This chapter is a tabular list of commonly used medications on the neurology wards for quick reference in text and table formats. A working pharmacotherapy knowledge base is essential to dosing and optimizing patient care. This chapter is intended to highlight practical dosing considerations and common problems associated with the pharmacologic management of patients with neurologic disorders. Pain management, cardiac medications including blood pressure management, antiplatelets, and anticoagulants are covered in this chapter. In addition, antidepressants, antipsychotics, antiepileptic drugs, and agents for the treatment of inflammatory and demyelinating diseases are covered in more detail. A complete discussion of the pharmacology and pharmacokinetics of all medications highlighted is beyond the scope of this chapter. Thus, this will not replace available tertiary references or the most valuable medication reference, the clinical pharmacist. The addition of a clinical pharmacist can provide you with further dosing and medication management considerations.

A working pharmacotherapy knowledge base is essential to optimizing patient care. This chapter is intended to highlight practical dosing considerations and common problems associated with the pharmacologic management of patients with neurologic disorders. A complete discussion of the pharmacology and pharmacokinetics of all medications highlighted is beyond the scope of this chapter. Thus, this will not replace available tertiary references or the most valuable medication reference, the clinical pharmacist. The addition of a clinical pharmacist has demonstrated improvement in clinical and cost-savings outcomes in a variety of settings. They are a vital part of interdisciplinary medicine and should routinely participate in clinical activities when available.

Pain and analgesia

Nonsteroidal anti-inflammatory drugs (NSAIDs)

• 
  

  Key features

  
  
  
  
  • 
    

    NSAIDs provide analgesic, anti-inflammatory, and antipyretic effects.

    
    
  • 
    

    Ibuprofen

    
    
    
    
    • 
      

      Dose:

      
      
      
      
      • 
        

        IV (Caldolor): 400–800 mg every 6 hours as needed; maximum 3200 mg daily

        
        
      • 
        

        PO: 200–400 mg every 4–6 hours; maximum 2400 mg daily

      
      
      
      
    • 
      

      Avoid in patients with moderate-to-severe renal dysfunction, hyperkalemia, history/active peptic ulcer disease/gastrointestinal (GI) bleeding, high risk of bleeding, and perioperative analgesia in the setting of coronary artery bypass graft (CABG)

    
    
    
    
  • 
    

    Naproxen

    
    
    
    
    • 
      

      Dose:

      
      
      
      
      • 
        

        PO: 220 mg every 8 hours; maximum 660 mg/day

      
      
      
      
    • 
      

      Avoid use in patients with CrCl <30 mL/min, hyperkalemia, history/active peptic ulcer disease/GI bleeding, high risk of bleeding, and perioperative analgesia in the setting of CABG

    
    
    
    
  • 
    

    Ketorolac (Toradol)

    
    
    
    
    • 
      

      Intended for short-term use; maximum combined 5 days of treatment (parenteral and oral)

      
      
    • 
      

      Dose:

      
      
      
      
      • 
        

        Patients <65 years old: IV, IM: 30 mg every 6 hours; maximum 120 mg daily; PO: 10 mg every 4 hours as needed; maximum 40 mg daily

        
        
      • 
        

        Patients >65 years old and/or <50 kg and/or mild-to-moderate renal dysfunction: IV, IM: 15 mg every 6 hours as needed; maximum 60 mg daily; PO: 10 mg every 4 hours as needed; maximum 40 mg daily

      
      
      
      
    • 
      

      Contraindicated in patients with hypersensitivity to NSAIDs (including aspirin), severe renal dysfunction, high risk of bleeding, perioperative analgesia in the setting of CABG, active or history of peptic ulcer disease or GI bleeding, and hyperkalemia

      
      
    • 
      

      Ketorolac is a potent COX-1 inhibitor and thus has greater risk of GI bleeding, renal failure, and platelet inhibition when compared to other NSAIDs.

    
    

  
  

Adjuncts for specific indications

Neuropathic pain

• 
  

  Key features

  
  
  
  
  • 
    

    There is currently no consensus regarding the optimal strategy for the treatment of neuropathic pain, despite an increasing number of clinical trials demonstrating pain relief with several different regimens.

