3.5 Other Weaker-Evidence Preventives

Grouped roughly from “has a positive RCT” down to “has a case series and a hope.”

3.5.1 Warfarin / anticoagulation — the surprising one

Hakim SM. Warfarin for refractory chronic cluster headache: a randomized pilot study. Headache 2011;51(5):713–725, PMID 21395575. peer-reviewed

• n=34, randomised crossover, refractory chronic CH
• Warfarin titrated to INR 1.5–1.9 (deliberately sub-therapeutic by cardiac standards)
• Remission ≥4 weeks: 50% (warfarin) vs 11.8% (placebo), p=0.004
• Absolute risk reduction 0.38 (95% CI 0.18–0.58)
• NNT 2.6 (95% CI 1.7–5.5)
• Hazard ratio 5.26 (95% CI 2.13–13.03)

This is, on paper, the single best NNT in this entire chapter — better than verapamil’s, in a refractory chronic population, from a randomised crossover design. The AHS 2016 guideline acknowledged it as a newly evaluated treatment with a positive study, but graded it only Level C (Robbins et al. 2016, PMID 27432623). peer-reviewed

Why isn’t everyone on warfarin? Because n=34, single-centre, never replicated in 15 years; because the mechanism is unexplained (possibly anti-inflammatory or endothelial rather than anticoagulant, since the target INR is low); and because indefinite anticoagulation in a young population carries real bleeding risk. But the near-total silence on this finding is odd, and it is the clearest example in this chapter of a positive result that the field simply did not pursue. A genuine unexplained gap.

3.5.2 Civamide / capsaicin (intranasal, TRPV1 desensitisation)

Saper JR, Klapper J, Mathew NT, Rapoport A, Phillips SB, Bernstein JE. Intranasal civamide for the treatment of episodic cluster headaches. Arch Neurol 2002;59(6):990–994, PMID 12056936. peer-reviewed n=28, civamide 50 µg/day intranasal × 7 days. Attack reduction −55.5% vs −25.9%, p=0.03. Adverse effects: nasal burning in 14/18, lacrimation in 9/18.

Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, Arrowsmith F. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993;13(2):114–116, DOI 10.1046/j.1468-2982.1993.1302114.x, PMID 8495452. peer-reviewed Capsaicin in the ipsilateral nostril × 7 days, severity recorded 15 days. On days 8–15 headaches were significantly less severe with capsaicin than placebo; within the capsaicin group severity significantly decreased days 8–15 vs days 1–7; no significant decrease in the placebo group. Episodic patients appeared to benefit more than chronic patients. Sample size, capsaicin concentration, exact p-values and CIs are not reported in the abstract. Rationale: topical capsaicin desensitises sensory neurons by depleting nerve terminals of substance P.

Two positive randomised trials for the same mechanism, 9 years apart, and neither drug is in routine use. Civamide was never commercialised for CH. The nasal burning (14/18) is presumably why. Note again the episodic > chronic pattern.

3.5.3 Sodium valproate / divalproex — negative RCT, positive open studies

El Amrani M, Massiou H, Bousser MG. A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia 2002;22(3):205–208, PMID 12047460. peer-reviewed (Direct PubMed fetch failed with an NCBI access block; the trial details below come from the review that reproduces them.)

Per PMC8748342: peer-reviewed

• Randomised, double-blind, placebo-controlled: n=96 (50 valproate, 46 placebo; 17 chronic), 1000–2000 mg/day × 2 weeks. Primary endpoint ≥50% reduction in mean weekly attacks: no statistical difference vs placebo
• Open-label study: 73% experienced pain reduction
• Open study n=15, 600–2000 mg/day: 11/15 treatment success, 9/15 cessation of attacks

The review’s verdict is blunt: “there is no scientific evidence that sodium valproate is effective in cluster headache.” Treatment of women of childbearing age is contraindicated (teratogenicity/neurodevelopmental risk). No valproate row appears in that review’s summary table. Note the internal inconsistency the review itself flags: its own abstract and key points describe divalproex as “possibly effective based on open trials” while the detailed section says there is no evidence. A contradiction within a single peer-reviewed paper — flagged, not resolved.

