Pain (Pathophysiology)

Non Verbal Pain Assessment

• Vocal complaints (moaning, groaning, crying out)

• Facial grimaces/winces (frowning, grimacing, clenched teeth)

• Bracing (holding/protecting a body part)

• Restlessness (pacing, fidgeting, shifting in bed)

• Rubbing (rubbing or massaging a painful area)

Pain Processing

1. Transduction

2. Transmission

3. Perception

4. Modulation

Transduction

• First step of pain processing

• Nociceptor (pain receptor) endings detect harmful stimuli

• Injury causes release of pain-producing chemicals

• What activates nociceptors?

  • Mechanical: pressure, swelling, incision, trauma

  • Thermal: burn, scald, extreme heat/cold

  • Chemical: toxins, infection, ischemia

• What chemicals get released? (Excitatory compounds)

  • Serotonin

  • Bradykinin

  • Histamine

  • Substance P

  • Prostaglandins (blocked by NSAIDs)

• Where does transduction occur?

  • In the periphery (at the site of injury)

Transmission

• Step 2 of pain processing

• Pain signal travels from periphery → spinal cord → brain (thalamus → cortex)

• How does the signal travel?

  • Action potential (pain signal) moves along Aδ fibers and C fibers

  • Signal enters the spinal cord and ends in the dorsal horn (CNS)

• What happens in the dorsal horn?

  • Excitatory neurotransmitters are released to keep the signal moving upward

  • Signal travels through ascending pathways toward the brain

• Key excitatory neurotransmitters

  • Glutamate

  • Neurokinins

  • Substance P

• Where is the signal processed?

  • Thalamus (but then sent to the cortex to perceive it)

A-δ Fibers

• Larger

• Myelinated (conducts signals fast)

• Faster

• Produces “first pain”

  • Sharp

  • Stinging

  • Well-localized

• Activated by mechanical or thermal pain 

C Fibers

• Smaller

• Unmyelinated (conducts signals slow)

• Slower

• Produces “second pain”

  • Dull

  • Achy

  • Burning

  • Diffuse (hard to localize)

• Reaches brain areas involved in emotion

• Activated by mechanical, thermal, or chemical stimuli

Where do A-δ Fibers and C Fibers send their signals to?

• Dorsal horn of the spinal cord

  • Where glutamate (for A-δ Fibers) or Substance P (for C Fibers) takes the signals to the brain

Ascending Pain Pathway

The route that the pain signal travels upward from the spinal cord → brain, responsible for carrying pain information so you can feel it

1. Pain starts at nociceptors (Aδ and C fibers)

   1. Detect painful stimulus

   2. Send signal → dorsal root ganglion

   3. Enter the dorsal horn of the spinal cord

2. Spinal Cord → Spinothalamic Tract

   1. Pain signal crosses over in the spinal cord

   2. Travels up the spinal cord through the spinothalamic tract

3. Brainstem (Pons & Medulla)

4. Midbrain

5. Thalamus

   1. Receives the pain signal

   2. Sends it to different brain regions:

      • Somatosensory Cortex (S1) → where you feel and localize pain

      • Cingulate Cortex → emotional reaction to pain

      • Limbic System → fear, anxiety, memory of pain

Which chemicals release Nociceptors?

• Bradykinin

• Cations (protons, potassium ions)

• Free radicals (nitric oxide)

• Histamine

• Prostanoids (prostaglandins, leukotrienes)

• Purines (ATP, adenosine)

• Serotonin

• Tachykinins (Substance P, Neurokinin A)

Super Easy Way to Understand Pain Pathway

1. Injury → damaged cells release chemicals (bradykinin, histamine, prostaglandins, etc.)

2. These chemicals activate nociceptors

3. Nociceptors send signals through:

   1. Aδ fibers (fast)

   2. C fibers (slow)

4. At the spinal cord, Aδ & C fibers release:

   1. Glutamate (fast pain)

   2. Substance P (slow pain)

5. Signal goes up spinal cord → thalamus → cortex → you feel pain

Perception

• The moment you become consciously aware of pain

• Happens when the brain interprets the pain signal

• Involves multiple higher brain regions, especially the cortex

• Key Brain Areas in Perception: 

  • Reticular System

  • Somatosensory Cortex (S1)

