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DHE IV for Intractable Migraine

Q: What were the key findings of the DHE IV for Intractable Migraine trial?

Repetitive IV DHE with metoclopramide was highly effective for terminating intractable migraine: 89% (49/55) became headache-free within 48 hours; per the abstract, 39/55 sustained benefits at mean 16-month follow-up, and 36/55 (65%) reported good-to-excellent long-term results, significantly superior overall to IV diazepam

Repetitive intravenous dihydroergotamine as therapy for intractable migraine

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Year of Publication: 1986

Authors: Neil H. Raskin

Journal: Neurology

Citation: Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology 1986;36:995-997

Link: https://www.neurology.org

PDF: https://www.neurology.org/doi/pdfdirect/10.1212/WNL.36.7.995

Clinical Question

Is repetitive IV dihydroergotamine effective for terminating cycles of chronic intractable migraine compared to IV diazepam?

Study Overview

Objective

To evaluate the efficacy of repetitive intravenous dihydroergotamine (DHE) compared to intravenous diazepam for treating chronic intractable migraine

Study Summary

89% (49/55) of DHE-treated patients became headache-free within 48 hours vs 13% (7/54) with diazepam within 3–6 days
DHE patients had shorter hospitalizations (3.8 vs 8.4 days, p<0.01)
At long-term follow-up (mean 16 months for DHE, mean 4 years for diazepam), 65% (36/55) DHE patients had good-excellent results vs 28% (15/54) diazepam patients

Intervention

IV dihydroergotamine (average 0.7 mg, range 0.3–1.0 mg) every 8 hours for 2 days, with IV metoclopramide 10 mg co-administered but stopped after 24 hours; followed by DHE suppositories 2 mg every 12 hours or SC injections 1 mg every 12 hours; propranolol 60 mg BID concomitantly

Patients per Arm

55 (DHE), 54 (diazepam)

Bottom Line

Repetitive IV DHE with metoclopramide was highly effective for terminating intractable migraine: 89% (49/55) became headache-free within 48 hours; per the abstract, 39/55 sustained benefits at mean 16-month follow-up, and 36/55 (65%) reported good-to-excellent long-term results, significantly superior overall to IV diazepam

        Major Points
        First report of repetitive IV DHE protocol for chronic intractable migraine (status migrainosus)
Nonblinded, nonrandomized comparison of DHE (1980-1983) vs diazepam (1975-1980) in consecutive patients
89% (49/55) DHE patients became headache-free within 48 hours vs only 13% (7/54) diazepam patients within 3-6 days
DHE highly effective even in drug-dependent patients: 36/55 (65%) DHE patients were dependent on analgesics, ergotamine, diazepam, or prednisone
No washout period required - DHE substituted directly for dependent medications without rebound
Significantly shorter hospitalizations with DHE: 3.8 days vs 8.4 days (p<0.01)
Long-term superiority of DHE: overall long-term ordinal distribution of headache outcomes significantly better with DHE (Kendall's tau=0.35, p<0.001); 65% (36/55) DHE good-excellent vs 28% (15/54) diazepam
DHE well-tolerated with minimal side effects: diarrhea (27%), leg pains (5%), abdominal discomfort (4%)
No cardiovascular complications: no claudication or angina pectoris despite ergot use
Protocol included transition to outpatient maintenance with DHE suppositories/SC injections plus propranolol or ergonovine

      

Design

Study Type: Nonblinded, nonrandomized, retrospective comparison study of two consecutive treatment cohorts

Randomization:

Blinding: Open-label; nonblinded for both patients and investigators; groups treated in different time periods (DHE 1980-1983, diazepam 1975-1980)

Enrollment Period: DHE group: 1980-1983; Diazepam group: 1975-1980

Follow-up Duration: DHE group: 12-24 months (mean 16 months); Diazepam group: 3-5 years (mean 4 years); no dropouts in either group

Centers: 1

Countries: United States

Sample Size: 109

Analysis: Student's t-test for continuous variables (hospital length of stay); Kendall's tau for ordinal outcomes (long-term headache frequency); descriptive statistics for categorical outcomes; no adjustment for multiple comparisons; no intention-to-treat specified; all patients analyzed as treated

