Opiods & Non-Opioids

Pain Overview

  • The experience of pain consists of four steps:

    1. Transduction: The process where a chemical, mechanical, or thermal stimulus is sensed by a nociceptor and converted into an action potential.

    2. Transmission: The afferent pain signal travels from the peripheral nervous system (PNS) to the central nervous system (CNS) via a 3-neuron pathway.

    3. Modulation: The pain signal is modified (either inhibited or augmented) as it advances towards the cerebral cortex.

    4. Perception: The pain signal is processed in the cerebral cortex and limbic system, resulting in the subjective experience of pain.

  • Key processes:

    • Transduction is the correct term for how nociceptors convert a chemical stimulus into an action potential.

Detailed Steps of Pain Experience

Transduction

  • Injured tissues release a variety of chemicals that activate peripheral nerves and stimulate immune cells.

  • These chemicals cause peripheral nerves to transduce this mixture into an action potential, allowing the brain to interpret the extent of tissue injury.

  • Types of nerve fibers involved:

    • A-delta fibers: Transmit "fast pain" (sharp and well localized).

    • C-fibers: Transmit "slow pain" (dull and poorly localized).

  • Inflammation contributes to:

    • Allodynia: Reduced threshold to pain stimulus.

    • Hyperalgesia: Increased response to pain stimulus.

  • Drugs targeting transduction include:

    • NSAIDs

    • Local anesthetics

    • Steroids

    • Antihistamines

    • Opioids

Transmission

  • The pain signal is relayed through a three-neuron afferent pain pathway along the spinothalamic tract:

    • First-order neuron: Transmits from periphery to the dorsal horn (cell body located in the dorsal root ganglion).

    • Second-order neuron: Travels from the dorsal horn to the thalamus (cell body in the dorsal horn).

    • Third-order neuron: Goes from the thalamus to the cerebral cortex (cell body in the thalamus).

  • Drugs targeting transmission:

    • Local anesthetics

Modulation

  • The modification of the pain signal occurs primarily in the substantia gelatinosa of the dorsal horn (Rexed lamina 2 and 3).

  • Mechanisms of modulation include:

    • Pain inhibition:

    1. Spinal neurons release GABA and glycine, which act as inhibitory neurotransmitters.

    2. The descending pain pathway releases norepinephrine (NE), serotonin, and endorphins.

    • Pain augmentation:

    1. Central sensitization

    2. Wind-up

  • Medications targeting modulation include:

    • Neuraxial opioids

    • NMDA antagonists

    • Alpha-2 agonists

    • AchE inhibitors

    • SSRIs

    • SNRIs

Perception

  • Refers to how pain signals are processed in the cerebral cortex and limbic system influencing our emotional response to pain.

  • Drugs targeting perception include:

    • General anesthetics

    • Opioids

    • Alpha-2 agonists

Opioid Receptors

General Overview

  • Opioid receptor stimulation leads to reduced neurotransmitter release from presynaptic neurons and hyperpolarization of postsynaptic neurons.

  • Locations:

    • Brain: Periaqueductal gray, locus coeruleus, and rostral ventral medulla.

    • Spinal cord: Primary afferent neurons in the dorsal horn and interneurons.

    • Peripheral: Sensory neurons and immune cells.

Types of Opioid Receptors

  1. Mu (MOP) Receptor: Key effects include analgesia, bradycardia, respiratory depression, euphoria, physical dependence, and constipation.

  2. Delta (DOP) Receptor

  3. Kappa (KOP) Receptor: Stimulation can alleviate shivering but may lead to dysphoria, delirium, and hallucinations.

  4. ORL1 (NOP) Receptor

Physiologic Effects of Receptors

  • Mu Receptor Effects:

    • Analgesia (supraspinal and spinal)

    • Bradycardia

    • Euphoria

    • Miosis

    • Urinary retention

    • Immune suppression (Mu-3).

