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Mechanistic Deep Dive
Pain Pathways
- Nociceptors â DRG â spinal cord dorsal horn â spinothalamic tract â thalamus â cortex
- Descending modulation (PAG, locus coeruleus, RVM)
- Inhibitory neurotransmitters: opioids, GABA, glycine, serotonin, NE
Central Sensitization
- NMDA receptor activation
- â excitability
- Allodynia + hyperalgesia
- Wind-up phenomenon
Neuropathic Pain Mechanisms
- Sodium channel dysfunction (ectopic firing)
- Glutamatergic signaling
- Glial activation (microglia, astrocytes)
- Cytokine release
- Disinhibition (loss of GABA, glycine)
Recent Trials & Updates
Suzetrigine (Vertex VX-548)
- Selective NaV1.8 inhibitor
- Non-opioid for acute pain
- FDA approved January 2025 (acute pain post-surgery)
- Phase 3 trials positive
Buprenorphine for Chronic Pain
- Partial agonist
- Lower OD risk
- Ceiling effect on respiratory depression
- Useful for OUD + pain
Cannabis-Based Medications
- Mixed evidence
- Sativex (UK, Canada â MS spasticity)
- Recreational legalization â research barriers
- Adverse: cognitive, psychiatric
Ketamine Infusions
- Low-dose IV
- Refractory chronic pain
- CRPS
- Neuropathic
- Dissociation, psychomimetic risks
Lasmiditan + Gepants (Migraine)
TRPV1 + TRPA1 Antagonists
- Investigational
- Capsaicin receptor + cold/menthol
High-Yield Specialist Points
Methadone in Chronic Pain
- NMDA antagonist component
- Useful in neuropathic refractory to other opioids
- ECG before + during titration (QT)
- Variable T1/2 (15-60 hr)
- Slow titration required
Opioid-Induced Hyperalgesia
- Paradoxical â pain with â opioid
- Often misdiagnosed as tolerance
- Distinguished by: spread of pain, diffuse, lower threshold
- Treatment: opioid rotation, taper, NMDA antagonist (methadone, ketamine)
Opioid Rotation
- For inadequate analgesia + intolerable side effects
- Convert to MME
- Reduce by 25-50% for incomplete cross-tolerance
- Then titrate
Pain in Renal Failure
- Avoid morphine (M6G accumulation)
- Avoid codeine (active metabolites)
- Avoid meperidine (normeperidine â seizures)
- Safe: methadone, fentanyl, buprenorphine
- Hydromorphone with caution
Pain in Liver Failure
- Acetaminophen safe in moderate doses (3 g/d max)
- NSAIDs avoid (renal, bleeding)
- Opioids: â doses, â intervals (most undergo hepatic metabolism)
- Tramadol: caution
- Methadone: caution (variable metabolism)
Cancer Pain Approach
- Identify nociceptive vs neuropathic vs mixed
- WHO ladder + adjuvants
- Strong opioids early if severe
- Adjuvants for specific pain (bone â bisphosphonates, RT; neuropathic â gabapentinoids, TCAs)
- Procedural â celiac plexus block (pancreatic), intrathecal pump (refractory)
Acute Pain Management
- Multimodal best
- Reduce opioid requirements
- Combinations of acetaminophen + NSAID + opioid
- Local anesthetic blocks
- Suzetrigine (NaV1.8 â new 2025)
Chronic Low Back Pain
- Multifactorial
- NSAIDs first-line
- Gabapentinoids (mixed evidence)
- Duloxetine
- PT, CBT
- Opioids: limited evidence, risk > benefit chronic
- Procedural: epidural injections, RFA
Fibromyalgia (Nociplastic)
- Diagnostic criteria (2016 ACR)
- Widespread pain + fatigue + sleep + cognitive
- Treatment: aerobic exercise (best evidence), pregabalin, duloxetine, milnacipran (FDA-approved)
- Avoid opioids
Pearls
- Three pain types: nociceptive + neuropathic + nociplastic
- WHO ladder still relevant
- Minimize opioids, multimodal approach
- Neuropathic: gabapentinoids + SNRIs + TCAs
- Trigeminal neuralgia: carbamazepine
- PHN prevention: Shingrix
- MME ⥠50 high risk
- Suzetrigine (NaV1.8) 2025 non-opioid acute pain
- Naloxone for OD
- MAT for OUD: buprenorphine, methadone, naltrexone