Contributing Factors for the Emergence of New Daily Persistent Headache

Asian doctors are reporting their results to patients.
The authors highlight what is known about the development of new daily persistent headache (NDPH), explain how to diagnose and manage patients with NDPH, and discuss possible future therapies.

A narrative review published in Current Neurology and Neuroscience Reports examined possible etiologies for new daily persistent headache (NDPH).1 The cause of NDPH is currently unknown, but researchers believe the condition likely has several contributing factors; however, clinical data evaluating potential causes and treatments are limited. The review seeks to explore possible causes for NDPH and provide insight into this puzzling disorder.

New daily persistent headache is recognized by the International Classification of Headache Disorders, 3rd Edition as a primary headache disorder.2 This rare primary headache disorder affects a small percentage of the population.3 Individuals with NDPH experience refractory chronic head pain, which often emerges within a single day.2 Symptoms can appear in all demographics, including individuals with no known risk factors for chronic pain.

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New daily persistent headache is a descriptive diagnosis, meaning there are no definitive laboratory or imaging tests that can identify NDPH. In order to meet the diagnostic criteria for NDPH, head pain must be continuous and unremitting for ≥3 months.2 Physicians must also exclude other diagnostic considerations, including disorders that may affect intracranial pressure. As NDPH symptoms can be similar to those of many other disorders, a thorough evaluation is needed before an accurate diagnosis can be made.

New daily persistent headache pain is often refractory to standard therapies, which can present significant challenges both for patients and physicians1; however, early identification and treatment can improve the prognosis. An individualized approach to treatment often provides the best results.

Physicians treating NDPH must work to identify any triggering events that may precede symptom onset. The individual’s psychophysical profile and symptoms can also provide valuable diagnostic information. Once physicians understand the type of headaches experienced by the individual, they can effectively treat the resulting symptoms.

A population-based study in Norway showed that individuals aged 30 to 44 years had a 1-year prevalence of NDPH in approximately 0.03% in their study population.4 In comparison, the population prevalence of chronic daily headache was approximately 5%.3 Thus, NDPH accounts for only a small percentage of chronic headaches.

Nevertheless, NDPH is a common differential diagnosis among physicians treating chronic daily headaches, thus necessitating that physicians stay informed about new research on this disorder and the ongoing efforts to determine global prevalence.

Disease phenotypes appear to vary. In clinical reports, both tension-type and migraine like presentations have been noted. The latter appears to comprise the majority of cases. One clinic-based series revealed that >60% of individuals with NDPH reported symptoms characteristic of migraines, including nausea, photophobia, or phonophobia.5

Nonetheless, current International Classification of Headache Disorders, 3rd Edition criteria for NDPH do not require the presence or absence of specific symptoms. Instead, the criteria merely specify that headache must be daily and unrelenting for ≥3 months, with pain becoming continuous and unremitting within 24 hours of symptom onset.2

Although a prior history of tension-type or migraine headaches has been noted in some individuals, the relationship between these symptoms is unclear. A diagnosis of other types of headache does not preclude a diagnosis of NDPH; however, researchers are unsure whether these symptoms indicate comorbidity or if they have further diagnostic significance.

Many cases of NDPH are preceded by an identifiable triggering event. Researchers have determined that approximately 50% of individuals with NDPH experienced an illness, injury, or trauma shortly before symptom onset. 1,6 Triggering events often include a flu-like illness, infection, stressful life event, or surgical procedure involving intubation.1

Prior infection has become a commonly identified trigger. Epstein-Barr virus (EBV) has been implicated in several studies. One study showed that 27 of 32 individuals with NDPH had active EBV infection compared with 8 of 32 control participants.7 A study of 40 children also found that 17 developed NDPH during or shortly after an infection, with >50% of children testing positive for EBV serology at symptom onset.8 Herpes simplex virus and cytomegalovirus have been noted as other possible agents.1

Cervical injury is another possible triggering event. Hyperextension of the neck during intubation or extubation may predispose some individuals to NDPH.6 A diagnosis of NDPH is also associated with joint hypermobility, with one study discovering that 11 of 12 patients have widespread hypermobility.9 Some physicians have reported resolution of NDPH symptoms after osteopathic manipulations, strengthening the possible link between neck injury and NDPH.

The wide variety of possible triggers and differences in phenotype suggests a heterogeneous source; however, the cause of NDPH remains a matter of conjecture.

Although researchers have thus far been unable to identify a single cause for NDPH, triggering events and comorbidities still provide useful data.

No significant variations have been observed when researchers evaluate different trigger categories with a focus on patients’ age and sex.1 This suggests that individuals with NDPH may have a shared susceptibility that increases their risk for the disease, regardless of the specific triggering event.

