1.3 Other Acute Options

1.3.1 Intranasal lidocaine

peer-reviewed Robbins L. “Intranasal lidocaine for cluster headache.” Headache. 1995;35(2):83–4 (PMID 7737866, DOI 10.1111/j.1526-4610.1995.hed3502083.x). 30 male patients. 4% lidocaine solution, four sprays ipsilateral to the pain, two more if needed.

Response	Proportion
Moderate relief	27%
Mild relief	27%
No relief	46%

Side effects minimal. Robbins’ own conclusion: “only a marginally helpful therapy,” though it “may remain worthwhile as an adjunctive medication.”

peer-reviewed Earlier work: Kittrelle et al. 1985, n=5 (reviewed at BestBETs). A systematic review (PMID 30098024) covering 6 studies found that benefit appeared only in the four poor-quality studies and not in the two fair-quality ones — a classic signature of a treatment whose apparent effect is an artefact of weak methodology. A case report describes application into the sphenopalatine fossa (PMC3359256).

peer-reviewed The EAN 2023 guideline gives lidocaine only a weak/consensus recommendation (EAN 2023).

Verdict: low cost, low risk, low ceiling. Reasonable as an add-on when oxygen is unavailable or partially effective; not a substitute for anything. The technique matters — the target is the sphenopalatine ganglion region high in the nasal cavity, which requires head extension and rotation toward the affected side, not a casual spray into the nostril.

1.3.2 Ergotamine and dihydroergotamine (DHE)

historical Ergotamine has been used for headache “since the middle ages, and as a pharmaceutical since 1926,” but was “limited by poor tolerability (nausea, vomiting, and cardiovascular effects)” (DHE narrative review, PMC7003832). Kudrow’s 1981 oxygen study used sublingual ergotamine as the comparator, which aborted attacks in 70% of patients — historically, ergotamine was the reference acute treatment before triptans existed peer-reviewed (Guo et al. 2019). “For many years, until the advent of the triptans, the ergotamines were the only specific antimigraine drugs” (PMC7003832).

Oral ergotamine is essentially obsolete for CH and was largely withdrawn from many markets. No modern controlled trial in CH was located.

DHE pharmacology

peer-reviewed From the DHE narrative review (PMC7003832):

• Synthesised by Stoll and Hofmann in 1943; approved 1946; “continues to be a choice today for acute migraine, status migrainosus, and cluster headaches.”
• Agonist at 5-HT1B, 5-HT1D, 5-HT1F, but also binds 5-HT1A, 5-HT2A, adrenergic, cholinergic and dopaminergic receptors — a far dirtier drug than a triptan.
• Receptor dissociation half-life 1.38 h (5-HT1B) and 1.28 h (5-HT1D), versus sumatriptan’s 0.17 h and 0.09 h. This is the pharmacological basis for DHE’s long duration and low recurrence rate — it stays on the receptor roughly eight to fourteen times longer.
• Systemic DHE has rapid onset and sustained effects lasting up to 48 hours.
• Oral bioavailability 0.07–0.14% — effectively zero; gut absorption 10–60% and erratic. “This molecule is limited to non-oral routes of administration.”
• Minimal risk of medication-overuse headache — a genuinely important property for a chronic daily patient, and a point of real differentiation from triptans.
• Often effective in patients who are “triptan resistant,” who wake with headache, or who have prolonged/severe attacks.

Routes and evidence

Route	Detail	Evidence
IV (D.H.E. 45)	1 mg every 8 h for 1–3 days, inpatient	“very high response rate for refractory migraine patients: 97% pain reduction, 60–78% pain freedom”
IV + metoclopramide (“Raskin protocol”)	every 8 h up to 2 days	Series of 55 intractable migraine patients: 49/55 headache-free by 48 h, 39 with sustained benefit up to 16 months; comparator 54 matched diazepam patients, only 7/54 headache-free
SC / IM	1 mg	“limited efficacy due to needle phobia and poor tolerability, including local irritation”
Nasal (Migranal)	2 mg delivered	32% bioavailability; four US RCTs
Orally inhaled (MAP0004/Levadex)	1–2 mg	NDA filed, never approved — FDA complete response letter June 2014 citing manufacturing concerns; “No issues related to clinical safety or efficacy were cited”; development apparently terminated

Sources: PMC7003832; Raskin’s original protocol Neurology 1986;36(7):995–7 (PMID 3520384, DOI 10.1212/wnl.36.7.995); inpatient 5-day IV DHE protocol described by Nagy et al., Neurology; further review at PMC7200221.