Community data agree with the negative RCT: valproic acid is in the low self-reported efficacy clade (Rusanen 2022, PMC9436841). citizen science This is a case where trial data and community experience converge cleanly on “no.”

3.5.4 Gabapentin

Vuković V, Lovrenčić-Huzjan A, Budišić M, Demarin V. Gabapentin in the prophylaxis of cluster headache: an observational open label study. Acta Clin Croat 2009;48(3):311–314, PMID 20055254. peer-reviewed (Croatian institution — Sestre milosrdnice University Hospital, Zagreb — published in English.)

n=14 (9 M, 5 F, mean age 42±15), maintenance 900–2400 mg/day (900 mg n=6, 1200 mg n=2, 1800 mg n=4, 2400 mg n=2), mean treatment 3.5 months (2–5). Response reported within 1–2 weeks.

• Headache days/4 weeks: 378 → 210 total; mean 27 → 15; a reduction of 12 headache days per 4 weeks = 44.94%
• Pain intensity: 25% reduction in 1 (7.14%), 50% reduction in 8 (57.14%), 75% reduction in 3 (21.4%), non-responders 2 (14.28%)
• No recurrent headaches after completing therapy
• Adverse events in 8/14 (57.14%), mild-moderate: drowsiness, dizziness, slowness, constipation. Zero drop-outs.
• No p-values, no confidence intervals, no control group reported

Other data (PMC8748342): a case report of refractory chronic CH becoming symptom-free on 1800 mg/day after lithium, verapamil and pizotifen failed; a small Italian study n=12 (8 ep, 4 chr) at 1000 mg showing significant reduction in cluster period length; an open-label study in refractory chronic CH n=8 with 6/8 responding.

Evidence level (+) = questionable; dose 1000–1800 mg; AEs dizziness, somnolence, peripheral oedema; contraindications suicidal thoughts, depression, myasthenia gravis, decreased lung function, COPD, chronic kidney disease.

Gabapentin is in the LOW self-reported efficacy clade in the community synthesis (PMC9436841), and one r/clusterheads user reported skipping gabapentin entirely on the basis that “many people had not responded well to gabapentin” (r/clusterheads NHS thread); another said flatly that gabapentin “did not help” (same thread). [CITIZEN-SCIENCE / COMMUNITY-REPORT] Again, community and evidence converge on “probably not.”

3.5.5 Baclofen

Hering-Hanit R, Gadoth N. The use of baclofen in cluster headache. Curr Pain Headache Rep 2001;5(1):79–82, DOI 10.1007/s11916-001-0014-1, PMID 11252142. Meir General Hospital, Sapir Medical Center, Kfar Saba, Israel. peer-reviewed

Pilot study, n=16 symptomatic patients, baclofen 15–30 mg daily in three divided doses, given through the cluster period plus 2 weeks after. No comparator, no randomisation or blinding stated, episodic/chronic split not stated.

• 12 patients reported cessation of attacks within 1 week
• 1 further patient substantially better, attack-free by end of the following week
• 3 patients’ attacks WORSENED — corticosteroids prescribed for all three, one also given verapamil
• 3 patients had a subsequent cluster period which cleared with a second course
• No adverse-event rate, no p-values, no CIs, no responder percentages reported
• Authors: baclofen “seemed to be effective, safe, and well tolerated”

13/16 apparent responses is a striking-looking result, but with no control group in a condition with a large documented placebo response and spontaneous bout termination, it means very little. That 3/16 got worse is at least as interesting and is essentially never mentioned when baclofen is listed as an option. No baclofen row appears in the PMC8748342 summary table. This trial has not been replicated in 25 years. Unknown.

