Two-case report: extremely low-dose norepinephrine titration eased refractory chronic cluster headache attacks

The authors report two cases of refractory chronic cluster headache (rCCH), framed as a severe form of trigeminal autonomic primary headache that frequently resists conventional pharmacological treatment and substantially impairs quality of life. Both patients had experienced recurrent paroxysmal headaches for several decades and had tried multiple medications over the long term with only suboptimal response, establishing a clinical context of truly refractory disease.

Because vasodilation is described as a key pathophysiological feature of rCCH, the clinicians administered an extremely low dose of norepinephrine during the acute phase of headache, leveraging its vasoconstrictive effect. Treatment was delivered as systematic and adjustable titration therapy over 1–2 weeks, with dose adjustments guided by the vasoconstrictive response rather than a fixed protocol.

Both patients experienced significant alleviation of their headaches. Improvements were documented across multiple headache-related instruments, including the Cluster Headache Impact Questionnaire, Migraine-Specific Quality of Life Questionnaire, Migraine Disability Assessment Questionnaire, Health-Related Quality of Life, Hamilton Rating Scale for Depression, and Hamilton Anxiety Scale. After the acute phase, both patients were transitioned to preventive medications.

At one-year follow-up, both patients remained attack-free on regular preventive therapy, had returned to normal daily activities, and maintained baseline scores on the headache-related scales.

The authors conclude that extremely low-dose norepinephrine may be a potential adjunctive option for acute exacerbations in rCCH patients unresponsive to multiple medications, while explicitly noting that further studies are needed to confirm efficacy and safety. As a two-patient report without a control group, randomization, or reported adverse-event data, the findings are hypothesis-generating only and should not yet drive routine practice changes.