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Verapamil Leone Cluster

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Year of Publication: 2000

Journal: Neurology

Link: https://doi.org/10.1212/WNL.54.6.1382

PDF: https://www.neurology.org/doi/pdf/10.1212/WNL.54.6.1382

Clinical Question

Does verapamil 360 mg/day reduce attack frequency compared with placebo in episodic cluster headache?

Bottom Line

In 30 patients with episodic cluster headache randomized double-blind to verapamil 360 mg/day vs placebo for 14 days, verapamil reduced attacks/day from 1.92 to 0.6 by the second week (vs 1.37 → 1.65 with placebo; p<0.001) and cut abortive-agent use in half (p<0.004). Eighty percent of verapamil patients were responders (≥50% reduction) vs zero on placebo. This trial provided the first randomized evidence for verapamil in cluster headache, cementing it as first-line prophylaxis.

        Major Points
        Multicenter double-blind double-dummy placebo-controlled parallel-group RCT in episodic cluster headache (Leone 2000)
N=30 adults 18-60 with IHS episodic cluster headache, in-cluster <10 days at entry
5-day run-in baseline + 14-day treatment phase; sumatriptan SC allowed as rescue
Primary endpoint: attacks/day during week 2 of treatment
Week-2 attacks/day: verapamil 0.6 ± 0.88 vs placebo 1.65 ± 1.01; p<0.001
Abortive sumatriptan use fell from 1.8 to 0.5/day with verapamil; p<0.004
Responder rate (≥50% reduction): 80% (12/15) verapamil vs 0/15 placebo
Placebo patients worsened naturally (effect size -0.49) while verapamil improved (+1.9)
Constipation in 53% of verapamil patients; mild asymptomatic BP/HR reduction; no discontinuations
First RCT evidence for verapamil in cluster headache — cemented it as first-line prophylaxis
Dose 360 mg/day lower than typical clinical doses (480-960 mg/day) used in refractory patients

      

Design

Study Type: Multicenter phase 3 double-blind double-dummy placebo-controlled parallel-group RCT

Randomization: 1

Blinding: Double-blind, double-dummy

Follow-up Duration: 14-day treatment after 5-day run-in

Sample Size: 30

Analyzed: 30

Analysis: Mann-Whitney rank sum test; effect size = mean change / baseline SD

Baseline Characteristics

Characteristic	Control	Active
N	15	15
Sex M/F	14/1	13/2
Age mean	43 ± 10	44 ± 8
Illness duration	15 ± 10 y	16 ± 11 y
Prior cluster duration	93 ± 92 days	50 ± 18 days
Baseline attacks/day	1.37 ± 0.8	1.92 ± 0.87

Arms

Field	Control	Verapamil
N	15	15
Intervention	Placebo capsule tid for 14 days	Verapamil 120 mg tid (total 360 mg/day) for 14 days
Duration	14 days	14 days

Outcomes

Outcome	Type	Control	Intervention	P-value
Attack frequency per day during week 2 of treatment	Primary	1.65 ± 1.01 attacks/day	0.6 ± 0.88 attacks/day	p<0.001
Abortive agent consumption/day at week 2	Secondary	1.2 ± 1.03/day	0.5 ± 0.87/day	p<0.004
Responder rate (≥50% attack reduction)	Secondary	0/15 (0%)	12/15 (80%)	Highly significant
Attack frequency week 1	Secondary	1.7 ± 1.12	1.1 ± 1.02	Not significant at week 1
Pain-free patients during week 2	Secondary	0	4 (27%)	Favorable
Blood pressure (mean change)	Secondary	Stable	Modest, asymptomatic reduction	Expected pharmacologic effect
Constipation	Adverse	0%	53% (8/15)	Most common; well tolerated
Nausea	Adverse	13% (2/15)	13% (2/15)	Similar
Vertigo	Adverse	7% (1/15)	7% (1/15)	Similar
Asthenia	Adverse	7% (1/15)	7% (1/15)	Similar
Swelling	Adverse	0%	7% (1/15)	Verapamil-specific
Hypotension (symptomatic)	Adverse	None	None reported	Asymptomatic BP reduction only
Bradycardia (symptomatic)	Adverse	None	None reported	Asymptomatic HR reduction only
Discontinuations for AE	Adverse	0	0	All completed 14-day treatment

Subgroup Analysis

5 verapamil-arm patients had prior open-label verapamil response; all 5 replicated prior response pattern, supporting consistency of effect. Placebo arm patients with cluster-period duration imbalance (93 vs 50 days) were actually more deeply into cluster than verapamil patients — argues against a natural remission confound favoring placebo. Post hoc analysis confirmed cluster-phase balance at entry.

