Week 2: Lecture 4
# Pain Management: Mechanisms and Therapeutics
Main Takeaway: Pain is a complex sensory and emotional experience crucial for survival, but chronic pain represents a significant health and economic burden. Understanding the intricate biochemical mechanisms of pain transmission, particularly involving ion channels and neurotransmitters in the periphery and spinal cord, has led to the development of both effective opioid analgesics and promising non-opioid alternatives, such as highly selective voltage-gated sodium channel inhibitors, with reduced risks of addiction and side effects.
## 1. Introduction to Pain
* Speaker: Laura Edgington-Mitchell, Lecturer in Biochemistry and Pharmacology, Lead of Protease Pathophysiology Lab at BIO21 Institute.
* Lecture Focus: Overview of drugs used to treat pain.
* Structure: Divided into three sections:
1. What is pain? (Definitions, types)
2. Biochemical mechanisms of pain (Neuron sensitization, signal propagation)
3. Common drugs for pain treatment.
* Aids: Color-coded slides for easy review.
## 2. What is Pain? - Definitions & Importance
### 2.1. Historical Perspectives on Pain
* Aristotle (Ancient Greece): Pain was purely an emotion (a "passion of the soul"), linked with pleasure.
* Hippocrates (Ancient Greece): Theorized pain from imbalance in vital fluids, related to the heart and emotions.
* Renaissance Era: Pain perceived as external, possibly divine punishment for sin; prayer was the only management.
* 1600s - Descartes: First to hypothesize the body as a machine and pain as a disturbance transmitted along a "wire" to the brain.
This concept marked a shift to thinking of pain as a mechanical sensation* that could be treated, not just endured or appeased.
### 2.2. Modern Definition & Importance
* International Association for the Study of Pain (IASP) Definition:
> "an unpleasant sensory and emotional experience associated with actual or potential tissue damage."
* Purpose of Pain:
Promotes survival* by signaling danger.
* Helps identify and eliminate noxious stimuli.
* Prevents further body damage.
* Provides time for healing by protecting injured parts.
### 2.3. Classification of Pain
#### 2.3.1. By Duration
* Acute Pain:
Generally protective* in nature.
* Short duration, resolves once noxious stimulus is removed and body heals.
* Chronic Pain:
* Occurs when pain pathway alterations lead to prolonged neuronal hypersensitivity.
* Outlives its usefulness, becomes debilitating, and a health condition on its own.
* Can persist long after injury has healed, leading to psychological debilitation.
* Examples: Arthritis, cancer pain, sciatica, back pain.
* Statistics (Australia):
* 1 in 5 Australians experience chronic pain.
* Economic burden: Over \$34 billion per year.
* Major analgesics only help a subset of patients, highlighting need for research.
#### 2.3.2. By Underlying Mechanisms
* Nociceptive Pain:
* Simplest type, similar to Descartes' "wire" concept.
Body senses painful stimulus, signal sent to brain via nociceptive neurons*.
* Functions to guard against tissue injury; must be unpleasant to compel action.
* Classic Example: Pinprick, leading to immediate withdrawal.
* Inflammatory Pain:
Response to tissue injury and inflammation*.
* Inflammatory mediators released, initiating signaling pathways.
Sensory nerves become hypersensitized*, producing pain from innocuous stimuli.
* Classic Example: Sunburn – light touch becomes painful, forcing protection and healing.
* Should resolve upon healing, but can become chronic.
* Neuropathic Pain:
Primarily results from damage to nerves*.
* Causes: Mechanical nerve injury (e.g., surgery), neurotoxic chemicals (e.g., chemotherapies).
* Nerves activate even without noxious stimuli, causing constant pain.
* Pathogenic, serves no protective or healing function.
Most often becomes chronic*.
## 3. How is Pain Produced? - Biochemical Mechanisms
### 3.1. Pain Pathway Overview
1. Periphery: Noxious stimulus detected by first-order neurons.
2. Spinal Cord: First-order neurons carry signal to dorsal horn, synapse onto second-order neurons.
3. Cross-over: Second-order neurons cross to the other side of the body.
4. Ascent to Brain: Travel up the spinothalamic tract to synapse onto third-order neurons in the somatosensory cortex.
5. Perception: Sensory input combined with cognition and emotion leads to pain perception.
* Pain sensed on the left side is processed in the right side of the brain.
