Abstract
New daily persistent headache is a chronic, treatment-resistant primary headache disorder with limited guidance on effective management. Despite its significant impact on headache-related quality of life, few studies have identified targeted therapies that contribute to symptom resolution. This study aims to describe the outcomes of pediatric patients diagnosed with new daily persistent headache and assess associations between specific interventions and headache resolution. A retrospective review was conducted using data from a patient registry at Children's National Hospital. Patients diagnosed with new daily persistent headache were included. Demographic characteristics, clinical features, prior treatments, and resolution rates were analyzed. Statistical comparisons were made between patients who experienced headache resolution and those with persistence of headache. A total of 182 pediatric patients were included (mean age: 15.5 years; 78% female). Headache resolution occurred in 47 patients (25.8%). For patients whose new daily persistent headache resolved, coenzyme Q10 (CoQ10) supplementation was the only treatment that reached statistical significance, being more frequently administered in the resolved group compared with the nonresolved group (17% vs 4%, P = .010). Additional treatments approaching statistical significance during resolution of new daily persistent headache included magnesium (P = .086), topiramate (P = .112), and onabotulinum toxin A injections (P = .179). Patients who engaged in regular exercise showed a trend toward higher resolution rates (P = .058). CoQ10 supplementation may play a role in new daily persistent headache resolution, with potential benefit from exercise, magnesium, topiramate, and onabotulinum toxin A injections approaching significance. Further prospective studies and randomized controlled trials are needed to establish causality and optimize treatment strategies for pediatric new daily persistent headache.
New daily persistent headache (NDPH) was first described as a benign headache disorder in 1986 by Vanast as headaches that would improve over time without therapy. 1 Since this initial description, we now recognize that patients with new daily persistent headache most often have severe headaches that are refractory to commonly used headache interventions. 2 Based on the third edition of the International Classification of Headache Disorders (ICHD-3) guidelines, the diagnostic criteria for new daily persistent headache include a history of a distinct and clearly remembered onset, with pain becoming continuous and unremitting within 24 hours, and duration of greater than 3 months.2,3 The headaches with new daily persistent headache have features of both tension-type and migraine and may be associated with photophobia, phonophobia, decreased activity, nausea, and other symptoms, making it difficult to differentiate it from other paroxysmal headache disorders.4,5
Although the prevalence of new daily persistent headache is thought to range from 21% to 28% in pediatric patients, the pathophysiology of new daily persistent headache has not been well studied.6,7 Many patients do not have a significant headache history prior to onset of new daily persistent headache. 8 However, precipitating factors such as flulike illness, minor head injuries, surgery, anesthesia, and high-altitude camping have been described before the onset of new daily persistent headache. 1 Risk factors include female sex, white race, and psychiatric comorbidities such as major depression and panic disorder.9,10
Despite the prevalence and refractory nature of new daily persistent headache, there is little guidance for its management. A variety of treatments have been described, ranging from steroids, antibiotics, nerve blockades, dihydroergotamine, ketamine, osteopathic manipulation, and more traditional headache medications such as gabapentin, amitriptyline, and topiramate. 1 Given the broad range of treatment and lack of data on efficacy, this study aims to describe treatments trialed by patients diagnosed with new daily persistent headache, and to determine which treatments patients were being administered when their headaches transformed from being continuous and unremitting to having periods of pain cessation.
Patients and Methods
Pediatric patients who attended the Headache Clinic and were evaluated by a headache specialist at Children's National Hospital between 2016 and 2021 were enrolled in an institutional review board–approved patient registry. These patients were evaluated using a standardized headache history, including headache-specific symptoms and details, prior imaging, red flag symptoms, prior and current medications and treatments, birth history, medical history, headache-oriented family history, and social history. The registry was queried for new daily persistent headache (International Classification of Diseases, Tenth Revision [ICD-10] code: G44.52), after which data from relevant medical records was entered into an online database to perform this retrospective review. Descriptive statistical analyses were used to analyze the data to determine treatments trialed by patients and the most common medications patients were receiving when they experienced remission of their daily headache. Descriptive statistics were presented in the form of means and medians and their accompanying SDs or interquartile ranges for numeric data. Categorical data were presented with counts and proportions. In the case of numeric data statistical testing between the headache resolution and headache nonresolution groups was performed using the Wilcoxon rank-sum test. Although the testing of proportions was done with either the χ2 test of independence or Fisher exact test. All analyses were performed in SAS V9.4 (SAS Institute, Cary, NC) with 2-sided tests and an a priori alpha of 0.05.
Results
Demographics
Data from the charts of 182 pediatric patients with new daily persistent headache were collected (Table 1). Average age of the patients was 15.5 years (range 13.4-16.7), and 78% of patients were female. A majority (63%) identified as White, whereas 11%, 10%, and 13% identified as Black or African American, Other, or unknown/not reported, respectively. Overall, 84% identified as Not Hispanic or Latino, with 6% identifying as Hispanic or Latino.