Researchers have also sought to examine the link between NDPH and psychiatric/somatic comorbidities. Individuals with NDPH appear more likely to have asthma, allergies, and hypothyroidism. When compared with other groups with chronic pain, patients with NDPH seem to experience higher levels of depression, generalized anxiety, and pain catastrophizing.1 One study discovered that 51 of 55 of individuals with NDPH had generalized anxiety disorder whereas 49 of 55 had significant depression.10

Researchers have cautioned that the link between these symptoms remains unclear. Affected individuals may experience a significant decrease in quality of life because of chronic pain; however, it is also possible that stress, depression, or anxiety may trigger the development of NDPH. It is currently unclear whether psychiatric disorders may predispose individuals to develop NDPH or if having NDPH is linked to an increased risk for psychiatric symptoms.

Some researchers have theorized that both psychiatric symptoms and head pain could be manifestations of a single disorder. One case series from Brazil studied treatment patterns in individuals who had been diagnosed with both NDPH and panic disorder, and researchers indicated that treating both sets of symptoms concurrently led to an improved response to treatment.11 Thus, psychiatric treatment may improve headache symptoms.

Although several possible causes for NDPH have been proposed, the neurophysiological mechanism involved is not yet well understood. An elevation of tumor necrosis factor-α in the cerebrospinal fluid has been documented in several individuals with NDPH.1 This may support the hypothesis that inflammatory response contributes to the development of the disease. Therapies that target inflammation may offer some benefits, but there are no controlled trials on this topic.

One ongoing open-label study is evaluating the use of low-dose naltrexone on glial cells within the nervous system. As both an anti-inflammatory and analgesic agent, naltrexone appears useful in treating pediatric NDPH.1 Another ongoing study has focused on comparing serum levels of calcitonin gene-related peptide and nerve growth factor levels. Researchers are comparing these serum levels in individuals with NDPH, chronic migraine, and healthy controls to better understand possible causes of NDPH.

Physicians often struggle to determine the appropriate treatment for NPHD. As NDPH pain is typically refractory to treatment, physicians may have difficulty identifying a treatment that provides symptom relief. Phenotype-driven treatment currently appears to offer the most promising results.

In addition, physicians must identify the triggering event and use this information to develop an individualized approach to treatment. In some cases, it may be appropriate to administer drugs that lower cerebrospinal fluid pressure. Anti-inflammatory and immune-modulating treatments may also be appropriate for patients with an infectious trigger.

Controlling immune system response appears essential for many patients. One case study in India showed promising results using a 5-day course of intravenous methylprednisolone, sometimes followed with additional oral steroids.12 Another retrospective study in India used a combination of steroids, sodium valproate, and tricyclic antidepressants. Approximately 46% of patients in this study experienced <1 headache/mo, and 30% achieved >50% reduction in headache frequency.12

Cervical blocks, nerve blocks, and physical therapy have also been used to treat NDPH with varying results. Some individuals found symptom relief through these treatments, but the relief was often short-lived. A few proposed therapies use onabotulinumtoxin A, and case reports suggest this approach may be useful. Ketamine and mexiletine have also been used in small studies with middling effects.1

According to recent research, physicians must refer patients with suspected NDPH to a headache specialist, as a careful review of potential secondary etiologies is needed. A specialist can effectively screen for other conditions with similar symptoms and offer guidance on longitudinal management on NDPH. Further, the early involvement of a multidisciplinary team, with treatment including self-management strategies and treatment for comorbidities, is essential for a favorable prognosis.


1. Riddle EJ, Smith JH. New daily persistent headache: a diagnostic and therapeutic odyssey. Curr Neurol and Neurosci Rep. 2019;19(5):21.

2. Headache Classification Committee of the International Headache Society. The international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.

3. Castillo J, Muñoz P, Guitera V, Pascual J. Kaplan Award 1998. Epidemiology of chronic daily headache in the general population. Headache. 1999;39(3):190-196.

4. Grande RB, Aaseth K, Lundqvist C, Russell MB. Prevalence of new daily persistent headache in the general population. The Akershus study of chronic headache. Cephalalgia. 2009;29(11):1149-1155.

5. Li D, Rozen TD. The clinical characteristics of new daily persistent headache. Cephalalgia. 2002;22(1):66-69.

6. Rozen TD. Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache. 2016;56(1):164-173.

7. Diaz-Mitoma F, Vanast WJ, Tyrrell DL. Increased frequency of Epstein-Barr virus excretion in patients with new daily persistent headaches. Lancet. 1987;1(8530):411-415.

8. Mack KJ. What incites new daily persistent headache in children? Pediatr Neurol. 2004;31(2):122-125.

9. Rozen TD, Roth JM, Denenberg N. Cervical spine joint hypermobility: a possible predisposing factor for new daily persistent headache. Cephalalgia. 2006;26(10):1182-1185.

10. Uniyal R, Paliwal VK, Tripathi A. Psychiatric comorbidity in new daily persistent headache: a cross-sectional study. Eur J Pain. 2017;21(6):1031-1038.

11. Peres MF, Lucchetti G, Mercante JP, Young WB. New daily persistent headache and panic disorder. Cephalalgia. 2011;31(2):250-253.

12. Prakash S, Saini S, Rana KR, Mahato P. Refining clinical features and therapeutic options of new daily persistent headache: a retrospective study of 63 patients in India. J Headache Pain. 2012;13(6):477-485.