing for rapid distribution to the brain. - All opioids cross the placental barrier and are distributed to the milk of nursing mothers. ### Elimination - Opioids are metabolized by digestive system enzymes, primarily in the liver. - Metabolites are excreted in urine, feces, and bodily fluids. - Opioid metabolism involves two phases: - Phase 1: modification of the drug molecule by cytochrome P450 enzymes. - Phase 2: conjugation of the drug molecule or metabolite with a hydrophilic substance. - Most opioids undergo both phase 1 and phase 2 metabolism until their metabolites are sufficiently hydrophilic to be eliminated. - The cytochrome P450 enzymes involved in opioid metabolism include CYP3A4, CYP2D6, CYP2B6, CYP2C8, and CYP2C19. - Some opioids are prodrugs, meaning that their active pharmacological properties are a result of their metabolites. ### Metabolism of Specific Opioids - **Morphine:** undergoes glucuronidation to yield inactive and active metabolites. - **Heroin:** extensively metabolized to morphine. - **Oxymorphone:** metabolized to active metabolites noroxycodone and oxymorphone. - **Fentanyl:** 99% metabolized by CYP3A4 to a nontoxic metabolite. - **Methadone:** metabolized to inactive primary and secondary metabolites. Long half-life, 25-40 hours. - **Buprenorphine:** metabolized to active metabolite norbuprenorphine. - **Codeine:** undergoes phase 1 and phase 2 metabolism to produce active metabolites norcodeine and morphine. ### Interaction with Other Drugs or Foods - **CYP3A4 inducers:** speed metabolism of opioids (St. John's wort, statins, antiretroviral agents, sedative-hypnotics, caffeine, etc.). - **CYP3A4 inhibitors:** slow metabolism of opioids (antibiotics, antipsychotics, grapefruit juice, etc.). - **Genetic polymorphisms:** individual differences in P450 enzyme expression can impact metabolism. ## Neuropharmacology of Opioids ### Opioid Receptors - There are four types of opioid receptors: - µ (mu) receptor: primary target of most opioids, mediates analgesia, sedation, euphoria, and dependence. - κ (kappa) receptor: involved in visceral pain, sedation, and dysphoria. - δ (delta) receptor: involved in analgesia, affective modulation, and reward. - ORL1 (opioid receptor-like) receptor: binds to the peptide nociceptin, its role is not fully understood. ### Endogenous Opioid Peptides - The brain produces opioid peptides, including: - Endorphins - Enkephalins - Dynorphins - Nociceptin ### Opioid Drug Actions - **Agonists:** bind to and activate opioid receptors. - **Antagonists:** bind to opioid receptors and block their activation. - **Mixed agonist-antagonists:** act as agonists at some receptors and antagonists at others. - **Partial agonists:** bind to receptors and activate them, but to a lesser degree than endogenous ligands. ### Examples of Opioid Drug Actions - **Morphine:** a full agonist at all three receptor subtypes. - **Hydromorphone:** full agonist at all three receptor subtypes. - **Meperidine (Demerol):** primarily active at µ receptors. - **Nalbuphine (Nubain):** mixed agonist-antagonist. - **Fentanyl:** highly selective for the µ receptor. - **Codeine:** selective full agonist at the µ receptor. - **Oxycodone:** full agonist at the µ receptor. - **Tramadol:** full agonist at the µ receptor, has activity at serotonin and norepinephrine reuptake sites. - **Pentazocine:** partial agonist at µ and κ receptors, full agonist at δ receptors. - **Methadone:** primarily active at the µ receptor, also acts as a serotonin-norepinephrine reuptake inhibitor and NMDA antagonist. ### Opioid Antagonists - **Nalorphine:** mixed agonist-antagonist, blocks µ receptors. - **Naloxone:** non-selective antagonist, blocks µ, κ, δ, and ORL1 receptors. - **Naltrexone:** non-selective antagonist, blocks µ, κ, δ, and ORL1 receptors. ## Opioid Abuse - *Routes of administration*: injection, inhalation, oral, and intranasal. - *Reinforcing effects*: the more rapid the onset of action, the more reinforcing the effects. - *Tolerance*: decreased sensitivity to opioids with repeated use. - *Dependence*: physical withdrawal symptoms occur upon discontinuation of opioid use. - *Overdose*: a potentially fatal complication of opioid abuse. - *Treatment*: opioid antagonists (naloxone, naltrexone), opioid substitution therapy (methadone, buprenorphine). ## Implications for Healthcare - Opioids are powerful medications, and their use should be closely monitored. - Healthcare providers should be aware of the risks and benefits of opioid therapy. - Patients should be educated about the risks and benefits of opioid use. - Strategies to prevent opioid abuse and overdose are essential. - This includes appropriate prescribing practices, access to treatment for opioid addiction, and harm reduction efforts. ## References - DePriest et al. 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