6.4 Neurologic, Psychiatric, and Pain Management Therapeutics

Neurological Pharmacotherapy

Epilepsy and Antiseizure Medications (ASMs)

Antiseizure medications are classified into broad-spectrum (effective for focal and generalized seizures) and narrow-spectrum (effective for focal onset seizures; potentially aggravating generalized absence or myoclonic seizures).

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|               ANTISEIZURE MEDICATION SPECTRUM OF ACTIVITY              |
+-------------------------------------------------------------------------+
|                                                                         |
|  BROAD-SPECTRUM (Focal + Generalized Onset):                            |
|  - Levetiracetam, Lamotrigine, Valproic Acid / Divalproex, Topiramate,  |
|    Clobazam, Brivaracetam                                               |
|                                                                         |
|  NARROW-SPECTRUM (Focal Onset Only):                                    |
|  - Carbamazepine, Oxcarbazepine, Phenytoin, Gabapentin, Pregabalin      |
|  *WARNING: Narrow-spectrum sodium channel blockers can WORSEN generalized|
|   absence and myoclonic seizures (e.g., in Juvenile Myoclonic Epilepsy) |
+-------------------------------------------------------------------------+

Status Epilepticus Protocol

1. Phase 1 (Emergent, 0-5 min): Support airway, breathing, circulation; verify blood glucose.
2. Phase 2 (Initial Therapy, 5-20 min): IV Lorazepam ($4\text{ mg}$ IV over 2 min, repeated once at 5-10 min) OR IM Midazolam ($10\text{ mg}$ IM once if no IV access).
3. Phase 3 (Urgent Control, 20-40 min): IV Levetiracetam ($60\text{ mg/kg}$, max $4500\text{ mg}$), IV Fosphenytoin ($20\text{ mg PE/kg}$), or IV Sodium Valproate ($40\text{ mg/kg}$).
4. Phase 4 (Refractory, $> 40\text{ min}$): General anesthesia with IV propofol, midazolam infusion, or ketamine.

Parkinson's Disease (PD)

• Levodopa/Carbidopa (Sinemet): Levodopa crosses the blood-brain barrier and is converted to dopamine; carbidopa inhibits peripheral DOPA decarboxylase to prevent peripheral dopamine formation and nausea. Gold standard therapy.
  • Motor Complications: "Wearing-off" (end-of-dose deterioration) managed by increasing dosing frequency, adding a COMT inhibitor (Entacapone $200\text{ mg}$ with each levodopa dose; causes orange/brown urine discoloration), or adding an MAO-B inhibitor (Rasagiline $0.5-1\text{ mg}$ daily, Selegiline).
  • Peak-Dose Dyskinesias: Managed by lowering individual levodopa doses or adding Amantadine (NMDA antagonist).
• Dopamine Agonists (Pramipexole, Ropinirole): Direct dopamine receptor stimulation. Adverse effects: Impulse control disorders (pathological gambling, hypersexuality, compulsive shopping), sudden sleep attacks, peripheral edema, hallucinations.
• Anticholinergics (Benztropine, Trihexyphenidyl): Used for resting tremor in younger patients ($< 60$ years); avoid in older adults due to confusion, memory impairment, urinary retention, and constipation.

Migraine Management

• Acute Abortive Therapy:
  • Mild-to-Moderate: NSAIDs (Naproxen, Ibuprofen) or Acetaminophen.
  • Moderate-to-Severe: Triptans (5-$HT_{1B/1D}$ receptor agonists: Sumatriptan, Rizatriptan, Zolmitriptan). Induce cranial vasoconstriction and inhibit trigeminal calcitonin gene-related peptide (CGRP) release. Contraindications: Ischemic heart disease, prior MI, coronary vasospasm (Prinzmetal angina), stroke/TIA, uncontrolled hypertension, peripheral vascular disease. CGRP Antagonists (Gepants: Ubrogepant, Rimegepant) provide alternatives without vasoconstrictive contraindications.
• Prophylactic Therapy (Indicated if $\ge 4$ headache days/month or disabling attacks):
  • First-Line Oral: Beta-blockers (propranolol, metoprolol), TCAs (amitriptyline), Antiseizure Drugs (topiramate, divalproex).
  • CGRP Monoclonal Antibodies: Erenumab (targets CGRP receptor), Fremanezumab, Galcanezumab, Eptinezumab (target CGRP ligand).
  • Medication-Overuse Headache (MOH): Caused by regular use of triptans/NSAIDs $\ge 10-15\text{ days/month}$ for $> 3$ months.