  • Limbic System

Reticular System

• Controls automatic and motor responses to pain

• Example: Pulling your hand away from a hot stove

• Part of survival reflexes

Somatosensory Cortex (S1)

• Main area where pain is felt and identified

• Interprets:

  • Intensity (how strong)

  • Type (sharp, dull, burning)

  • Location (where it is)

• Connects pain to past experiences (e.g., “This feels like when I broke my ankle”)

Limbic System

• Controls the emotional part of pain

• Responsible for:

  • Fear

  • Anxiety

  • Suffering

  • Memory of pain

• Plays a big role in chronic pain and how stressful pain feels

Analgesia

• Pain reduction (relief of pain)

Modulation

• The descending pain pathway that sends signals down from the brain

• Its job is to block or reduce the pain signal in the spinal cord

• This process creates analgesia (pain reduction)

• The brain releases inhibitory neurotransmitters that STOP or WEAKEN pain signals

• These signals travel down to the spinal cord and:

  • Inhibit Aδ and C fiber transmission

  • Reduce glutamate and substance P release

  • “Turn down the volume” on the pain signal

Modulation → Inhibitory Neurotransmitters

• Endogenous opioids

• Serotonin

• Norepinephrine

• GABA

Endogenous Opioids

• Bind to opioid receptors located in the brain and the spinal cord

Serotonin (5-HT)

• Binds to 5-HT and 5-HT3 receptor located in the medulla

Norepinephrine (NE)

• Binds to alpha-2 adrenergic receptors, located in the brainstem

GABA

• Binds to GABA-A receptors and GABA-B receptors

Modulation → Referred Pain

• Pain that starts in one organ or tissue, but is felt in a different location

• Why does this happen? (Convergence-Projection Theory)

  • Somatic pain fibers (from skin, muscles) and visceral pain fibers (from organs) both synapse on the same spinal neuron

  • Because they share the same ascending pathway, the brain gets “confused” and thinks the pain is coming from the somatic (outer body) area, not the organ

• Examples: 

  • Heart attack → pain in left arm

  • Diaphragm irritation → pain at the tip of the shoulder

  • Ureteral distension → pain in the testicle

Maladaptive (Pathologic) Pain

• Pain caused by damage or abnormal function of the peripheral or central nervous system

• Pain persists even when the original injury has healed

• Pain becomes a disease itself, not just a symptom

• Types:

  • Neuropathic Pain = nerve damage

  • Centralized Pain = brain/spinal cord problem

Types of Pain

• Nociceptive Pain

• Neuropathic Pain

• Inflammatory Pain

Nociceptive Pain

• Actual tissue injury → activates nociceptors (pain receptors) at the specific site that’s in pain 

• Types of Nociceptive pain: 

  • Somatic pain

  • Visceral pain

Somatic Pain

• Comes from:

  • Bones

  • Joints

  • Muscles

  • Skin

  • Connective tissue

• How it feels:

  • Throbbing

  • Aching

  • Sharp or well-localized (you can point to exactly where it hurts)

Visceral Pain

• Comes from:

  • Internal organs

    • Examples: GI tract, stomach, pancreas, intestines

  How it feels:

  • Can be achy or pressure-like

  • Can be localized (like a tumor pressing on something)

  • OR diffuse and crampy (like an obstruction or blockage)

  • Harder to pinpoint than somatic pain

  • May cause referred pain (felt in another area)

Neuropathic Pain

• Pain caused by damage or disease of the somatosensory nervous system (in the spinal cord) 

• Neuropathic pain has very distinct sensations:

  • Burning

  • Electric / shock-like

  • Searing

  • Tingling

  • Traveling / migrating pain

• Types of Neuropathic pain: 

  • Peripheral nerve injury → phantom limb pain

  • Central nerve injury (spinal cord or brain) → burning, continuous pain

• Common causes

  • Amputation → phantom limb pain

  • Herpes zoster (shingles)

  • HIV / AIDS neuropathy

  • Diabetic neuropathy

  • Fibromyalgia

  • Cancer affecting the spinal cord or nerves

Hyperalgesia

• Pain feels STRONGER than it should

• A stimulus that normally causes mild pain…now causes WAY more pain

• Example: A small pinprick feels like a deep stab

Allodynia

• Pain from something that should NOT hurt at all

• A stimulus that normally does NOT cause pain…now causes pain

• Example: A soft blanket feels painful

Peripheral Sensitization

• The nerves outside the spinal cord become extra easy to activate, so pain signals fire more often

