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DHE IV for Intractable Migraine

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?

Bottom Line

Repetitive IV DHE with metoclopramide was highly effective for terminating intractable migraine, with 89% of patients becoming headache-free within 48 hours and sustained benefits in 65% at mean 16-month follow-up, significantly superior to IV diazepam treatment

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: 65% good-excellent results vs 28% for diazepam (tau=0.35, p<0.001)
  • 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 International Headache Society criteria) before headache became chronic and continuous
  • Severity and frequency of migrainous attacks at onset similar between groups
  • 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
  • Presumably excluded patients with contraindications to ergot alkaloids
  • Presumably excluded patients with significant cardiovascular disease (though ECG monitored in patients >60 years during first two DHE doses)

Baseline Characteristics

CharacteristicDHE 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)4239
Age range20-72 years21-65 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 analgesics26 patients30 patients
Dependent on ergotamine7 patients7 patients
Dependent on diazepam2 patients1 patient
Dependent on prednisone1 patient
Previous migraine severitySimilar to diazepam groupSimilar to DHE group
Previous migraine frequencySimilar to diazepam groupSimilar to DHE group

Arms

FieldIV Dihydroergotamine + MetoclopramideControl
InterventionInpatient 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 forbidden10 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
Duration2 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 successfulInpatient treatment averaging 8.4 days, followed by prophylaxis with propranolol or ergonovine

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Proportion of patients becoming headache-free during acute treatment phasePrimary7/54 (13.0%) headache-free within 3-6 days49/55 (89.1%) headache-free within 48 hoursApproximately 1.3 (calculated from 89% vs 13% response rates)Not explicitly stated for primary outcome comparison
Improvement >50% during acute treatmentSecondary31/54 (57.4%) improved >50% within 10 daysNot separately reported (included in 89% headache-free within 48h)
No substantial benefit during acute treatmentSecondary16/54 (29.6%)6/55 (10.9%)
Pattern of improvementSecondaryGradual improvement in diazepam group37/49 responders had gradual improvement; others noted dramatic improvement after first injection
Hospital length of stay (days, mean ± SE)Secondary8.4 ± 2.2 (range 5-13)3.8 ± 0.5 (range 2.5-6)Difference: -4.6 daysp<0.01 (Student's t-test)
Long-term headache-free statusSecondary5/54 (9.3%)17/55 (30.9%)Overall long-term comparison: Kendall's tau = 0.35, p<0.001
Long-term occasional headaches (<monthly)Secondary10/54 (18.5%)19/55 (34.5%)
Long-term good-excellent results (headache-free or <monthly headaches)Secondary15/54 (27.8%)36/55 (65.5%)p<0.001 (Kendall's tau = 0.35)
Long-term headache 1-2x monthlySecondary10/54 (18.5%)9/55 (16.4%)
Long-term headache >weeklySecondary15/54 (27.8%)4/55 (7.3%)
Long-term constant headacheSecondary14/54 (25.9%)6/55 (10.9%)
Long-term drug dependence recurrenceSecondary16/54 (29.6%) again drug-dependent at follow-upNegligible recurrence - DHE used instead of analgesics for continuing headaches
ECG changes during treatmentSecondaryNot reportedECG recorded during first two DHE doses for patients >60 years; no abnormalities reported
DiarrheaAdverseNot reported15/55 (27.3%), invariably controlled with diphenoxylate; dosage reduction always lessened symptoms
Leg muscle painsAdverseNot reported3/55 (5.5%); reduction of dosage lessened symptoms sufficiently to continue therapy
Abdominal discomfortAdverseNot reported2/55 (3.6%); reduction of dosage lessened symptoms sufficiently to continue therapy
Claudication painAdverseNot reported0/55 (0%)
Angina pectorisAdverseNot reported0/55 (0%)
Serious adverse eventsAdverseNot reportedNone reported
Study discontinuations due to adverse eventsAdverseNot reported0/55 (0%) - all side effects managed with dose reduction or symptomatic treatment
DeathsAdverseNot reported0

Subgroup Analysis

Drug-dependent patients (36/55 DHE group, 38/54 diazepam group) responded similarly to non-dependent patients. 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 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

Supported by United Parkinson Foundation fellowship, USPHS grant RR00044 (University of Rochester Clinical Research Center), and Eli Lilly Company

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

Authors: Neil H. Raskin

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

Reviewed by: Fatima Traoré, MD

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