Opioids: Mechanisms, Effects, and Clinical Considerations

Chapter 11: The Opioids

Introduction to Opioids

Opioids are a class of drugs that act on the nervous system to produce pain-relieving and euphoric effects.

They include both natural and synthetic compounds

• Opioid Analgesics: Drugs that relieve pain by binding to opioid receptors in the brain and spinal cord.

• Examples: Morphine, heroin, codeine, methadone, fentanyl.

• Key Effects: Analgesia (pain relief), euphoria, drowsiness, and, at higher doses, respiratory depression.

• Opium flower is the source, scratch the outside and liquid is converted to drug

• Opioid used to be prescribed and given as medicine freely until Harrison Act regulated

• Highly addictive

Opioid Pharmacology

Opioid Receptors

Opioid effects are mediated by specific receptors in the central and peripheral nervous systems.

• Types of Receptors: μ (mu), δ (delta), κ (kappa), and NOP-R (nociceptin/orphanin FQ receptor).

• Receptor Structure: Each receptor has between 660 and 700 amino acids and twelve transmembrane domains.

• Ligands: Endogenous peptides (endorphins, enkephalins, dynorphins) and exogenous drugs (morphine, heroin).

Agonists, Partial Agonists, and Antagonists

• Full Agonists: Bind and activate opioid receptors fully (e.g., morphine, heroin).

• Partial Agonists: Bind and activate receptors but produce a smaller effect (e.g., pentazocine).

• Antagonists: Bind receptors but do not activate them, blocking the effects of agonists (e.g., naloxone, naltrexone).

Endogenous Opioid Peptides

The body produces its own opioid peptides, which modulate pain and other physiological functions.

• Propeptides: Large precursor proteins (e.g., POMC, proenkephalin, prodynorphin) that are cleaved to form active peptides.

• POMC are synthesized in anterior pituitary, genetic control, not selective (bind to MU, KAPPA, DELTA)

• Examples: β-endorphin (from POMC), enkephalins, dynorphins.

Pain:

• ascending pathways

  • C and A delta fibers cross at Pons

  • synapsis in thalamus nuclei

  • early pain: somatosensorial cortex

    • activates contralaterally

    • activates sencodary somatosensory cortex bilaterally

  • late pain: orbitotemporal cortex

    • activates sencodary somatosensory cortex bilaterally

    • activates anterior cingulate cortex

• descending pathways

  • synapse at periaqueductal gray

  • descend through pons, medulla and raphe nuclei

  • synapse at spinal chord

Mechanisms of Action

Cellular Effects

Opioids act on Gi protein-coupled receptors to modulate neuronal activity.

• Inhibition of Neurotransmitter Release: Opioids close calcium channels and open potassium channels, leading to hyperpolarization and reduced neurotransmitter release.

• Inhibit GABA release, therefore are excitatory

• Presynaptic Autoreceptors: Reduce the amount of transmitter released.

• INCREASES DOPAMINE IN NUCLEUS ACCUMBENS

Pain Modulation

• Ascending Pathways: Opioids inhibit the transmission of pain signals from the periphery to the brain.

• Descending Pathways: Opioids activate descending inhibitory pathways (e.g., from the midbrain PAG) that suppress pain transmission in the spinal cord.

Effects on Synaptic Transmission

• Opioids act on receptors coupled to G proteins that open potassium channels, close calcium channels, and inhibit adenylyl cyclase.

• They reduce synaptic transmission by decreasing neurotransmitter release.

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Physiological and Behavioral Effects

Therapeutic Effects

• Analgesia: Relief of moderate to severe pain.

• Antitussive: Suppression of cough (e.g., codeine).

• Antidiarrheal: Reduction of gastrointestinal motility (e.g., loperamide).

• Methadone: used in opioid addictions as lower-risk alternative

  • can cause euphoria if injected IV, it is administered orally

Side Effects and Risks

• Common Side Effects: Drowsiness, constipation, nausea, respiratory depression, miosis (pupil constriction).

• High Dose Risks: Suppression of the brainstem respiratory center, leading to potentially fatal respiratory depression.

• Peripheral Effects: Slowing of gastrointestinal function/motility, reduction in saliva, decreased body temperature.

Abuse, Dependence, and Tolerance

• Abuse Potential: Significant due to euphoria and reinforcing effects.

• Tolerance: Develops to many effects (e.g., analgesia, euphoria) but less so to constipation and miosis.

  • CAN BECME TOLERANT TO OTHER OPIOIDS -> CROSS-TOLERANCE

• Withdrawal: Characterized by hyperactivity of the CNS, flu-like symptoms, and dysphoria.

