Basic analgesic pharmacology

define pain

an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual, or potential tissue damage

T/F: pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors

true

How are pain and nociception different phenomena?

pain cannot be inferred solely from activity in sensory neurons

although pain usually serves an adaptive role, it may have ____________________

adverse effects on function and social and psychological well-being

T/F: inability to communicate do not negate the possibility that a human or a nonhuman animal experiences pain

true

What are the phases of pain?

Transduction, Conduction, Transmission, Perception, and Modulation

What are the mechanisms of pain?

noxious stimulus, nociceptive stimulus, nociceptive neuron, nociceptor, nociception, and nociceptive pain

What is glutamate’s role in pain?

Is a primary excitatory neurotransmitter that transmits pain signals from first order afferent neurons to second order afferent neurons (periphery —> CNS). Activates NMDA and AMPA receptors 

what is substance P?

Is an excitatory ligand that binds to the neurokinin-1 receptors.

What is substance P’s role in pain in CNS?

Centrally is released from first order neurons to second order afferent neurons.

What is substance P’s role in pain in the periphery?

Has a role in the inflammatory response. Induces the release of cytokines, histamine, and other inflammatory mediators from immune cells, leading to vasodilation, increased vascular permeability, and plasma extravasation (redness, swelling, and pain associated with inflammation)

What is calcitonin gene-related peptide (CGRP)?

An excitatory ligand that binds to the calcitonin-like receptor (CLR) in combination with receptor activity-modifying protein 1 (RAMP1).

What is CGRP’s role in the CNS?

is released from the first order afferent to the second order afferent.

What is CGRP’s role in the periphery?

Induces vasodilation which promotes inflammation through release of other inflammatory mediators and facilitating the migration of immune cells to the site of injury (particularly associated with migraine headaches)

What are prostaglandins?

Excitatory ligands derived from arachidonic acid through the action of COX enzymes

What is the role of prostaglandins (PG)?

They are produced at sites of tissue damage or infection, where they cause inflammation, pain, and fever. PG, particularly PGE2, sensitize nociceptors, lowering threshold, more responsive to stimuli. PG bind to specific G-protein coupled receptors on the surface of nociceptors which activates intracellular signaling pathways that enhance the excitability of these neurons.

What are NaV1.8 sodium channels?

Voltage-gated channels that help transmit pain signals and generate action potentials - expressed in primary sensory neurons, mostly C fibers, including dorsal root ganglion (DRG) neurons

what are the inhibitory endogenous opioids?

Endorphins, enkephalins, and dynorphins.

What are endogenous opioids?

They bind to opioid receptors (GPCRs) mu, delta, and kappa (each receptor type has a different distribution and function in the body). They inhibit the release of substance P and glutamate and promote feelings of euphoria and well-being

GABAergic neurons release GABA which bind to:

GABAa, GABAb, and GABAc receptors

What is the role of GABA in pain?

Opens chloride channels which leads to hyperpolarization and inhibition of action potentials. This process reduced the transmission of pain signals.

What is GABA’s role in presynaptic inhibition?

Can inhibit the release of excitatory neurotransmitters from presynaptic terminals. This presynaptic inhibition is crucial for controlling the strength of nociceptive signals and differentiating between pain and non-painful stimuli

What is norepinephrine’s role in pain?

Has a2 adrenergic receptors pre- and post-synaptic. Activates the descending pathway in brainstem, and inhibits release of substance P and glutamate in spinal cord

What is serotonin’s role in pain inhibition?

Inhibits pain transmission (activates 5-HT1A and 5-HT1B receptors). Activates the descending pathway in brainstem and inhibits release of substance P and glutamate in spinal cord.

What is serotonin’s role in facilitation of pain transmission?

