SYNONYMS: Headache NOS, headache not otherwise specified, undifferentiated headache, unclassified headache, cephalgia unspecified, cephalalgia NOS, head pain unspecified, acute headache NOS, nonspecific headache, headache of unknown etiology, headache under evaluation, primary headache NOS, new headache NOS, recurrent headache unspecified
SCOPE: Empiric treatment-focused management of undifferentiated or unspecified headache when the diagnosis is unclear, pending further evaluation, or does not fit a specific headache category. Emphasizes acute headache management in the ED and hospital (parenteral headache cocktail: ketorolac, metoclopramide, diphenhydramine, dexamethasone), empiric abortive treatment, and outpatient follow-up planning. Applies when the patient presents with headache and a definitive primary or secondary headache diagnosis has not yet been established. Differs from the Headache Evaluation plan, which focuses on the diagnostic workup algorithm. Excludes thunderclap headache (separate protocol), confirmed secondary headaches (SAH, meningitis, mass lesion), and specific primary headache disorders once diagnosed (migraine, tension-type, cluster -- see dedicated plans).
DEFINITIONS:
- Headache, Unspecified: Headache not yet classified into a specific primary or secondary headache disorder per ICHD-3 criteria; used when diagnosis is pending or features are atypical/overlapping
- Undifferentiated Headache: Clinical presentation where headache is the chief complaint but does not clearly meet diagnostic criteria for a single headache subtype at the time of evaluation
- Headache Cocktail: A combination of parenteral medications (typically ketorolac, dopamine antagonist, diphenhydramine, with or without dexamethasone) used empirically in the ED for acute headache regardless of subtype
- Red Flag Headache: Headache with features suggesting a secondary (dangerous) cause requiring urgent imaging or LP (thunderclap onset, fever, focal deficits, papilledema, altered mental status, new onset after age 50)
PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting
Suspected SAH with negative CT, suspected meningitis, suspected IIH
Normal OP (10-20 cm H2O); clear CSF; WBC <5; protein 15-45; glucose >60% serum
Coagulopathy, mass lesion with risk of herniation
C-spine MRI (72141)
-
ROUTINE
ROUTINE
-
Suspected cervicogenic headache component
Normal cervical alignment; no disc herniation
MRI contraindications
IMAGING RED FLAGS (SNNOOP10): Obtain imaging if any of the following present:
- Systemic symptoms (fever, weight loss) or systemic disease (HIV, cancer, immunosuppression)
- Neurological symptoms or abnormal signs (focal deficits, papilledema)
- New onset or sudden onset (thunderclap)
- Onset after age 50
- Other associated conditions (pregnancy, postpartum, anticoagulation)
- Pattern change from previous headaches
- Positional (worse lying down or standing)
- Precipitated by Valsalva (cough, sneeze, exertion)
- Papilledema
- Progressive headache or atypical features
- Painful eye with autonomic features
First-line oral analgesic in pregnancy for any headache