* This lecture focuses mainly on peripheral mechanisms.
### 3.2. First-Order Neurons: Nociceptors
Also called primary sensory neurons*.
Cell body in the dorsal root ganglion*.
Project to both the periphery and spinal cord; bidirectional signaling machines*.
* Types of Nociceptors (Peripheral Nerve Terminals):
* A-delta fibers: Myelinated, transmit signals rapidly, cause sharp, well-localized pain.
* C fibers: Unmyelinated, transmit signals slowly, cause dull, diffuse pain.
### 3.3. Sensing Noxious Stimuli
#### 3.3.1. TRP Channel Family (Transient Receptor Potential)
* Major receptor family on nociceptor cell membranes (26 members).
* Detects a wide range of noxious stimuli:
* Temperature: $8^{\circ}\text{C}$ up to $52^{\circ}\text{C}$.
* Chemicals: Cinnamon, garlic, mint (activates cold receptor TRPM8), capsaicin (chili, activates heat receptor TRPV1).
* Mechanical disruption: Stretch of the membrane from damage.
* Mechanism:
* Non-selective cation channels.
Activation opens pore, allowing positively charged ions (e.g., $\text{Ca}^{2+}$) to flow into* the cell.
Increases resting membrane potential, triggering an action potential*.
* Example: TRPV1 binds capsaicin, opening pore for $\text{Ca}^{2+}$ influx.
#### 3.3.2. Inflammatory Soup & Neuronal Sensitization
* Inflammation/Injury: Release of various factors that sensitize neurons.
* Direct action: Provoke action potential firing.
* Hypersensitization: Make cells respond painfully to normally unharmful stimuli.
* Key Mediators:
* Bradykinin: Peptide activated by proteases in plasma. Activates G protein-coupled receptor (GPCR) Bradykinin-2 (BR2).
BR2 activity enhanced by prostaglandins*.
* Prostaglandins: Lipid mediators generated by COX-2 (cyclooxygenase enzyme).
* COX-2 is a target for NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), which can reduce inflammatory pain.
* Proteases: Released during inflammation, activate Protease-Activated Receptors (PARs) (GPCRs on neurons).
* Intracellular Signaling: BR2 and PAR2 activate Protein Kinase C (PKC).
PKC phosphorylates TRP channels, leading to hyperactivation* (open more easily, increased ion flow, easier action potential firing). This is a key mechanism of neuronal hypersensitization.
* ATP: Released from damaged cells (danger sign). Activates P2X3 receptors (ligand-gated ion channels), directly contributing to action potential firing.
* Acidosis: Increased extracellular protons (low pH). Activates acid-sensing ion channels (ASIC) and TRPV1 (if pH drops below 6).
* Nerve Growth Factor (NGF): Activates receptor tyrosine kinase TrkA, promoting neuronal sensitization.
* Cytokines & Chemokines: Produced during inflammation, increase production of other pain mediators (e.g., bradykinin), and in the long term, alter gene expression of pain signaling players (e.g., ion channels).
### 3.4. Action Potential & Signal Transduction
* Cation Influx: Increased flow of $\text{Ca}^{2+}$ or other cations into the neuron raises membrane potential.
* Threshold: When membrane potential reaches a threshold, voltage-gated sodium channels open.
* Depolarization: Rapid influx of $\text{Na}^{+}$ ions, leading to maximal membrane depolarization.
* Repolarization: Voltage-gated potassium channels open, allowing $\text{K}^{+}$ ions to flow out of the cell, returning to resting potential.
* Action Potential Propagation: This cycle propagates down the axon to the central nerve terminal.
* Neurotransmitter Release: At the terminal, voltage-gated calcium channels activate, triggering release of neurotransmitters into the synaptic space to activate second-order neurons.
### 3.5. Voltage-Gated Sodium Channels ($\text{Na}_{\text{V}}$)
* Critical Role: Play essential roles in pain signaling.
* Genetic Evidence (NaV1.7):
Loss-of-function mutations in the gene for $\text{Na}_{\text{V}}1.7$ lead to congenital insensitivity to pain*.