Inclusion Criteria

Continuous headache for at least 2 months
Met criteria for common migraine (per Friedman/Ad Hoc Committee 1962 classification, ref 3) before headache became chronic and continuous
No specific age restrictions mentioned
Drug-dependent patients allowed (no washout period required)
Patients using analgesics (codeine, aspirin-caffeine-butalbital, oxycodone), ergotamine, diazepam, or prednisone eligible

Exclusion Criteria

Not explicitly stated in publication

Baseline Characteristics

Characteristic	DHE Group (N=55)	Diazepam Group (N=54)
Female (%)	85.5 (47/55)	83.3 (45/54)
Male (%)	14.5 (8/55)	16.7 (9/54)
Age (years, mean)	42	39
Age range	20-72 years	21-65 years
Continuous headache >2 years (%)	63.6 (35/55)	70.4 (38/54)
Continuous headache >5 years (%)	32.7 (18/55)	29.6 (16/54)
Drug-dependent (%)	65.5 (36/55)	70.4 (38/54)
Dependent on analgesics	26 patients	30 patients
Dependent on ergotamine	7 patients	7 patients
Dependent on diazepam	2 patients	1 patient
Dependent on prednisone	1 patient
Previous migraine severity	Similar to diazepam group (severity/frequency at onset did not differ)	Similar to DHE group (severity/frequency at onset did not differ)
Previous migraine frequency	Similar to diazepam group	Similar to DHE group

Arms

Field	IV Dihydroergotamine + Metoclopramide	Control
Intervention	Inpatient protocol: Test dose 0.5 mg DHE IV with 10 mg metoclopramide; if no nausea and no pain relief after 1h, additional 0.5 mg given, then 1.0 mg DHE + 10 mg metoclopramide every 8h for 2 days; if nausea after first dose, 0.5 mg every 8h continued; if nausea after second dose, reduced to 0.3 mg every 8h; average dose 0.7 mg (range 0.3-1.0 mg); metoclopramide stopped after 24h; administered through heparin-lock needles over 1-2 minutes. Outpatient continuation: After IV treatment, DHE 2 mg suppositories every 12h; if ineffective, patients taught SC self-injection of 1 mg DHE every 12h if headache persisted; propranolol 60 mg BID given concomitantly; if DHE still needed after 1 month, propranolol discontinued and ergonovine 1.2 mg daily started; DHE stopped when headache occurred <3 times weekly and only mild intensity; DHE used 1 week to 4 months post-IV treatment (average 3 weeks); all analgesics and ergotamine forbidden	10 mg diazepam IV every 8 hours through heparin-lock needles, given over 1-2 minutes; duration of treatment not explicitly specified but patients hospitalized 5-13 days (mean 8.4 days); propranolol and ergonovine also given after hospital discharge (same as DHE group); all analgesics and ergotamine forbidden after discharge
Duration	2 days IV treatment, followed by suppositories/SC injections for 1 week to 4 months (average 3 weeks), with propranolol or ergonovine continued for 1 year if successful	Inpatient treatment averaging 8.4 days, followed by prophylaxis with propranolol or ergonovine

