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Abstract

Background

Headache following traumatic brain injury (TBI) is a common, yet disabling, disorder with diverse mechanisms and treatment needs that remain poorly defined. Pharmacological regimens are the primary source of remedies for individuals with post-traumatic headaches (PTH). The main objective of this review is to describe the efficacy of pharmacological medications for the treatment of PTH with a specific focus on the effect of these medications on headache characteristics and headache-related quality of life (QoL).

Methods

This systematic review (CRD42024537719) followed PRISMA and SWiM guidelines. PubMed, CINAHL, Scopus, PsycINFO and the Cochrane Library were searched in April 2024 for peer-reviewed articles published in English between 2009 and 2024. Eligible studies included randomized controlled trials, controlled cohort studies, and systematic reviews or meta-analyses evaluating pharmacological treatments for PTH in adults. Studies were excluded if they did not assess outcomes related to PTH pain, only included pediatric populations, used animal models, investigated only non-pharmacological interventions, were case reports, narrative reviews, editorials or conference abstracts, or did not involve human participants with TBI-related headache. Risk of bias was assessed using RoB-2 for Randomized controlled trials (RCTs) and ROBINS-I for the non-randomized studies of the effects of interventions.

Results

Sixteen studies were included in the final review, comprising retrospective observational (n = 7), non-randomized prospective (n = 4) and randomized controlled trials (n = 5). Most studies reported some improvements in headache frequency and intensity following pharmacological treatment, although findings for headache-related QoL were inconsistent. Erenumab showed potential benefits for persistent PTH in small, uncontrolled studies of civilian samples. However, findings on its impact on headache-related QoL should be interpreted with caution, given the high discontinuation rate observed. Prazosin demonstrated similar benefits in military populations, with minimal side effects. In the acute care setting, metoclopramide, co-administered with diphenhydramine to minimize side effects, was associated with short-term relief of headache symptoms. Of the RCTs, only two had a low risk of bias, of which only one specifically focused on PTH.

Conclusions

Pharmacological treatments for PTH may provide improvements in headache frequency and intensity; however, evidence for their efficacy is limited and inconsistent. Given the limited high-quality evidence overall, no specific clinical recommendations can be made at this time. Future research should prioritize rigorous, controlled studies, particularly comparative effectiveness trials, and explore holistic, personalized approaches that incorporate treatment of psychiatric comorbidities and consider patient context.

Keywords

efficacy headache frequency headache management headache-related quality of life pharmacological treatment post-traumatic headache (PTH)randomized controlled trials (RCTs)systematic review traumatic brain injury

Post-traumatic headache (PTH) is a common secondary headache disorder.^1–6 By definition, headache onset begins within seven days of traumatic brain injury (TBI), whiplash or similar physical injuries.⁷ Acute PTH resolves within 3 months, and PTH that continues beyond 3 months is considered persistent (PPTH).⁸ About 60% of patients report headache within the first few weeks post-concussion, and roughly 30% continue to experience persistent headache at one year.^9,10 The persistence of PTH is influenced by a number of factors, including the specific population studied (e.g. athletes, military personnel or general population), injury severity, age and sex differences.^11–13 In US military populations, headache is the most common symptom after sustaining a TBI,¹⁴ with estimates suggesting that up to half may develop persistent headaches.^15,16

The clinical management of PTH is challenging and is associated with significant occupational and functional consequences.^17–19 Clinically, PTH often presents with overlapping features of primary headache, including migraine-like hallmarks (e.g. photophobia and nausea) and/or tension-type qualities (e.g. pressure/steady pain, bilateral distribution).^20–29 Current treatment guidelines from the AAN/AHS³⁰ and VA/DoD³¹ recommend phenotype-targeted pharmacological interventions, but these are largely repurposed from primary headache disorders.^32–34 Preventative (e.g. topiramate, amitriptyline) and abortive (e.g. non-steroidal anti-inflammatory drugs (NSAIDs)) medications are used, yet their efficacy in PTH is inconsistent.^34,35

This reliance on borrowed therapies stems in part from the application of the neurogenic inflammation model, one of several proposed mechanisms in migraine pathophysiology.^36,37 This model posits that neuropeptides like calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38 (i.e. PACAP-38) drive pain through activation of the trigeminovascular system and peripheral neurogenic inflammation.^38,39 Although PTH shares clinical features with primary headache disorders (including migraine), mechanisms may vary temporally. Indeed, by definition, the onset of PTH is dependent on trauma-based triggering, which is considered to initiate migraine-like biology in early phases, although, notably, may also be more likely to give way to broader central sensitization^40,41 and is strongly influenced by other psychosocial factors that are not captured by the neurogenic inflammation model. Accordingly, while this framework has informed the implementation of promising treatments for PTH (including CGRP monoclonal antibodies and small-molecule CGRP receptor antagonists, commonly referred to as gepants), the intersection of neurobiological and psychological processes is central. Specifically, affective distress is highly prevalent in TBI populations, which can prolong and exacerbate pain.^41–43 In military service members, conditions like depression and PTSD are common and have been directly linked to greater headache-related disability in PPTH.^44–47 Assuming that co-occurring psychological factors actively influence the underlying biology, PTH may be more accurately understood through models that emphasize interactions between neurobiological and psychological mechanisms (i.e. a biopsychosocial model).

Given the lack of therapies specifically developed for PTH, and the yet incompletely understood pathophysiology, we hypothesize that available pharmacologic treatments, largely repurposed from primary headache disorders, may incompletely address the therapeutic needs of the condition and that the associated evidence risks being fragmented and/or methodologically heterogeneous. Thus, the aim of this review is to synthesize and critically appraise the existing evidence on pharmacologic treatments for acute and persistent PTH in adults, with a specific focus on their effects on headache frequency, pain intensity and headache-related quality of life, aiming to provide clinicians with a clear synthesis of current evidence and identify priorities for future mechanism-driven research for this unique patient population.

Methods

Search strategy

This systematic review was registered in PROSPERO with the registration number (CRD42024537719), where the protocol can be accessed. Searches were conducted in April 2024 in five bibliographic databases: PubMed, CINAHL, Scopus, PsycINFO and Cochrane Library. The search strategy was developed in coordination with a librarian and is detailed in the Supplementary material (Doc. S1 ). The search string combined keywords and subject headings related to PTH treatments. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)⁴⁸ and the Synthesis Without Meta-analysis extension (SWiM).⁴⁹ The search was subjected to PRESS peer review using a modified version of the PRESS document⁵⁰ and was then translated into all included databases.

Two investigators (SS and ES) initially screened articles by title and abstract, followed by a comprehensive full-text review to determine eligibility for inclusion. Web-based Rayyan⁵¹ was used to screen and select studies that met the inclusion criteria. Two additional investigators (DDM and MJP) reassessed all selected articles. By consensus among the four investigators, article selection was finalized. Key methodological details, sample characteristics (including headache persistence and TBI severity), pharmacological agents and outcome measures were reported.

Eligibility criteria

We included peer-reviewed randomized controlled trials (RCTs), controlled cohort studies, observational studies and systematic reviews or meta-analyses published in English between 2009 and 2024 to capture contemporary evidence on pharmacological treatments for PTH in adults (≥ 18 years). Eligible studies had to report at least one outcome related to headache frequency, headache intensity or headache-related quality of life (QoL) in participants with TBI-related headache.

We excluded studies that: (i) did not assess outcomes related to PTH pain; (ii) included only pediatric populations; (iii) used animal models; (iv) investigated only non-pharmacological interventions; (v) were case reports, narrative reviews, editorials or conference abstracts; or (vi) did not involve human participants with TBI-related headache.

Synthesis methods and effect estimates

SWiM (Synthesis Without Meta-analysis) guideline⁴⁹ and the Effect Direction Plot method^52,53 were used to summarize and group each study into conceptual outcome domains (e.g. headache frequency, intensity or headache-related QoL). Effect Direction plots are particularly useful in reviews that incorporate non-randomized studies, such as the present study, due to the variety of study designs and outcomes often reported in these trials.⁵² Following recommended procedures,⁵² related outcomes within each study were grouped into domains, and the overall effect direction was determined by vote counting. Where multiple outcomes within a study all pointed in the same direction, that direction was recorded. Where outcomes varied, we applied the SWiM guideline convention of requiring ≥ 70% concordance to assign a direction as recommended by the 2019 Cochrane Handbook; if < 70% of outcomes agreed, the result was classified as mixed/unclear.⁵² To avoid dominance of studies reporting multiple outcomes or timepoints, each study contributed only one ‘vote’ per domain.

The direction and strength of treatment effects across all studies evaluating pharmacologic interventions for PTH were summarized and categorized by outcome domains (headache frequency, intensity, headache-related QoL) and study design in Table 1.

Table 1.
Effect direction across studies (grouped by risk of bias).

Study Intervention Design Frequency Intensity Disability RoB

Ruff et al. (2009)(72) Prazosin Contr cohort ▴ ▴ Serious

DiTommaso et al. (2013)(60) Combination Contr cohort ▴ Serious

Friedman et al. (2018)(58) Metoclopramide + diphenhydramine Contr cohort ▴ ▴ ▴² Serious

Ashina et al. (2020)(61) Erenumab Contr cohort ▴² ▴ ▴ Serious

Erickson (2011)(71) Topiramate, triptans Retro Obs ▴ ▴ Serious

Yerry et al. (2015)(67) Botulinum toxin Retro Obs ▴ ▴ ▴ Serious

Kazerooni et al. (2015)(68) Botulinum toxin Retro Obs ▴ ▴ Serious

Carabenciov et al. (2019)(69) Amantadine Retro Obs ▴ Serious

Cushman et al. (2019)(70) TCAs, gabapentin Retro Obs ▴ ▴ Serious

Charles (2019)(62) Erenumab Retro Obs ▴ ▴ Serious

Buture et al. (2023)(63) Erenumab Retro Obs ▴ ▴² Serious

Hoffer et al. (2013)(57) N-acetylcysteine RCT ▴ Low

Hurwitz et al. (2020)(65) Amitriptyline RCT ◀▶ ◀▶ High

Zirovich et al. (2021)(66) Botulinum toxin RCT ▴² ▴ Some

Friedman et al. (2021)(59) Metoclopramide + diphenhydramine RCT ▴ ▴² ▴ Low

Mayer et al. (2023)(64) Prazosin RCT ▴² ▴ Some

Contr cohort: ‘controlled cohort’; non-randomized prospective study; Retro Obs: retrospective observational study; RCT: randomized controlled trial; RoB: risk of bias. Effect direction: upward arrow ▴: positive effect; downward arrow ▾: negative effect; sideways arrow ◀▶: no change; mixed effects/conflicting results. Sample size in studies: large arrow ▴: > 300; medium arrow: ▴ 50–300; small arrow: ▴< 50. Superscript numbers indicate the number of outcomes reported within each outcome domain. If not shown, the number is 1 by default. Study quality was visually incorporated using a traffic light color code: green = low risk of bias, amber = some concerns, pink = high risk of bias and red = serious risk of bias.

