What are the latest treatment options for new daily persistent headache (NDPH) refractory to treatment?

Latest Treatment Options for Refractory New Daily Persistent Headache (NDPH)

For refractory new daily persistent headache (NDPH), the most promising treatment options include CGRP monoclonal antibodies, onabotulinumtoxinA, and intravenous ketamine or lidocaine, though evidence remains limited and treatment response is often poor.

Understanding NDPH

NDPH is characterized by:

• Sudden onset headache that becomes persistent within 24 hours
• Patient can typically recall the exact date of headache onset
• Continuous headache lasting at least 3 months
• Often treatment-refractory nature
• Variable clinical presentation (may resemble chronic migraine or tension-type headache)

Current Treatment Approaches for Refractory NDPH

First-Line Preventive Options

1. CGRP Monoclonal Antibodies

   • Strong recommendation for erenumab, fremanezumab, or galcanezumab based on evidence in chronic migraine 1
   • May be beneficial in refractory NDPH cases 2
   • Intravenous eptinezumab is another option with weak recommendation 1

2. OnabotulinumtoxinA

   • Suggested for prevention of chronic headache conditions 1, 2
   • Weak recommendation but may be effective in NDPH with migraine features 1

3. Conventional Preventive Medications

   • Candesartan or telmisartan (strong recommendation) 1
   • Topiramate (weak recommendation) 1
   • Memantine for episodic migraine (weak recommendation) 1
   • Amitriptyline for chronic tension-type headache features 1
   • Valproate (weak recommendation, contraindicated in women of childbearing potential) 1

Interventional Approaches

1. Nerve Blocks

   • Greater occipital nerve blocks (weak recommendation) 1
   • More efficacious in pediatric than adult populations 2

2. Intravenous Therapies for Highly Refractory Cases

   • IV ketamine (though evidence is mixed) 2
   • IV lidocaine 2
   • IV methylprednisolone 3

Addressing Specific Pathophysiological Mechanisms

1. For suspected post-infectious or inflammatory NDPH:

   • Consider antiviral medications or anti-inflammatory treatments 2

2. For NDPH with CSF pressure abnormalities:

   • CSF-pressure modifying medications may be helpful, especially if headache started with thunderclap or Valsalva maneuver 2
   • Consider evaluation for CSF-venous fistulas in refractory cases 4

3. For NDPH with comorbid psychiatric conditions:

   • SSRIs, SNRIs, or benzodiazepines may be beneficial 2

Treatment Algorithm for Refractory NDPH

1. Initial Assessment:

   • Confirm NDPH diagnosis (sudden onset, persistent for >3 months)
   • Rule out secondary causes (CSF leak, venous sinus thrombosis, etc.)
   • Identify predominant headache phenotype (migraine-like or tension-type-like)

2. First-tier Treatment:

   • For migraine-like NDPH: CGRP monoclonal antibodies (erenumab, fremanezumab, or galcanezumab)
   • For tension-type-like NDPH: Amitriptyline or topiramate

3. Second-tier Treatment:

   • OnabotulinumtoxinA injections (especially for migraine-like NDPH)
   • Candesartan or memantine

4. Third-tier Treatment:

   • Greater occipital nerve blocks
   • Consider IV therapies (lidocaine, ketamine, or methylprednisolone)

Challenges and Limitations

• NDPH remains one of the most treatment-refractory headache disorders 3, 5
• No randomized controlled trials specifically for NDPH treatment 3
• Treatment approaches are largely extrapolated from chronic migraine and tension-type headache management 4
• Even aggressive treatment is often ineffective 3

Important Considerations

• Avoid medication overuse, which can worsen headache (limit simple analgesics to <15 days/month and triptans/combination medications to <10 days/month) 1
• Non-pharmacological interventions (improved sleep hygiene, stress management, diet modifications) should be incorporated 2
• Consider neuromodulation devices as adjunctive therapy 1
• Patients should be warned that NDPH often has a poor prognosis despite treatment 4

Despite the challenging nature of refractory NDPH, a systematic approach targeting the predominant headache phenotype and underlying pathophysiological mechanisms offers the best chance for symptom improvement. Multi-center randomized controlled trials are urgently needed to establish evidence-based treatments for this debilitating condition.