    
    
  • 
    

    Always start at the lowest recommended dose and titrate to response to minimize adverse effects.

    
    
  • 
    

    Titration of these agents may be limited by the following adverse effects: somnolence and dizziness.

  
  
  
  
• 
  

  Highlighted agents (Table 52-1)

  
  
  
  
  • 
    

    Duloxetine

    
    
  • 
    

    Gabapentin

    
    
  • 
    

    Pregabalin

  
  

Skeletal muscle relaxants

• 
  

  Key features

  
  
  
  
  • 
    

    Muscle spasms related to musculoskeletal disorders and upper motor neuron disorders may significantly contribute to pain in the acute setting. Opiates and traditional analgesics are often ineffective in managing pain associated with muscle spasms and spasticity.

    
    
  • 
    

    Little evidence is available to provide guidance on the most efficacious empiric agents for many conditions. Choice of initial agent is largely based on medication adverse effects.

    
    
  • 
    

    Oral medications alone often fail to provide adequate relief to patients with severe or chronic symptoms. In these patients, consideration should be made for referral therapies, such as intrathecal medications.

  
  
  
  
• 
  

  Highlighted agents (Table 52-2)

  
  
  
  
  • 
    

    Baclofen

    
    
  • 
    

    Dantrolene

    
    
  • 
    

    Diazepam

    
    
  • 
    

    Tizanidine

    
    
  • 
    

    Cyclobenzaprine

    
    
  • 
    

    Carisoprodol

  
  

Headaches and migraines

Key features

• 
  

  Rebound headaches, or medication overuse headaches, may occur with available agents. To minimize this risk, use simple analgesics less than 15 days per month, and ergots, triptans, opioids, or analgesic combinations less than 10 days per month (see Chapters 27 and 50).

  
  
• 
  

  It is thought that there is decreased gastric motility following migraine onset, which reduces oral absorption of abortive therapy. Alternative routes of administration have been developed for the triptans and ergotamine to address this concern.

  
  
• 
  

  There are little data to support drug combinations to abort headaches; however, these interventions are used in clinical practice.

Initial treatment:

• 
  

  Simple analgesics and combination products: aspirin, acetaminophen, and NSAIDs (see “Nonopioid pain medications: nonsteroidal anit-inflammatory drugs” in Chapter 2)

  
  
• 
  

  Combination products: Most formulations include low doses of aspirin, acetaminophen, and caffeine.

  
  
• 
  

  Administer at the first sign of headache and every 4 hours as needed. Do not exceed 4 gm of acetaminophen, 2 gm of aspirin, or 520 mg of caffeine per day.

  
  
  
  
  • 
    

    Highlighted agents (Table 52-3)

    
    
    
    
    • 
      

      Fiorinal (butalbital/aspirin/caffeine)

      
      
    • 
      

      Fioricet (butalbital/acetaminophen/caffeine)

      
      
    • 
      

      Excedrin (aspirin/acetaminophen/caffeine)

      
      
    • 
      

      Goodys (aspirin/acetaminophen/caffeine)

      
      
    • 
      

      Metoclopramide

      
      
    • 
      

      Prochlorperazine

      
      
    • 
      

      Promethazine

    
    

  
  

• 
  

  Triptan comparison chart (see Table 52-4)

  
  
  
  
  • 
    

    All triptans cause vasoconstriction, which may result in blood pressure elevations and coronary, carotid, and limb ischemia. To minimize these risks, do not exceed recommended dosage limits and avoid use in patients with coronary artery disease, heart failure, hypertension, recent myocardial infarction or stroke, glaucoma, or renal/hepatic disease.

    
    
  • 
    

    Triptans are not indicated for migraine prophylaxis. Furthermore, the safety of treating >4 headaches in 30 days has not been established.

  
  
  
  
• 
  

  Ergotamine

  
  
  
  
  • 
    

    May produce rebound headaches if used >10 days out of a month. Dihydroergotamine mesylate has similar actions to triptans.