Quality and risk of bias assessment

Version 2 of the Cochrane Risk-of-Bias tool for RCTs (RoB-2)⁵⁴ was used to assess RCTs across five domains: randomization process, deviations from the intended interventions, missing outcome data, outcome measurement and selection of the reported result.⁵⁵ For non-randomized (non-RCTs) studies of interventions, including both controlled cohorts and retrospective observational designs, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool⁵⁶ was applied. ROBINS-I evaluates seven domains: confounding, participant selection, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes and selection of the reported result.⁵⁶ Overall risk-of-bias judgments in RCTs (low, some concerns or high) were assigned based on the highest level of bias identified across domains. Similarly, the overall risk of bias for non-RCTs was determined following the ROBINS-I guidance (low, moderate, serious or critical). Studies rated as ‘serious’ or ‘high’ in any domain were classified accordingly. All outcomes reported in the included studies were extracted and incorporated into the synthesis. For simplicity, the overall risk-of-bias judgments for both RCTs and non-RCTs are visually represented as color codes in the Effect Direction table. Detailed domain-level risk-of-bias assessments are provided in Tables 2 and 3.

Table 2.
Judgment of risk of bias by domain for selected non-randomized studies of intervention based on ROBINS-I.

Source Study design Risk of bias by domain Overall risk of bias

Pre-intervention At intervention Post-intervention

Confounding Selection participants Classifying exposure Deviating from intended intervention Missing data Measuring outcomes Selective reporting of results

Charles et al. (2019)(62) RO Serious Serious Serious Serious Low Serious Serious Serious risk of bias

Buture et al. (2023)(63) RO Serious Serious Serious Serious Low–Moderate Serious Serious Serious to critical

Erickson (2011)(71) RO Serious Serious Serious Moderate Serious Moderate Moderate Serious risk of bias

Yerry et al. (2015)(67) RO Serious Serious Serious Serious Serious Serious Serious Serious to critical

Kazerooni et al. (2015)(68) RO Serious Serious Serious Moderate Serious Serious Serious Serious risk of bias

Carabenciov et al. (2019)(69) RO Serious Moderate Serious Serious Serious Serious Moderate to Serious Serious risk of bias

Cushman et al. (2019)(70) RO Serious Serious Serious Serious Serious Serious Moderate to Serious Serious risk of bias

Ashina et al. (2020)(61) CC Serious Serious Serious Moderate Serious Serious Moderate Serious risk of bias

DiTommaso et al. (2013)(60) CC Serious Moderate Serious Serious Moderate Serious Moderate Serious risk of bias

Friedman et al. (2018)(58) CC Serious Moderate Low Moderate Moderate Serious Low–Moderate Serious risk of bias

Ruff et al. (2009)(72) CC Serious Serious Moderate Serious Serious Serious Moderate to Serious Serious risk of bias

RO: retrospective observational study; CC: ‘controlled cohort’ non-randomized prospective study.

Table 3.
Judgment of risk of bias by domain for selected randomized studies of intervention based on ROB-2.

Source Study design Trial ID Risk of bias by domain Overall risk of bias

Randomization process Deviations from intended interventions Missing outcome data Measurement of the outcome Selection of the reported result

Mayer et al. (2023)(64) Parallel RCT NCT03928496 Low risk Low risk Some concerns Low risk Low risk Some concerns

Zirovich et al. (2021)(66) DB, PC, crossover RCT NCT01856270 Low risk High risk High risk Low risk Low risk High risk

Hurwitz et al. (2020)(65) Single-center, 2-arm, phase II RCT NCT02266329 Low risk Low risk Some concerns Low risk Low risk Some concerns

Friedman et al. (2021)(59) DB, PC, parallel RCT NCT00822263 Low risk Low risk Low risk Low risk Low risk Low risk

Hoffer et al. (2013)(57) DB, PC RCT NCT03220958 Low risk Low risk Low risk Low risk Low risk Low risk

RCT: randomized controlled trial; DB: double-blind; PC: placebo-controlled.

Results

The database search yielded 2280 search results, and two additional articles were identified through a manual search of the reference lists of relevant primary articles. After removing duplicates, 1693 articles were screened by title and abstract and 21 were retrieved for full-text assessment. Ultimately, 16 articles met the inclusion criteria and were reviewed in this report (Figure 1).

Figure 1.
PRISMA flow chart depicting the selection process of studies for systematic review.

Of the 16 studies, four focused on abortive treatments^57–60 and the other 12 either specifically evaluated preventive medications or combined pharmacotherapies.^61–72 Study populations were highly heterogeneous: nine included civilians or athletes with acute or persistent PTH,^58–63^,65,69,70 while seven enrolled military service members and/or veteran populations.^{57,65,66–68}^,71,72 Designs included five RCTs,^{57,59,64–66} four controlled cohort^58,60,61,72 and seven retrospective observational studies.^{62,63,67–71} Tables 4 and 5 summarize the study characteristics for all 16 included studies, categorized by non-RCTs and RCTs. To facilitate interpretation, a concise summary of findings is provided in Table 6, presenting key quantitative results for each study, including absolute and relative changes or responder rates where available, alongside a synthesis of reported adverse events.

Table 4.
Overview of the observational studies on pharmacological headache treatment

Source Study design Cohort characteristics Intervention (dose/type/adverse events/) Outcome measures Desired effects (intensity, frequency, duration) Key findings

Erenumab (CGRP monoclonal antibody)

Ashina et al. (2020)(61)
Non-randomized, single-arm trial

Screening 0–2 weeks; baseline 4 weeks; open-label 12 weeks

n = 100, Civilian

F = 75%, M = 25%

Mean age: 35.1 years

PPTH

HA phenotype: Chronic migraine-like (53%), combined episodic migraine-like/TTH-like HA (34%), chronic TTH-like (13%)

Erenumab

140 mg monthly by two subcutaneous 1-ml injections

Preventative

AE: in 78 patients (constipation, injection-site reactions, dizziness, worsened HA)

HA frequency and intensity

≥ 25/50/75% reduction in HA days

HIT-6

2.8 ± 6.8-day reduction in moderate to severe HA by weeks 9–12

28% achieved ≥ 50% reduction in mean number of moderate to severe HA days

HIT-6 score decreased from 61.6 ± 5.2 at baseline to 57.0 ± 8.2 at week 12

44% of patients achieved a ≥ 5-point reduction in HIT-6

Erenumab reduced the frequency of moderate to severe HA days in patients with PPTH

Well-tolerated: 89% of patients received all three doses

Low discontinuation rate due to adverse events

Charles et al. (2019)(62)
Retrospective case series

Pre -post comparison

2 months FU

n = 7, Civilian

F = 5, M = 2

Acute PTH

HA phenotype: Migraine

Erenumab

140 mg x1

Preventative

AE: low incidence of injection site reactions and constipation

Baseline MHDs

HIT-6

95% reduction in the mean number of HA days (SD = 1.22, p < 0.001)

HIT-6 scores decreased from > 60 to < 49 2–3 months after treatment

Effective in treating PTH with migraine phenotype

Buture et al. (2023)(63)
Retrospective, open-label, observational audit in a real-world setting

Measures collected every 3-12 months until study ended in 2019

n = 82, Civilian

F = 54, M = 28

F mean age: 44 ± 13 years

M mean age: 45 ± 14 years

PPTH

HA phenotype: Treatment-refractory headache conditions

Erenumab

70 mg for 3–4 months; increase to 140 mg if inadequate response/no side effects; 21% started at 140 mg (BMI > 30)

Preventative

AE = NS

HIT-6

MIDAS

MSQ

35% improved headache intensity and migraine symptoms

Median reduction in HIT-6 (4.25-5 points) over the first year

MIDAS reduced by 14 points compared to baseline

Erenumab offers a meaningful benefit in a subset of highly refractory patients

High discontinuation (65%) mainly due to lack of efficacy, or side effects

Antidepressants, anticonvulsants and triptans

Erickson (2011)(71)
Retrospective cohort study

3 months FU

n = 100 (77 Blast, 23 non-blast), Active-duty US Army

F = 1, M = 99

Mean age: 28.7 years

PPTH

HA phenotype: Mostly migraine

Amitriptyline 25–50 mg, Nortriptyline 25–50 mg (antidepressants); Topiramate 100 mg, Propranolol LA 80 mg, Valproate ER 500 mg (prophylactic); Triptans

Abortive

AE = NS

Headache frequency

MIDAS

Response to abortive medications

HA frequency reduced from 17.1 to 14.5 days /month

Non-blast PPTH patients showed a greater reduction in headache frequency (41%) compared to blast PTH patients (9%)

Topiramate users: 23% reduction in HA frequency (p = 0.02)

Triptan users: 70% relief within 2 h (p = 0.01)

Topiramate effective for PPTH in military

Triptans are often effective for aborting acute headaches in PPTH

Low-dose TCAs show little efficacy

Blast-related PTH may be less responsive to prophylactics

Cushman et al. (2019)(70)
Retrospective study with 3 groups (no meds, gabapentin, TCAs)

1-year FU

n = 277, Civilian/athletes

No-Med group (n = 123), M = 56, Mean age: 20.9 years

Gabapentin group (n = 60), M = 36, Mean age: 24.8 years

TCA group: (n = 94), M = 47, Mean age: 24.6 years

PPTH

TCAs and gabapentin

Median doses: Gabapentin 900 mg, TCAs 20 mg

Preventative

AE = cognitive side effects, including drowsiness, mental slowness and nausea

PCSS

HA dropped from 4.4 to 3.2 after TCAs, not significant

Symptom score decreased significantly with TCAs (64 to 33, p = 0.005)

No significant symptom decreases with gabapentin

More sustained improvement with TCAs compared to gabapentin

Prazosin (alpha-1 blocker)