• Here’s what happens:

  • More ion channels appear: this makes the nerve more reactive

  • Depolarization threshold is lowered: meaning the nerve fires more easily

• Even a small stimulus triggers an action potential → more pain signals sent

Inflammation Pain

• When tissue becomes irritated, injured, or infected, and the body launches an inflammatory response

  • Redness

  • Swelling

  • Warmth

  • Pain

  • Sometimes loss of function

• This inflammation makes nociceptors (pain receptors) more sensitive → so even normal movements can hurt

• Example: 

  • Appendicitis

  • Rheumatoid arthritis

  • Inflammatory bowel disease (IBD)

Pain Classification

• Acute 

• Chronic 

• Cancer 

Acute → Pain Classification

• Short-term pain, caused by something obvious

  • Lasts less than 3 months

  • Has a clear cause (surgery, broken bone, infection, injury)

  • Goes away when the problem is fixed

Chronic → Pain Classification

• The pain stays even though the body has healed

  • Lasts more than 3–6 months

  • The original injury/illness may be healed, but the pain signals keep firing

  • Nervous system becomes “sensitized” → keeps sending pain messages

Cancer → Pain Classification

• Pain that comes from tumors, cancer treatment, or cancer spreading (metastasis)

  • Can be acute (new, sudden)

  • Can be chronic (ongoing)

Neuroplasticity

1. Injury or inflammation (acute pain)

2. Pain nerves fire normally

3. Pain nerves keep firing → become sensitized (subacute pain) 

4. Brain + spinal cord change (“hyperactive”)

5. Pain continues even after healing (chronic pain)

Pain → Treatment 

• NSAIDs

• Acetaminophen

• Aspirin

• Alpha-2 Agonists

• Anticonvulsants

• Antidepressants

• Opioid Agonists

• Opioid Agonist/Antagonist

• Mixed opioid/norepinephrine reuptake inhibitor (NRI) combo

• Opioid/non-opioid combo

• NMDA antagonist

• TRPV1 Agonist

NSAIDs → MOA

• Block COX-1 and COX-2 enzymes, which decreases prostaglandins (usually released from nociceptors)

  • ↓ inflammation

  • ↓ pain

  • ↓ fever

  • BUT ↑ risk of stomach irritation, bleeding, and kidney issues

Acetaminophen → MOA

• Works in the brain, not in the peripheral tissues

  • Inhibits central COX enzymes (weak peripheral activity)

  • Increases the brain’s pain threshold

  • Very little anti-inflammatory action

Aspirin → MOA

• Irreversibly inhibits COX-1 and COX-2 → ↓ prostaglandins AND ↓ thromboxane (anti-platelet)

Alpha-2 Agonists → MOA

• Work mainly in the spinal cord (dorsal horn)

• Activate alpha-2 receptors on nociceptive (pain) neurons

• ↓ norepinephrine release → less pain signal sent to sensory relay neurons

• Inhibits pain transmission from nociceptors to the spinal cord relay neurons

• Can reduce opioid needs (opioid sparing)

• Also lower BP → possible adverse effects: hypotension, bradycardia, sedation

• Commonly used in anesthesia for sedation and pain control

Opioid Receptors → MOA

• All are G-protein–coupled receptors (GPCRs)

  • Coupled to Gi (Mu, Delta, Kappa)

  • Activate K⁺ channels

  • Inhibit Ca²⁺ channels

• Three main types of receptors:

  • Mu (μ)

  • Delta (δ)

  • Kappa (κ)

Pain and Opioid Pathway

• Pain starts at the injury site → activates nociceptors (pain-sensing neurons)

• Pain signal travels along primary afferent neurons → enters dorsal horn of spinal cord

• Signal goes up the spinal cord to the brain (ascending pathway)

• Brain can send signals down the spinal cord to reduce pain (descending pathway)

• Opioid effects in pathway:

  • Bind opioid receptors on peripheral nerves, spinal cord, and brain

  • ↓ neurotransmitters (SP, CGRP, glutamate)

  • ↑ potassium channels → hyperpolarization

  • ↓ calcium channels → ↓ pain signal release

Opioid → Side Effects (Dry) 

