A woman taking diltiazem for migraine prophylaxis developed a drug rash; how should I manage the rash and what alternative preventive medication should I use?

Management of Diltiazem-Induced Drug Rash and Alternative Migraine Prophylaxis

Immediate Rash Management

Discontinue diltiazem immediately and do not rechallenge, as there is no evidence supporting its use for migraine prevention and the drug rash indicates hypersensitivity. 1

Acute Rash Treatment

• Stop the infusion/medication immediately and monitor for progression of symptoms 1
• Administer a second-generation antihistamine such as loratadine 10 mg orally or cetirizine 10 mg IV/orally for urticaria 1
• Consider hydrocortisone 200 mg IV (or equivalent corticosteroid) if symptoms do not improve after 15 minutes or if the rash is moderate-to-severe 1
• Avoid first-generation antihistamines like diphenhydramine, as these can cause sedation and other adverse effects that may complicate assessment 1
• Monitor the patient until complete resolution of symptoms 1

Patient Education on Delayed Reactions

• Inform the patient that delayed reactions can occur hours to days after exposure, including flu-like symptoms, arthralgias, and fever lasting up to 24 hours 1
• Symptoms lasting more than a few days require provider evaluation to rule out other pathologies 1

Alternative Migraine Prophylaxis Selection

Switch to propranolol 80-160 mg orally once or twice daily in long-acting formulations as first-line preventive therapy, as it has the strongest evidence for efficacy and safety in migraine prevention. 1

First-Line Preventive Options (Choose One)

The 2021 Nature Reviews Neurology guidelines establish a clear hierarchy for migraine prevention 1:

• Beta-blockers (preferred):

  • Propranolol 80-160 mg oral once or twice daily (long-acting formulation) 1
  • Metoprolol 50-100 mg oral twice daily OR 200 mg modified-release once daily 1
  • Atenolol 25-100 mg oral twice daily 1
  • Bisoprolol 5-10 mg oral once daily 1
  • Contraindications: Asthma, cardiac failure, Raynaud disease, atrioventricular block, depression 1

• Topiramate 50-100 mg oral daily:

  • Particularly beneficial if the patient is obese 1, 2
  • Contraindications: Nephrolithiasis, pregnancy, lactation, glaucoma 1
  • Common adverse effects: Cognitive inefficiency, paresthesia, fatigue, weight loss 2

• Candesartan 16-32 mg oral daily:

  • Particularly useful if hypertensive 1, 2
  • Contraindication: Co-administration with aliskiren 1

Second-Line Options (If First-Line Fails or Contraindicated)

• Amitriptyline 10-100 mg oral at night:

  • Particularly useful with coexisting anxiety or depression 1, 2
  • Contraindications: Age <6 years, heart failure, co-administration with MAO inhibitors and SSRIs, glaucoma 1

• Flunarizine 5-10 mg oral once daily:

  • Should be avoided in patients with Parkinsonism or depression 1, 2
  • Adverse effects: Sedation, weight gain, depression, extrapyramidal symptoms (especially in elderly) 1

Third-Line Options (For Refractory Cases)

• CGRP monoclonal antibodies: 1, 2

  • Erenumab 70 or 140 mg subcutaneous once monthly
  • Fremanezumab 225 mg subcutaneous once monthly OR 675 mg quarterly
  • Eptinezumab 100 or 300 mg intravenous quarterly
  • Assess efficacy after 3-6 months 1, 2

• OnabotulinumtoxinA 155-195 units to 31-39 sites every 12 weeks:

  • For chronic migraine with vestibular symptoms 1, 2
  • Assess efficacy after 6-9 months 1, 2

Treatment Implementation Algorithm

Initiation Strategy

1. Start with low dose and titrate slowly until clinical benefits are achieved or limited by adverse events 1
2. Allow adequate trial period: Clinical benefit may take 2-3 months to manifest for oral medications 1, 2
3. Simplify dosing: Once-daily regimens improve adherence 1
4. Maintain headache diary: Track frequency and severity to assess treatment response 2

Duration and Reassessment

• Assess efficacy after 2-3 months at therapeutic dose for oral preventive medications 1, 2
• Consider pausing treatment after 6-12 months of successful control to determine if preventive therapy can be stopped 1, 2
• Failure of one preventive treatment does not predict failure of other drug classes (except when due to poor adherence) 1

Critical Pitfalls to Avoid

• Never use diltiazem for migraine prevention: There is no evidence supporting its efficacy, and calcium-channel blockers as a class show only modest effects with poor-quality evidence 1
• Avoid oral ergot alkaloids, opioids, and barbiturates: These have questionable efficacy with considerable adverse effects and dependency risk 1, 2
• Do not abandon treatment prematurely: Efficacy takes weeks to months to establish 1, 2
• Limit acute medication use: Restrict simple analgesics to <15 days/month and triptans to <10 days/month to prevent medication overuse headache 1, 2
• Do not rechallenge with diltiazem: The drug rash indicates hypersensitivity, and there is no therapeutic benefit to justify the risk 1

Lifestyle Modifications (Essential Adjunct)

• Maintain regular sleep schedule with adequate hours 1, 2
• Ensure proper hydration throughout the day 2
• Encourage regular moderate-to-intense aerobic exercise 1, 2
• Identify and avoid specific triggers using a headache diary 1, 2
• Manage modifiable risk factors: obesity, caffeine overuse, stress, psychiatric comorbidities 2