Ruff et al. (2009)(72)
Observational study with pre- and post-assessment

FU: 9-week and 6-month

n = 74, Veterans

F = 5, M = 69

Mean age: 29.4 years

PPTH

HA phenotype: 40.5% TTH, 18.9% migraine-like HA and 40.5% mixed-type HA

Prazosin + Sleep hygiene counseling

Dose started at 1 mg QHS (at bedtime) and increased weekly to 2 mg, 4 mg, 5 mg and 7 mg. Final treatment dose was 7 mg at bedtime

Preventative

AE = Abnormalities in liver function, changes in bowel habits, skin rash or pruritis, daytime somnolence, light-headedness, postural hypotension

Headache pain intensity (NRS)

Headache frequency per month

MOCA

Sleep quality

Peak HA pain decreased from 7.28 to 4.08 (SD = 0.19)

HA per month reduced from 12.40 to 4.77 (SD = 0.34)

Cognitive performance improved from 24.5 to 28.6 (SD = 0.59) after 9 weeks

Sleep gains from prazosin maintained at 6 months

Improving sleep is an effective first step for treating PPTH in OIF/OEF veterans

Botulinum toxin

Yerry et al. (2015)(67)
Real-time retrospective consecutive case series between August 2008 to August 2012

Charts reviewed using pharmacy records searched by ICD-9 code for chronic migraine and PTH

n = 64, Active-duty service members

F = 1, M = 63

Mean age: 31.3 years

PPTH

HA phenotype: mixed (chronic TTH/migraine/CD)

BoNT/A

FDA FSFD (155U) was the primary protocol; some received FSFD+CD or FSFD+FTP (∼200U); a few had FTP only or focal injections (e.g. 50 U for nummular pain)

Preventative

AE = neck pains and HA

GEC

Occupational outcome

HA characteristics

GEC improved in 41 (64.1%), unchanged in 18 (28.5%), worsened in 2 (3.2%)

Of 48 soldiers with continuous HA, 26 (54.1%) stopped treatment, 11 (22.9%) experienced some or much improvement, 22 (46%) left the military

2/3 of patients reported improvement with BoNT/A

Patients treated further from injury more likely to remain on active duty

BoNT/A offers a well-tolerated preventive option for PPTH

Kazerooni et al. (2015)(68)
Retrospective case series with electronic chart reviews

Typical FU at 3 months after initial injection

n = 21, US veterans

F = 52%, M = 48%

Mean age: 40 years

PPTH

HA phenotype: Migraine

Incobotulinumtoxin A

150 units of incobotulinumtoxin A per injection cycle

Preventative

AE = NS

Headache days/month

Headache intensity

Duration of action

Significant reduction in HA days per month: 19.1 vs. 9.1 days (p < 0.001)

Significant reduction in HA intensity: 8.3 vs. 4.1 (p < 0.001)

Those with a history of TBI, HA days/month decreased from 19.5 to 6.7

Duration of action averaged 81.9 days (median 70 days)

IncobotulinumtoxinA was effective in a small patient population

Analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)

DiTommaso et.al. (2013)(60)
Observational cohort study

Patients in level 1 trauma center in Seattle

FU at 3, 6 and 12 months post injury

n = 212, Civilian (analysis focused on 167 with HA symptoms)

F = 25%, M = 75%

Mean age: 42.1 years

Acute and PPTH

HA phenotype: Migraine, TTH, cervicogenic and unclassified

Self-reported medication use patterns rather than administering specific interventions

Most commonly NSAIDS and acetaminophen, but also triptans, opiates, antiseizure, anxiolytics and antidepressants

Doses varied by medication type

AE = NS

Self-reported effectiveness of headache treatment by participants following mTBI

Most participants reported that their medications provided partial or no relief

Only 26% of those with migraine/probable migraine and 70% with TTH reported complete relief

Overall, headache treatment was generally inadequate, especially for migraine phenotypes

Amantadine (Antidyskinetic)

Carabenciov et al. (2019)(69)
Retrospective review of consecutive patients with PCS at Mayo Clinic

No comparison group or placebo

33% dropout rate before completing a full course

n = 33 (11 discontinued for AE; 22 completed a full trial), Civilian

F = 13, M = 20

Mean age: 35 years

PPTH

HA phenotype: Mixed presentation

Amantadine

Complete trial was defined as 100 mg twice per day for 2 months

Preventative

AE = 11 discontinued for dizziness, nausea, and/or worsened HA

Symptom improvement based on physician documentation

80% of patients (n = 22) had improvement in their HAs

Amantadine was prescribed for PCS, not specifically PTH

HA improvement noted

Metoclopramide + Diphenhydramine (Antiemetic)

Friedman et al. (2018)(58)
Prospective, open-label study for patients with acute PTH in the ED

FU at 1 h, 2 h, 48 h and 7 days for some outcomes

n = 21, Civilian

F = 16, M = 5

Mean age: 45 years

Acute PTH

HA phenotype: NS

IV metoclopramide + diphenhydramine

Metoclopramide 20 mg + diphenhydramine 25 mg across 15 minutes

Abortive

AE = sleepiness

Pain scale

Functional status

Patient satisfaction

PCSS

SCAT

Headache frequency

95% reported HA improvement to no worse than mild

Mean PCSS Score improved from 47.5 (SD 29.4) before treatment to 10.9 (SD 14.8) at ED discharge

Score remained at 11.4 (SD 21.4) 1 week after treatment

IV metoclopramide 20 mg + diphenhydramine 25 mg is effective and well-tolerated for acute PTH in ED

2/3 report no relapse after discharge

75% report continued relief 1 week later

F: females; M: males; HA: headache; PTH: post-traumatic headache; PPTH: persistent post-traumatic headache; mTBI: mild traumatic brain injury; AE: adverse events; TTH: tension-type headache; FU: follow-up; HIT-6: headache impact test-6; MIDAS: migraine disability assessment; MSQ: migraine specific quality of life; MHDs: monthly headache days; NS: not specified; OIF: operation Iraqi freedom; OEF: operation enduring freedom; BMI: body composition index; TCAs: tricyclic antidepressants; MOCA: Montreal cognitive assessment; NRS: numeric rating scale; SY: symptom; ICD-9: International Classification of Diseases, 9th edition; BoNT/A: onabotulinum toxin A; FDA: Food and Drug Administration; FSFD: fixed site, fixed dose; CD: cervical dystonia; FTP: follow the pain; U: units; GEC: global evaluation of change; NSAIDs: non-steroidal anti-inflammatory drugs; PCS: post-concussion syndrome; ED: emergency department; IV: intravenous; PCSS: post-concussion symptom scale; SCAT: sport concussion assessment tool.

Table 5.
Overview of the clinical trials on pharmacological headache treatment.

Source Study design Study cohort baseline characteristics Intervention (dose/type/adverse events/) Outcome measures Desired effects (changes in intensity, frequency, duration) Findings/key points

Prazosin (alpha-1 blocker)

Mayer et al. (2023) (64)
Parallel-group RCT, 22 weeks total

4-week baseline, 5–7-week dose titration, 12-week maintenance

2:1 prazosin to placebo ratio

Completion rates: prazosin 94%, placebo 88%

n = 48, Veterans and Active duty US service members

F = 44, M = 4

Mean age: 43 years

PPTH

HA phenotype: Migraine, TTH, and mixed

Prazosin

Titrated gradually upward; maximum dose of 5 mg morning and 20 mg evening, or as tolerated,

Preventative

AE = Dizziness/vertigo, Syncope/fall, Palpitations, Nasal congestion, Nausea/vomiting, Morning drowsiness/lethargy, Peripheral edema, Urinary incontinence, Hypotension

Change in the 4-week frequency of qualifying headache days

Reduction in qualifying headache days

Change in HIT-6 scores

Baseline HA: prazosin 18.3 (±1.6), placebo 18.6 (±2.3) per 4 weeks

At week 12, prazosin group had 11.9 ± 1.0 fewer HA days vs. 6.7 ± 1.5 for placebo (5.2 days difference, 95% CI [−8.8, −1.6], p = .005)

≥ 50% reduction in HA frequency (p = 0.004)

Prazosin group had lower HIT-6 scores (p = 0.004)

Study drug was generally well tolerated

Botulinum toxin

Zirovich et al. (2021) (66)
Prospective, double-blind, randomized, placebo-controlled, cross-over trial

Monthly FU for 11 weeks

n = 40, Veterans from LA, CA

F = 2, M = 38

Mean age: ∼34 years

PPTH

HA phenotype: Mixed migraine and TTH

BoNT/A

0.1 ml of either BoNT/A or normal saline was injected into 31 facial and cervical muscle sites as per BoNT/A clinical trials

Preventative

AE = pain, forehead paresthesia, injection site itching, sinusitis, dizziness, blurred vision, eyelid ptosis, eye irritation, neck weakness, sensitivity to light and twitching eye

Headache frequency

Headache days per week

Headache pain severity

HA per week decreased by 2.24 (43.3%) with BoNT/A (p < 0.001)

HA days per week decreased by 2.24 (44.4%) at 16 weeks (p < 0.001)

HA pain severity reduced by 0.06 with BoNT/A (p = 0.02)

Significant reduction in number of HA days/week in the BoNT/A group compared to placebo over 16 weeks

AE were generally mild and transient, typical of injection site responses

Amitriptyline (antidepressants)

Hurwitz et al. (2020) (65)
Single-center, 3-month, 2-arm (immediate vs. delayed) prospective phase II trial

Assessing efficacy and feasibility

90-day duration

n = 50 (24 immediate, 26 delayed), Civilian

F = 22, M = 28

Mean age: 35.7 years

PPTH

HA phenotype: NS

Amitriptyline

Gradually increased from 10 to 50 mg daily

Preventative

AE = Increased QTc, dry mouth, decreased libido, daytime fatigue, increased HA

Headache frequency

Headache intensity

Medication compliance

Diary compliance

Cognitive testing

Low compliance with daily HA diary: 58% (29/50) completed daily entries

Only 10 participants had 100% completion

No differences in HA frequency or severity between immediate and delayed medication start

Could not determine the benefit of amitriptyline as a HA preventive due to challenges with recruitment, retention, and compliance

Metoclopramide + Diphenhydramine (Antiemetic)

Friedman et al. (2021) (59)
Randomized, double-blind, placebo-controlled, parallel-group study

