Health Module Final Exam

Pain

Defined by the International Association for the Study of Pain as “An unpleasant sensory and emotional experience associated with actual or potential tissue damage”

Pain Perception

based on complex interactions between nociceptive, neuropathic, psychological, emotional, and environmental factors; it is very subjective.

Acute pain

Acts as a critical warning system that promotes protective withdrawal and healing behaviors

Nociceptors

Detect noxious stimuli and begin the transduction process

• Activated by heat, acidity/inflammation, mechanical force/pressure, cold, and capsaicin

• Activity level depends on inflammation and tissue injury

Transduction

Process by which the stimuli detected by nociceptors is converted into an electrical signal.

Aδ and C fibers

Two types of nerve fibers that transmit the signal from transduction to the central nervous system

A Fibers

Fast and myelinated. Aδ is sharp/shooting pain, Aβ is not meant to be a pain sensor, but a light touch sensor.

C fibers

Slow and unmyelinated (“burning” pain/chronic pain).

Peripheral sensory transduction

The initial signal when tissue damage or inflammation occurs and activates nociceptors

Pain Transmission Pathway

Nociceptive sensory information follows this pathway.

• Primary afferent neurons relay signals from nociceptors into the spinal cord

• Second‑order neurons transmit information through the spinal cord, including via the spinothalamic tract

• The thalamus acts as a relay and processing center

• Parabrachial nuclei relay facial and visceral nociceptive input from cranial nerves V, VII, IX, and X

• The cortex generates the conscious perception of pain

Speed of conduction

Depends on nerve diameter and degree of myelination (Larger diameter and degree of myelination = faster)

Nociception

Refers to the process by which nociceptors detect noxious (painful or algesic) stimuli and transmit signals to the central nervous system

Hyperalgesia

An increased sensitivity to painful stimuli, that occurs with inflammation or tissue damage. Serves as a protective role.

Associated with increased activity of the SCN9A sodium channel, EP1 and EP4 prostaglandin receptors, and mediators like PGE₂ and PGI₂

SCN9A

Activation heightens nociceptive input, loss of function results in the absence of pain reception

Allodynia

Pain response to a normally non-painful stimulus (light touch)

Associated with central sensitization, where sustained activation of nociceptors leads to pathological changes in the spinal cord and brain

Peripheral Sensitization

Occurs with inflammation and/or tissue damage. Initially protective to encourage healing, mediators released locally include: Histamine, Acidity (H⁺ ), Prostaglandins (PGE₂, PGI₂)

Involves post-translational modifications such as phosphorylation and trafficking of ion channels

Leads to acute hyperalgesia (short-term, reversible)

Central Sensitization

Occurs after sustained activation of nociceptors. Leads to increased excitability in dorsal horn neurons, medullary spinal cord, and brain. Involves transcriptional and translational modifications (increased RNA and protein synthesis, constitutively active sodium channels). May result in cell death or neuronal sprouting, maintaining chronic pain conditions. Produces allodynia even in the absence of a pain signal.

NSAIDs and Acetaminophen (APAP)

Block the production of local mediators (prostanoids) that contribute to pain and sensitization. NSAIDs do not alter cognitive perception of pain.

MOA: Inhibition of cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins

COX-1 and COX-2 inhibition decreases the synthesis of prostanoids involved in inflammation and pain signaling

Aspirin (Acetylsalicylic acid)

Irreversibly inhibits COX-1 and COX-2 by acetylation.

Deacetylated to salicylic acid in tissues and blood.

Highly protein-bound.

Analgesic effect duration depends on the turnover rate of COX proteins in tissues.

Platelet inhibition lasts 8–12 days (platelet lifespan)

Vascular effects last 2–3 days

Non-salicylate NSAIDs (ibuprofen, naproxen, meloxicam)

Reversibly inhibit COX enzymes

Provide analgesic and anti-inflammatory effects

Celecoxib

COX-2 Selective Inhibitor. Preferentially inhibit COX-2 to reduce inflammation with less gastric irritation.