1000 mg :: PO :: q6h :: 1000 mg PO q6h; max 3000 mg/day
Hepatic disease
LFTs if frequent use
STAT
STAT
ROUTINE
-
Acetaminophen IV (CPT 96374)
IV
First-line parenteral analgesic in pregnancy when oral not tolerated
1000 mg :: IV :: q6h :: 1000 mg IV over 15 min q6h; max 3000 mg/day
Hepatic disease
LFTs if frequent use
STAT
STAT
-
-
Metoclopramide (CPT 96374)
IV
Safe in pregnancy; anti-headache and anti-emetic
10 mg :: IV :: q8h :: 10 mg IV q8h
Parkinson's disease
Akathisia
STAT
STAT
ROUTINE
-
Metoclopramide
PO
Safe in pregnancy; anti-headache and anti-emetic for outpatient use
10 mg :: PO :: q8h :: 10 mg PO q8h
Parkinson's disease
Akathisia
-
ROUTINE
ROUTINE
-
Ondansetron (CPT 96374)
IV
Anti-emetic adjunct; caution in first trimester
4 mg :: IV :: q8h :: 4 mg IV q8h
QT prolongation; first trimester (relative -- limited data)
QTc
URGENT
ROUTINE
-
-
Ondansetron
PO
Anti-emetic adjunct for outpatient use; caution in first trimester
4 mg :: PO :: q8h :: 4 mg PO q8h
QT prolongation; first trimester (relative -- limited data)
QTc
-
ROUTINE
ROUTINE
-
Magnesium sulfate (CPT 96365)
IV
Adjunct for headache in pregnancy; also seizure prophylaxis benefit
2 g :: IV :: x1 :: 2 g IV over 20-30 min
Renal failure; myasthenia gravis
Reflexes, respiratory rate, Mg level
URGENT
URGENT
-
-
Occipital nerve block - lidocaine (CPT 64405)
Local injection
Non-systemic option; safe in pregnancy
2-3 mL :: SC :: PRN :: 2% lidocaine 2-3 mL per side at greater occipital nerve
Local anesthetic allergy
Local reaction; vasovagal
-
ROUTINE
ROUTINE
-
3F. Empiric Outpatient Bridging (Discharge from ED/Hospital)¶
Treatment
Route
Indication
Dosing
Contraindications
Monitoring
ED
HOSP
OPD
ICU
Naproxen sodium
PO
Bridge therapy for recurrent headache pending outpatient evaluation
500 mg :: PO :: BID :: 500 mg PO BID with food for 5-7 days; then PRN
Renal impairment; GI bleed; aspirin allergy; 3rd trimester pregnancy
GI symptoms; renal function
ROUTINE
ROUTINE
ROUTINE
-
Dexamethasone taper (short)
PO
Prevent headache recurrence after ED discharge; bridging for refractory cases
4 mg :: PO :: BID :: 4 mg PO BID x 2 days, then 4 mg daily x 2 days, then stop
Active infection; uncontrolled DM
Blood glucose; insomnia; mood changes
ROUTINE
ROUTINE
ROUTINE
-
Prochlorperazine suppository
PR
Rescue therapy at home for recurrent nausea/headache
25 mg :: PR :: q12h :: 25 mg PR q12h PRN; max 3 days
Parkinson's disease; QT prolongation
Akathisia; sedation
ROUTINE
ROUTINE
ROUTINE
-
Ondansetron ODT
PO
Anti-emetic rescue for nausea/vomiting with headache recurrence
4 mg :: PO :: q8h :: 4 mg ODT q8h PRN
QT prolongation; severe hepatic impairment
QTc if chronic use; constipation
ROUTINE
ROUTINE
ROUTINE
-
MEDICATION OVERUSE HEADACHE WARNING:
Limit acute analgesic use to <10 days/month for combination analgesics, opioids, or triptans, and <15 days/month for simple analgesics (NSAIDs, acetaminophen). Exceeding these thresholds risks transformation to medication overuse headache (MOH). Educate all patients at discharge. If MOH suspected, refer to medication overuse headache protocol.