FU at 48 h and 7 days later

n = 160 (79 placebo, 81 exp), Civilian

F = 107, M = 53

Mean age: ~44.5

HA phenotype: Acute PTH

IV metoclopramide + diphenhydramine

Metoclopramide 20 mg + diphenhydramine 25 mg across 15 min

Abortive

AE = drowsiness, akathisia, dizziness, diarrhea, and typical PCS symptoms

Improvement in headache intensity

Sustained headache relief over 48 h

PCS measured by the PCSS • Use of rescue medication

Patient satisfaction

Headache frequency

Placebo group reported a mean improvement of 3.8 (SD 2.6)

M + D group improved by 5.2 (SD 2.3)

Difference favoring metoclopramide was 1.4 (95% CI 0.7–2.2, p < 0.01)

M + D was more effective than placebo for relief of PTH in the ED

N-acetylcysteine (Glutathione-restoring antioxidant)

Hoffer et al. (2013) (57)
Randomized, double-blind, placebo-controlled at a forward deployed field hospital in Iraq

Evaluations at 3 and 7 days post-baseline

n=81 (Placebo = 40, NAC = 41), Service members

F = 1, M = 80

Mean age: 22 years

Acute PTH

HA phenotype: NS

NAC

4 grams NAC/day (8 x 500 mg pills)

Abortive

AE = NS

Complete symptom resolution by day 7

Improvement in neuropsychological performance (TMT, COWA, AN)

Subjects receiving NAC within 24 h of blast had an 86% chance of symptom resolution

Compared to 42% symptom resolution for placebo

NAC is an effective short-term countermeasure for cognitive and PCS symptoms from blast damage

Early treatment shows greater efficacy

RCT: randomized controlled trial; BoNT/A: botulinum toxin type; PTN: posttraumatic neuralgia; PGIC: Patient Global Impression of Change; NPSI: Neuropathic Pain Symptom Inventory; TMT: trail making test A & B; COWA: Controlled Oral Word Association; AN: animal naming; QTc: corrected QT interval.

Table 6.
Concise summary of findings on pharmacological treatments for post traumatic headache.

Intervention class Evidence base Population Phase Magnitude of effect/responder ate Adverse events

Erenumab Open label Ashina et al., 2020)(61) Civilian Persistent ↓ 2.8 ± 6.8 monthly HA days (moderate–severe); ↓ 1.7 ± 6.9 (any); ↓ HIT-6 by 4.6 pts. Responder ≥ 25/≥ 50/≥ 75%: 47/28/13% (mod-severe); 21/13/6% (any) Constipation, injection-site reactions, dizziness, worsened HA

Not specified

Obs. (Charles et al., 2019)(62) Civilian Acute ↓ 95% monthly HA days; HIT-6 > 60 → < 49 (post-Tx) Not specified

Obs. (Buture et al., 2023)(63) Civilian Persistent ↓ HIT-6 by 4–11 pts; ↓ MIDAS by ≈ 140 pts; ↓ MSQ by 12–16 pts; 35% reported QoL improvement Not specified

Prazosin RCT (Mayer et al., 2023)(64) Military Persistent −11.9 ± 1.0 vs. −6.7 ± 1.5 monthly HA days; −6.0 vs. +0.6 HIT-6 pts; ≥ 50% response 70% vs. 29% Dizziness, vertigo, syncope, palpitations, drowsiness, hypotension, rash, bowel or urinary changes

Obs. (Ruff et al., 2009)(72) Military Persistent Pain 7.3 → 4.1; HA freq 12.4 → 4.8/mo; at 6 mo: 1.9 vs. 7.0 (HA freq); 2.4 vs. 5.8 (pain). Severe pain 8% vs. 75%; ≥ 3 HA/mo 24% vs. 83%. Mild LFT changes, bowel or skin reactions, daytime somnolence, light-headedness

Botulinum Toxin RCT (Zirovich et al., 2021)(66) Military Persistent −2.2 HA days/wk (−44%); pain −0.06 pts/wk vs. +0.04 (placebo) Neck pain, ptosis, eye irritation, weakness, local pain

Obs. (Yerry et al., 2015)(67) Military Persistent 64% improved, 29% unchanged, 3% worsened. Mild HA or neck pain in some

Obs.(Kazerooni et al., 2015)(68) Military Persistent HA days 19.1 → 9.1; Pain 8.3 → 4.1; 81% showed improvement. Not specified

TCAs/Gabapentin Obs. (Cushman et al., 2019)(70) Civilian/Athlete Persistent Gabapentin ↓ HA 1.3 pts (4.5 → 3.2, p = 0.004); TCA ↓ HA 0.9 pts (p = 0.006); TCA symptom score 64 → 33 (p = 0.005). Cognitive side effects (drowsiness, mental slowness, nausea)

Topiramate/Triptans Obs. (Erickson, 2011)(71) Military Persistent Topiramate −4.5 d/mo (−23%, p = 0.02; 48% responders); TCAs −1.8 d/mo (29%); Propranolol −3.2 d/mo (33%); Valproate +1.3 d/mo (20%). Triptans: 70% relief < 2 h Not specified

Amantadine Obs. (Carabenciov et al., 2019)(69) Civilian Persistent 80% improved (headache relief); 33% discontinued due to AEs Dizziness, nausea, worsened HA

Metoclopramide + Diphenhydramine RCT (Friedman et al., 2021)(59) Civilian Acute Change in pain 1.4 pts vs. placebo (95% CI 0.7–2.2, p < 0.01); sustained relief ↑ at 48 h vs. placebo. Drowsiness, akathisia, dizziness, diarrhea

Open label (Friedman et al., 2018)(58) Civilian Acute 71% relief at 1 h; 95% at 2 h; sustained 55–60%; PCSS 47.5 → 10.9 (at discharge) → 11.4 (at 1 wk). Sleepiness

N-Acetylcysteine (NAC) RCT (Hoffer et al., 2013)(57) Military Acute OR 3.6 (p = 0.006) for no day 7 symptoms; symptom resolution 86% (early NAC) vs. 42% (early placebo) and 11% (late placebo) Not specified

Amitriptyline RCT (Hurwitz et al., 2020)(65) Civilian Acute Magnitude of effect not reported; proportions only for ≥ weekly HA and severe pain at day 90 Dry mouth, fatigue, worsened HA

HA: headache; d/mo: days per month, d/wk: days per week, pts: points, QoL: quality of life; MIDAS: Migraine Disability Assessment; HIT-6: Headache Impact Test; MSQ: Migraine-Specific Quality of Life; PCSS: Post-Concussion Symptom Scale; LFT: liver function test; TCA: tricyclic antidepressant; AE: adverse event; Arrows (↓) indicate improvement/reduction, OR: odds ratio, CI: confidence interval, Tx: treatment

The narrative results below are stratified by phase (acute vs. persistent) and population (civilian vs. military/veteran) to highlight differences in treatment contexts and outcomes.

Acute phase treatments

Civilian populations

Anti-nausea (metoclopramide). Two related studies investigated the efficacy of nausea medication as a treatment for acute PTH rescue. Friedman et al.⁵⁸ conducted a prospective, open-label study of IV metoclopramide (plus diphenhydramine, M + D) for patients presenting to the emergency department (ED) with acute PTH. 71% of patients (n = 21) reported headache relief within 1 h of treatment with M + D, and effectiveness increased to 95% by 2 h. At 48 h, 55% of patients maintained sustained headache relief without needing rescue medication. By one week, headache recurrence was reported in >25% of patients, and 21% sought further medical care. Affective/mood changes were minimal.

Building on previous findings, Friedman et al. (2021) conducted a double-blind, placebo-controlled RCT to evaluate the efficacy of M + D for patients (n = 160) experiencing acute PTH following head trauma presented in the ED.⁵⁹ Similar to earlier results, M + D was associated with significant improvement in headache frequency and pain at one hour compared to placebo. There may have been a trend toward fewer mood-related symptoms in the treatment group compared to placebo, although these should be interpreted cautiously.

Analgesics, NSAIDs and triptans. A single study investigated the usage patterns of specific rescue agents as treatment for acute and persistent PTH. Ditommaso et al.⁶⁰ examined medication usage patterns for headache treatment 3, 6 or 12 months after mild TBI (mTBI) using a prospective observational design. Over 70% of patients used over-the-counter analgesics such as acetaminophen and NSAIDs for headache control, with mixed results. Triptans were underutilized in this sample (8%); no conclusions can be drawn regarding their effectiveness in PTH.

Military populations

Glutathione-restoring antioxidant

A single study investigated the efficacy of a glutathione-restoring antioxidant as a treatment for acute PTH following mTBI. Hoffer et al.⁵⁷ implemented an RCT to evaluate the effect of N-acetylcysteine (NAC) versus placebo, both administered in addition to standard mTBI care, on the symptoms associated with blast exposure mTBI in a combat setting (n = 81), of whom 53 reported headache symptoms. NAC, especially when initiated early (within 24 h), was associated with faster resolution of all mTBI-related symptoms by day seven post-blast. Participants who received early NAC had substantially higher odds of being headache-free at day seven compared to those who received placebo after 24 h. NAC also improved neuropsychological performance and balance dysfunction.

Persistent phase treatments

Civilian populations

Monoclonal antibody treatments. Three studies investigated the efficacy of erenumab, a CGRP receptor monoclonal antibody, as a preventative treatment for PTH. Charles⁶² conducted a retrospective case series (n = 7) to evaluate the effect of erenumab in the acute phase of PTH after sustaining mTBI. All patients had normal exam and imaging, were disabled by high-frequency/intense headaches, had failed or been intolerant of conventional migraine preventatives, and most had no prior history of migraine.⁶² The medication was generally well-tolerated. Patients reported improvement in monthly headache days and headache-related disability within days to 4 weeks, with most requiring only one dose.

Buture et al.⁶³ assessed erenumab among patients (n = 82) with treatment-refractory headache conditions, including 15 individuals with PPTH following minor head trauma. Of these, nine reported subjective improvement with erenumab. Some 65% of patients discontinued treatment within 6–25 months.

Ashina et al.⁶¹ conducted an open-label study evaluating the effectiveness of erenumab for PPTH following mTBI (n = 100). A ≥ 50% reduction in monthly headache days of moderate to severe intensity was observed in 28% of participants, while the ≥ 50% responder rate for headache days of any intensity was 13% during weeks 9–12. Erenumab was generally well tolerated, but placebo-controlled RCTs are needed to confirm efficacy and safety.