• Respiratory depression

• Nausea & vomiting

• Cough suppression

• Sedation / drowsiness

• Constipation

• Urinary retention

• Miosis (pin-point pupils)

• Histamine release → itching, hypotension

  • Morphine = worst

  • Fentanyl = best (least histamine release)

Respiratory Depression

• Seen with all opioids and is dose-dependent

• Caused by direct inhibition of brainstem respiratory centers

• Mediated by μ-receptor activation in the rostral ventral medulla / rostral dorsal pons

• Slows breathing drive → ↓ respiratory rate & depth

• Some tolerance develops, but increased doses = higher risk

• Reversed with naloxone (Narcan) or naltrexone

The Medulla Oblongata

• Nausea & Vomiting

  • Opioids directly activate the chemoreceptor trigger zone (CTZ) in the medulla

  • When opioids stimulate CTZ, the brain thinks there is something harmful → leads to nausea + vomiting

  • This happens with all μ-opioid agonists (morphine, oxycodone, hydromorphone, etc.)

  • Tolerance often develops → nausea becomes less intense after repeated doses

• Mechanism behind CTZ stimulation

  • μ-receptors in the medulla increase dopamine & serotonin signaling

  • These neurotransmitters activate the vomiting center

  • Morphine causes delayed gastric emptying → worsens nausea

• Cough Suppression

  • Opioids depress the cough center in the medulla

  • This is why codeine is used in cough syrups

  • μ-agonists decrease the sensitivity of the cough reflex → less coughing

  • This is separate from respiratory depression but can occur alongside it

• Clinical takeaway

  • Nausea = very common with opioids

  • Cough suppression = useful therapeutically but can mask symptoms

  • Both effects originate from medulla oblongata opioid receptor activation

Constipation

• Most common chronic opioid side effect

• Can be severe enough to require stopping the opioid

• Caused by μ-receptor activation in the GI tract

• μ-receptors on enteric neurons ↑ K⁺ efflux → ↓ excitability

• Leads to less smooth muscle contraction → ↓ peristalsis

• Slows GI transit, hardens stool → constipation

• Patients often need PAMORs (peripheral μ-antagonists) to manage it

• Very little to no tolerance develops → constipation continues even after weeks/months

Miosis

• Most μ and κ opioid agonists cause miosis (pin-point pupils)

• Happens due to excitation of the parasympathetic nerve that controls pupil constriction

• Opioids increase activity of the Edinger–Westphal nucleus → pupil constricts

• Minimal tolerance develops; even heavy chronic users often still have pinpoint pupils

• Useful diagnostic sign in suspected opioid intoxication/overdose

Mood Alterations

• Opioids can cause euphoria, relaxation, tranquility

• Mood effects come from dopamine reward pathways, not from the pain pathways

• μ-receptor activation → ↑ dopamine release

• These pathways mediate reinforcement, contributing to misuse/addiction

• Analgesia and euphoria occur through different neural circuits

Opioid Family Groups

• Phenanthrenes

• Benzomorphans

• Phenylpiperidines

• Diphenylheptanes

• Phenylpropylamines

Phenanthrenes → Drugs 

• Morphine

• Buprenorphine

• Butorphanol

• Codeine

• Dextromethorphan

• Dihydrocodeine

• Heroin (diacetyl-morphine)

• Hydrocodone

• Hydromorphon

• Levorphanol

• Methylnaltrexone

• Nalbuphine

• Naloxone

• Naloxegol

• Naltrexone

• Oxycodone

• Oxymorphone

Phenanthrenes → Drugs (mixed agonist/antagonist → less N/V options)

• Buprenorphine

• Butorphanol

• Dextromethorphan

• Hydrocodone

• Hydromorphone

• Levorphanol

• Nalbuphine

• Naloxone

• Naloxegol

• Naltrexone

• Oxycodone

• Oxymorphone

Benzomorphans → Drugs

• Diphenoxylate

• Loperamide

• Pentazocine

Phenylpiperidines → Drugs

• Fentany

• Alfentanil

• Sufentanil

• Remifentanil

• Meperidine

Illicit Fentanyl Analogs → Drugs 

• Furanyl fentanyl

• Acetyl fentanyl

• Fluoro-fentanyl

• Carfentanil

Diphenylheptanes → Drugs

• Methadone

• Propoxyphene

Phenylpropylamines → Drugs

• Tramadol

• Tapentadol

Morphine 

• Has a specific shape and specific chemical pieces that let it bind to the mu-opioid receptor