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Psychiatric Pharmacotherapy

Major Depressive Disorder (CANMAT Guidelines)

The Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines establish evidence-based first-line antidepressant therapies:

• First-Line Classes:
  • SSRIs: Escitalopram, Citalopram, Sertraline, Fluoxetine, Paroxetine, Fluvoxamine.
  • SNRIs: Venlafaxine, Duloxetine, Desvenlafaxine.
  • NDRI: Bupropion (no sexual dysfunction, promotes weight loss; contraindicated in seizure disorders and eating disorders [anorexia/bulimia]).
  • Alpha-2 Antagonist / NaSSA: Mirtazapine (potent $5-HT_2, 5-HT_3$, and $H_1$ antagonism; causes sedation and increased appetite/weight gain; useful in depression with severe insomnia and anorexia).
  • Multimodal: Vortioxetine (SSRI + receptor modulator; improves cognitive symptoms).
• Clinical Timeline: Initial improvement in sleep/appetite at 1-2 weeks; mood/energy at 2-4 weeks; full therapeutic trial requires 4 to 8 weeks at optimized doses. Continue maintenance therapy for 6 to 12 months following remission of a first episode.
• Serotonin Syndrome (Hunter Criteria): Caused by excessive central serotonergic agonism (e.g., combining SSRI/SNRI with MAOIs, tramadol, linezolid, triptans, or St. John's Wort). Diagnosed by spontaneous clonus, inducible clonus with agitation/diaphoresis, ocular clonus with tremor/hyperreflexia, or hypertonia and temperature $> 38^\circ\text{C}$ with clonus. Treat by stopping serotonergic agents, supportive care, and cyproheptadine ($5-HT_{2A}$ antagonist).
• Antidepressant Discontinuation Syndrome (FINISH): Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances (electric shock sensations), Hyperarousal. Highest with short half-life agents (paroxetine, venlafaxine); lowest with fluoxetine.

Bipolar Disorder

• Mood Stabilizers:
  • Lithium: Gold standard for acute mania, bipolar depression, and suicide prevention. Therapeutic Range: Acute mania $0.8-1.2\text{ mmol/L}$; Maintenance $0.6-0.8\text{ mmol/L}$. Toxicity ($> 1.5\text{ mmol/L}$): Coarse hand tremor, ataxia, dysarthria, nausea, vomiting, confusion, seizures. Drug Interactions: Lithium clearance is decreased (toxicity risk increased) by Thiazide diuretics, ACE inhibitors / ARBs, and NSAIDs. Monitor TSH (hypothyroidism risk) and eGFR (nephrogenic diabetes insipidus / chronic kidney disease).
  • Divalproex / Valproic Acid: Acute mania.
  • Lamotrigine: First-line for Bipolar Depression maintenance; ineffective for acute mania.
• Atypical Antipsychotics: Quetiapine, Lurasidone, Olanzapine-Fluoxetine, Cariprazine for bipolar depression; Aripiprazole, Risperidone, Asenapine for acute mania.

Antipsychotic Pharmacotherapy and Adverse Effect Profiles

Antipsychotics block dopamine $D_2$ receptors (FGAs and SGAs) and serotonin $5-HT_{2A}$ receptors (SGAs).

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Pain Management and Opioid Stewardship

Pain Classification and First-Line Management

• Nociceptive Pain (Somatic/Visceral): Responds to Acetaminophen, NSAIDs (Naproxen preferred for lower cardiovascular risk; Celecoxib for lower GI ulceration risk; Topical Diclofenac for localized osteoarthritis), and short courses of opioids for severe acute pain.
• Neuropathic Pain (Peripheral/Central): Characterized by burning, tingling, allodynia, lancinating pain. First-line therapies:
  1. Gabapentinoids: Gabapentin ($300-3600\text{ mg/day}$) or Pregabalin ($150-600\text{ mg/day}$) — binds $\alpha_2\delta$ voltage-gated calcium channels.
  2. SNRIs: Duloxetine ($60-120\text{ mg/day}$) — enhances descending noradrenergic inhibition.
  3. Tricyclic Antidepressants (TCAs): Amitriptyline or Nortriptyline ($10-75\text{ mg}$ at bedtime; nortriptyline causes less orthostatic hypotension and anticholinergic sedation).

Canadian Opioid Stewardship Guidelines

• Morphine Milligram Equivalent (MME) Thresholds:
  • Keep daily opioid doses below $50\text{ MME/day}$ for chronic non-cancer pain.
  • Avoid or carefully justify escalating doses above $90\text{ MME/day}$ (significantly increased risk of non-fatal and fatal overdose without clinically meaningful improvements in pain or function).
• High-Risk Combinations: Never coprescribe opioids and benzodiazepines or sedating muscle relaxants due to profound synergistic respiratory depression.
• Opioid-Induced Constipation (OIC): Tolerance does not develop to constipation. Prescribe a prophylactic bowel regimen containing a stimulant laxative (Senna or Bisacodyl) PLUS an osmotic laxative (PEG 3350). Docusate monotherapy is ineffective.
• Opioid Use Disorder (OUD) First-Line Maintenance: Buprenorphine/Naloxone (Suboxone) is preferred first-line over Methadone due to its ceiling effect on respiratory depression, lower overdose risk, and milder withdrawal profile. Administer only when the patient exhibits objective mild-to-moderate opioid withdrawal (COWS score $\ge 12-13$) to avoid precipitating acute withdrawal.