* Example: Ashlyn Blocker: Does not feel pain; severely burned hands at age 2, broke ankle unnoticed, grabbed spoon from boiling water without feeling it. Can distinguish warm/cool but not extreme temps.
Highlights the evolutionary importance of pain* for protection.
* Ashlyn's words: > "Not feeling pain is a disaster."
* Mechanism:
* Expressed on nociceptor cell membranes, normally closed.
* Open in response to voltage changes (neuronal depolarization).
* $\text{Na}^{+}$ ions rapidly enter, causing depolarization and action potential firing.
* Types: Nine different channels, $\text{Na}_{\text{V}}1.1$ to $\text{Na}_{\text{V}}1.9$.
$\text{Na}_{\text{V}}1.7$: Important for initiation* of action potentials (mutated in congenital insensitivity).
$\text{Na}_{\text{V}}1.8$: Essential for propagation* of action potentials downstream.
* Both are targets for drug development.
### 3.6. Key Neurotransmitters from Primary Neurons
* Glutamate:
* Released from primary nociceptors.
* Rapid transmission by activating AMPA receptors on second-order neurons.
* Neuropeptides (Slow Transmitters):
* Substance P: Activates GPCR neurokinin-1 receptor (NK1R).
* Targeted for analgesics, but limited success in human clinical trials (effective in animals).
NK1R antagonists (e.g., Aprepetant) are clinically approved for nausea and vomiting* after surgery (antiemetic).
* Calcitonin Gene-Related Peptide (CGRP): Activates GPCR calcitonin-like receptor (CLR).
* Promise in animal models, but not for pain in humans.
CLR antagonists are approved to treat migraine headaches*.
## 4. Therapeutic Interventions
### 4.1. Opioid Drugs
* Mechanism: Exploit the body's natural pain dampening (descending pathway from brain to periphery).
* Opioid Receptors: GPCRs on pre- and post-synaptic neurons, activated by endogenous enkephalins (pentapeptides with N-terminal tyrosine).
* Mu Opioid Receptor ($\mu$-OR):
* Inhibitory GPCR.
* Action:
* Inhibits $\text{Ca}^{2+}$ channels $\rightarrow$ less neurotransmitter release from presynaptic neurons.
* Activates $\text{K}^{+}$ channels $\rightarrow$ postsynaptic neurons hyperpolarized (harder to trigger action potentials).
* Net result: Less neuronal activation, less pain transmission.
* Source: Opium poppy (*Papaver somniferum*), used for 10,000 years (Neolithic Stone Age). Extracts contain ~20 alkaloids.
* Examples:
* Morphine, Codeine: Natural alkaloids, $\mu$-OR agonists.
* Heroin: Morphine derivative with acetyl groups, more lipophilic, crosses blood-brain barrier readily. 2 times more potent than morphine. Causes sharper "high" due to central activation.
* Fentanyl: Synthetic morphine derivative, 100 times more potent than morphine.
* Structural Features (Mimic Enkephalins): Phenol group and amine separated by two carbons.
* Clinical Uses (Moderate to Severe Pain, especially short-term):
* Pain Relief: Very effective.
* Cough Suppressants: Opioid receptors in medulla control cough reflex (e.g., codeine, pholcodine). Effective within 20 minutes.
* Antidiarrheals: Activate opioid receptors on enteric neurons, slowing gut contractions (e.g., codeine, loperamide).
* Sedatives.
* Unwanted Side Effects:
* Nausea and vomiting.
* Severe constipation (due to slowed gut contractions).
* Respiratory Depression: Most dangerous side effect, suppresses respiratory driver neurons in brain stem. Accounts for many opioid-related deaths.
* Euphoria/High Feeling: Promotes dependence and addiction (inhibition of GABA release in nucleus accumbens stimulates dopamine release).
* Tolerance: Effectiveness decreases over time, requiring higher doses, leading to more side effects. Not all effects develop tolerance at same rate (e.g., pain relief vs. respiratory depression).
* Opioid Epidemic:
* Early 2000s: Pharmaceutical companies and doctors promoted them as safe/effective.
* Wide availability and addictive nature led to widespread misuse and millions of deaths.