  
  
  
  
• 
  

  Adjunctive therapy

  
  
  
  
  • 
    

    Nonpharmacologic: stress management, relaxation, biofeedback, improved sleep hygiene

    
    
  • 
    

    Hydration

    
    
  • 
    

    Antiemetics

    
    
  • 
    

    Consider IV therapy

    
    
  • 
    

    Options include metoclopramide, promethazine, and ondansetron

  
  
  
  
• 
  

  Corticosteroids: dexamethasone and methylprednisolone preferred

  
  
• 
  

  Valproic acid—while more commonly utilized for migraine prophylaxis, bolus doses have been utilized as abortive therapy 300–1200 mg (5–10 mg/kg)

Chronic headaches/migraines

• 
  

  Prophylactic therapy is recommended for patients experiencing >2–3 headaches/migraines per month and should be tried for 6 months to a year. See Table 52-5 for specific agents.

  
  
• 
  

  A headache calendar and diary are helpful in properly identifying triggers, medication use, and side effects. Follow-up on response and triggers with the diary is critical for managing chronic headaches.

  
  
• 
  

  Triggers can be environmental, hormonal (associated with menstrual periods), dietary (foods containing tyramine, wine), or behavioral (irregular sleep patterns, skipped meals).

  
  
• 
  

  Special conditions

  
  
  
  
  • 
    

    Tension headaches

    
    
    
    
    • 
      

      Nonpharmacological therapies

      
      
    • 
      

      Cyclobenzaprine 5–10 mg PO 3 times daily if needed (1 hour before bedtime initially due to daytime drowsiness)

    
    
    
    
  • 
    

    Cluster headache prophylaxis

    
    
    
    
    • 
      

      Dexamethasone, verapamil, and topiramate have the most evidence

      
      
    • 
      

      Avoiding alcohol and smoking during the cycle

    
    
    
    
  • 
    

    Menstrual-related migraines

    
    
    
    
    • 
      

      Naproxen 220 mg PO 2–3 times a day starting 2–3 days prior to menses when the headaches normally begin and then if needed.

      
      
    • 
      

      Consider estrogen-containing birth control if there are no contraindications (eg, hypercoaguable state, heart disease, hypertension, migraine aura). If estrogen is contraindicated or if estrogen therapy is not successful, consider trying progesterone methods of birth control.

    
    
    
    
  • 
    

    Pregnancy

    
    
    
    
    • 
      

      In the third trimester and in the peripartum period, headache may be a manifestation of a complication of pregnancy such as eclampsia or dural sinus thrombosis.

      
      
    • 
      

      All migraine treatments except the following are contraindicated or inadvisable during pregnancy: nonpharmacologic therapy, acetaminophen, nasal lidocaine, opioids, metoclopramide, ondansetron, and corticosteroids.

    
    

  
  

Opiate agonists

• 
  

  Key features

  
  
  
  
  • 
    

    Opioid analgesics vary principally in their onset, duration of action, available dosage forms, and side effect profiles.

    
    
  • 
    

    All opioids produce dose-dependent depression of brain-stem ventilatory centers. The risk of respiratory depression may be minimized by making conservative dose adjustments. Patients who experience respiratory depression may require ventilation assistance and reversal with IV naloxone (see table with the dosing for naloxone.)

    
    
  • 
    

    Constipation is a common side effect of all opioid analgesics and can be effectively managed in most patients with the combination of a stool softener (ie, polyethylene glycol) and stimulant laxative (ie, senna).

    
    
  • 
    

    Changing patients from one opioid to another may be accomplished using available equianalgesic potency tables. Conservative adjustments are recommended to account for cross-tolerance, interpatient variability, and to minimize the risk of side effects.

  
  
  
  
• 
  

  Highlighted agents (Table 52-6)

  
  
  
  
  • 
    

    Fentanyl

    
    
  • 
    

    Hydrocodone

    
    
  • 
    

    Hydromorphone

    
    
  • 
    

    Meperidine

    
    
  • 
    

    Methadone

    
    
  • 
    

    Morphine

    
    
  • 
    

    Oxycodone

  
  

Sedative agents

• 
  

  The choice of sedative should be individualized based on indication, sedation goal, onset/offset of a drug, and adverse effects.

  
  
• 
  

  Studies evaluating a benzodiazepine regimen versus dexmedetomidine or propofol suggested that benzodiazepine use is associated with prolonged time on mechanical ventilation, longer ICU stays, and increased transition to delirium.