Antidepressants. Two studies investigated the efficacy of antidepressant agents as preventatives for PPTH. In an RCT, Hurwitz et al.⁶⁵ evaluated the efficacy and safety of amitriptyline in preventing the development of PPTH after mTBI (n = 50). Participants were recruited from ED acute care admissions, outpatient clinics and community brain injury events. This study could not determine the efficacy of amitriptyline for preventing PPTH because of recruitment and adherence problems.

Using a retrospective cohort design, Cushman et al.⁷⁰ evaluated the association of gabapentin and tricyclic antidepressants (TCAs) with headache symptoms over time after mTBI. Headache and symptom scores, which comprised 22 post-concussion related symptoms, improved over time for all patients (n = 277), regardless of medication status, but piecewise regression analysis suggested that symptoms may have improved more rapidly with gabapentin or TCAs compared to the no-med group.

Antidyskinetics. A single study investigated the efficacy of amantadine in the treatment of post-concussion syndromes, including headaches. Using a retrospective observational design, Carabenciov et al.⁶⁹ evaluated the effect of amantadine on post-concussion symptoms, particularly PPTH; 33 patients were reported by physician documentation to have PPTH. One-third (11/33) discontinued because of adverse effects (dizziness, nausea, worsened headaches) and no symptom improvement was recorded in those who discontinued. Of those who completed a full trial, 80% showed improvement in headache symptoms.

Military populations

Antihypertensives

Two studies investigated the efficacy of prazosin, an antihypertensive agent, for PPTH. In a prospective observational cohort, Ruff et al.⁷² evaluated whether treating impaired sleep using prazosin was associated with PPTH headache frequency and severity among operation Iraqi freedom/operation enduring freedom veterans with blast-exposure mTBI (n = 74). The study was conducted as part of quality-assurance monitoring during routine care, with no control group or blinding. Of the 71 participants diagnosed with PTSD, 69 reported poor sleep. Veterans who completed prazosin showed large improvements in headache frequency (from 12.4 to 4.8) and pain intensity (from 7.3 to 4.1) at 9 weeks. Restful sleep rose from 2% at baseline to 100% by 6 months with a significant decrease in daytime sleepiness. A positive result was also significant in cognitive performance.

In an RCT, Mayer et al.⁶⁴ evaluated the efficacy of prazosin for the prophylactic treatment of PPTH in active-duty service members and veterans with blast or blunt mTBI (n = 48). PTSD was present in 66% of the prazosin group and 81% of the placebo group. The prazosin group was associated with a significantly decreased incidence of headaches. Self-reported disability related to headaches was also significantly lower in the prazosin group relative to placebo. Overall, this RCT was assessed to have some concerns of bias.

Botulinum toxins

Three studies investigated the efficacy of botulinum toxins as a treatment for PTH. In a retrospective, uncontrolled design, Yerry et al.⁶⁷ provided preliminary data on the use of onabotulinumtoxinA (BoNT/A) for PPTH in military service members (n = 64). All participants had mTBI; 56.3% of these injuries were blast-related. 64.1% reported being ‘better’ on the global evaluation of change (GEC); 28.5% unchanged; 3.2% worse. Slightly more than half of the cohort were able to maintain or return to active military service.

In an RCT, Zirovich et al.⁶⁶ evaluated the efficacy of a single dose of BoNT/A versus saline placebo in treating PPTH patients (n = 40) reporting mixed complicated and uncomplicated mTBI. BoNT/A treatment was associated with a significant reduction in headache burden, with a cumulative decrease of 2.24 headache days per week over 16 weeks, compared to a slight increase in the placebo group; the between-group difference in headache days was statistically significant. There was also a small but significant reduction in pain severity with BoNT/A versus a non-significant increase with placebo.

Kazerooni et al.⁶⁸ designed a retrospective case series to support the off-label use of incobotulinumtoxinA in reducing headache frequency and intensity among veterans with chronic migraine (n = 21), including a subset with PPTH (n = 6) following TBI. Among these individuals with PPTH, five reported clinically meaningful improvement, with a reduction in headache days per month from a mean of 19.5 to 6.7.

Topiramate, TCAs and triptans

A single retrospective study examined treatment patterns and outcomes for topiramate, tricyclic antidepressants and triptans in service members with PPTH. Erickson et al.⁷¹ conducted a retrospective observational study with follow-up to evaluate treatment outcomes in US Army soldiers (n = 100) with PPTH attributable to mTBI. At baseline, 52% screened positive for PTSD and 38% for depression. Triptans were often effective for aborting acute headache attacks, including both blast-related and non-blast-related PPTH. Topiramate was associated with a significant reduction in headache frequency. In contrast, low-dose TCAs did not show a significant impact on headache frequency. This study supported that a comprehensive headache management plan that addresses PTSD and sleep issues was associated with lower headache-related disability.

Discussion

Overview and key findings

This systematic review highlights the emerging landscape of pharmacological interventions for headaches following TBI. Beyond evaluating overall efficacy, we aimed to assess the extent to which included studies addressed adverse effects, headache frequency, pain intensity and headache-related QoL. Although the effect direction summary indicated predominantly positive effects, the overall strength of the evidence was limited. Most reviewed studies were small in size (all but two of them had n ≤ 100) and often lacked a priori power analyses to justify sample size. In addition, few employed rigorous randomized or controlled designs, and almost all studies suffered from moderate to serious risk of bias. Taken together, these findings support our hypothesis that current pharmacologic treatments for PTH, largely adapted from primary headache disorders, are supported by a fragmented and methodologically heterogeneous evidence base and may not fully meet the therapeutic needs of this population.

Currently, there is insufficient evidence to support the use of erenumab in both acute and persistent PTH in the civilian population. Across the three identified studies, two were uncontrolled and underpowered^62,63 and one was an open-label, single-arm design without a placebo control.⁶¹ While a reduction in headache frequency and intensity was observed, these findings should be viewed as hypothesis-generating rather than evidence for ereumab efficacy. Controlled randomized trials are needed to determine whether erenumab has a clinically meaningful effect in PPTH.

Among veterans and military populations, prazosin has been examined primarily in small and methodologically limited studies. Prazosin has previously been associated with improvements in headache pain in individuals with severe trauma-related sleep issues,⁷³ but larger studies are needed to determine its efficacy for persistent PTH. Thus, the findings should be interpreted cautiously and require validation in larger, controlled trials. Dose-finding studies also help determine whether a lower dose could retain efficacy while decreasing the frequency of adverse events.

Metoclopramide, a dopamine receptor antagonist with analgesic properties, is often administered off-label as a first-line treatment in the ED setting due to its effectiveness in relieving both headache pain and associated nausea in acute migraine management.^74,75 Diphenhydramine is often co-administered in EDs to reduce the side effects of metoclopramide. In the included open-label study, patients experienced headache relief within one hour of M + D administration; however, the lack of a comparison group, small sample size and diminishing effects by one week limit the conclusions.⁵⁸ Subsequent RCT confirmed early benefits when greater pain reduction was observed at one hour in the M + D group compared to placebo.⁵⁹ Although the trial was assessed as low risk of bias, its generalizability is limited by its urban ED setting, and no long-term follow-up was reported.

Antidepressants are considered to offer therapeutic benefits for headache symptoms,⁷⁶ potentially reducing some of the comorbid affective burden. Mechanistically, it is considered that antidepressants may help reduce the frequency and severity of headaches by influencing serotonin and other neurotransmitters.^77,78 However, evidence for their use in preventing PPTH remains limited and inconclusive. In the RCT evaluating amitriptyline,⁶⁵ the risk of bias was assessed as high due to recruitment difficulties, poor medication adherence and incomplete daily diary records. Amitriptyline may be effective for migraine prevention,⁷⁸ but this trial did not demonstrate efficacy for PPTH. A large retrospective cohort examining gabapentin and TCAs reported symptom improvement across all groups,⁷⁰ but findings were constrained by the retrospective design, substantial loss to follow-up and absence of a control group.

Evidence supporting the use of botulinum toxin for PTH remains limited and methodologically weak. Mechanistically, BoNT/A is considered to exert its effects through presynaptic inhibition of nociceptive neurotransmitters and neuropeptide release (e.g. glutamate, substance P and CGRP), which may lead to muscle relaxation.^68,79 Although the blocking mechanism could be relevant to PTH, the retrospective and open-label study designs included in this review limit the strength of inference. IncobotulinumtoxinA was evaluated in one small retrospective case series and was associated with clinically meaningful improvement in a subset of patients with PPTH. Larger, controlled trials are needed to determine whether either formulation provides consistent benefit for PPTH.

Preliminary evidence suggests that N-acetylcysteine (NAC) may improve post-concussive symptoms when administered early after blast exposure.⁵⁷ The included RCT, conducted in an active combat zone, reported improvements in multiple areas and was judged to have a low risk of bias. However, limitations included a short follow-up period, a homogeneous military sample, and logistical challenges inherent to the combat environment.

Generalizability and other studies

These findings align with prior literature indicating that most pharmacological approaches for PTH have been extrapolated from treatments for primary headache disorders such as migraine and tension-type headache. Erenumab and other CGRP-targeting monoclonal antibodies, for example, have been widely used in migraine prophylaxis since 2018 by blocking CGRP signaling(80). An obvious next step was the evaluation of these therapies for PTH treatment. Individuals with PPTH demonstrate hypersensitivity to CGRP; CGRP infusions reliably induce migraine-like headaches in this population.^81,82 Preclinical models indicated that early and continuous blockade of CGRP using MaB-derived therapies after mTBI prevents both acute PTH and the establishment of a sensitized state that leads to PPTH.⁸³ Although these biological parallels make CGRP antagonists such as erenumab attractive as mechanism-based treatments, the clinical evidence remains too limited to support any definitive conclusions.

Treatment approaches for military populations must account for common comorbidities, including PTSD, which affects almost 30% of veterans and service members,⁴⁵ as well as high rates of anxiety, depression and medication overuse.⁸⁴ Among individuals with comorbid PPTH and affective distress, some pharmacologic interventions that target psychiatric and/or sleep-related conditions, such as prazosin, appear to be effective.^73,85 A multidisciplinary care model that combines headache management medication with behavioral interventions may be especially effective.⁴¹

Headache remains a common complaint among the 1.4 million patients who visit US EDs annually after head trauma,⁸⁶ and future research should explore optimal dosing and duration of rescue medications, such as metoclopramide, and whether early intervention can improve longer-term outcomes, including comorbid symptoms like depression, sleep disturbances, and anxiety, which often affect individuals with PTH.