Demographic Characteristics of All Patients (N = 182).
Abbreviation: IQR, interquartile range.
Clinical Characteristics
Of 182 total patients, 47 (25.8%) patients had resolution of new daily persistent headache, whereas 135 (74.2%) patients had persistence of headache at the last visit recorded (Table 2). The median duration of headache to resolution was 119 days (range 57-261). There was no statistically significant difference in sex (P = .256) or race (P = .811) in those with and without resolution of new daily persistent headache.
Clinical Characteristics of Patients with and Without Resolution of New Daily Persistent Headache.
Abbreviation: IQR, interquartile range.
Initial Management and Lifestyle Habits
At the initial visit, 64% of patients had trialed an over-the-counter medication and 19% of patients had trialed a triptan as a headache abortive (Table 3). Fifty-three percent of patients had not been on a preventative medication and 79% had not trialed a nutraceutical supplement. For those who had received a prescription preventative medication prior to intervention at the Headache Clinic, topiramate (12%), gabapentin (10%), and amitriptyline (8%) were used most frequently. Riboflavin (12%) was the most frequently used nutraceutical supplement prior to intake. Patients were drinking a median of 60 ounces per day of water, and 32% were skipping at least 1 meal per day (Table 4).
Management at Initial Visit, Including Abortive Agents, and Preventative Medications and Nutraceuticals.
Lifestyle Habits at Initial Visit (N = 182).
Abbreviation: IQR, interquartile range.
Management and Lifestyle Habits in Patients With Resolution of New Daily Persistent Headache
Forty-seven (25.8%) of 182 patients with new daily persistent headache had resolution of their headaches, leaving 135 (74.2%) without resolution at the conclusion of data analysis. Of the patients with resolution of new daily persistent headache compared with those who did not have resolution, coenzyme Q10 supplementation was the only treatment showing statistical significance (n = 8 vs 6, P = .010). The remainder of treatments showed no statistical benefit; however, magnesium (n = 7 vs 9, P = .086), topiramate (n = 10 vs 16, P = .112), and onabotulinum toxin A injections (n = 3 vs 3, P = .179) approached statistical significance (Table 5). Other agents, including amitriptyline, valproic acid, gabapentin, and duloxetine, did not meet statistical significance or approach it (P = .349, .999, .326, and .451, respectively). At the time of the final visit, 36% of patients with resolution of headache and 44% of patients without resolution of headache were not prescribed any preventive headache medication (P = .367).
Preventative Medications and Nutraceutical Supplements in Patients With and Without Resolution of New Daily Persistent Headache.
In regard to lifestyle modification for headache, patients with resolution of new daily persistent headache reported a median exercise frequency of 5 times per week (P = .058) in comparison to once per week in those without resolution (Table 6). There were no significant differences between resolved and unresolved headache groups when examining hydration, sleep, or dietary habits.
Lifestyle Habits in Patients With and Without Resolution of New Daily Persistent Headache.
Abbreviation: IQR, interquartile range.
Discussion
New daily persistent headache accounts for up to 28% of headaches in children and adolescents in patients with daily chronic headaches, and because of its refractory nature, can be highly debilitating.1,6 Despite this, there are limited studies and no controlled trials describing effective treatments that result in resolution of the unremitting headache associated with NPDH. Some experts recommend treating the headache based on the predominant headache phenotype, though this may lead to multiple medication trials, polypharmacy, and delay in adequate pain control. 1
Upon initial evaluation by our headache program, 64% of patients had already trialed over-the-counter rescue medications without resolution, and 19% had trialed triptans without improvement. This corresponds with prior publications showing that many patients with new daily persistent headache had failed rescue medications at the time of presentation, and most headache specialists forgo rescue treatments in patients with new daily persistent headache given this consistent lack of responsiveness. 11 Similarly, our study aligns with prior studies showing that the nearly half (47%) of patients with new daily persistent headache had trialed a variety of preventative medications and nutraceutical supplements without clear benefit. 12 Notably, more than 50% of patients had not trialed any preventative medication or nutraceutical treatment at the time of referral to our headache center, suggesting that referring providers may require more education with initiating treatment for new daily persistent headache.