Acetaminophen (APAP)

Weak COX inhibitor in peripheral tissues

Acts primarily in the CNS to reduce pain and fever

Does not significantly reduce inflammation

Hepatotoxicity occurs with overdose due to metabolism by CYP450 enzymes, forming toxic metabolites

Aspirin and Non-selective NSAIDs - Adverse Effects

GI: abdominal pain, nausea, diarrhea, gastric erosions, hemorrhage, perforation, anemia

Bleeding and hemorrhage due to platelet inhibition

Respiratory hypersensitivity: asthma exacerbation, bronchospasm

Renal: decreased urate excretion, angioedema

Tinnitus

Toxic doses cause respiratory alkalosis followed by compensatory metabolic acidosis

Reye’s Syndrome

Specific adverse effect of aspirin and NSAIDs. Occur children with viral illness—liver dysfunction and acute encephalopathy

MOA: COX inhibition reduces protective gastric prostaglandins and alters platelet function

Celecoxib - Adverse Effects

Still causes gastric ulceration, but less than non-selective NSAIDs

Impaired renal function

Hypersensitivity reactions

No significant effect on platelet function or bleeding

Acetaminophen (APAP) - Adverse Effects

Hepatotoxicity due to the accumulation of toxic P450 metabolites (NAPQI) when glutathione is depleted

Overdose is potentially fatal despite its relatively safer profile at therapeutic doses

MOA: Overwhelmed hepatic metabolism leads to covalent binding of NAPQI to liver proteins, causing necrosis

Opioid receptor superfamily

Consists of 4 receptors, which are G protein-coupled receptors (GPCRs) coupled to Gi/Go

Proopiomelanocortin (POMC)

Endogenous opioid peptide. Produces ACTH, α-MSH, β-lipotropin → β-endorphin

Proenkephalin

Endogenous opioid peptide. Produces Met-enkephalin and Leu-enkephalin

Prodynorphin

Endogenous opioid peptide. Produces dynorphin A, dynorphin B, and neoendorphin

Pronociceptin

Endogenous opioid peptide. Produces N/OFQ, N/OFQ II, and nocistatin.

Receptors for endogenous peptides

Mu opioid peptide receptor (MOP or μ; MOR)

Kappa opioid peptide receptor (KOP or κ; KOR)

Delta opioid peptide receptor (DOP or δ; DOR)

Nociceptin/orphanin FQ peptide receptor (NOP or ORL1)

Common Features of Opioid Receptors

Splice variants of each receptor

Receptor dimerization

Found in the brain, spinal cord, immune cells, and peripheral tissues

Modulate protein function and gene transcription through kinase activation

1. Presynaptic Inhibition: MOA of Opioid Analgesics

Opioid receptor activation inhibits Ca²⁺ influx, reducing the release of nociceptive neurotransmitters in the spinal cord and brain

2. Postsynaptic Hyperpolarization: MOA of Opioid Analgesics

Mu receptor agonists increase K⁺ conductance, hyperpolarizing neurons and decreasing excitability

3. Activation of Descending Analgesic Pathway: MOA of Opioid Analgesics

Opioids inhibit GABA release in the periaqueductal gray (PAG) and medulla

This disinhibits the descending pain pathway, allowing release of norepinephrine (NE) from the locus coeruleus and serotonin (5-HT) from the nucleus raphe magnus

4. Reduction of Pain Perception: MOA of Opioid Analgesics

Opioid agonists reduce the perception and emotional response to pain at cortical levels

Mechanisms of Opioid Antagonists

Bind to opioid receptors without activating them, thereby blocking the effects of opioid agonists. Examples include Naloxone and Naltrexone. Used to reverse opioid overdose and prevent opioid-induced euphoria in addiction treatment.