Pharmacological treatments remain the most accessible pain management option for many individuals with PTH, particularly those with limited resources or time. This review provides an updated synthesis of available evidence to support clinical decision-making, although consistent with prior reviews,^34,87 our conclusions are limited by the scarcity of high-quality, powered trials across both abortive and preventive therapies. Nevertheless, this work adds value by reassessing the literature and interpreting the data through the most recent lens. Unlike previous reviews that included multiple treatment types and mixed populations,³⁴ this review focuses solely on pharmacological interventions in adults to deliver a precise assessment of treatment effectiveness.

Future research direction

There is a clear need for powered, randomized, placebo-controlled clinical trials to rigorously evaluate the efficacy and safety of both abortive and preventative treatments for PTH. Current evidence is largely observational or based on expert opinion, with few RCTs. Further research is warranted to evaluate newer treatment options or re-evaluate old treatment paradigms across diverse populations and headache phenotypes.

It is important to recognize that, while the neurogenic inflammation model informs our understanding of the pathophysiology of primary headaches and has effectively provided key targets for pharmacotherapies, it may be an incomplete model to guide the development of treatments for secondary headaches. Injury mechanisms leading to PTH, such as motor vehicle collisions, combat-related blast exposures and physical assaults, are often accompanied by significant psychological stressors that can influence symptom expression, treatment response and recovery trajectories. Investigators who explore pathophysiology and treatment models that account for both biological and psychological dimensions of PTH may develop more consistently effective and personalized therapies.

Strengths and limitations

This systematic review provides a comprehensive synthesis of pharmacological treatments for PTH in adults, incorporating both RCTs and observational studies across military and civilian populations. Key strengths include a registered protocol (PROSPERO), a librarian-assisted and PRESS-reviewed search strategy, adherence to PRISMA and SWiM guidelines, and rigorous risk-of-bias assessments using validated tools (RoB-2 and ROBINS-I). The review offers clinically relevant insights by focusing on adult populations and well-defined headache outcomes. However, the findings are limited by methodological heterogeneity among controlled studies, and the rest were retrospective or observational. Additionally, the exclusion of non-English and unpublished literature may have introduced bias. Despite these limitations, the review identifies important gaps and offers direction for future high-quality research. Finally, while we acknowledge that meta-analyses may often provide added insight, the substantial clinical and methodological heterogeneity across studies was assessed to be more likely to introduce additional bias than to answer questions, and so a meta-analysis was not conducted.

Conclusions

Pharmacological therapies are a key component of guideline-based, multimodal treatment for PTH, yet none are specifically developed, nor approved, for this condition. Among military population with PPTH and comorbid psychiatric distress, prazosin has demonstrated preliminary benefits; among civilians without such comorbidities, erenumab may warrant further study as a potential mechanism-based therapy. Metoclopramide plus diphenhydramine appears effective for short-term relief in emergency settings. However, these findings are largely derived from small or uncontrolled studies, underscoring the urgent need for adequately powered randomized trials. Future research should aim to clarify the underlying mechanisms distinguishing PTH from primary headache disorders and to develop targeted, evidence-based pharmacologic strategies for both acute and persistent PTH.

Public health relevance

Pharmacological therapies remain the first-line and most accessible treatment for PTH, with behavioral interventions serving as adjuncts rather than replacements.

Early studies of CGRP monoclonal antibodies (e.g. erenumab) suggest possible benefit, but current data are small, uncontrolled, or retrospective.

Prazosin may help some patients with co-occurring PTSD and sleep disturbance, although findings come from limited and heterogeneous studies.

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Supplemental material, sj-docx-1-cep-10.1177_03331024261441563 for Efficacy and outcomes of pharmacological treatments for headaches after traumatic brain injury: A systematic review by Shirin Saleh, Elizabeth M Sanford, Donald D McGeary, Melissa M Cortez, Matt Hayward, Erin D Bouldin, Jacob Kean and Mary Jo V Pugh in Cephalalgia

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sj-docx-3-cep-10.1177_03331024261441563 - Supplemental material for Efficacy and outcomes of pharmacological treatments for headaches after traumatic brain injury: A systematic review

Supplemental material, sj-docx-3-cep-10.1177_03331024261441563 for Efficacy and outcomes of pharmacological treatments for headaches after traumatic brain injury: A systematic review by Shirin Saleh, Elizabeth M Sanford, Donald D McGeary, Melissa M Cortez, Matt Hayward, Erin D Bouldin, Jacob Kean and Mary Jo V Pugh in Cephalalgia

Study	Intervention	Design	Frequency	Intensity	Disability	RoB
Ruff et al. (2009)(72)	Prazosin	Contr cohort	▴	▴		Serious
DiTommaso et al. (2013)(60)	Combination	Contr cohort		▴		Serious
Friedman et al. (2018)(58)	Metoclopramide + diphenhydramine	Contr cohort	▴	▴	▴²	Serious
Ashina et al. (2020)(61)	Erenumab	Contr cohort	▴²	▴	▴	Serious
Erickson (2011)(71)	Topiramate, triptans	Retro Obs	▴		▴	Serious
Yerry et al. (2015)(67)	Botulinum toxin	Retro Obs	▴	▴	▴	Serious
Kazerooni et al. (2015)(68)	Botulinum toxin	Retro Obs	▴	▴		Serious
Carabenciov et al. (2019)(69)	Amantadine	Retro Obs		▴		Serious
Cushman et al. (2019)(70)	TCAs, gabapentin	Retro Obs		▴	▴	Serious
Charles (2019)(62)	Erenumab	Retro Obs	▴		▴	Serious
Buture et al. (2023)(63)	Erenumab	Retro Obs		▴	▴²	Serious
Hoffer et al. (2013)(57)	N-acetylcysteine	RCT		▴		Low
Hurwitz et al. (2020)(65)	Amitriptyline	RCT	◀▶	◀▶		High
Zirovich et al. (2021)(66)	Botulinum toxin	RCT	▴²	▴		Some
Friedman et al. (2021)(59)	Metoclopramide + diphenhydramine	RCT	▴	▴²	▴	Low
Mayer et al. (2023)(64)	Prazosin	RCT	▴²		▴	Some

Source	Study design	Risk of bias by domain	Overall risk of bias
Charles et al. (2019)(62)	RO	Serious	Serious	Serious	Serious	Low	Serious	Serious	Serious risk of bias
Buture et al. (2023)(63)	RO	Serious	Serious	Serious	Serious	Low–Moderate	Serious	Serious	Serious to critical
Erickson (2011)(71)	RO	Serious	Serious	Serious	Moderate	Serious	Moderate	Moderate	Serious risk of bias
Yerry et al. (2015)(67)	RO	Serious	Serious	Serious	Serious	Serious	Serious	Serious	Serious to critical
Kazerooni et al. (2015)(68)	RO	Serious	Serious	Serious	Moderate	Serious	Serious	Serious	Serious risk of bias
Carabenciov et al. (2019)(69)	RO	Serious	Moderate	Serious	Serious	Serious	Serious	Moderate to Serious	Serious risk of bias
Cushman et al. (2019)(70)	RO	Serious	Serious	Serious	Serious	Serious	Serious	Moderate to Serious	Serious risk of bias
Ashina et al. (2020)(61)	CC	Serious	Serious	Serious	Moderate	Serious	Serious	Moderate	Serious risk of bias
DiTommaso et al. (2013)(60)	CC	Serious	Moderate	Serious	Serious	Moderate	Serious	Moderate	Serious risk of bias
Friedman et al. (2018)(58)	CC	Serious	Moderate	Low	Moderate	Moderate	Serious	Low–Moderate	Serious risk of bias
Ruff et al. (2009)(72)	CC	Serious	Serious	Moderate	Serious	Serious	Serious	Moderate to Serious	Serious risk of bias

Source	Study design	Trial ID	Risk of bias by domain	Overall risk of bias
Mayer et al. (2023)(64)	Parallel RCT	NCT03928496	Low risk	Low risk	Some concerns	Low risk	Low risk	Some concerns
Zirovich et al. (2021)(66)	DB, PC, crossover RCT	NCT01856270	Low risk	High risk	High risk	Low risk	Low risk	High risk
Hurwitz et al. (2020)(65)	Single-center, 2-arm, phase II RCT	NCT02266329	Low risk	Low risk	Some concerns	Low risk	Low risk	Some concerns
Friedman et al. (2021)(59)	DB, PC, parallel RCT	NCT00822263	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Hoffer et al. (2013)(57)	DB, PC RCT	NCT03220958	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk

Source	Study design	Cohort characteristics	Intervention (dose/type/adverse events/)	Outcome measures	Desired effects (intensity, frequency, duration)	Key findings
Erenumab (CGRP monoclonal antibody)
Ashina et al. (2020)(61)	Non-randomized, single-arm trial Screening 0–2 weeks; baseline 4 weeks; open-label 12 weeks	n = 100, Civilian F = 75%, M = 25% Mean age: 35.1 years PPTH HA phenotype: Chronic migraine-like (53%), combined episodic migraine-like/TTH-like HA (34%), chronic TTH-like (13%)	Erenumab 140 mg monthly by two subcutaneous 1-ml injections Preventative AE: in 78 patients (constipation, injection-site reactions, dizziness, worsened HA)	HA frequency and intensity ≥ 25/50/75% reduction in HA days HIT-6	2.8 ± 6.8-day reduction in moderate to severe HA by weeks 9–12 28% achieved ≥ 50% reduction in mean number of moderate to severe HA days HIT-6 score decreased from 61.6 ± 5.2 at baseline to 57.0 ± 8.2 at week 12 44% of patients achieved a ≥ 5-point reduction in HIT-6	Erenumab reduced the frequency of moderate to severe HA days in patients with PPTH Well-tolerated: 89% of patients received all three doses Low discontinuation rate due to adverse events
Charles et al. (2019)(62)	Retrospective case series Pre -post comparison 2 months FU	n = 7, Civilian F = 5, M = 2 Acute PTH HA phenotype: Migraine	Erenumab 140 mg x1 Preventative AE: low incidence of injection site reactions and constipation	Baseline MHDs HIT-6	95% reduction in the mean number of HA days (SD = 1.22, p < 0.001) HIT-6 scores decreased from > 60 to < 49 2–3 months after treatment	Effective in treating PTH with migraine phenotype
Buture et al. (2023)(63)	Retrospective, open-label, observational audit in a real-world setting Measures collected every 3-12 months until study ended in 2019	n = 82, Civilian F = 54, M = 28 F mean age: 44 ± 13 years M mean age: 45 ± 14 years PPTH HA phenotype: Treatment-refractory headache conditions	Erenumab 70 mg for 3–4 months; increase to 140 mg if inadequate response/no side effects; 21% started at 140 mg (BMI > 30) Preventative AE = NS	HIT-6 MIDAS MSQ	35% improved headache intensity and migraine symptoms Median reduction in HIT-6 (4.25-5 points) over the first year MIDAS reduced by 14 points compared to baseline	Erenumab offers a meaningful benefit in a subset of highly refractory patients High discontinuation (65%) mainly due to lack of efficacy, or side effects
Antidepressants, anticonvulsants and triptans
Erickson (2011)(71)	Retrospective cohort study 3 months FU	n = 100 (77 Blast, 23 non-blast), Active-duty US Army F = 1, M = 99 Mean age: 28.7 years PPTH HA phenotype: Mostly migraine	Amitriptyline 25–50 mg, Nortriptyline 25–50 mg (antidepressants); Topiramate 100 mg, Propranolol LA 80 mg, Valproate ER 500 mg (prophylactic); Triptans Abortive AE = NS	Headache frequency MIDAS Response to abortive medications	HA frequency reduced from 17.1 to 14.5 days /month Non-blast PPTH patients showed a greater reduction in headache frequency (41%) compared to blast PTH patients (9%) Topiramate users: 23% reduction in HA frequency (p = 0.02) Triptan users: 70% relief within 2 h (p = 0.01)	Topiramate effective for PPTH in military Triptans are often effective for aborting acute headaches in PPTH Low-dose TCAs show little efficacy Blast-related PTH may be less responsive to prophylactics
Cushman et al. (2019)(70)	Retrospective study with 3 groups (no meds, gabapentin, TCAs) 1-year FU	n = 277, Civilian/athletes No-Med group (n = 123), M = 56, Mean age: 20.9 years Gabapentin group (n = 60), M = 36, Mean age: 24.8 years TCA group: (n = 94), M = 47, Mean age: 24.6 years PPTH	TCAs and gabapentin Median doses: Gabapentin 900 mg, TCAs 20 mg Preventative AE = cognitive side effects, including drowsiness, mental slowness and nausea	PCSS	HA dropped from 4.4 to 3.2 after TCAs, not significant Symptom score decreased significantly with TCAs (64 to 33, p = 0.005) No significant symptom decreases with gabapentin	More sustained improvement with TCAs compared to gabapentin
Prazosin (alpha-1 blocker)
Ruff et al. (2009)(72)	Observational study with pre- and post-assessment FU: 9-week and 6-month	n = 74, Veterans F = 5, M = 69 Mean age: 29.4 years PPTH HA phenotype: 40.5% TTH, 18.9% migraine-like HA and 40.5% mixed-type HA	Prazosin + Sleep hygiene counseling Dose started at 1 mg QHS (at bedtime) and increased weekly to 2 mg, 4 mg, 5 mg and 7 mg. Final treatment dose was 7 mg at bedtime Preventative AE = Abnormalities in liver function, changes in bowel habits, skin rash or pruritis, daytime somnolence, light-headedness, postural hypotension	Headache pain intensity (NRS) Headache frequency per month MOCA Sleep quality	Peak HA pain decreased from 7.28 to 4.08 (SD = 0.19) HA per month reduced from 12.40 to 4.77 (SD = 0.34) Cognitive performance improved from 24.5 to 28.6 (SD = 0.59) after 9 weeks	Sleep gains from prazosin maintained at 6 months Improving sleep is an effective first step for treating PPTH in OIF/OEF veterans
Botulinum toxin
Yerry et al. (2015)(67)	Real-time retrospective consecutive case series between August 2008 to August 2012 Charts reviewed using pharmacy records searched by ICD-9 code for chronic migraine and PTH	n = 64, Active-duty service members F = 1, M = 63 Mean age: 31.3 years PPTH HA phenotype: mixed (chronic TTH/migraine/CD)	BoNT/A FDA FSFD (155U) was the primary protocol; some received FSFD+CD or FSFD+FTP (∼200U); a few had FTP only or focal injections (e.g. 50 U for nummular pain) Preventative AE = neck pains and HA	GEC Occupational outcome HA characteristics	GEC improved in 41 (64.1%), unchanged in 18 (28.5%), worsened in 2 (3.2%) Of 48 soldiers with continuous HA, 26 (54.1%) stopped treatment, 11 (22.9%) experienced some or much improvement, 22 (46%) left the military	2/3 of patients reported improvement with BoNT/A Patients treated further from injury more likely to remain on active duty BoNT/A offers a well-tolerated preventive option for PPTH
Kazerooni et al. (2015)(68)	Retrospective case series with electronic chart reviews Typical FU at 3 months after initial injection	n = 21, US veterans F = 52%, M = 48% Mean age: 40 years PPTH HA phenotype: Migraine	Incobotulinumtoxin A 150 units of incobotulinumtoxin A per injection cycle Preventative AE = NS	Headache days/month Headache intensity Duration of action	Significant reduction in HA days per month: 19.1 vs. 9.1 days (p < 0.001) Significant reduction in HA intensity: 8.3 vs. 4.1 (p < 0.001) Those with a history of TBI, HA days/month decreased from 19.5 to 6.7	Duration of action averaged 81.9 days (median 70 days) IncobotulinumtoxinA was effective in a small patient population
Analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)
DiTommaso et.al. (2013)(60)	Observational cohort study Patients in level 1 trauma center in Seattle FU at 3, 6 and 12 months post injury	n = 212, Civilian (analysis focused on 167 with HA symptoms) F = 25%, M = 75% Mean age: 42.1 years Acute and PPTH HA phenotype: Migraine, TTH, cervicogenic and unclassified	Self-reported medication use patterns rather than administering specific interventions Most commonly NSAIDS and acetaminophen, but also triptans, opiates, antiseizure, anxiolytics and antidepressants Doses varied by medication type AE = NS	Self-reported effectiveness of headache treatment by participants following mTBI	Most participants reported that their medications provided partial or no relief Only 26% of those with migraine/probable migraine and 70% with TTH reported complete relief	Overall, headache treatment was generally inadequate, especially for migraine phenotypes
Amantadine (Antidyskinetic)
Carabenciov et al. (2019)(69)	Retrospective review of consecutive patients with PCS at Mayo Clinic No comparison group or placebo 33% dropout rate before completing a full course	n = 33 (11 discontinued for AE; 22 completed a full trial), Civilian F = 13, M = 20 Mean age: 35 years PPTH HA phenotype: Mixed presentation	Amantadine Complete trial was defined as 100 mg twice per day for 2 months Preventative AE = 11 discontinued for dizziness, nausea, and/or worsened HA	Symptom improvement based on physician documentation	80% of patients (n = 22) had improvement in their HAs	Amantadine was prescribed for PCS, not specifically PTH HA improvement noted
Metoclopramide + Diphenhydramine (Antiemetic)
Friedman et al. (2018)(58)	Prospective, open-label study for patients with acute PTH in the ED FU at 1 h, 2 h, 48 h and 7 days for some outcomes	n = 21, Civilian F = 16, M = 5 Mean age: 45 years Acute PTH HA phenotype: NS	IV metoclopramide + diphenhydramine Metoclopramide 20 mg + diphenhydramine 25 mg across 15 minutes Abortive AE = sleepiness	Pain scale Functional status Patient satisfaction PCSS SCAT Headache frequency	95% reported HA improvement to no worse than mild Mean PCSS Score improved from 47.5 (SD 29.4) before treatment to 10.9 (SD 14.8) at ED discharge Score remained at 11.4 (SD 21.4) 1 week after treatment	IV metoclopramide 20 mg + diphenhydramine 25 mg is effective and well-tolerated for acute PTH in ED 2/3 report no relapse after discharge 75% report continued relief 1 week later