Important honesty caveat: the impressive IV DHE numbers above (97% pain reduction, 49/55 headache-free) are from migraine and status migrainosus populations, not cluster headache. They are frequently quoted in cluster contexts without that qualification. Cluster-specific controlled data for IV DHE could not be located. The rationale for using it in refractory CH is inpatient clinical experience plus mechanistic plausibility, not RCT evidence.

Migranal nasal spray efficacy (migraine data)

peer-reviewed Four randomised double-blind placebo-controlled US studies (PMC7003832):

Study	n (Migranal/placebo)	2-h response	Therapeutic gain	4-h response	Gain
1	105 / 98	61%* vs 23%	38%	70%** vs 28%	42%
2	103 / 102	47% vs 33%	14%	56%* vs 35%	21%
3	50 / 50	32% vs 20%	12%	48%* vs 22%	26%
4	47 / 50	30% vs 20%	10%	47% vs 30%	17%

(*P<.01, **P<.001.) The review’s own verdict: therapeutic gain ranged from 10% to 42%, “suggesting a variability in response that might translate into a lack of clinical reliability — especially in the initial 2 hours after dosing.” Adverse effects: rhinitis 26%, disturbed taste 8%.

Two-hour endpoints are close to useless for cluster headache, where untreated attacks last 15–180 minutes. This is a fundamental mismatch between the available DHE evidence and the disease.

peer-reviewed EAN 2023 gives DHE nasal spray only a weak/consensus recommendation for acute CH (EAN 2023).

Current status, summarised honestly: DHE is a real option in refractory, inpatient, or bridge settings, delivered IV, and its long receptor occupancy and low MOH risk are genuinely attractive in chronic daily disease. But the cluster-specific evidence is essentially absent, the non-IV routes are weak or unreliable, and the inhaled formulation that might have solved the delivery problem was never approved. Availability in Australia is limited and it is not a realistic outpatient option — this route generally requires a headache specialist and hospital admission.

1.3.3 Octreotide

peer-reviewed Matharu MS, Levy MJ, Meeran K, Goadsby PJ. “Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study.” Ann Neurol. 2004;56(4):488–94 (PMID 15455406, DOI 10.1002/ana.20210). 57 recruited; efficacy data from 46 octreotide-treated and 45 placebo-treated attacks. Octreotide 100 µg subcutaneous.

Outcome at 30 min	Octreotide 100 µg SC	Placebo	p
Headache response	52%	36%	<0.01

The authors’ framing is the key point: “Nonvasoconstrictor treatment of acute cluster headache is possible.”

peer-reviewed CNS Drugs rates octreotide 100 µg SC as evidence level 2B, “probably effective,” with mild gastrointestinal disturbance and injection-site reactions as the main adverse effects (Brandt et al. 2020, PMC7018790).

Why this matters and why nobody uses it. Octreotide is a somatostatin analogue with no vasoconstrictor action, which in principle makes it the acute option for patients with ischaemic heart disease, cerebrovascular disease, or peripheral vascular disease — exactly the patients triptans are forbidden in. That is a meaningful unmet need. But: the response rate (52% vs 36% placebo, a 16-point therapeutic gain) is substantially weaker than sumatriptan; it is another subcutaneous injection; it is expensive; and it has essentially no follow-up literature in twenty-plus years. It remains a niche option for triptan-contraindicated patients, and is rarely used in practice. No community discussion of octreotide was located in the sources reviewed — it appears to be effectively absent from patient-community practice, which is itself informative.