Respiratory depression

Most dangerous adverse effect of opioids. Dose-dependent, Mediated by mu receptors in the brainstem, Produces irregular breathing

Nausea and vomiting (Opioid induced)

Common AE

Direct stimulation of the chemoreceptor trigger zone in the medulla

Tolerance develops

Pruritus (Opioid induced)

Histamine release from mast cells. No tolerance develops

Constipation (Opioid induced)

Mu and delta receptor-mediated

Increased GI tone and decreased motility

No tolerance develops

Sedation (Opioid induced)

Ranges from drowsiness to cognitive impairment, Tolerance develops

Sweating (Opioid induced)

Mu receptor modulation of hypothalamic thermoregulation.

Tolerance develops

Orthostatic hypotension, bradycardia, fainting (Opioid induced)

Due to histamine release and reduced vasomotor reflexes

Euphoria (Opioid induced)

Mu receptor inhibition of GABA brake on dopamine release

Other AE (Opioid induced)

Biliary spasm and increased pancreatic enzymes

Urinary retention (Opioid induced)

Mu and delta receptor-mediated

Hyperalgesia (Opioid induced at high doses)

Involves TLR4 activation and PKC signaling

Endocrine effects (Opioid induced)

Decreased cortisol, testosterone, LH, and FSH

Increased prolactin

Reduced libido and fertility

Pentazocine, butorphanol, propoxyphene

increased cardiac workload

Meperidine metabolite normeperidine

seizures and CNS excitation

Morphine metabolite M3G

CNS excitation and possible seizures

Partial agonists and KOR agonists

Precipitate withdrawal

Methadone

QT prolongation - can lead to irregular heart rhythms

Kappa agonists

dysphoria and diuresis

CYP2D6 Polymorphism

Affects the metabolism of prodrug opioids

Poor/Intermediate Metabolizers (PM/IM)

CYP2D6. Codeine and tramadol are not converted to active metabolites

Leads to decreased efficacy and poor analgesic response

Ultra-rapid Metabolizers (UM)

Convert prodrugs (codeine, tramadol) rapidly to active metabolites

Results in exaggerated effects and toxicity

Codeine metabolism to morphine can cause overdose in breastfed infants of UM mothers

Examples of Opioids Affected by CYP2D6

Codeine: converted to morphine

Tramadol: converted to active metabolite M1

Clinical Implications of CYP2D6

Genetic testing for CYP2D6 status can help predict patient response

Ultra-fast metabolizers are at high risk of toxicity; poor metabolizers may experience no pain relief

Tolerance

Decrease in analgesic response over time despite the same dosage

Results from receptor desensitization, internalization, or downregulation

Requires increasing doses to maintain the same level of pain relief

Tolerance refers to decreased drug effect

Physical Dependence

A physiological state where withdrawal symptoms occur when the drug is stopped, or an antagonist is given

Results from neuroadaptive changes with prolonged opioid use

Preventable by tapering the dose gradually

Physical dependence refers to withdrawal symptoms upon cessation

Physical Dependence: Withdrawal symptoms

Diarrhea, Vomiting and nausea, Dilated pupils, Fever and chills, Muscle aches, Hyperventilation, Increased heart rate and blood pressure, Restlessness and hostility, Watery eyes and a runny nose

Nociceptive pain

Somatic: sharp, dull, aching; skin, bone, joints, soft tissue; well-localized

Visceral: diffuse, gnawing, cramping, squeezing, pressure; difficult to localize; afferent nerve stimulation

Neuropathic pain

Burning, numbness, tingling, stabbing, shooting, electrical sensations

Caused by damage or dysfunction of the peripheral or central nervous system

Radiation of pain can occur

Examples: diabetic neuropathy, post-herpetic neuralgia, drug-induced neuropathy

Acute pain

Sudden onset and time-limited (<1 month)