Pain controlled (NRS <4); able to tolerate PO; no red flags on history/exam/imaging; ambulatory; close follow-up arranged (PCP or neurology 2-4 weeks); MOH counseling provided; headache diary instructions given; return precautions reviewed
Admit to hospital (observation or floor)
Headache refractory to 2 rounds of ED cocktail; unable to tolerate PO; severe dehydration requiring prolonged IV fluids; pending further workup for red flag features; concern for secondary headache requiring LP or serial imaging
ICU admission
Rare for primary headache; indicated if suspected secondary cause with hemodynamic instability, altered mental status, or evolving neurological deficits pending workup
Outpatient neurology follow-up
Within 2-4 weeks for recurrent unspecified headache requiring formal classification; sooner (1-2 weeks) if frequent (>4 headache days/month) or disabling
Primary care follow-up
Within 1-2 weeks after ED visit for first-time headache; reassess response to acute treatment; determine if prevention needed
This plan is TREATMENT-focused for undifferentiated headache; for diagnostic algorithms and workup pathways, see the Headache Evaluation plan
The ED headache cocktail (ketorolac + metoclopramide + diphenhydramine with or without dexamethasone) is effective regardless of headache subtype and is first-line for moderate-severe headache in the ED
Always screen for red flags (SNNOOP10) before initiating empiric treatment; do not delay imaging for red flag headaches
Dexamethasone single dose is added to the ED cocktail routinely as it reduces headache recurrence at 24-72 hours (NNT ~9)
Avoid opioids for primary headache management; associated with worse outcomes, ED revisits, and medication overuse headache
If response to sumatriptan is diagnostic of migraine, transition to the Migraine plan for ongoing management
Instruct all patients to start a headache diary at discharge to facilitate classification at follow-up
Medication overuse headache is the most common reason for chronic daily headache; counsel all patients on analgesic limits
Pregnancy: acetaminophen, metoclopramide, and nerve blocks are safest options; avoid NSAIDs in third trimester, avoid ergotamines and most triptans
v1.1 (February 2, 2026)
- Added Section A/B structural dividers (═══) per template convention (C1)
- Added REVISED date and updated STATUS line (C2)
- Converted all hedging language to directive throughout (C3, R3): removed "consider", "may", "should"; replaced "+/-" with "with or without"
- Split dual-route medications in Section 3E into separate rows (PO and IV) for acetaminophen, metoclopramide, and ondansetron (M2, M3, M4, R4)
- Renamed "Excedrin (ASA/APAP/caffeine)" to "Acetaminophen/Aspirin/Caffeine (Excedrin)" for generic-first naming; expanded contraindications (M6, R5)
- Added IM ketorolac as separate row in Section 3A for IV-access-unavailable scenarios
- Added CPT code for occipital nerve block (64405) and sumatriptan injection (96372) in Section 3C
- Standardized route column: replaced dual routes with single route per row
- Updated SNNOOP10 callout to directive language ("Obtain imaging if any of the following present")
- Updated monitoring Section 6 language to directive ("indicates" instead of "may indicate")
- Incremented version to 1.1
v1.0 (February 2, 2026)
- Initial template creation
- Treatment-focused plan for undifferentiated/unspecified headache
- Comprehensive ED headache cocktail protocol (ketorolac, metoclopramide, diphenhydramine, dexamethasone)
- Alternative dopamine antagonists (prochlorperazine, chlorpromazine)
- Second-line parenteral options (magnesium, valproate, acetaminophen IV, sumatriptan, nerve block)
- Oral/outpatient acute treatment section
- Pregnancy-safe options section
- Empiric outpatient bridging therapy for discharge
- SNNOOP10 red flags for imaging decisions
- Structured dosing format for order sentence generation
- Real PubMed citations with verified PMIDs
- Differentiated from Headache Evaluation plan (diagnostic workup) by TREATMENT focus
APPENDIX A: ED Headache Cocktail Administration Sequence¶
Recommended Order of Administration:
Start IV access and fluids -- NS or LR 500-1000 mL bolus
ECG -- Check QTc before dopamine antagonist (contraindicated if QTc >500 ms)
Diphenhydramine 25 mg IV push -- Give first to prevent akathisia
Metoclopramide 10 mg IV over 15 min (or prochlorperazine 10 mg IV over 5-10 min) -- Give immediately after diphenhydramine
Ketorolac 30 mg IV push (15 mg if elderly, renal impairment, or <50 kg) -- Give simultaneously with step 4
Reassess at 30 minutes -- If inadequate response, repeat metoclopramide 10 mg IV x1
Dexamethasone 10 mg IV push -- Give before discharge to reduce recurrence
Reassess at 60 minutes -- If still refractory, proceed to second-line agents (magnesium, valproate, nerve block, or sumatriptan)
Key Reminders:
- Always co-administer diphenhydramine with any dopamine antagonist
- Do not use ketorolac if patient received NSAIDs within 24h or has renal/GI contraindications
- Total ED ketorolac: maximum 2 doses (30 mg each, or 15 mg if dose-reduced)
- Do not combine sumatriptan with ergotamines or give within 24h of each other