Prochlorperazine vs. Hydromorphone for Migraine

In Review

Friedman BW et al. "Randomized study of IV prochlorperazineplus diphenhydramine vs IV hydromorphone for migraine". Neurology. 2017. 89(20):2075-2082.
PubMed • Full text

Clinical Question

In adult patients that present to the Emergency Department with a migraine, does prochlorperazine + diphenhydramine produce more sustained headache relief as compared to IV hydromorphone?

Bottom Line

Compared to hydromorphone alone, prochlorperazine with diphenhydramine was more effective at creating sustained headache relief with fewer side effect and a faster ED put-through time.

Major Points

Prochloperazine, an antidopaminergic, has been compared to several other medications with success for treating acute migraine in the Emergency Department. A common problem, acute migraine accounts for over a million ED visits annually in the US alone. First line agents include antidopaminergic agents, triptans, NSAIDs, and opioids. The expert recommendations discourage the use of opioids due to the risk of dependence with patients.

This randomized control trial compared parenteral hydromorphone 1mg against prochlorperazine 10mg. Diphenhydramine 25mg was added to help prevent akethesia, a commonly reported side effect from prochlorperazine. Conducted in two neighbourhoods in New York, the trial had a set interim analysis set after 120 patients had accumulated 48 hours of data. For both the primary and secondary outcomes, prochlorperazine outperformed the hydromorphone arm. At 48 hours, after one dose, twice as many patients had sustained relief and after two doses that ratio decreased to 2/3.

With a non-statistical difference in adverse events between groups, the trial was halted early by data monitoring committee due to the overwhelming superiority of prochlorperazine. This trial also did not observe the formation of a dependence cycle in the patients that received opioids. The generalizability of this trial suffers due to not including all comers, only selecting patients from New York, and may not have used equipotent doses of study agents.

Guidelines

The American Headache Society 2016(summarized):

• Management of Acute Headache in the Emergency Department
  • SHOULD OFFER (level B):
    • Metoclopramide
    • Prochlorperazine
    • Sumatriptan
  • OFFER (level C)
    • IV Acetaminophen
    • IV Acetylsalicylic Acid
    • chlorpromazine
    • dexketoprofen
    • dipyrone
    • droperidol
    • haloperidol
    • ketorolac
    • valproate
  • AVOID (level C)
    • diphenhydramine
    • hydromorphone
    • lidocaine
    • morphine
    • octreotide
  • NO RECOMMENDATION
    • dexamethasone
    • dihydroergotamine
    • ergotamine
    • ketamine
    • lysine clonixinate
    • magnesium
    • meperidine
    • nalbuphine
    • propofol
    • promethazine
    • tramadol
    • trimethobenzamide

Design

• Two-centre, randomized, double-blind, control trial
• N=127
  • Prochlorperazine + diphenhydramine (n=63)
  • Hydromorphone + Placebo (n=64)
• Setting: Urban teaching centre, USA
• Enrollment: March 2015 - June 2016
• Mean follow-up: 3 months
• Analysis: ITT
• Primary Outcome: sustained headache relieffor 48 hours after 1 dose of investigational medication

Population

Inclusion Criteria

• ≥21 years of age
• Patient presented to the EDs for treatment of migraine
  • International Classification of Headache Disorders 3 beta
  • rated as moderate or severe in intensity

Exclusion Criteria

• treating physician had suspicion for a disease process other than migraine
  • patients who required emergent brain imaging
  • temperature ≥100.4 degF (≥38 degC)
  • patients with objective neurologic findings
• allergy or contraindications to investigational medications
  • pregnancy or breast-feeding
• patient-reported use of opioids within the previous month
• history of addiction to prescription or illicit opioids, or prior use of methadone

Baseline Characteristics

Prochlorperazine group shown

• Female: 79%
• Age, mean(SD): 32(9)
• Days with-activity limiting headache in previous 3 months, median(IRQ): 2(1-4)
• Duration of headache, median(IRQ): 72(24-96)
• Experience aura symptoms: 37%
• Used medication for headache before ED presentation: 68%
• Used preventative medication: 1(2)
• Pain at baseline
  • Moderate: 24%
  • Severe: 76%

Interventions

• prochlorperazine 10 mg IV + diphenhydramine 25 mg IV
• hydromorphone 1 mg IV + placebo

Outcomes

Comparisons are Prochlorperazine + diphenhydramine vs. Hydromorphone + Placebo.

Primary Outcomes

Sustained headache relief for 48 hours after 1 dose of study medication

60% vs. 31%, difference 28%, 95% CI 12–45, NNT 4, 95% CI 2–9

Secondary Outcomes

Sustained headache relief after 1 or 2 doses of study medication

60% vs. 41%, difference 19%, 95% CI 2–36, NNT 6, 95% CI 3–52

Improved to pain levels of mild or none before ED discharge

29% vs. 33%, difference 4%, 95% CI -15 to 23 NNT 25

Subgroup Analysis

In Emergency Department Outcomes

Headache 1 hour after drug administration

Difference Severe/moderate vs. mild/none: -34% (95% CI -49 to 19)

Severe: 2% vs. 17%

Moderate: 13% vs. 31%

Mild: 39% vs. 27%

None: 47% vs. 25%

Functional Impairment 1 hour after drug administration

difference Severe/moderate vs. mild/none: -33% (95% CI -46 to -20)

Severe: 0% vs. 9%

Moderate: 5% vs. 28%

Mild: 41% vs. 39%

None: 54% vs. 23%

Requested second dose of study medication

8% vs. 31%, difference 23% (95% CI 10 to 36)

Required off protocol medication to manage other symptoms

2% vs. 14%, difference 30% (95% CI 16 to 43)

Length of Stay, median (IRQ), min

105 (77–135) vs. 193 (114–277), mean difference -82 (95% CI -122 to -43)

Outcomes at 48 hours

Functional Impairment after ED discharge

difference Severe/moderate vs. mild/none: -8% (95% CI -19 to 3)

Severe: 2% vs. 6%

Moderate: 5% vs. 8%

Mild: 24% vs. 29%

None: 69% vs. 56%

Would request same treatment again?

difference yes vs. mild/none: -33% (95% CI -46 to -20)

Yes: 74% vs. 68%

Not sure: 7% vs. 8%

No: 19% vs. 24%

Adverse Events

All adverse events

11% vs. 20%, difference 9% (95% CI -3 to 22)

Restlessness from Medication (reported at 48 hour follow-up)

Difference A Lot vs. A little/no: -5% (95% CI -21% to 11%)

No: 68% vs. 76%

A Little: 19% vs. 15%

A Lot: 13% vs. 10%

Drowsiness from Medication (reported at 48 hour follow-up)

Difference A Lot vs. A little/no: 3% (95% CI -14% to 20%)

No: 27% vs. 21%

A Little: 35% vs. 39%

A Lot: 37% vs. 40%

Criticisms

• Risk of over estimation of benefit since trial was stopped early due to benefit of prochlorperazine + diphenhydramine arm
• Risk of population bias due to recruitment of subject from two neighbourhoods in the Bronx, NY
• Generalizability challenged with excluding patients with previous history with opioids within one month
• Unblinding possible if participants had previous exposure with study medication
• Did not exclude patients with medication overuse
• Potential recall bias for functional status and headache days outcomes

Funding

None disclosed.