Related to trauma, surgery, and acute illness

Beneficial physiological response to noxious stimuli

Can progress to chronic pain if untreated

Chronic pain

Lasts over 3 months

Causes include underlying disease, injury, treatment, and inflammation

Often difficult to treat

Breakthrough pain

Up to 90% of patients experience it

Episodic, transient, incident pain

Negatively impacts quality of life

Red flag symptoms (exclusions to self-care)

New onset of numbness, weakness, vision changes, dizziness, syncope

Sudden severe pain

Persistent pain >3 days

Worsening pain despite treatment

Chest pain, especially severe or crushing

Suspected fracture

Shortness of breath or worsening with exertion

Bleeding disorders

Pregnancy

Fever, nausea/vomiting, unintentional weight loss, systemic symptoms

Severe pain is preventing activities of daily living

Opioid Naïve

Not receiving opioids regularly

Opioid Tolerant

Chronic use of opioids. FDA definition: 1 week or longer, 60 mg oral morphine per day, etc.

Mitigation Strategies (Opioid Use)

Prescription drug monitoring programs (PDMP)

Opioid agreements/consents

Urine drug screens

Validated risk screening tools

Patient education

Non-Aspirin NSAIDs boxed warnings: Cardiovascular disease

Increased risk of serious cardiovascular thrombotic events, including stroke and myocardial infarction

Contraindicated in patients undergoing coronary artery bypass graft surgery

Risk Occurrence: Early in treatment, and may increase with use

Non-Aspirin NSAIDs boxed warnings: Gastrointestinal disease

Increased risk of serious GI events, including bleeding, ulceration, and perforation

Higher risk in elderly patients and those with a history of peptic ulcer disease or GI bleeding

Proton pump inhibitor use may be initiated with chronic NSAID therapy

Risk Occurrence: Any time during use

NSAID Select Drug Interactions: Anticoagulants and corticosteroids

Increased bleeding and hemorrhage risk, and increased GI ulceration

NSAID Select Drug Interactions: Antihypertensives, including ACE inhibitors and ARBs, especially when combined with diuretics

Decreased renal function and increased edema

Reduced antihypertensive efficacy

Electrolyte abnormalities, including decreased potassium

NSAID Select Drug Interactions: Probenecid

Increased NSAID concentrations and decreased probenecid efficacy

NSAID Select Drug Interactions: Lithium and Methotrexate

Increased lithium levels, Increased methotrexate levels

NSAIDs in special populations: Pregnancy

Premature closure of the ductus arteriosus leading to infant heart failure

Do not use in the third trimester at or after 30 weeks of gestation

Data support a possible association with spontaneous abortion, cardiac defects, and oral clefts

NSAIDs in special populations: Pediatrics

Avoid aspirin in children younger than 18 years recovering from viral illness, including chickenpox or flu symptoms

NSAIDs in special populations: Ketorolac

Avoid combined use with other NSAIDs - Increased risk of toxicities.

IV Toradol

Nasal Spray Sprix

5 days combined- Increased risk for GI Bleeding with extended use

Ibuprofen Dosing

Onset of action: 30-60 minutes

Duration: 4-6 hours

~2 hours half life elimination

Max daily doses: ≥ 18 yrs: 3200 mg (Rx), 1200 mg (OTC)

≤ 17 Yrs: Wt. Based: 2400 mg

≤ 11 Years, Fixed dose: 4 doses / day

Naproxen Dosing

Onset of action: 30-60 minutes

Duration: < 12 hrs

Half Life Elimination: 12-17 hrs

Max daily doses: ≥ 18 yrs: 1250 mg Day 1 —> 1000 mg (Rx), 600 mg (OTC)

<18 yrs: 1000 mg (Rx), 600 mg (OTC)

Acetaminophen Dosing

Adults: 325 – 1000 mg/dose

Pediatric: 10-15 mg/kg/dose, Not to exceed 5 doses/day (2.6 g/day)

Hepatotoxicity risk requires monitoring the total daily dose from all acetaminophen sources

