Opioids (Narcotic) Analgesics and Antagonists

Vocabulary practice flashcards covering opioid classifications, endogenous peptides, receptor mechanisms, clinical pharmacology, pharmacokinetics, and individual agents from Pharmacology Chapter 6.

Opos

The Greek word for 'juice', referring to the resin harvested from the opium poppy and used medicinally for thousands of years.

Opium

A naturally occurring substance containing Papaver somniferum alkaloids, including morphine, codeine, thebaine, and papaverine.

Opiates

Drugs that are naturally or semi-synthetically derived directly from opium.

Opioids

All compounds, whether natural, semi-synthetic, or synthetic, that display pharmacological properties characteristic of an opiate.

Narcotics

Drugs that possess abuse and addictive potential, derived from the Greek term narkotikos, meaning stupor.

Enkephalins

Endogenous opioid pentapeptides (Leu-enkephalin and Met-enkephalin) derived from the precursor prohormone preproenkephalin.

Endorphins

Endogenous opioid peptides, primarily $\beta$-endorphin, derived from the precursor molecule prepro-opiomelanocortin (POMC).

Dynorphins

Endogenous opioid peptides, including dynorphin A and dynorphin B, derived from the precursor preprodynorphin.

Orphanin FQ / Nociceptin

An endogenous opioid-like peptide system derived from pro-orphanin, comprising orphanin/nociceptin and nocistatin, which binds NOP-R.

Mu ($\mu$) Opioid Receptor (MOR)

The primary opioid receptor responsible for supraspinal/spinal analgesia, respiratory depression, euphoria, miosis, reduced GI motility, and physical dependence; its main endogenous ligands are endorphins and endomorphins.

Kappa ($\kappa$) Opioid Receptor (KOR)

An opioid receptor primarily activated by dynorphins, responsible for spinal analgesia, dysphoria, psychotomimetic effects, sedation, and neuroendocrine regulation.

Delta ($\delta$) Opioid Receptor (DOR)

An opioid receptor located predominantly in the neocortex, striatum, and olfactory areas; activated by enkephalins to produce analgesia in chronic pain, reinforcement, and mood improvement.

NOP-R

The nociceptin/orphanin FQ receptor located throughout the brain and spinal cord, involved in spinal analgesia, supraspinal pronociception, feeding, and learning.

G-Protein Coupling of Opioid Receptors

Coupling to the $G_i/G_o$ class of GPCRs, which leads to adenylate cyclase inhibition ($\downarrow \text{cAMP}$), activation of receptor-linked $\text{K}^+$ channels (hyperpolarization), and suppression of voltage-gated $\text{Ca}^{2+}$ channels.

Postsynaptic Inhibition by Opioids

The opening of postsynaptic $\text{K}^+$ channels upon opioid receptor activation, resulting in outward potassium current, membrane hyperpolarization, and decreased neuronal excitability.

Axoaxonic / Presynaptic Inhibition by Opioids

The closure of voltage-gated $\text{Ca}^{2+}$ channels at the presynaptic terminal, which blocks calcium influx and prevents the release of neurotransmitters such as Substance P.

WHO Analgesic Ladder

A 3-step guideline for pain relief: Step 1 uses non-opioid analgesics $\pm$ adjuvants; Step 2 escalates to weak opioids $\pm$ non-opioids $\pm$ adjuvants; Step 3 utilizes strong opioids $\pm$ non-opioids $\pm$ adjuvants.

Opioid-Induced Euphoria Mechanism

The stimulation of $\mu$-opioid receptors on GABAergic interneurons in the ventral tegmental area (VTA), causing disinhibition and an increased release of dopamine in the nucleus accumbens.

Opioid Toxicity Triad

The classical triad indicating acute opioid poisoning: central nervous system depression (coma), respiratory depression (cyanosis), and pinpoint pupils (miosis).

Miosis

Pupillary constriction caused by opioid-mediated disinhibition of the Edinger-Westphal (EW) nucleus through the oculomotor nerve (CN III); persists in the dark and does not develop tolerance.

Opioid-Induced Constipation (OIC)

A universal peripheral adverse effect resulting from $\mu$-receptor activation in the gut, which reduces propulsive peristalsis, decreases secretions, increases fluid absorption, and elevates anal sphincter tone with no development of tolerance.

Chemoreceptor Trigger Zone (CTZ)

An area in the medulla stimulated directly by $\mu$-opioid agonists to produce nausea and emesis, an effect exacerbated by vestibular activation during patient movement.

Pre-Bötzinger Complex (Pre-BötC)

The rhythm-generating inspiratory center within the ventrolateral medulla possessing $\mu$-opioid receptors; its depression by opioids is a key mechanism of respiratory arrest.