Source	Study design	Study cohort baseline characteristics	Intervention (dose/type/adverse events/)	Outcome measures	Desired effects (changes in intensity, frequency, duration)	Findings/key points
Prazosin (alpha-1 blocker)
Mayer et al. (2023) (64)	Parallel-group RCT, 22 weeks total 4-week baseline, 5–7-week dose titration, 12-week maintenance 2:1 prazosin to placebo ratio Completion rates: prazosin 94%, placebo 88%	n = 48, Veterans and Active duty US service members F = 44, M = 4 Mean age: 43 years PPTH HA phenotype: Migraine, TTH, and mixed	Prazosin Titrated gradually upward; maximum dose of 5 mg morning and 20 mg evening, or as tolerated, Preventative AE = Dizziness/vertigo, Syncope/fall, Palpitations, Nasal congestion, Nausea/vomiting, Morning drowsiness/lethargy, Peripheral edema, Urinary incontinence, Hypotension	Change in the 4-week frequency of qualifying headache days Reduction in qualifying headache days Change in HIT-6 scores	Baseline HA: prazosin 18.3 (±1.6), placebo 18.6 (±2.3) per 4 weeks At week 12, prazosin group had 11.9 ± 1.0 fewer HA days vs. 6.7 ± 1.5 for placebo (5.2 days difference, 95% CI [−8.8, −1.6], p = .005) ≥ 50% reduction in HA frequency (p = 0.004) Prazosin group had lower HIT-6 scores (p = 0.004)	Study drug was generally well tolerated
Botulinum toxin
Zirovich et al. (2021) (66)	Prospective, double-blind, randomized, placebo-controlled, cross-over trial Monthly FU for 11 weeks	n = 40, Veterans from LA, CA F = 2, M = 38 Mean age: ∼34 years PPTH HA phenotype: Mixed migraine and TTH	BoNT/A 0.1 ml of either BoNT/A or normal saline was injected into 31 facial and cervical muscle sites as per BoNT/A clinical trials Preventative AE = pain, forehead paresthesia, injection site itching, sinusitis, dizziness, blurred vision, eyelid ptosis, eye irritation, neck weakness, sensitivity to light and twitching eye	Headache frequency Headache days per week Headache pain severity	HA per week decreased by 2.24 (43.3%) with BoNT/A (p < 0.001) HA days per week decreased by 2.24 (44.4%) at 16 weeks (p < 0.001) HA pain severity reduced by 0.06 with BoNT/A (p = 0.02)	Significant reduction in number of HA days/week in the BoNT/A group compared to placebo over 16 weeks AE were generally mild and transient, typical of injection site responses
Amitriptyline (antidepressants)
Hurwitz et al. (2020) (65)	Single-center, 3-month, 2-arm (immediate vs. delayed) prospective phase II trial Assessing efficacy and feasibility 90-day duration	n = 50 (24 immediate, 26 delayed), Civilian F = 22, M = 28 Mean age: 35.7 years PPTH HA phenotype: NS	Amitriptyline Gradually increased from 10 to 50 mg daily Preventative AE = Increased QTc, dry mouth, decreased libido, daytime fatigue, increased HA	Headache frequency Headache intensity Medication compliance Diary compliance Cognitive testing	Low compliance with daily HA diary: 58% (29/50) completed daily entries Only 10 participants had 100% completion No differences in HA frequency or severity between immediate and delayed medication start	Could not determine the benefit of amitriptyline as a HA preventive due to challenges with recruitment, retention, and compliance
Metoclopramide + Diphenhydramine (Antiemetic)
Friedman et al. (2021) (59)	Randomized, double-blind, placebo-controlled, parallel-group study FU at 48 h and 7 days later	n = 160 (79 placebo, 81 exp), Civilian F = 107, M = 53 Mean age: ~44.5 HA phenotype: Acute PTH	IV metoclopramide + diphenhydramine Metoclopramide 20 mg + diphenhydramine 25 mg across 15 min Abortive AE = drowsiness, akathisia, dizziness, diarrhea, and typical PCS symptoms	Improvement in headache intensity Sustained headache relief over 48 h PCS measured by the PCSS • Use of rescue medication Patient satisfaction Headache frequency	Placebo group reported a mean improvement of 3.8 (SD 2.6) M + D group improved by 5.2 (SD 2.3) Difference favoring metoclopramide was 1.4 (95% CI 0.7–2.2, p < 0.01)	M + D was more effective than placebo for relief of PTH in the ED
N-acetylcysteine (Glutathione-restoring antioxidant)
Hoffer et al. (2013) (57)	Randomized, double-blind, placebo-controlled at a forward deployed field hospital in Iraq Evaluations at 3 and 7 days post-baseline	n=81 (Placebo = 40, NAC = 41), Service members F = 1, M = 80 Mean age: 22 years Acute PTH HA phenotype: NS	NAC 4 grams NAC/day (8 x 500 mg pills) Abortive AE = NS	Complete symptom resolution by day 7 Improvement in neuropsychological performance (TMT, COWA, AN)	Subjects receiving NAC within 24 h of blast had an 86% chance of symptom resolution Compared to 42% symptom resolution for placebo	NAC is an effective short-term countermeasure for cognitive and PCS symptoms from blast damage Early treatment shows greater efficacy

Intervention class	Evidence base	Population	Phase	Magnitude of effect/responder ate	Adverse events
Erenumab	Open label Ashina et al., 2020)(61)	Civilian	Persistent	↓ 2.8 ± 6.8 monthly HA days (moderate–severe); ↓ 1.7 ± 6.9 (any); ↓ HIT-6 by 4.6 pts. Responder ≥ 25/≥ 50/≥ 75%: 47/28/13% (mod-severe); 21/13/6% (any)	Constipation, injection-site reactions, dizziness, worsened HA
	Not specified
	Obs. (Charles et al., 2019)(62)	Civilian	Acute	↓ 95% monthly HA days; HIT-6 > 60 → < 49 (post-Tx)	Not specified
	Obs. (Buture et al., 2023)(63)	Civilian	Persistent	↓ HIT-6 by 4–11 pts; ↓ MIDAS by ≈ 140 pts; ↓ MSQ by 12–16 pts; 35% reported QoL improvement	Not specified
Prazosin	RCT (Mayer et al., 2023)(64)	Military	Persistent	−11.9 ± 1.0 vs. −6.7 ± 1.5 monthly HA days; −6.0 vs. +0.6 HIT-6 pts; ≥ 50% response 70% vs. 29%	Dizziness, vertigo, syncope, palpitations, drowsiness, hypotension, rash, bowel or urinary changes
	Obs. (Ruff et al., 2009)(72)	Military	Persistent	Pain 7.3 → 4.1; HA freq 12.4 → 4.8/mo; at 6 mo: 1.9 vs. 7.0 (HA freq); 2.4 vs. 5.8 (pain). Severe pain 8% vs. 75%; ≥ 3 HA/mo 24% vs. 83%.	Mild LFT changes, bowel or skin reactions, daytime somnolence, light-headedness
Botulinum Toxin	RCT (Zirovich et al., 2021)(66)	Military	Persistent	−2.2 HA days/wk (−44%); pain −0.06 pts/wk vs. +0.04 (placebo)	Neck pain, ptosis, eye irritation, weakness, local pain
	Obs. (Yerry et al., 2015)(67)	Military	Persistent	64% improved, 29% unchanged, 3% worsened.	Mild HA or neck pain in some
	Obs.(Kazerooni et al., 2015)(68)	Military	Persistent	HA days 19.1 → 9.1; Pain 8.3 → 4.1; 81% showed improvement.	Not specified
TCAs/Gabapentin	Obs. (Cushman et al., 2019)(70)	Civilian/Athlete	Persistent	Gabapentin ↓ HA 1.3 pts (4.5 → 3.2, p = 0.004); TCA ↓ HA 0.9 pts (p = 0.006); TCA symptom score 64 → 33 (p = 0.005).	Cognitive side effects (drowsiness, mental slowness, nausea)
Topiramate/Triptans	Obs. (Erickson, 2011)(71)	Military	Persistent	Topiramate −4.5 d/mo (−23%, p = 0.02; 48% responders); TCAs −1.8 d/mo (29%); Propranolol −3.2 d/mo (33%); Valproate +1.3 d/mo (20%). Triptans: 70% relief < 2 h	Not specified
Amantadine	Obs. (Carabenciov et al., 2019)(69)	Civilian	Persistent	80% improved (headache relief); 33% discontinued due to AEs	Dizziness, nausea, worsened HA
Metoclopramide + Diphenhydramine	RCT (Friedman et al., 2021)(59)	Civilian	Acute	Change in pain 1.4 pts vs. placebo (95% CI 0.7–2.2, p < 0.01); sustained relief ↑ at 48 h vs. placebo.	Drowsiness, akathisia, dizziness, diarrhea
	Open label (Friedman et al., 2018)(58)	Civilian	Acute	71% relief at 1 h; 95% at 2 h; sustained 55–60%; PCSS 47.5 → 10.9 (at discharge) → 11.4 (at 1 wk).	Sleepiness
N-Acetylcysteine (NAC)	RCT (Hoffer et al., 2013)(57)	Military	Acute	OR 3.6 (p = 0.006) for no day 7 symptoms; symptom resolution 86% (early NAC) vs. 42% (early placebo) and 11% (late placebo)	Not specified
Amitriptyline	RCT (Hurwitz et al., 2020)(65)	Civilian	Acute	Magnitude of effect not reported; proportions only for ≥ weekly HA and severe pain at day 90	Dry mouth, fatigue, worsened HA

Footnotes

Acknowledgements

Dr Pugh was also supported by a Research Career Scientist Award (IK6 HX002608; RCS 17-297).

ORCID iDs

Shirin Saleh

Elizabeth M Sanford

Melissa M Cortez

Matt Hayward

Mary Jo V Pugh

Author contributions

Study concept and design: Shirin Saleh, Elizabeth M. Sanford, Donald D. McGeary and Mary Jo V. Pugh. Analytic planning and/or analyses: Shirin Saleh, Elizabeth M. Sanford, Donald D. McGeary and Mary Jo V. Pugh. Interpretation and discussion of results: Shirin Saleh, Elizabeth M. Sanford, Donald D. McGeary, Melissa M. Cortez, Matt Hayward, Erin D. Bouldin, Jacob Kean and Mary Jo V. Pugh. Drafting the manuscript: Shirin Saleh, Elizabeth M. Sanford, Donald D. McGeary, Melissa M. Cortez, Matt Hayward, Erin D. Bouldin, Jacob Kean and Mary Jo V. Pugh. Revisions for intellectual content and final approval: All authors were involved in the revision process and approval of the final manuscript submitted for publication.

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by the US Department of Defense through the US Army Medical Research and Materiel Command, Congressionally Directed Medical Research Programs, Psychological Health and Traumatic Brain Injury Research Program award (E01 HT9425-23-1-1046) (PI: Donald D. McGeary, PhD).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Data availability statement

The data that supports the findings of this study are available in the supporting information of this article.

Prospero link

Open practices

Supplemental material

Supplemental material for this article is available online.

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Source	Study design	Risk of bias by domain							Overall risk of bias
		Pre-intervention		At intervention	Post-intervention
		Confounding	Selection participants	Classifying exposure	Deviating from intended intervention	Missing data	Measuring outcomes	Selective reporting of results
Charles et al. (2019)(62)	RO	Serious	Serious	Serious	Serious	Low	Serious	Serious	Serious risk of bias
Buture et al. (2023)(63)	RO	Serious	Serious	Serious	Serious	Low–Moderate	Serious	Serious	Serious to critical
Erickson (2011)(71)	RO	Serious	Serious	Serious	Moderate	Serious	Moderate	Moderate	Serious risk of bias
Yerry et al. (2015)(67)	RO	Serious	Serious	Serious	Serious	Serious	Serious	Serious	Serious to critical
Kazerooni et al. (2015)(68)	RO	Serious	Serious	Serious	Moderate	Serious	Serious	Serious	Serious risk of bias
Carabenciov et al. (2019)(69)	RO	Serious	Moderate	Serious	Serious	Serious	Serious	Moderate to Serious	Serious risk of bias
Cushman et al. (2019)(70)	RO	Serious	Serious	Serious	Serious	Serious	Serious	Moderate to Serious	Serious risk of bias
Ashina et al. (2020)(61)	CC	Serious	Serious	Serious	Moderate	Serious	Serious	Moderate	Serious risk of bias
DiTommaso et al. (2013)(60)	CC	Serious	Moderate	Serious	Serious	Moderate	Serious	Moderate	Serious risk of bias
Friedman et al. (2018)(58)	CC	Serious	Moderate	Low	Moderate	Moderate	Serious	Low–Moderate	Serious risk of bias
Ruff et al. (2009)(72)	CC	Serious	Serious	Moderate	Serious	Serious	Serious	Moderate to Serious	Serious risk of bias