• Small changes to the morphine structure can turn it from an agonist (activator) into an antagonist (blocker)

• Opioid receptors bind the (–) version much better

  • This is why natural morphine (which is the – isomer) works strongly

• What it’s used for: 

  • Moderate to severe acute pain

  • Chronic pain

  • Pain from myocardial infarction (MI)

  • Preanesthetic (used before anesthesia to reduce anxiety/pain)

• Morpine is glucuronidated in the liver

  • Forms M6G → ACTIVE metabolite

• Low oral bioavailability → need high oral doses

• Onset of Action

  • Oral: ~30 minutes

  • IV: 5–10 minutes (much faster)

• Half-life: 

  • Immediate-release: 2–4 hours

  • ER formulations: 11–13 hours (last much longer)

• Renal Clearance

  • Must not give to someone w renal issues!!!!

If you tweak morphine slightly → you can create ……………

• Antagonists like naloxone or naltrexone

What parts of morphine are needed for mu-agonist activity?

• Basic Nitrogen (N)

• 3-Hydroxy group (phenol)

• Aromatic ring (A ring)

Codeine

• Is basically morphine with one small change

• That change = at the 3-position, instead of an OH (phenol) like morphine, it has an O-CH₃ (methoxy group)

• It makes codeine a weak mu agonist

  • Morphine needs that 3-OH to strongly bind the mu receptor

  • Codeine has O-CH₃ instead → weaker binding → weaker analgesia

• Antitussive (cough suppressant)

  • Codeine suppresses cough reflex in the medulla

  • This effect does not require conversion to morphine, which is why even poor metabolizers still get some cough suppression

• Good for mild pain (only) + cough

• Good oral absorption

• Short half-life (2–3 hrs)

• Excreted in urine

Why is Codeine never prescribed for acute pain?

• For codeine to work, it needs to be converted to morphine by CYP2D6

  • Takes too long if person is in pain NOW

Why doesn’t Codeine work in some people?

• CYP2D6 (changed codeine to morphine) 

  • People come in different CYP2D6 “types”:

  • Poor Metabolizers (PM)

    • Little or no CYP2D6.

    • They cannot convert codeine → morphine

  • Ultra-Rapid Metabolizers (UM)

    • Too much CYP2D6 activity.

    • Convert codeine → morphine very quickly

How is Codeine converted to Morphine to work?

• Must undergo O-demethylation

Full Agonists Opioids

• Morphine

• Codeine

• Hydromorphone

• Hydrocodone

• Oxycodone

• Oxymorphone

• Levorphanol

• Methadone

• Meperidine

• Fentanyl

• Oliceridine

Opioids → Pregnancy 

• Opioids cross the placenta

  • Classified as Pregnancy Category C or D (depends on the opioid)

Opioids → Black Box Warning Pregnancy

• Prolonged maternal use of opioids can cause a risk of withdrawal in neonates

Opioids → Interactions

• Avoid taking with other CNS depressants

Morphine / Naltrexone Combination

• If taken correctly (swallowed whole):

  • Only the outer ER morphine layer is released

  • Naltrexone stays trapped and does nothing 

• If crushed, chewed, injected, or tampered (taken the bad way):

  • Naltrexone is released

  • Stops the euphoric effect (pain comes back)

  • May precipitate withdrawal in opioid-dependent individuals

• Onset: ~8 hours

Hydromorphone

• Strong opioid for moderate–severe pain

• Hydromorphone (Dilaudid) HP = dangerously concentrated → only for opioid-tolerant patients

• Metabolized by glucuronidation

• Fast onset:

  • IR oral: 15–30 minutes

  • IV: ~5 minutes

  • ER: ~6 hours

• Half-life:

  • IR 2–3 hrs

  • ER 11 hrs

• Multiple routes available

  • Oral, IV, IM, SubQ, PCA (patient-controlled analgesia), Epidural, Rectal

Is the quickest opioid to work

Can be used in pts w bad renal function, it does not add up inside their body like morphine

Hydrocodone

• Moderate to severe pain

  • Especially when daily, long-term opioid therapy is needed

• Alcohol will increase plasma levels or ER formulation

• Metabolism: CYP2D6 (changed to hydromorphone) and CYP3A4

• Half-life:

