New daily persistent headache (NDPH) is one type of chronic daily headache, along with chronic migraine , chronic tension headache, and hemicrania continua. NDPH is being increasingly recognized as an important type of headache, both because of the frequency and also the refractory nature of the head pain.

NDPH develops quickly, usually within hours or 1 day, but within 3 days the headache must be constant [39]. Many patients remember exactly what they were doing when the headaches began. The pain is usually bilateral, with aching pressure and/or throbbing. The intensity may vary from mild to severe, but tends to be mild to moderate. The headache is usually constant. At least half of patients describe migraine-associated features, such as nausea, phonophobia, lightheadedness, photophobia, etc. Allodynia, often seen in chronic migraine, is present in approximately a quarter of patients [37]. Autonomic symptoms (nasal stuffiness, conjunctival injection, etc.) may occur.

NDPH is somewhat a diagnosis of exclusion. Infection (including meningitis and sinusitis), mass lesions, subdural hematomas, cerebral venous thrombosis, low or high cerebrospinal fluid (CSF) pressure headaches, arteritis, arterial dissection, posttraumatic, etc., all need to be excluded [10]. Usually the history, along with MRI/magnetic resonance angiogram (MRA), will exclude these entities. There are several newer proposed diagnostic classifications; generally, diagnosis includes:

NDPH is unilateral in a small number of patients, and if this occurs with autonomic symptoms, it may represent a variant of hemicrania continua.

While we do not know the pathophysiology of NDPH, central nervous system (CNS) inflammation is one possibility. Tumor necrosis factor-α (TNF-α) has been implicated in neuro-inflammation. TNF-α is a cytokine that enhances inflammation. In one study, CSF evaluations of NDPH patients resulted in almost all samples showing an increase in CSF TNF-α [40].

Glial cell disruption may play a role; glial cells manufacture CNS cytokines. Glial cells are very sensitive to viral infection and stress; surgery may impact glials as well [11]. Cervical joint hypermobility, along with hypermobility of other joints, may play a role [42]. Patients with NDPH often are tall and thin, with long necks.

CDH occurs in approximately 3.5 % of the population, but the prevalence of NDPH is not known. One study from a headache center concluded that 10.8 % of 638 CDH patients had NDPH [8]. A similar study in the pediatric population revealed that, among those with CDH, 13 % had NDPH [19]. NDPH may well be more prevalent among adolescents than in adults. Females outnumber males with NDPH by approximately 2.5 to 1 [10]. Most patients do not have a previous history of headache. A prior history of anxiety or depression is seen in about half of the NDPH patients [10]. After the onset of NDPH, many patients experience depression.

Approximately, 50 % of patients have an identifiable trigger. Stress may be a trigger in some patients. Infection, particularly viral, is often cited as a trigger [39]. In one study, the Epstein–Barr virus was implicated as an initiating culprit [7]. Exposure to certain toxins may also precede the onset of NDPH. Surgical procedures have occasionally triggered the onset of NDPH. Head injury, even when mild, may be an initial event. Cervical trauma or other pathology, particularly in those who have thin necks with cervical hypermobility, may initiate the onset of NDPH.

NDPH is more resistant to treatment than is chronic migraine, which is usually transformed migraine (slow onset over years). The usual daily preventive migraine medications are given, as they may be helpful for some NDPH patients. These include tricyclic antidepressants (amitriptyline, protriptyline, etc.), anticonvulsants (valproate, topiramate, etc.), antihypertensives (β-blockers, calcium channel blockers, etc.), Petadolex (natural butterbur), SSRIs (fluoxetine, sertraline, etc.), SNRIs (duloxetine, venlafaxine, etc.), and muscle relaxants (tizanidine, etc.). OnabotulinumtoxinA (Botox) may be helpful as well; there are no published controlled trials of treatment for NDPH. Benzodiazepines, particularly clonazepam, have had some limited success. Intravenous dihydroergotamine (IV DHE) is more likely to be of help with chronic migraine. A course of high-dose IV corticosteroids, followed by oral steroids, has shown some promise, but the high doses can predispose to serious side effects [36]. IV magnesium may provide short-term relief. Doxycycline, given over several months, may help some patients with NDPH. Greater occipital nerve blocks sometimes are useful, particularly with unilateral headaches. Sphenopalatineganglion (SPG) frontal blocks , with the newer devices SphenoCath, Allevio, or Tx360, may help.

Outside of medication, psychotherapy is worthwhile for those with anxiety or depression. Biofeedback is helpful for some headache patients. Exercise is always encouraged, as is yoga and Pilates. Acupuncture, physical therapy, or chiropractic may help for some patients.

While the results of treatment may be discouraging, it is crucial to stick with the patient, continue to try different medications or modalities, and not to give up on the NDPH sufferer.

Several studies have evaluated long-term outcomes. One study revealed that, after 2 years with NDPH, about 25 % of the patients were free of headache, and 66 % had at least a 50 % reduction in pain levels [33]. Another study reported that 76 % of patients continued to have headaches over time, while 15 % remitted; median time to remission was 21 months. Eight percent had a cyclic form, with a relapsing-remitting pattern. A small study of children and adolescents discovered that 8 out of 28 patients were free of headache within 1–2 years, while most (20) continued to suffer long-term from head pain [53].