Demographically, our patients with new daily persistent headache were more likely to be female (78%) and a median of 15.5 years of age. This aligns with prior studies on new daily persistent headache showing a female predominance and teenage age of onset. 13 57% of our patients identified as White, followed by 11% identifying as Black or African American, which again corresponds to prior publications on new daily persistent headache. 13
Nearly 75% of our patients had continuation of headache at completion of data analysis, which is similar to prior research suggesting that new daily persistent headache remains refractory, despite treatment. 14 However, of the 25% of patients with resolution of their continuous headache, there was a statistical likelihood they were being administered coenzyme Q10 during their cessation (17% in resolved vs 4% in unresolved, P = .010). Fourteen patients received coenzyme Q10 in total between both resolved and unresolved groups, which was substantially lower than other supplements prescribed, including riboflavin (n = 41), magnesium (n = 16), and melatonin (n = 8), which is likely a reflection of prescribing habits. Coenzyme Q10 supplementation has been studied in both adult and pediatric migraine headaches with mixed results. 15 One study by Sandor et al 16 showed that 47.6% of patients on CoQ10 had an improvement in headache frequency compared with 14.4% in the placebo group. The pathophysiology is proposed to occur through several mechanisms including acting as an antioxidant and anti-inflammatory, along with its involvement in energy production in the electron transport chain of the mitochondria. 17 Patients with migraine can be deficient in coenzyme Q10 and can have clinical improvement with supplementation. 18 Although data support the use of coenzyme Q10 use in patients with migraine headaches, this is the first study to suggest that coenzyme Q10 may also be effective in patients with new daily persistent headache.
Of the 47 patients with resolution of new daily persistent headache, 22% were on topiramate (12% in unresolved group, P = .112), 6% underwent onabotulinum toxin injections (2% in unresolved group, P = .086), and 15% were on magnesium (7% in unresolved group, P = .058). Although these associations did not reach statistical significance, they approached statistical significance, suggesting a potential trend that warrants further investigation in larger studies. These treatments are all commonly also used in migraine headache disorders, but have not yet been studied in new daily persistent headache.19–21 Given these common agents used in migraine prevention approached clinical significance in new daily persistent headache, the authors of this study believe the differentiation of NPDH from chronic migraine may be arbitrary and unnecessary. Given new daily persistent headache and continuous headache are common exclusion criteria for clinical trials for pediatric migraine, this practice should be reexamined to determine if patients with this intractable headache disorder could benefit from newer agents, like CGRP-receptor antagonists, for example. It is important to advocate for patients affected by new daily persistent headache so we can better understand their condition and offer treatments that could improve their headache-related quality of life, including school and sports participation among others.
Regular use of aerobic exercise also approached statistical significance (5% in resolved vs 1% in unresolved group, P = .058), suggesting that exercise may play a role in the resolution of new daily persistent headache. Similarly, exercise has been shown to be prophylactic in migraines but has not been studied in new daily persistent headache. 22
There are many strengths to this study. Because all patients were evaluated at a single center, there is a more standardized approach to diagnosis and treatment, reducing variability in clinical decision making. Additionally, the sample size of 182 patients provides a substantial data set for analysis.
However, there are several limitations to this study. As this was a retrospective chart review, we cannot conclude that the use of coenzyme Q10 directly leads to the resolution of new daily persistent headache. Rather these findings suggest a correlation between coenzyme Q10 and new daily persistent headache resolution, warranting further prospective investigation. Additionally, because all patients in this study were evaluated at a single center, there may be a greater likelihood of uniform management approaches among providers, which could influence the results. These findings may also reflect prescribing habits, as medications that are more commonly prescribed are also more frequently studied and can lead to a higher perceived rate of resolution. Furthermore, lifestyle factors were self-reported by patients, which introduces the potential for recall bias. Nerve blocks and nonpharmacologic therapies such as cognitive behavioral therapy, acupuncture, massage therapy, and remote electrical neuromodulation devices were not included in this analysis and may have contributed to symptom improvement in those with resolution of new daily persistent headache.
In conclusion, this study highlights the potential role of coenzyme Q10 and other treatments in resolution of new daily persistent headache. Future research should focus on prospective, controlled trials to further explore the efficacy of coenzyme Q10, topiramate, magnesium, and exercise in treating new daily persistent headache. Randomized controlled trials would help establish causality and guide standardized treatment protocols. Additionally, longitudinal studies assessing the long-term impact of lifestyle modifications, such as exercise, on new daily persistent headache resolution could provide further insights into nonpharmacologic interventions.
Footnotes
Acknowledgements
We thank the entire neurology team at Children's National Hospital for their exceptional care and dedication to patients.
Ethical Approval
The Institutional Review Board (IRB) at Children’s National Hospital approved the study titled Pediatric Headache Patient Registry of Clinical Management and Treatment Outcomes (Pro00008962) to permit waiver of consent and the retrospective review of all pediatric patients who attended the Headache Clinic at Children’s National Hospital and Pediatric Specialists of Virginia. There were no known ethical issues present in this study.
Author Contributions
MT performed the roles of original draft, and writing. JS, RL, AT, WM, and MD performed the role of review and editing. MD also assisted in the role of supervision. AD, OG, and EM performed the role of data curation. JB performed the role of statistical analysis.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.