Pathophysiology
- Nociceptive Pain: Arises from the stimulation of specialized nerve endings called nociceptors, which respond to actual or potential tissue damage. This process occurs in four key stages:
- 1. Transduction: Conversion of a noxious stimulus (thermal, mechanical, or chemical) into an electrical signal (action potential) at the peripheral nociceptor. Prostaglandins, bradykinin, and histamine are key chemical mediators released from damaged cells that activate nociceptors.
- 2. Transmission: The action potential is conducted along primary afferent nerve fibers to the spinal cord.
- A-delta fibers: Myelinated, fast-conducting fibers that transmit sharp, well-localized pain.
- C fibers: Unmyelinated, slow-conducting fibers that transmit dull, aching, and poorly localized pain.
- These first-order neurons synapse in the dorsal horn of the spinal cord, releasing neurotransmitters like glutamate and substance P.
- 3. Perception: The pain signal ascends from the spinal cord to the brain via tracts like the spinothalamic tract. It then reaches higher centers, including the thalamus, somatosensory cortex, and limbic system, where the conscious awareness and emotional response to pain occur.
- 4. Modulation: The brain and spinal cord can alter the intensity of the pain signal through descending pathways. These pathways release neurotransmitters like serotonin, norepinephrine, and endogenous opioids (e.g., endorphins) to inhibit the transmission of pain signals in the dorsal horn.
- Neuropathic Pain: Caused by a lesion or disease of the somatosensory nervous system itself. This results in abnormal signal processing, leading to pain that can be spontaneous or evoked by non-painful stimuli (allodynia) or an exaggerated response to painful stimuli (hyperalgesia). Mechanisms include ectopic impulse generation, central sensitization (an increased responsiveness of nociceptive neurons in the CNS), and structural changes in the nervous system.
Analgesics
| Drug | Mechanism of action |
|---|---|
| Tricyclic antidepressants (eg, amitriptyline, nortriptyline) SNRIs (eg, duloxetine) | ↓ Reuptake of serotonin & norepinephrine Inhibition of pain signals |
| Anticonvulsants (eg, gabapentin, pregabalin) | • Decreased depolarization of neurons in the CNS |
| Opioids | • Activation of central opioid receptors |
| Capsaicin (topical) | Loss of membrane potential in nociceptive fibers |
| Lidocaine (topical) | • Decreased depolarization of neurons in peripheral nerves |
- Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
- Examples: Ibuprofen, naproxen, aspirin, ketorolac, diclofenac.
- Mechanism: Primarily act by reversibly inhibiting cyclooxygenase (COX) enzymes (COX-1 and COX-2), which blocks the conversion of arachidonic acid to prostaglandins. This reduces inflammation and the sensitization of nociceptors to painful stimuli.
- COX-1 is constitutively expressed and has a protective role in the gastric mucosa and kidneys.
- COX-2 is an inducible enzyme that is upregulated during inflammation.
- Celecoxib is a selective COX-2 inhibitor, which spares COX-1, theoretically reducing GI side effects.
- Toxicity: Gastric ulcers (due to ↓ prostaglandin protection), renal insufficiency (prostaglandins are needed for renal vasodilation), and increased risk of cardiovascular events.
- Opioids
- Examples: Morphine, fentanyl, oxycodone, hydrocodone, codeine, heroin, methadone.
- Mechanism: Act as agonists at opioid receptors (mu, kappa, delta) which are G-protein coupled receptors. They work at multiple levels:
- Presynaptically: Close voltage-gated Ca²⁺ channels on the primary afferent neuron, reducing the release of pain neurotransmitters (glutamate, substance P) in the dorsal horn.
- Postsynaptically: Open K⁺ channels on the second-order neuron, leading to hyperpolarization and making it harder to depolarize.
- Centrally: Enhance the activity of the descending inhibitory pain pathways.
- Toxicity: Respiratory depression (most common cause of death in overdose), sedation, constipation, miosis (pupillary constriction), and a high potential for addiction and tolerance.
- Local Anesthetics
- Examples: Lidocaine, bupivacaine, ropivacaine.
- Mechanism: Block voltage-gated sodium (Na⁺) channels within the nerve axon, preventing the generation and propagation of action potentials. They have a higher affinity for channels in the open or inactivated state, which means they are more effective on rapidly firing neurons.
- They must penetrate the nerve membrane in their uncharged form and then become charged intracellularly to bind to the receptor site inside the channel.
- Toxicity: Can cause CNS excitation (seizures) followed by depression, cardiovascular toxicity (arrhythmias, hypotension), and methemoglobinemia (especially benzocaine).
- Adjuvant Analgesics
- These are drugs with other primary indications that are also effective for certain types of pain, especially neuropathic pain.
- Antidepressants:
- Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, nortriptyline): Inhibit the reuptake of serotonin and norepinephrine, which strengthens the descending modulatory pain pathways.
- SNRIs (e.g., duloxetine, venlafaxine): Also inhibit serotonin and norepinephrine reuptake.
- Anticonvulsants:
- Gabapentin & Pregabalin: Bind to the α2δ subunit of voltage-gated Ca²⁺ channels, which decreases the release of excitatory neurotransmitters. Primarily used for neuropathic pain.
- Carbamazepine: Primarily used for trigeminal neuralgia; blocks Na⁺ channels.
- NMDA Receptor Antagonists (e.g., ketamine): Block the N-methyl-D-aspartate receptor, which is involved in central sensitization and the “wind-up” phenomenon of chronic pain.