3.5.6 Clonidine (transdermal)

D’Andrea G, Perini F, Granella F, Cananzi A, Sergi A. Efficacy of transdermal clonidine in short-term treatment of cluster headache: a pilot study. Cephalalgia 1995;15(5):430–433, DOI 10.1046/j.1468-2982.1995.1505430.x, PMID 8536305. Este Hospital USL 22, Este, Italy. peer-reviewed

Open pilot, no control, n=13 (8 episodic, 5 chronic), transdermal clonidine 5–7.5 mg for 1 week after a run-in week:

Endpoint	Before	During	p
Weekly attack frequency	17.7 ± 7.0	8.7 ± 6.6	0.0005
Pain intensity (VAS, mm)	98.0 ± 7.2	41.1 ± 36.1	0.001
Attack duration (min)	59.3 ± 21.9	34.3 ± 24.6	0.02

Rationale: reduced noradrenergic tone in both active and remission phases of CH; sharp sympathetic fluctuations as attack triggers; clonidine as an α2-presynaptic agonist producing central sympathoinhibition. No adverse-event data reported at all — which for a drug that causes sedation and hypotension is a conspicuous omission. No responder rate, no NNT, no episodic-vs-chronic breakdown, no follow-up beyond one week.

A 50% attack reduction with p=0.0005 looks impressive until you remember there was no placebo arm and CH attack frequency fluctuates enormously week to week. Unreplicated, 30 years old, no clonidine row in modern summary tables. Unknown.

3.5.7 Pizotifen

Pizotifen (a 5-HT2 antagonist, still available in Australia and the UK, unavailable in the US) has essentially no modern CH evidence. The only CH-specific data traceable is Ekbom 1969, pizotifen up to 2.5 mg/day, n=28, catalogued in the placebo-response review (Nilsson Remahl AIM, Laudon Meyer E, Cordonnier C, Goadsby PJ. Placebo Response in Cluster Headache Trials: A Review, Cephalalgia 2003, DOI 10.1046/j.1468-2982.2003.00531.x). peer-reviewed It appears in the Rusanen review’s list of drugs with “positive clinical studies” for CH prophylaxis (PMC9436841) but with no numbers attached. It also appears in the literature as a drug that had failed before gabapentin worked in a refractory case (PMC8748342).

Most contemporary pizotifen evidence is for migraine, not CH, and even there certainty is very low (systematic review and meta-analysis, Headache Medicine). peer-reviewed No pizotifen row appears in any modern CH summary table reviewed here. Verdict: essentially unevidenced in CH. If offered it, ask what the evidence is.

3.5.8 Botulinum toxin

Three distinct approaches, none established:

Sphenopalatine ganglion injection — Trondheim pilot, PMC4853809, NCT02019017. peer-reviewed n=10, 25 or 50 IU onabotulinumtoxinA: attacks/week 18±12 → 11±14, p=0.038. But 7/10 had adverse events, including one severe posterior epistaxis. n=10, open-label, wide standard deviations — the p-value should not be over-read.

Other data (PMC8748342): peer-reviewed

• Open trial in chronic CH, 17 male completers, 28 weeks: 59% achieved >50% reduction in cumulative headache minutes
• Open-label, n=10, injections toward the otic ganglion: no statistically significant reduction in attacks/week at month 2 vs baseline
• A further SPG trial listed as ongoing

No botulinum toxin row appears in that review’s summary table. Rationale is CGRP-linked: botulinum toxin reduces plasma CGRP levels in chronic migraine, and CGRP is elevated in CH (PMC4646474). peer-reviewed Given §6, that rationale now looks shakier than it did.

Verdict: promising signal in SPG injection, meaningful procedural risk, no controlled evidence. Unknown.

3.5.9 Briefly: agents evaluated and found negative

From the AHS 2016 guideline (PMID 27432623): peer-reviewed

Treatment	Level	Study direction
Suboccipital steroid injection	A	Positive (2nd Class I study added) — the only Level A preventive
Deep brain stimulation	B	Negative
Warfarin	C	Positive
Cimetidine/chlorpheniramine	C	Negative
Candesartan	C	Negative
Frovatriptan	U	Not characterised

Also negative or unevidenced elsewhere: methysergide has no placebo-controlled trials, benefit 20–73% across open studies, more effective in episodic CH, and carries long-term risk of retroperitoneal, pulmonary, cardiac and pleural fibrosis — the manufacturer ceased production (PMC4646474). peer-reviewed Amitriptyline, propranolol and indomethacin all sit in the low self-reported efficacy clade and none are recommended in current guidance (PMC9436841). citizen science