Morphine-6-glucuronide (M6G)

An active hepatic metabolite of morphine produced via UGT2B7 that is more potent than morphine itself, responsible for much of its chronic analgesia, and capable of accumulating to toxic levels in renal disease.

Codeine

A weak natural opioid agonist commonly used in dentistry and as an antitussive; acts largely as a prodrug converted to morphine by hepatic CYP2D6.

Oxycodone

A semi-synthetic opioid agonist $10\text{--}12\times$ more potent than codeine, used alone or combined with aspirin (Percodan) or acetaminophen (Percocet), and available as an extended-release formulation (OxyContin).

Oxymorphone

A potent semi-synthetic metabolite of oxycodone that is $3\times$ more potent than oral morphine.

Hydrocodone

A semi-synthetic opioid agonist $6\times$ more potent than codeine, metabolized to hydromorphone, and available in combination with acetaminophen or ibuprofen (e.g., Vicodin).

Hydromorphone (Dilaudid)

A strong semi-synthetic opioid agonist $2\text{--}8\times$ more potent than morphine, characterized by superior oral bioavailability, high lipid solubility, rapid CNS penetration, and high abuse liability.

Meperidine (Demerol)

A synthetic opioid agonist for acute pain management ($24\text{--}48\text{ hours}$) and postanesthetic shivering, requiring $100\,\text{mg}$ to equal $10\,\text{mg}$ morphine; contraindicated in chronic use due to toxic metabolite accumulation causing CNS excitation and seizures, and severely reactive with MAOIs.

Diphenoxylate

A strongly constipating opioid agonist used to treat diarrhea; co-formulated with subtherapeutic atropine sulfate to deter abuse by preventing blood-brain barrier penetrance and causing anticholinergic side effects at high doses.

Loperamide (Imodium)

A peripherally acting anti-diarrheal opioid that does not cross the blood-brain barrier under normal conditions because it is an active substrate for the P-glycoprotein efflux transporter.

Methadone

A synthetic, long-acting full $\mu$-opioid agonist with prolonged half-life and slow receptor dissociation, utilized for agonist-substitution maintenance therapy and gradual detoxification in opioid dependence.

Fentanyl

A highly lipophilic synthetic $\mu$-opioid agonist $100\times$ more potent than morphine with rapid onset and short duration, used perioperatively and in transdermal patches for chronic cancer pain.

Sufentanil

A synthetic opioid agonist approximately $1000\times$ more potent than morphine, used for acute parenteral analgesia and chronic malignant pain management.

Remifentanil

An ultra-short-acting fentanyl analog administered by continuous IV infusion for procedural analgesia; contraindicated for intraspinal administration because its formulation vehicle contains glycine, which induces motor paralysis.

Pentazocine

A mixed agonist-antagonist opioid that acts as a weak $\mu$ antagonist or partial agonist and a $\kappa$ agonist; can precipitate withdrawal in opioid-dependent individuals and cause dysphoria.

Buprenorphine

A Schedule III mixed opioid acting as a partial agonist at $\mu$ receptors and an antagonist at $\kappa$ and $\delta$ receptors; $25\text{--}50\times$ more potent than morphine with a ceiling effect on respiratory depression.

Naloxone (Narcan)

A pure, nonselective competitive opioid receptor antagonist with complete first-pass hepatic metabolism that must be administered parenterally to rapidly reverse acute opioid overdose.

Naltrexone (Vivitrol)

An orally effective, long-acting competitive opioid receptor antagonist used for the maintenance treatment of opioid addiction and alcoholism, as well as weight management when combined with bupropion.

Tramadol (Ultram)

A dual-mechanism centrally acting analgesic that acts as a weak $\mu$-opioid agonist and inhibits the neuronal reuptake of norepinephrine and serotonin (5-HT), carrying a risk of seizures and serotonin syndrome.

Opioid Tolerance

A decrease in drug effect after repeated administration due to homeostatic adaptations such as counter-activation of adenylyl cyclase, requiring increasing doses to maintain the initial pharmacological response.

Cross-Tolerance

The development of tolerance to other opioid agonists with similar pharmacological actions and receptor targets after repeated exposure to a specific opioid.

Physical Dependence

An adaptive neurobiological state resulting from chronic receptor stimulation, revealed when withholding the drug or administering an antagonist precipitates a rebound withdrawal syndrome.

Five C's of Addiction

A diagnostic framework for addiction consisting of Chronic condition, Compulsive use, impaired Control, Craving, and Continued use despite harm.