  • Delta Receptor Effects:

    • Analgesia

    • Respiratory depression

    • Urinary retention

  • Kappa Receptor Effects:

    • Analgesia

    • Dysphoria

    • Hallucinations

Molecular Mechanisms of Opioid Action

  • Opioid receptor binding activates a G protein that inhibits adenylate cyclase, leading to the following intracellular changes:

    1. Decreased cAMP production.

    2. Decreased Ca++ conductance.

    3. Increased K+ conductance leading to hyperpolarization of the postsynaptic neuron.

    • This overall minimizes neuronal function.

Systemic Effects of Opioids

Key Effects

a. Respiratory Depression

  • Opioids shift the CO2 response curve to the right.

b. Nausea and Vomiting

  • Caused by stimulation of the chemoreceptor trigger zone in the medulla and potential vestibular apparatus interactions.

c. Cardiovascular Effects

  • Opioids lead to minimal blood pressure effects in healthy patients.

  • Contraction of the sphincter of Oddi (increased biliary pressure) may occur, reversible with naloxone or glucagon.

  • Morphine and meperidine can cause increased histamine release.

d. Neurologic Effects

  • Shifts in the ventilatory response to CO2 and affect on muscle tone.

Sex Differences in Opioid Pharmacokinetics/Pharmacodynamics

  • In women, morphine shows:

    • Greater analgesic potency

    • Slower onset

    • Longer duration of action

    • Lower postoperative opioid consumption

Opioid Classification and Potency

Classification

  • Opioids are classified as:

    1. Naturally occurring (e.g., Morphine)

    2. Semisynthetic (e.g., Hydromorphone)

    3. Synthetic (e.g., Fentanyl)

Relative Potency (most to least)

  • Sufentanil > Fentanyl = Remifentanil > Alfentanil > Hydromorphone > Morphine > Meperidine

Key Terms

  • Dependence: Withdrawal symptoms upon cessation of the drug.

  • Tolerance: Requirement of higher doses to achieve the same effect.

  • Addiction: A disorder with continued drug use despite negative consequences.

  • Exceptions: Tolerance does not develop to miosis and constipation.

Administration and Effects of Opioids

Withdrawal Symptoms

  • Early symptoms: Diaphoresis, insomnia, restlessness.

  • Later symptoms: Abdominal cramping and N/V.

  • Withdrawal timeframes based on drug type:

    • Fentanyl/Meperidine: 2-6 hrs onset, 6-12 hrs peak.

    • Morphine/Heroin: 6-18 hrs onset, 36-72 hrs peak.

    • Methadone: 24-48 hrs onset, 3-21 days peak.

Metabolism

  • All opioids except remifentanil undergo hepatic biotransformation.

  • The opioids which produce active metabolites include:

    • Morphine: morphine-3-glucuronide (hyperalgesia, agitation) and morphine-6-glucuronide (respiratory depression).

    • Meperidine: normeperidine (CNS irritability).

  • Clinical implications: Active metabolites may necessitate dosage adjustment in renal or hepatic failure patients.

Specific Opioid Mechanisms and Effects

Meperidine

  • Toxicity: Normeperidine lowers seizure threshold, increases CNS irritability, causing muscle twitches and seizures.

Hydromorphone

  • Conflicting reports on active metabolites exist, though renal excretion implications should be considered.

Remifentanil

  • Recognized for its rapid metabolism and unique viability for use without being affected by pseudocholinesterase deficiency.

Alfentanil

  • Known for rapid onset of action linked to its non-ionized fraction's ability to cross the blood-brain barrier. Lower pKa leads to fast uptake.

Oliceridine and Methadone

  • Oliceridine: Selects primarily for mu receptor in treating acute pain; contraindications include paralytic ileus.

  • Methadone: Acts through multiple mechanisms; caution for QT interval prolongation.

IV PCA Dosing Regimens

  • Morphine: Demand dose 0.5-2.5 mg, lockout interval 5-10 min.

  • Fentanyl: Demand dose 10-20 mcg, lockout interval 4-10 min.

  • Hydromorphone: Demand dose 0.05-0.25 mg, lockout interval 5-10 min.

  • Key points: Demand doses must balance with lockout intervals to avoid toxicity and maintain effectiveness.