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Contributing Factors for the Emergence of New Daily Persistent Headache


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.

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.

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.

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.

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.

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

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

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.

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

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

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.

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

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

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.

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

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.

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.

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.

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.

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.

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

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

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

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.

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