  • 8 hours

Hydrocodone IR formulated w/:

• Chlorpheniramine → for cough/cold

• Pseudoephedrine → decongestant

• Ibuprofen → for additional pain/anti-inflammatory effect

Oxycodone

• Moderate to severe pain

  • Often combined with non-opioid analgesics (APAP, ibuprofen, aspirin)

• Metabolism: CYP2D6 (changed to oxymorphone) and CYP3A4

• Onset of Action

  • 10–15 minutes

• Good oral bioavailability

Oxycodone formulated w/:

• Acetaminophen

• Aspirin

• Ibuprofen

• Naloxone

Fentanyl

• VERY Potent

  • 75–100 times stronger than morphine

• Very Lipophilic

  • Gets into the brain FAST

• Used in: 

  • Sedation

  • Pre-operative use

  • Anesthesia

  • Moderate to severe chronic pain

  • Breakthrough cancer pain (ONLY in opioid-tolerant patients)

• Metabolism: CYP3A4

• Half Life:

  • IV: short (2–4 hr)

  • Patch: long (20–27 hr)

  • Lozenge/Buccal: moderate (3–14 hr)

  • Nasal spray: moderate (15–25 hr)

Fentanyl Derivatives

• Sufentanil

• Alfentanil

• Remifentanil

Very potent, Fast onset, Short-acting, Used mainly for anesthesia

Methadone

• What it’s used for

  • Moderate to severe pain

  • Detox for opioid withdrawal

  • Maintenance treatment for opioid dependence

• Metabolism: Many CYPs, N-demethylation

• Half-life: 

  • 8–59 hours (HUGE range!)

  • Increases with repeated doses

  • Methadone accumulates in the body

  • Pain relief fades quicker than the drug leaves the body → Risk of unintentional overdose if patients keep redosing

_________________ can prolong the QT prolongation 

• Methadone

Methadone for Opioid Dependence

• Very long acting

• Suppresses craving

• Smoothes out “peaks and valleys”

  • Heroin causes:

    • Big peak → euphoria

    • Steep valley → withdrawal, cravings

• Blocks urge to seek heroin

  • Because methadone occupies the mu receptor for a long time

  • Heroin won’t “hit” the receptor as strongly → the high is blocked or reduced

• Administered in a highly structured environment

  • Given at methadone clinics

  • Patients usually go daily

  • Allows monitoring for:

    • Misuse

    • Diversion

    • Overdose

    • QT prolongation

    • Dosing adjustments

Partial Opioid Agonists

• Buprenorpine

Buprenorpine

• μ (mu) partial agonist + κ (kappa) antagonist

• Used for: 

  • Moderate to severe pain

  • Opioid dependence

• Metabolism: CYP3A4

• Onset of Action

  • IM: ~15 minutes

• Half-life: 

  • IV: 2–3 hrs

  • Sublingual: 37 hrs

  • Patch: 26 hrs

• Excretion

  • Mostly feces (70%)

Buprenorphine + Naloxone (the yellow pack!)

• Used for: 

  • Opioid dependence

• Naloxone has very poor oral/sublingual bioavailability

  • When taken as prescribed (sublingual) → Naloxone does NOTHING

  • Buprenorphine is the active drug

• If someone tries to INJECT it

  • Naloxone WILL work (because IV = good bioavailability)

  • It blocks opioids → causes withdrawal

    • Discourages abuse

Atypical Opioids

• Tramadol

• Tapentadol

• Olicerdine

Tramadol

• Used for: 

  • Moderate to severe pain 

• Weak μ-opioid receptor agonist + SNRI-like action

Tapentadol

• What is it used for?

  • Moderate to severe pain

  • ER form can treat neuropathic pain from diabetic peripheral neuropathy (DPN)

• μ-opioid receptor agonist + Norepinephrine (NE) reuptake inhibitor (NOOO seretonin effects) 

Tramadol vs. Tapentadol

• Tramadol:

  • A racemic mixture
    → Contains two enantiomers (mirror-image forms)

  Each enantiomer does something different:

  • Positive (+) enantiomer
    → Must be metabolized (CYP2D6) into the active metabolite M1 to activate the μ-opioid receptor
    → If CYP2D6 is poor → tramadol barely works

  • Negative (−) enantiomer
    → Responsible for NE reuptake inhibition
    → (Also some serotonin reuptake inhibition → serotonin syndrome risk)