Can facilitate pain transmission through 5-HT2 and 5-HT3 receptors. Activation of these receptors can enhance the excitability of neurons in the spinal cord and brain, contributing to the sensation of pain

Where does transduction occur?

out in the periphery

describe transduction:

chemicals produced by damaged tissues and/or mast cells and neuropeptides are attached to the free nerve terminals to produce the signals which are sent to the spinal cord by A-delta or C fibers and then the brain through the spinal tract

describe conduction:

Movement of the pain signal (action potential) from the peripheral site via primary afferent neuron (nociceptor) along peripheral nerves → spinal cord (interneurons)→ brain.

describe what happens in transmission

Involves the spinal cord circuitry and pathways (second-order neurons). Incoming action potentials from periphery activates presynaptic voltage-gated calcium channels, leading to calcium influx and subsequent synaptic vesicle release. The released NTs act on post synaptic receptors and stimulation of ionotropic glutamate receptors leads to fast postsynaptic depolarization, while activation of other modulatory receptors mediates slow depolarization. Postsynaptic depolarization, if sufficient, leads to action potential production in the secondary relay neuron.

What are primary sensory neurons?

Neurons coming in from the periphery

What are secondary relay neurons?

what is going to go into the brain

What is included in the anteriolateral sensory pathway (spinothalamic)

Neospinothalamic tract, Paleospinothalamic tract

What is the neospinothalamic tract?

Aδ fibers are fast/myelinated which tell use where pain is located

what is the paleospinothalamic tract?

C fibers are slow/unmyelinated located in the thalamic region/limbic system which is involved in the emotional or affective portion of pain

What are spinorecticular fibers?

our avoidance reflexes (withdrawal reflex and reflex arc)

describe perception

The neospinothalamic (involved w thalamus) is the area for primary somatosensory cortex interconnections which allows for localization and identification of where the pain is happening (precision and discrimination). The parietal cortex is involved in our learned meaningfulness (if something hurts, don’t do it again).

The paleospinothalamic (involved with limbic cortex) is associated with hurtfulness, mood-altering, and attention-narrowing

What is central modulation?

Endogenous analgesic mechanism such as the endogenous opiate system (enkephalins, dynorphins, b-endorphins and mu, delta, and kappa receptors) and reduced activity of glutamate at NMDA receptors. Postsynaptic efflux of K+ will lead to hyperpolarization so the neurons cannot fire

What releases enkephalins?

periaqueductal gray (PAG) stimulation

Which things have positive central modulation effects?

substance P, glutamate, NMDA channels

which things have negative central modulation effects?

GABA, glycine, opiates, serotonin, and norepinephrine

What ligands are involved in the ascending nociceptive pathway?

glutamate, NK-1, substance P, CGRP

What ligands are involved in the descending inhibitory pathway?

GABA, opioids, noradrenalin, serotonin.

where are NaV1.8 sodium channels?

outside of the modulation system

Which COX enzyme is constitutive and inhibition would be undesirable?

COX-1

Which COX enzyme is inducible and inhibition would be desirable?

COX-2

role of COX-1

homeostatic functions in the GI/renal tract, platelet function, and macrophage differentiation

role of COX-2

inflammation

why do we inhibit COX-2

for relief of pain

What things activate COX-2?

cytokines, IL-1, TNF growth factors

what things inhibit COX-2

glucocorticoids, cytokines, IL-4

what does acetaminophen block?

COX-2 and COX-3 in the CNS (no effect in the periphery)

What do NSAIDs block?

COX-1 and COX-2 in the periphery and CNS

What are the three opioid receptors?

mu, kappa, delta

what is an example of an opioid agonist?

morphine

what is an example of a mixed opioid agonist/antagonist

buprenorphine

what is an example of a partial opioid agonist

pentazocine

what is an example of an opioid antagonist?

naloxone

describe the absorption of opioids:

Are well absorbed orally, also SL, buccal, rectal, nasal, and transdermal. High first-pass metabolic (1st pass effect) especially for morphine

morphine oral:IV dose

3:1

describe opioid distribution

concentrate in highly perfused organs such as the brain, lungs, liver, kidneys, and spleen

Opioids are metabolized to ____________________

polar metabolites (glucuronides)

Why do we want opioids to be metabolized to more polar metabolites?

the more polar the more it is filtered out via the kidneys

what are morphine’s metabolites?

morphine-3-glucuronide (M3G) - neuroexcitatory properties

morphine-6-glucuronide (M6G), an active metabolite with analgesic potency 4-6X that of its parent compound

metabolite of codeine

morphine

metabolite of oxycodone

oxymorphone

metabolite of hydrocodone

hydromorphone

which opioids are oxidative to inactive metabolites?

phenylpiperidines such as fentanyl (except for meperidine)

What is meperidine’s metabolite?