  
  
  
  
  • 
    

    Therefore, a nonbenzodiazepine strategy (either dexmedetomidine or propofol) may be preferred over a benzodiazepine strategy (either midazolam or lorazepam) to improve outcomes in mechanically ventilated ICU patients.

    
    
  • 
    

    However, benzodiazepines still remain important sedatives in the ICU for the management of seizures, alcohol withdrawal, when deep sedation is warranted, and in combination with other sedatives.

  
  

Benzodiazepines

• 
  

  Key features

  
  
  
  
  • 
    

    Benzodiazepines are a class of medications that are clinically used as anticonvulsants, antianxiety agents, muscle relaxants, treatment for alcohol withdrawal, and sedatives.

    
    
  • 
    

    Mechanism of action: all benzodiazepines bind highly to the GABA receptor complex without displacing GABA.

    
    
  • 
    

    All benzodiazepines are classified as controlled substances (schedule IV).

    
    
  • 
    

    All benzodiazepines are metabolized by the liver, and clearance may be reduced in those with severe hepatic dysfunction and in elderly patients.

  
  
  
  
• 
  

  Highlighted agents (Table 52-7)

  
  
  
  
  • 
    

    Alprazolam

    
    
  • 
    

    Chlordiazepoxide

    
    
  • 
    

    Clorazepate

    
    
  • 
    

    Diazepam

    
    
  • 
    

    Lorazepam

    
    
  • 
    

    Midazolam

    
    
  • 
    

    Oxazepam

    
    
  • 
    

    Temazepam

  
  

Nonbenzodiazepine sedatives

• 
  

  Key features

  
  
  
  
  • 
    

    Dexmedetomidine (Precedex)

    
    
    
    
    • 
      

      Mechanism: selective alpha₂ adrenergic agonist

      
      
    • 
      

      Dose-limiting side effects: hypotension and bradycardia

      
      
    • 
      

      Loading doses are often omitted in clinical practice, as it may precipitate hemodynamic compromise (ie, hypotension/hypertension, bradycardia)

      
      
    • 
      

      Does not cause respiratory depression

    
    
    
    
  • 
    

    Propofol

    
    
    
    
    • 
      

      Dose-limiting side effect: hypotension

      
      
    • 
      

      Caution: propofol-related infusion syndrome (PRIS)

      
      
      
      
      • 
        

        Characterized by the following:

        
        
        
        
        • 
          

          Metabolic acidosis

          
          
        • 
          

          Acute kidney injury/severe rhabdomyolysis

          
          
        • 
          

          Hyperkalemia

          
          
        • 
          

          Severe arrhythmias

        
        
        
        
      • 
        

        Risk factors for the development of PRIS:

        
        
        
        
        • 
          

          Doses >80 mcg/kg/min

          
          
        • 
          

          Prolonged infusion >48 hours

          
          
        • 
          

          Young age

          
          
        • 
          

          Low BMI

          
          
        • 
          

          Concurrent vasopressor use

        
        
        
        
      • 
        

        Treatment: stop propofol and provide supportive care

      
      

    
    

  
  

Reversal agents for opioids and benzodiazepines

• 
  

  Key features

  
  
  
  
  • 
    

    Specific antagonists are available for opioids and benzodiazepines.

    
    
  • 
    

    Naloxone and flumazenil may be administered to improve respiratory status in patients who are experiencing opioid and benzodiazepine overdose, respectively.

  
  
  
  
• 
  

  Highlighted agents

  
  
  
  
  • 
    

    Naloxone

    
    
    
    
    • 
      

      Mechanism of action: competitive mu-opioid receptor antagonist

      
      
    • 
      

      Route of administration

      
      
      
      
      • 
        

        May be administered intravenously or via endotracheal tube for the reversal of systemic symptoms (ie, respiratory depression)

        
        
      • 
        

        Endotracheal doses require 2 times the intravenous dose

        
        
      • 
        

        Oral administration may be considered for the reversal of opioid-induced refractory constipation

      
      
      
      
    • 
      

      Dosing

      
      
      
      
      • 
        

        Initial IV naloxone dose = 0.04–2 mg

        
        
        
        
        • 
          

          If there is no response, the dose should be increased every 2 minutes to a maximum of 15 mg

          
          
        • 
          

          If there is no change in respiratory status after administration of 15 mg, the cause is unlikely opioid overdose

        
        
        
        
      • 
        

        Continuous infusion

        
        
        
        
        • 
          

          Since long-acting opioids are of particular concern for the recurrence of opioid toxicity, patients with known overdose of long-acting opioids (methadone) or sustained-release products (OxyContin) may require a continuous infusion of naloxone to prevent recurrent toxicity.