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Proportion of patients becoming headache-free during acute treatment phase	Primary	7/54 (13.0%) headache-free within 3-6 days	49/55 (89.1%) headache-free within 48 hours	Approximately 1.3 (calculated from 89% vs 13% response rates)	Not explicitly stated for primary outcome comparison
Improvement >50% during acute treatment	Secondary	31/54 (57.4%) improved >50% within 10 days	0/55 (0%) per Table 1 (all responders classified as headache-free within 48h)
No substantial benefit during acute treatment	Secondary	16/54 (29.6%)	6/55 (10.9%)
Pattern of improvement	Secondary	7 diazepam-treated patients rendered headache-free in 3-6 days; 31 improved somewhat in 10 days	37/49 responders had gradual improvement; others noted dramatic improvement after first injection
Hospital length of stay (days, mean ± SE)	Secondary	8.4 ± 2.2 (range 5-13)	3.8 ± 0.5 (range 2.5-6)	Difference: -4.6 days	p<0.01 (Student's t-test)
Long-term headache-free status	Secondary	5/54 (9.3%)	17/55 (30.9%)		See overall long-term comparison (Kendall's tau=0.35, p<0.001)
Long-term occasional headaches (<monthly)	Secondary	10/54 (18.5%)	19/55 (34.5%)
Long-term good-excellent results (headache-free or <monthly headaches)	Secondary	15/54 (27.8%)	36/55 (65.5%)		Not directly reported for this dichotomized comparison; overall long-term ordinal distribution favored DHE (Kendall's tau=0.35, p<0.001). Note: DHE follow-up mean 16 months; diazepam follow-up mean 4 years
Long-term headache 1-2x monthly	Secondary	10/54 (18.5%)	9/55 (16.4%)
Long-term headache >weekly	Secondary	15/54 (27.8%)	4/55 (7.3%)
Long-term constant headache	Secondary	14/54 (25.9%)	6/55 (10.9%)
Long-term drug dependence recurrence	Secondary	16/54 (29.6%) again drug-dependent at follow-up	Negligible recurrence - DHE used instead of analgesics for continuing headaches
ECG monitoring during treatment	Secondary	Not reported	ECG recorded during first two DHE doses for patients >60 years; ECG results not reported in publication
Diarrhea	Adverse	Not reported	15/55 (27.3%), invariably controlled with diphenoxylate; dosage reduction always lessened symptoms
Leg muscle pains	Adverse	Not reported	3/55 (5.5%); reduction of dosage lessened symptoms sufficiently to continue therapy
Abdominal discomfort	Adverse	Not reported	2/55 (3.6%); reduction of dosage lessened symptoms sufficiently to continue therapy
Claudication pain	Adverse	Not reported	0/55 (0%)
Angina pectoris	Adverse	Not reported	0/55 (0%)
Serious adverse events	Adverse	Not reported	None reported
Study discontinuations due to adverse events	Adverse	Not reported	0/55 (0%) - all side effects managed with dose reduction or symptomatic treatment
Deaths	Adverse	Not reported	Not reported

Subgroup Analysis

Drug-dependent patients numbered 36/55 in the DHE group and 38/54 in the diazepam group; the paper does not report a formal subgroup analysis comparing response in drug-dependent vs non-dependent patients. Author notes that DHE successfully substituted for ergotamine dependence without rebound effect when discontinued. No separate subgroup analyses by specific drug dependence type, age, sex, or duration of chronic headache were reported

Criticisms

Nonblinded, nonrandomized design - major limitation acknowledged by author
Groups treated in different time periods (DHE 1980-1983, diazepam 1975-1980), introducing potential temporal bias
No efforts made to match groups beyond age and sex
Unequal follow-up periods (DHE mean 16 months vs diazepam mean 4 years)
No standardized outcome measures or validated headache scales used
Subjective assessment of 'headache-free' status without clear definition
No placebo control group - though author notes intractable migraine historically resistant with rare placebo responses
Small sample size (55 DHE, 54 diazepam) limits statistical power
Single-center study from specialized headache center, limiting generalizability
No standardized criteria for 'drug dependence' - defined clinically as severe exacerbation if single dose delayed
Inconsistent concomitant treatments (propranolol, ergonovine) used in both groups after hospitalization
No washout period used, though this may actually support DHE's practical utility
Diazepam may not be optimal comparator - unclear if it was standard therapy at time
No cost-effectiveness analysis despite significantly shorter hospitalizations
Mechanism of action unclear - paper speculates about venous effects and 5-HT receptor activity
No data on optimal DHE dosing regimen, frequency, or duration
Long-term outcomes assessed at variable time points, not standardized
Author was unblinded to treatment and assessed outcomes personally
No independent outcome adjudication
Statistical analysis limited - no adjustment for baseline differences or multiple comparisons

Funding

Not stated in publication (the Raskin DHE article carries no funding statement; the 'United Parkinson Foundation / USPHS RR00044 / Eli Lilly' acknowledgment on the preceding page belongs to the Kurlan pergolide article from the University of Rochester)

Based on: DHE IV for Intractable Migraine (Neurology, 1986)