Criticisms

Very small sample size (N=30) — limits power for safety signals and subgroup analysis
Short 14-day treatment period does not address long-term efficacy or high-dose verapamil (some patients need 480-960 mg/day)
No ECG monitoring beyond BP/HR — high-dose verapamil in clinical practice requires ECG monitoring for AV block (established in later literature)
Chance imbalance in baseline attack frequency (verapamil higher than placebo) — could potentially exaggerate effect via regression to mean, though direction favors conservative estimate
5 patients had prior verapamil exposure — limits blinding integrity
Dose 360 mg/day is lower than typical clinical practice doses (480-960 mg/day often needed); trial may underestimate higher-dose efficacy

Funding

Authors report no disclosed funding source; no pharmaceutical sponsorship indicated

Based on: Verapamil Leone Cluster (Neurology, 2000)

Content summarized and formatted by NeuroTrials.ai.

Verapamil Leone Cluster

(2000)

Objective

Verapamil 120 mg tid (360 mg/day) vs placebo — to test efficacy for prevention of attacks in episodic cluster headache.

Study Summary

• Verapamil 360 mg/day significantly reduced cluster attack frequency vs placebo in a 14-day double-blind trial.
• Week-2 attacks/day: 0.6 (verapamil) vs 1.65 (placebo); p<0.001.
• 80% (12/15) of verapamil patients were ≥50% responders; zero responders in placebo group.
• Abortive-agent (subcutaneous sumatriptan) consumption fell from 1.8 to 0.5/day with verapamil; p<0.004.
• Effect sizes: +1.9 verapamil vs -0.49 placebo at week 2 — placebo patients worsened as expected in active cluster.
• AEs were mild (constipation 53%); cemented verapamil as first-line cluster headache prophylaxis.

Intervention

Verapamil 120 mg tid (total 360 mg/day) or matching placebo tid for 14 days after a 5-day run-in, double-blind double-dummy. Subcutaneous sumatriptan allowed for acute treatment throughout.

Inclusion Criteria

Adults 18-60 with episodic cluster headache per IHS criteria, prior cluster period ≥1 month, in-cluster for <10 days at entry, expected remaining cluster duration ≥20 days.

Study Design

Arms: Verapamil 120 mg tid vs Placebo tid

Patients per Arm: Verapamil 15; Placebo 15

Outcome

• Primary: Attacks/day at week 2 — verapamil 0.6 ± 0.88 vs placebo 1.65 ± 1.01; p<0.001
• Abortive-agent use at week 2: verapamil 0.5 ± 0.87/day vs placebo 1.2 ± 1.03/day; p<0.004
• Responder rate (≥50% attack reduction): 80% (12/15) verapamil vs 0% (0/15) placebo
• Effect size week 2: +1.9 verapamil vs -0.49 placebo (placebo patients worsened naturally in active cluster)
• Side effects mild: constipation 53%, nausea 13%, mild asymptomatic BP/HR reduction; no discontinuations

Bottom Line

Major Points

Multicenter double-blind double-dummy placebo-controlled parallel-group RCT in episodic cluster headache (Leone 2000)
N=30 adults 18-60 with IHS episodic cluster headache, in-cluster <10 days at entry
5-day run-in baseline + 14-day treatment phase; sumatriptan SC allowed as rescue
Primary endpoint: attacks/day during week 2 of treatment
Week-2 attacks/day: verapamil 0.6 ± 0.88 vs placebo 1.65 ± 1.01; p<0.001
Abortive sumatriptan use fell from 1.8 to 0.5/day with verapamil; p<0.004
Responder rate (≥50% reduction): 80% (12/15) verapamil vs 0/15 placebo
Placebo patients worsened naturally (effect size -0.49) while verapamil improved (+1.9)
Constipation in 53% of verapamil patients; mild asymptomatic BP/HR reduction; no discontinuations
First RCT evidence for verapamil in cluster headache — cemented it as first-line prophylaxis
Dose 360 mg/day lower than typical clinical doses (480-960 mg/day) used in refractory patients

Study Design

Study Type: Multicenter phase 3 double-blind double-dummy placebo-controlled parallel-group RCT
Randomization: Yes
Blinding: Double-blind, double-dummy
Sample Size: 30
Follow-up: 14-day treatment after 5-day run-in

Primary Outcome

Definition: Attack frequency per day during week 2 of treatment

Control	Intervention	HR/OR	P-value
1.65 ± 1.01 attacks/day	0.6 ± 0.88 attacks/day	- (Not reported; Mann-Whitney test used)	p<0.001

Limitations & Criticisms

Very small sample size (N=30) — limits power for safety signals and subgroup analysis
Short 14-day treatment period does not address long-term efficacy or high-dose verapamil (some patients need 480-960 mg/day)
No ECG monitoring beyond BP/HR — high-dose verapamil in clinical practice requires ECG monitoring for AV block (established in later literature)
Chance imbalance in baseline attack frequency (verapamil higher than placebo) — could potentially exaggerate effect via regression to mean, though direction favors conservative estimate
5 patients had prior verapamil exposure — limits blinding integrity
Dose 360 mg/day is lower than typical clinical practice doses (480-960 mg/day often needed); trial may underestimate higher-dose efficacy

Citation

View Original Publication →

Verapamil Leone Cluster

Clinical Question

Bottom Line

Major Points

Design

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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