Analgesia

Pharmacology of Analgesia

• Analgesia is the unpleasant sensory and emotional experience associated with actual or potential tissue damage
• Types of pain: Physiologic (intense/noxious stimulus), Inflammatory (tissue injury/inflammation causing heightened sensitivity, e.g., rheumatoid arthritis), Neuropathic (nerve injury, e.g., amputation or diabetes), and Dysfunctional (pain without noxious stimuli, e.g., tension-type headache or fibromyalgia).

Mechanisms of Pain

• Transduction of intense/noxious stimuli depolarizes peripheral terminals of high-threshold primary sensory neurons (nociceptors), requiring a strong stimulus.
• Action potentials are conducted to the CNS via peripheral nerves and dorsal roots, synapsing on neurons in the dorsal horn of the spinal cord.
• Secondary projection neurons transmit information to the brainstem and thalamus, then relay signals to the cortex, hypothalamus, and limbic system.
• Transmission is regulated by inhibitory and excitatory interneurons.

Neurotransmission in the Spinal Cord Dorsal Horn

• Neurotransmission in the dorsal horn relays signals to CNS neurons that signal to the brain, part of a circuit also receiving descending modulatory control.

Descending and Local Inhibitory Regulation in the Spinal Cord

• Spinal cord synaptic transmission is regulated by local inhibitory interneurons and descending projections from the brainstem.
• These systems limit incoming sensory information, a crucial site for pharmacologic intervention.
• Key inhibitory neurotransmitters include opioid peptides, norepinephrine, serotonin (5-HT), glycine, and GABA.

Pain Management

• Pain treatment depends on the type (nociceptive or neuropathic) of pain.
• Nociceptive pain (e.g., mild to moderate arthritic pain) can be managed with non-opioid analgesics (like NSAIDs).
• Chronic inflammatory pain can be treated with NSAIDs, DMARDs , TNF-α inhibitors, immunosuppressants, and monoclonal antibodies.
• Neuropathic pain can be treated with TCAs, serotonin-norepinephrine reuptake inhibitors,and anticonvulsants.
• Severe acute pain and chronic pain may include opioid use.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• NSAIDs inhibit the activity of cyclooxygenase enzymes (COX-1 and COX-2) required for prostaglandin production.
• Major classes: Salicylates (e.g., aspirin), Propionic acid derivatives (e.g., ibuprofen, naproxen), Phenylacetic acid derivatives (e.g., diclofenac, ketorolac), and Selective COX-2 inhibitors (e.g., celecoxib).
• NSAIDs affect pain pathways by reducing prostaglandin synthesis, decreasing leukocyte recruitment, and preventing prostaglandin generation in the spinal cord.
• Adverse effects of non-selective COX inhibitors can include gastric mucosa and kidney injury.

Analgesic-Antipyretic Acetaminophen (Paracetamol)

• Low anti-inflammatory effects; primarily reduces prostaglandin synthesis in the CNS.
• Frequently combined with weak opioids for moderate pain.
• Major concern is low therapeutic index; overdose can cause liver failure.
• Works by penetrating the blood-brain barrier, blocking COX-3 in the brain, blocking PGE formation/release, and inhibiting pyrogens on heat-regulating centers of the brain, resulting in antipyretic effect.

NSAIDs and COX-2 Inhibitors

• NSAIDs and COX-2 inhibitors act centrally and peripherally.
• Celecoxib is a prominent COX-2 inhibitor and still in use, minimizing GI, renal, and hematological adverse effects.

Neuropathic Pain

• Nerve injury involves both functional and structural alterations in the nervous system.
• Peripheral and central alterations, including inflammation and loss of nerve growth factors, contribute.
• Positive signals such as inflammatory cytokines (by macrophages and Schwann cells); negative signals like loss of peripheral support.
• Sodium channel expression pattern changes in injured primary sensory neurons.

Treatment for Neuropathic Pain

• Treatment options for neuropathic pain include tricyclic antidepressants (TCAs), dual NE/serotonin reuptake inhibitors, and antiepileptic drugs (AEDs).

Analgesic Use of Antidepressants

• TCAs like amitriptyline and dual NE/serotonin reuptake inhibitors like venlafaxine are used as adjuvants in chronic pain management, to increase antinociceptive noradrenergic and serotonergic projections to the spinal cord.

Analgesic Use of Antiepileptics

• Drugs like gabapentin, pregabalin, and carbamazepine are often used to reduce neuronal excitability, treating chronic pain conditions.

Gabapentin, Pregabalin and Carbamazepine (AEDs)

• Gabapentin and pregabalin are structural GABA analogs with no effect on GABA receptors but bind to a2δ subunit of voltage-dependent calcium channels.
• Gabapentin is useful in trigeminal neuralgia, diabetic neuropathy, and post-op pain.
• Pregabalin is similar but has faster onset and more predictable bioavaibility.
• Carbamazepine is a sodium channel blocker and oxcarbazepine is its derivative, useful in trigeminal neuralgia.

Severe Acute Pain or Chronic Pain

• Management could utilize opioids.
• Opioid receptor agonists are primary class for moderate to severe acute pain.

Opioid Receptors and Agonists

• Opioids (e.g., Morphine, Hydromorphone, Codeine, Oxycodone, Methadone, Fentanyl, Meperidine).
• Partial and Mixed Opioid Agonists (e.g., Buprenorphine, Butorphanol, Nalbuphine).
• Opioid Receptor Antagonists (e.g., Naloxone, Naltrexone).

Opioid Receptor Agonist Mechanism

• Activation of presynaptic and postsynaptic μ-opioid receptors by descending/local circuit inhibitory neurons inhibits central relaying of nociceptive stimuli.
• In the presynaptic terminal, decrease in calcium influx; postsynaptic increase in K+ conductance, decreasing the postsynaptic response to excitatory neurotransmission.

Adverse Effects of Opioids

• Cardiovascular (decreased sympathetic tone → hypotension, bradycardia); respiratory (suppression, apnea); gastrointestinal (constipation, nausea, vomiting); central nervous system (sedation, dizziness, confusion); and addiction potential.

Migraine Therapy

• Migraine is a headache disorder characterized by headache lasting up to 3 days typically accompanied by light and sound avoidance, and nausea. In some cases, aura, transient neurological symptoms are associated with the migraine.
• Tryptan serotonin receptor agonists (e.g., sumatriptan) act on 5HT-1B/1D receptors, reducing vascular and nociceptive transmission.
• Other treatments with acute attacks include NSAIDs, opioids, caffeine, and antiemetics.
• Prophylactic drugs may include β-blockers, valproic acid, serotonin antagonists, Ca2+ channel blockers, or TCAs.

Summary

• Polypharmacy often used for effective pain management.
• Analgesic targets continue to be identified for potential new therapies.
• Effective pain management extends beyond pharmacology with physical therapy, etc., and, at times, surgery, needed to address multi-factorial issues.

Test your knowledge on various pain mechanisms and types. This quiz covers concepts such as neuropathic pain, allodynia, and the role of N-type voltage-gated calcium channels in pain transmission. Challenge yourself to understand the intricacies of how pain is perceived and processed in the body.