Normeperidine which is active and accumulates with poor renal function which can leads to seizures and other ADRs

describe opioid excretion

Polar metabolites are eliminated in the urine and small amounts in bile. Small amounts of unchanged drug in urine, metabolites can accumulate. Metabolites accumulate in reduced renal function which increases ADRs

T/F: opioids have two well-established direct G_i/0 protein-coupled actions on neurons

true

What are the two well-established direct G_i/0 protein-coupled actions that opioids have on neurons?

They close voltage-gated calcium channels on presynaptic nerve terminals and thereby reduce transmitter release.

They also open K+ channels and hyperpolarize, and this inhibit postsynaptic neurons

T/F: opioids have a dual mechanism

true

CNS effects of opioids

analgesia (sensory and emotional component), euphoria (dysphoria) from dopamine rush, sedation, drowsiness, clouding of mentation, respiratory depression, miosis, cough suppression, N/V (brainstem chemoreceptor trigger zone), temperature, sleep architecture (sleep-disordered breathing and central sleep apnea)

Which CNS effect of opioids are dose related?

respiratory depression

facts regarding opioid induced respiratory depression

is a cause of fatal overdoses, truncal rigidity contributes, can be utilized palliatively to reduce dyspnea

What are the peripheral effects of opioids?

little to no effect on the cardiovascular system, opioid induced constipation, biliary tract, renal function depression, prolonged labor, low testosterone with chronic use, pruritis, immune system

T/F: tolerance develops to opioid-induced constipation

false

why does opioid-induced constipation happen?

reduced peristaltic activity throughout along with a tight sphincter which makes hard/dry poops hard to let out

when is pruritus relatively common with opioids?

with morphine use d/t histamine release (other mechanisms exist)

T/F: pruritus from opioids is not well treated by antihistamines

true

Which opioids are phenanthrenes?

morphine, hydromorphone, oxymorphone, levorphanol, codeine, butorphanol, hydrocodone, oxycodone, nalbuphine, burprenorphine

Which opioids are phenylpiperidines?

meperidine, fentanyl, sufentanil, alfentanil, remifentanil

which opioids are bennzomorphans

pentazocine, diphenoxylate, loperamide

which opioids are phenyproylamines

tramadol and tapentadol

what tolerance?

With repeated doses, there are diminished effects. An increased dose is needed to achieve previous analgesic effects

What is cross-tolerance

tolerance exists with introduction of a different opioid (especially with pure mu agonists)

What are the mechanisms of tolerance?

receptor desensitization and downregulation, receptor internalization and recycling, compensatory mechanisms, inflammatory responses, cAMP pathway activtion

what is withdrawal (abstinence syndrome)?

cause by reducing or stopping opioids - can present as rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility

T/F: withdrawal onset and duration are variable d/t different opioids’ PKPD

true

what would be seen in patients with opioid dependence?

withdrawal when stopping/reducing dose or antagonist-precipitated withdrawal

What mechanisms are involved in withdrawal?

rebound cAMP pathway, neurotransmitter imbalance (DA, NE, Serotonin), activation of stress systems (HPA axis), increased noradrenergic activity (surge in norepinephrine release), altered pain perception (hyperalgesia)

what is addiction

Primary, chronic disease of brain reward, motivation, memory, and related circuitry

How does dependence differ from addiction?

Dependence = physiological adaptation.

Addiction = behavioral and psychological disorder.

which opioid ADRs have high degree of tolerance?

analgesia, euphoria/dysphoria, mental clouding, sedation, respiratory depression, antidiuresis, N/V, cough suppression

which opioid ADRs have moderate degree of tolerance?

bradycardia

which opioid ADRs have minimal or no development of tolerance?

miosis (constricted pupils), constipation, and convulsions

which medication is involved with the NaV1.8 channels?

Suzetrigine

T/F: suzetrigine has no signs of toxicity, dependence or withdrawal

true

PK of suzetrigine

eliminated via feces and urine, reaches ss at day 3, absorbed in 3 hours when fasting and absorbed in 5 hours fed, metabolized by 3A4, and has a half-life of 26.6 hours