5.3 The Chronic-CH Problem

Chronic CH — attacks continuing for more than a year without a remission of at least three months — is the harder-to-treat, more research-neglected form of the disease, and this pass found consistent, multi-source evidence for why.

The trial-failure pattern is stark and repeats across every drug class tried. Galcanezumab worked in episodic CH and failed in chronic CH. Fremanezumab failed in both, but the effect estimates were directionally worse in chronic. Eptinezumab failed its efficacy trial in episodic CH and never ran a dedicated chronic-CH efficacy trial at all — CHRONICLE’s primary endpoint was safety. Erenumab, tested only in chronic CH, failed outright. No CGRP-pathway drug has ever succeeded in chronic CH. The authors of the erenumab trial explicitly recommended that future research “revisit the role of CGRP in chronic CH” — a striking admission from within the field that the leading drug mechanism of the last decade may simply be the wrong mechanism for this specific patient population.

Why chronic CH might be biologically distinct, based on this pass’s findings:

• peer-reviewed The Danish cytokine biobank study is the one dataset that specifically separates chronic from episodic-in-bout biology, and it places chronic CH on the pro-inflammatory side of the ledger (elevated IL-6, CCL7, CXCL9, HGF, MMP12, TGFα) while episodic-in-bout looks broadly anti-inflammatory (Ann Neurol 2025).
• peer-reviewed PACAP-38 elevation is largest in chronic CH (+49.8%) of any subgroup measured, larger than episodic in-bout (+39.5%) or in remission (+34.1%) (Eur J Neurol 2025).
• peer-reviewed Chronic CH shows a different circadian phenotype — an “ultradian pattern with multiple less-predictable peaks” — compared to episodic CH’s single early-morning peak (Cephalalgia 2025).
• A 2025 Cephalalgia paper argues chronic CH should itself be treated as a rare disease for research and regulatory purposes (PMID 40836704 peer-reviewed) — a framing that matters because rare-disease designation carries specific funding and regulatory levers (orphan drug incentives, smaller-trial statistical allowances) that chronic CH is not currently leveraging in most jurisdictions.

What is specifically in the pipeline for refractory/chronic patients right now:

• preprint / trial BASIC — botulinum toxin A blockade of the sphenopalatine ganglion, Phase 3, treatment-refractory chronic CH, multi-country (Germany, Italy, Norway, Spain, UK), recruiting since 2019.
• preprint / trial KETALGIA — ketamine + magnesium sulfate, refractory chronic CH, France, now completed (23 December 2025), results pending.
• preprint / trial SUNCET oxybate specifically targets nocturnal chronic-CH attacks (§5.1.5).
• preprint / trial Multiple neuromodulation device trials specifically enrol drug-resistant/refractory chronic patients: occipital nerve stimulation, combined trigeminal+occipital stimulation, and (suspended) bilateral occipital nerve field stimulation.
• peer-reviewed A 2025 systematic review of hypothalamic/ventral-tegmental deep brain stimulation in refractory CH is available, and is notable because DBS’s delayed onset of benefit and its mixed sham-controlled trial history have themselves been used as an argument against pure hypothalamic causality, not just as a treatment option (PMC12382023).

The honest summary: chronic CH is failing drug trials at a higher rate than episodic CH across every mechanism tested so far, there is now real biomarker evidence (cytokines, PACAP) that it may be mechanistically distinct rather than just “worse episodic,” and the current refractory-CH research agenda is leaning heavily on procedural and device interventions (botox, neuromodulation, DBS) precisely because the pharmacological pipeline keeps failing this specific population.