Increased risk for medication errors and need for accurate dose calculations

Max dose 4 g per day (Rx), 3 g/day (OTC)

2 g/day if liver toxicity

Pearls: Not anti-inflammatory, reduces fever, does not significantly affect platelet function

Anticonvulsants: Carbamazepine and Oxcarbazepine

MOA: Inhibition of sodium channels, potentiates GABA

Oxcarbazepine: keto derivative (metabolized to active)

Used for trigeminal neuralgia, FDA approved: carbamazepine, neuropathic pain

Dosing: Titrate to effect

Carbamazepine: Max 1.2g/day, titrate over weeks

Oxcarbazepine: Max 1.8g/day, titrate every ≥ 3 days

Anticonvulsants: Carbamazepine and Oxcarbazepine - AE

Dizziness, sedation, fatigue

Major: Hyponatremia, serious skin reactions (e.g. SJS/TENs, DRESS)

Rare: Aplastic anemia, agranulocytosis

Anticonvulsants: Carbamazepine and Oxcarbazepine - Pearls

HLA-B 1502 allele testing: Those with increased genetic risk for severe skin reaction (Asian ancestry, incl. South Asian)

Withdrawal Syndrome - Need to taper if discontinuing chronic use

Significant medication interactions:

Carbamazepine > Oxcarbazepine

Primary metabolic pathway = CYP3A4

Antidepressants: Tricyclic Antidepressants (TCA)

Amitriptyline, Imipramine (Tertiary amines)

Nortriptyline, Desipramine (Secondary Amines)

Uses: Fibromyalgia, low back pain, migraine prophylaxis, neuropathic pain

Antidepressants: Tricyclic Antidepressants (TCA) - AE

Anticholinergic - Caution use with elderly, BPH, glaucoma, cardiac arrythmias, etc.

Sedation - Give at bedtime

Cardiac effects - Slowed conduction, QTc prolongation, arrhythmias

Antidepressants: Tricyclic Antidepressants (TCA) - Pearls

Lower doses for analgesia vs. anti-depression

Secondary amines may have better tolerability - less anticholinergic a/e

Withdrawal syndromes if chronic use - taper if discontinuing

Duloxetine (Cymbalta)

Selective Serotonin Norepinephrine Reuptake Inhibitors (SNRI). Used for fibromyalgia, chronic MSK pain, DPN (FDA Approved), Chemotherapy PN (Off-label)

Venlafaxine (Effexor)

SNRI. Used for neuropathic pain, low back pain, migraine/tension type headache ppx, fibromyalgia

Milnacipran (Savella)

Fibromyalgia

SNRIs - Adverse Effects

Nausea, anorexia, dry mouth, constipation, somnolence, erectile dysfunction.

SNRIs - Pearls

Transient hypertension can occur

Increased risk of bleeding esp. if combined with NSAIDs, anticoagulants, corticosteroids.

Withdrawal syndrome if chronic use and discounting - taper

Muscle Relaxers

Should Be used only short term, known CNS depressant effects include dizziness, drowsiness, and confusion.

Spasticity

Involves upper motor neuron disorder.

Symptoms: Stiffness, hypertonicity, hyperreflexia

Associated causes: MS, Cerebral palsy, spinal cord injury, TBI, post-stroke syndrome.

Spasms

Involuntary contractions of muscle

Symptoms: Jerks, twitches, cramps

Associated causes: MSK pain, fibromyalgia, mechanical low back pain, disk herniation, sciatica.

Opioid General Principles

Next step in managing acute pain and cancer-related chronic pain, Controversial in managing non-cancer pain

Trialing an opioid requires a complete pain assessment, establishing functionality goals, and evaluating risk factors for opioid use disorder or overdose.

Choice depends on patient acceptance, analgesic effectiveness, pharmacokinetics, pharmacodynamics, and adverse effect profiles

Pain is not eliminated, only decreased unpleasantness.