          
          
        • 
          

          The rate of a continuous infusion should be equal to two thirds of the bolus dose required for adequate reversal every hour, started when the bolus dose is administered. A second bolus dose should be considered after the continuous infusion is started to prevent a decrease in naloxone levels.

        
        

      
      
      
      
    • 
      

      Onset and duration

      
      
      
      
      • 
        

        Naloxone onset of action when given intravenously is <2 minutes in adults.

        
        
      • 
        

        Naloxone is only active for 20–90 minutes.

        
        
        
        
        • 
          

          This is a much shorter duration of action than most opioids. Respiratory depression may recur as naloxone wears off.

          
          
        • 
          

          Multiple doses of naloxone may be required to fully reverse toxicity.

        
        

      
      

    
    
    
    
  • 
    

    Flumazenil

    
    
    
    
    • 
      

      Mechanism of action: selectively antagonizes the effects of benzodiazepines in the central nervous system by competitively inhibiting their actions at the benzodiazepine binding site of the GABA-benzodiazepine receptor complex.

      
      
    • 
      

      Route of administration: IV only

      
      
    • 
      

      Dosing

      
      
      
      
      • 
        

        In adults, the recommended initial dose is 0.2 mg IV over 30 seconds.

        
        
      • 
        

        Repeated doses of 0.2 mg, to a maximum of 1 mg, can be given until the desired effect is achieved.

      
      
      
      
    • 
      

      Onset and duration

      
      
      
      
      • 
        

        The peak effect of a single dose occurs approximately 6–10 minutes after IV administration.

        
        
        
        
        • 
          

          The duration of flumazenil is short (0.7–1.3 hours).

          
          
        • 
          

          The duration of effect of a long-acting benzodiazepine or large benzodiazepine dose can exceed that of flumazenil. Retreatment may be required.

        
        

      
      
      
      
    • 
      

      In long-term benzodiazepine users, flumazenil may precipitate withdrawal and seizures.

    
    

  
  

Cardiovascular medications

Antiplatelets

• 
  

  In addition to aspirin, the P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor are the most commonly utilized antiplatelet agents.

  
  
• 
  

  As the role of newer antiplatelet agents has evolved for cardiovascular indications, little available evidence suggests clear superiority of any single agent for stroke prophylaxis or other neurovascular indication.

  
  
• 
  

  The ACCP 2012 ischemic stroke guidelines recommend, in patients with a history of noncardioembolic ischemic stroke or TIA, long-term treatment with aspirin (75–100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended-release dipyridamole (25 mg/200 mg BID), or cilostazol (100 mg BID) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), and the combination of clopidogrel plus aspirin (Grade 1B).

  
  
• 
  

  Of the recommended antiplatelet regimens, the ACCP guidelines suggest clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or cilostazol (Grade 2C).

  
  
• 
  

  In patients with a history of stroke or TIA and atrial fibrillation, ACCP guidelines recommend oral anticoagulation over no antithrombotic therapy, aspirin, and combination therapy with aspirin and clopidogrel (Grade 1B).

  
  
• 
  

  Platelet inhibition assays are commercially available for aspirin and the P2Y12 inhibitors. Their role in clinical practice is evolving. The availability of specific antiplatelet assays and how they are utilized vary regionally by institution. See Table 52-8.

  
  
• 
  

  Table 52-8. Antiplatelet agent comparison table

  
  
• 
  

  Highlighted agents

  
  
  
  
  • 
    

    Aspirin

    
    
  • 
    

    Aspirin/dipyridamole (Aggrenox)

    
    
  • 
    

    Cilostazol (Pletal)

    
    
  • 
    

    Clopidogrel (Plavix)

    
    
  • 
    

    Prasugrel (Effient)

    
    
  • 
    

    Ticagrelor (Brilinta)

  
  

Anticoagulants

For details on dosing and monitoring management based on indication and clinical scenario not covered in this section, please see the UW Anticoagulation medicine service website: http://depts.washington.edu/anticoag/home.