• Tapentadol:

  • Does NOT require metabolism to become active
    → Works immediately in its original form
    → No CYP2D6 dependence

  • Both actions come from the SAME molecule:

    • μ-opioid agonist

    • NE reuptake inhibitor

  • Has stronger analgesic potency than tramadol

Olicerdine

• A novel IV opioid

• A G-protein–biased μ-opioid receptor agonist

• Traditional opioids activate TWO pathways:

  1. G-protein pathway → gives pain relief

  2. β-arrestin pathway → causes side effects

     • Respiratory depression

     • Constipation

     • Nausea/vomiting

  ⭐ Oliceridine mainly activates G-protein, NOT β-arrestin

  → Less β-arrestin recruitment
  → Goal: fewer GI effects and possibly less respiratory depression

  ⚠ BUT: It STILL carries the same black box warnings as all opioids
  (respiratory depression, addiction, etc.)

• Metabolism: CYP 3A4 and 2D6

Opioid Antagonists

• Naloxone

• Naltrexone

• Nalmefene

Naloxone

• Reverses opioid overdose, especially respiratory depression

  • It kicks opioids off the μ-receptor

• In people dependent on opioids, naloxone can cause sudden, intense withdrawal (because it rapidly reverses all opioid activity)

• Onset: minutes (VERY fast)

• Half-life: 20–60 minutes
  → Much shorter than most opioids
  → Must be re-dosed, or patient may “re-sedate” once naloxone wears off

Naltrexone

• Used for: 

  • Alcohol dependence

  • Opioid-induced emergency

• Side Effects

  • Syncope (fainting)

  • Headache

  • Nausea / Vomiting

• Metabolism

  • Via dehydrogenase enzymes

• Onset of action

  • Minutes

• Half-life

  • 13 hours

Nalmefene

• A new opioid antagonist (approved 2023)

• Prescription-only

• Structurally similar to naltrexone

• Reversal of opioid-induced respiratory depression

  • Works like naloxone, but longer-lasting

• Onset of Action

  • Minutes

• Half-life

  • 11 hours
    → MUCH longer than naloxone (20–60 min)
    → Helps prevent re-narcotization after fentanyl or long-acting opioids

• Longer duration of action

• Higher affinity for opioid receptors
  → Better at reversing potent opioids (fentanyl, analogs)

OPRM1

• The gene that codes for the mu-opioid receptor (MOR)

• This is the receptor that opioids bind to

• Highly polymorphic

  • More than 200 genetic variants

  • People naturally differ in how they respond to opioids

• What does it bind? 1. Endogenous opioids (your body’s natural pain modulators)

  • Endorphins

  • Enkephalins

  • Dynorphins

  2. Exogenous opioids

  • Morphine

  • Hydrocodone

  • Oxycodone

  • Fentanyl

  • Heroin
    (and all others)

• Major role in pain perception

• Major role in response to opioid drugs

• Some variants may affect how strongly opioids work
  (e.g., some people need higher or lower doses)

• Right now, variations are NOT linked to a specific disease

• Not routinely used in clinical decision-making (unlike CYP2D6 or CYP2C19 testing)

COMT

• Catechol-O-methyltransferase

• An enzyme on nerve terminals

• Breaks down neuroamines:

  • Dopamine

  • Norepinephrine

  • Epinephrine

• hese neurotransmitters help modulate pain, especially in the descending pain pathway

• So COMT activity can influence:

  • Pain sensitivity

  • Pain modulation

  • Response to opioids

• Because NE + DA affect pain pathways, differences in COMT may change how people respond to opioids

• But this is not clinically actionable yet

• Variations exist

• No COMT variants are currently linked to any specific disease

• Not used in clinical pharmacogenomic testing for opioid prescribing

MTHFR

• Enzyme that converts homocysteine → methionine

• Methionine is used for:

  • Protein building

  • Making neuroamines (dopamine, NE, etc.)

• Also helps activate dietary folate

• Like COMT, it can influence:

  • Pain modulation

  • Pain sensitivity

  • Opioid response

• Because the descending pain pathway is affected by noradrenergic modulation

• 50–60% of people have reduced MTHFR activity

• Reduced activity may influence neurotransmitter levels → may slightly change pain experience
  (Not clinically used in opioid prescribing)