  • withdrawal can be suppressed by increased dynorphin synthesis

  • electroacupuncture is also effective for withdrawal symptoms

  • Clonidine is a2-adrenergic agonist that reduces NE activity in locus coeruleus

• Causes physical dependence because of overexpression of MU receptors, rebound hyperactivity

Clinical and Social Considerations

Natural:

Morphine -> oral, IV, IM -> 2-3hrs half life with active metabolite

• not very lipid soluble

• doesn't cross BBB fast

• excreted by kidneys quickly

• not stored in tissues

• Active metabolite: Morphine-6-glucoronide

• Effect of 5-10mg:

  • analgesia (thalamus, amygdala, cerebral cortex, hypothalamus, ares involved in pain perception), euphoria, nausea, constipation, anxiolytic, respiration depression, pupil constriction (key sign of overdose are pin pupils, cerebral stem is affected, occulomotor nerve)

• Toxic effects:

  • comatose state, minimal respiration, pin pupils, low arterial pressure, flacid muscles, low body temp.

Codeine -> oral -> half life 3hrs, metabolized to morphine

• differs from morphine in a hydroxy -> methoxy group

Semi synthetic:

Heroin -> IV, IM, smoked -> less tha 1hr half life (causes higher frequency and dosage), metabolized to morphine

• replaces Hydroxyl groups in morphine to two CH3COO

• immediate tickling sensation

• orgasm-like feeling

• intense euphoria

• in 3-4hrs effect of calm and sleepiness

• low sexual drive

Buprenorphine -> sublingual, subcutaneous, IV, IM -> half-life 24hrs, slow action, inactivated by first-pass effect

• partial agonist of MU receptors

• weaker effetc, longer duration

• can be prescribed by psychiatrist

Synthetic:

Methadone -> oral, IV, IM -> more than 24hrs half-life with no active metabolite

*higher half-life = more therapeutic potential due to less risk of addiction

Fentanyl -> IV, epidural, transdermal -> 1-2hrs half life (stronger analgesic effect than morphine)

Meperidine/Demerol/Sublimaze/Fentanyl: analgesic, fast action, short duration

Loperamide/Imodium: antidiarrheal over the counter, half-life 7-12 hrs (reduces water in intestines) (MU receptor agonist)

Endogenous opioids:

• Endorphins

• Enkephalins

• Dynorphins

Medical Use and Regulation

• Historical Perspective: Opiates were once widely used with little regulation; modern laws (e.g., Harrison Narcotics Act) now control their use.

• Prescription Guidelines: CDC guidelines recommend careful use to reduce opioid deaths and abuse.

• Maintenance Therapies: Methadone and buprenorphine are used for opioid dependence treatment.

• Immediate release opioids have more abuse risk than extended release opioids

• 35 million people in US have used Rx opioids non-medically in their lifetime

1898: Bayer company synthesized heroine (two more methyl groups than morphine)

• more soluble than morphine and crosses BBB faster and then is metabolized to morphine

Risk Factors for Misuse

• Psychosocial stress, chronic pain, and genetic variants increase risk.

• Older age is not a significant risk factor.

• Risk of combining opioid use with marihuana use or alcohol consumption

Opioid Antagonists and Overdose Treatment

• Naloxone: Rapidly reverses opioid overdose by displacing opioids from receptors (temporary use)

• Naltrexone: Used for long-term relapse prevention.

Summary Table: Opioid Receptors and Ligands

• Humans have a lot of opioid receptors in intestinal system, regulating water in intestines

• Metabotropic receptors (G-protein coupled)

Receptor	Endogenous Ligand	Main Effects
μ (mu)	β-endorphin (POMC), endomorphins	Analgesia, euphoria, respiratory depression, antitussive, vomiting, dependence Stops water from being absorbed in intestines
δ (delta)	Enkephalins	Analgesia, mood regulation
κ (kappa)	Dynorphins	Analgesia, dysphoria, psychotomimetic effects, water balance, temp. control
NOP-R	Nociceptin/orphanin FQ	Modulation of pain, stress, and feeding behavior

Key Equations and Concepts

• G Protein-Coupled Receptor Signaling:

$\text{Opioid Receptor Activation} \rightarrow \text{G}_i \text{ protein activation} \rightarrow \downarrow \text{cAMP} \rightarrow \text{K}^+ \text{ efflux} \rightarrow \text{hyperpolarization}$

• Enzyme Cleavage of Propeptides:

$\text{Propeptide} \xrightarrow{\text{proteases}} \text{Active Opioid Peptides}$

Metabolism: opioid is metabolized by hepatic enzymes

poppy seeds -> morphine -> hydromorphone

codeine -> hydrocodone -> morphine/ hydromorphone

heroine -> 6-monoacetylmorphine