Subcutaneous anticoagulants

• 
  

  Key features

  
  
  
  
  • 
    

    Available subcutaneous anticoagulants include heparin, dalteparin, enoxaparin, and fondaparinux.

    
    
  • 
    

    Dosing regimens vary by indication, weight, and renal function. Common inpatient indications include acute coronary syndrome, deep vein thrombosis (DVT)/pulmonary embolism (PE) treatment, and DVT prophylaxis.

    
    
  • 
    

    The patient or caregiver can be trained to administer dalteparin, enoxaparin, and fondaparinux to bridge to oral anticoagulant treatment.

    
    
  • 
    

    Dose adjustments of subcutaneous regimens to reach a particular lab target are not routinely recommended. In patients with renal impairment or bleeding risks, an anti-factor Xa level can be checked for dalteparin, enoxaparin, and fondaparinux. However, no optimal target range is correlated with clinical endpoints. Peak anti-factor Xa levels drawn 4 hours after the dose and trough levels drawn prior to the next dose have been utilized in clinical practice (Table 52-9).

    
    
  • 
    

    Side effects

    
    
    
    
    • 
      

      Spinal or epidural hematomas may occur if administered with recent or anticipated neuroaxial anesthesia (epidural, spinal, or spinal puncture) and are generally considered contraindicated in patients undergoing neuroaxial anesthesia. Patients should be observed for bleeding if agents are administered during or immediately after diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia.

      
      
    • 
      

      Delaying placement of neuronal catheters at least 12 hours after administration for low dose and 24 hours for high dose may minimize this risk (see institutional policies). Patients with a CrCl <30 mL/min may need additional time, since anti-factor Xa levels are still detectable at these points.

      
      
    • 
      

      If spinal hematoma is suspected, diagnose and treat immediately; spinal cord decompression may be considered, although it may not prevent or reverse neurological sequelae. See ‘Management of bleeding and major hemorrhage’ and Table 52-13.

    
    

  
  

Oral anticoagulants

• 
  

  Key features

  
  
  
  
  • 
    

    Available oral anticoagulants include warfarin and the novel oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban. All agents are subject to clinically meaningful drug interactions. Review concomitant medications prior to initiation.

    
    
  • 
    

    Warfarin

    
    
    
    
    • 
      

      Most institutions offer pharmacy consults to assist with warfarin dosing.

      
      
    • 
      

      Most patients can be started on warfarin 5–10 mg for the first 1–2 days. Patients who are at an increased risk of bleeding (eg, elderly, patients with CHF, liver dx, debilitated, recent major surgery, or patients receiving medications known to strongly potentiate the action of warfarin) should be started on <5 mg.

      
      
    • 
      

      Age and gender significantly affect warfarin dosing. Studies have reported that for each additional year of age, the weekly warfarin dose declined by 0.4 mg (eg, for age <65, it is ∼6 mg; for age 65–75, it is ∼4 mg; for age 76–80, it is ∼3.5 mg; and for age >80, it is ∼3 mg).

      
      
    • 
      

      In all cases, subsequent dosing should be based on the INR response.

    
    
    
    
  • 
    

    Novel oral anticoagulants

    
    
    
    
    • 
      

      Routine laboratory testing is not required.

      
      
    • 
      

      A specific reversal agent is only available for dabigatran. (See Table 52-10.)

      
      
    • 
      

      Dose regimens vary by indication for many of the novel anticoagulants. (See Table 52-11 for VTE and atrial fibrillation dose recommendations.)

      
      
    • 
      

      Head-to-head comparisons of the novel anticoagulants are lacking. Clear superiority of any single agent has not been established. For primary and secondary stroke prophylaxis, choice of agent is largely dependent on affordability.

    
    

  
  
  
  
• 
  

  Highlighted agents

  
  
  
  
  • 
    

    Dabigatran

    
    
  • 
    

    Rivaroxaban

    
    
  • 
    

    Apixaban

    
    
  • 
    

    Edoxaban