* Lawsuits against pharmaceutical companies.
* Limited long-term effectiveness due to tolerance; side effects often worse than pain.
* Treatment for Opioid Overdose:
* Naloxone (Narcan): $\mu$-OR antagonist.
Similar structure to morphine but with bulkier substitutions at amine group, binds tightly but cannot activate* receptor.
* Administered intravenously, occupies receptors within 2 minutes, causing abrupt cessation of opioid signaling.
* Can cause severe withdrawal symptoms due to rapid action.
* Treatment for Opioid Addiction:
* Buprenorphine: Partial agonist of $\mu$-OR.
* Activates signaling less than morphine.
* Binds with much stronger affinity than morphine (and naloxone), displacing morphine.
* Reduces the "high" feeling, alleviates withdrawal symptoms, suppresses cravings and drug-seeking behaviors.
* An example where a "less good" agonist provides therapeutic benefit.
### 4.2. Non-Opioid Alternatives: Voltage-Gated Sodium Channel Blockers
* Target: Voltage-gated sodium channels due to their central role in pain transmission.
* Local Anesthetics:
* Block the pore of sodium channels, preventing $\text{Na}^{+}$ influx.
* Low concentrations: Decrease action potential firing rate.
* Higher concentrations: Complete prevention of action potential firing.
Most are non-selective*, blocking many $\text{Na}_{\text{V}}$ types.
* Systemic Administration: Can lead to serious side effects (e.g., respiratory depression, death) due to widespread $\text{Na}_{\text{V}}$ blockade.
* Local Administration: Very effective anesthetics.
* Lidocaine: Fast-acting, injected locally (e.g., dental cavity fillings).
* Bupivacaine: Slower onset, longer duration. Injected into spinal cord or epidural space (e.g., surgery, childbirth labor).
### 4.3. Next-Generation NaV Inhibitors
#### 4.3.1. $\text{Na}_{\text{V}}1.7$ Inhibitors
* Initial Promise: Strong genetic evidence, less widely expressed, hypothesized to have fewer side effects.
* Clinical Trials: Relatively limited effects on pain, leading major pharmaceutical companies (Pfizer, Roche) to discontinue trials.
* Challenges:
* Couldn't completely prevent action potential firing (only dampened currents).
* Question of how much $\text{Na}_{\text{V}}1.7$ inhibition is required to block pain (possibly 100% loss for initiation).
* Total inhibition could result in loss of protective pain response (dangerous, like Ashlyn Blocker's case).
* Higher doses for greater inhibition could lead to loss of selectivity and more side effects.
* Current Status: Still some interest, but narrow therapeutic window suggests limited success.
#### 4.3.2. $\text{Na}_{\text{V}}1.8$ Inhibitors
* Focus Shift: Companies like Vertex hedging bets on $\text{Na}_{\text{V}}1.8$ (critical for action potential propagation downstream of $\text{Na}_{\text{V}}1.7$).
* Suzetrigine (Journavix):
* FDA Approved: January 2025, in the US for moderate to severe acute pain.
* Significance: First drug in this class, first new non-opioid analgesic approved in over two decades.
* Phase III Trials: Extremely encouraging results for abdominoplasty and bunionectomy surgeries.
* Side Effects: Minimal (rashes, itching, some nausea, headaches).
* Key Advantage: Drastically reduced risks of dependence and addiction due to peripheral mechanism of action (does not act in the brain).
* Selectivity: Highly selective ( $>10,000$-fold) for $\text{Na}_{\text{V}}1.8$ over other $\text{Na}_{\text{V}}$ channels, partly due to allosteric binding mechanism.
* Future Directions: Vertex has follow-up $\text{Na}_{\text{V}}1.8$-targeted drugs in pipeline.
Currently investigating usefulness for chronic pain* (approved for acute use ~1 week).
* Phase III trials ongoing for neuropathic pain indications (e.g., diabetic neuropathy), offering hope to patients with limited options.
## 5. Conclusion
* Significant progress since Descartes' "telephone wire" theory of pain.
* Molecular mechanisms are better understood, leading to targeted therapies.
* Continued research is essential for new and improved treatments across all pain types, especially for chronic conditions and to overcome the challenges associated with opioid use.