NDPH is an important category of headache, as it is often difficult to treat, and results in considerable disability. It is unique in that more than 50 % of patients have an identifiable trigger, although these range from infection to surgery to head trauma. We are just beginning to identify the pathophysiology that leads to NDPH. Treatment of NDPH is scattershot and varied at present; further studies will undoubtedly lead to more effective therapies. Note this is a version of an article that originally was published in Practical Pain Management, Vol. 12, July 2012.

Calcitonin gene-related peptide (CGRP) in an inflammatory neuropeptide involved at every level of migraine pathophysiology, including the meninges, trigeminal ganglion, trigeminocervical complex, brain stem nuclei, thalamus, and the cortex. Upon initiation of migraine at the brain stem or cortex level, neurogenic inflammation occurs such that peripheral trigeminocervical neurons are activated. We then observe a release of CGRP and other neuroinflammatory peptides. CGRP induces neurogenic vasodilation that leads to further plasma protein extravasation (PPE) and the influx of mast cells and other pro-inflammatory cells [21]. The process of neurogenic inflammation sensitizes the peripheral nociceptors transmitting via the trigeminal axon, through the brain stem and the thalamus, and finally into the cortex.

In animal models, CGRP is released following stimulation of the CNS—similar to what is observed in migraine. Triptans inhibit the animal’s CGRP release. In humans, injections of CGRP into migraine patients result in delayed headache. Certain studies have suggested that relief of migraine corresponds to a reduction of CGRP levels in the blood and that migraine-specific therapy with triptans decreases CGRP [45]. These studies have led to the development of CGRP-receptor antagonists that could conceivably block neurogenic vasodilation in the meninges. CGRP activity in the trigeminal ganglion may limit vasoconstriction.

Two CGRP-receptor antagonists, olcegepant and telcagepant, were tested for the abortive treatment of migraine; unfortunately, their development is on hold [22]. There are ongoing studies of monoclonal antibody injections, once per month, for the prevention of migraine.

It is possible that onabotulinumtoxin type A (Botox) may work via anti-inflammatory neuroimmune mechanisms. The effect of Botox may partially be due to its effect on CGRP, or other similar inflammatory compounds.

Recent studies have revealed that the neuropeptide CGRP triggers the secretion of cytokines via stimulation of CGRP receptors found on T cells [5, 23]. Cytokines are involved in inflammation, in modulation of the pain threshold, and also in trigeminal nerve fiber sensitization. In small trials, cytokines have been proven to precipitate headache [51].

In trials where TNF was injected, headaches were shown to be induced while, on the other hand, the TNF antibody was shown to reduce pain in humans [54]. Plasma levels of both pro- and anti-inflammatory cytokines are enhanced during migraine attacks. TNF levels increase after migraine pain onset and decrease progressively over time after the onset of the attack [34]. Plasma levels of a pro-inflammatory cytokine, interleukin (IL)-1, are also enhanced after the initiation of headache. IL-1 release is induced by TNF and may lead to hyperalgesia. The amount of an anti-inflammatory cytokine, IL-10, has also been shown to increase after the onset of a headache and may be involved in analgesia. One study revealed IL-10 inhibited release of TNF, which is antinociceptive [49].

Cytokine levels in the CSF of migraineurs have been studied with varied results. Increases in IL-1 receptor antagonist (IL-1ra), monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-1 (TGF-1) were measured in patients with migraine and episodic tension-type headache (TTH) versus pain-free controls. Rather than being the cause of headache, changes in the level of cytokines in the CSF are thought to be due to pain [4]. No correlation has linked increased cytokine levels to a decrease in pain and there has not been a difference found in cytokine levels with migraine versus episodic TTH [4].

TNF is a pro-inflammatory cytokine involved in inflammation and it is crucial in the activation of pain. A small number of patients with NDPH develop symptoms after viral infection. It is possible that a pro-inflammatory cytokine such as TNF could initiate and maintain CNS inflammation even after the infection resolves. Rozen et al. [41] reported elevated levels of CSF TNF in 19 of 20 NDPH patients, in 16 of 16 chronic migraine patients, and in 2 of 2 chronic tension headache patients. The study suggests that TNF plays a role in the etiology of these types of headache. Refractory chronic daily headache could involve increased levels of CSF TNF. Patients with NDPH (and, theoretically, elevated TNF) often are refractory to a variety of medication regimens.

TNF is important in a number of conditions such as sinusitis and rhinitis, as well as headache [6]. The development of drugs that modulate TNF may prove beneficial to these conditions as well as headache.

Obesity is a known to be a major risk factor for the development of chronic migraine [35]. Adipose tissue secretes adipocytokine adiponectin, which is believed to modulate several inflammatory mediators important in migraine. A large amount of adipose tissue leads to decreased secretion of adiponectin [16]. Adiponectin has a protective role in limiting the development of insulin resistance, dyslipidemia, and atherosclerosis. It also has an anti-inflammatory action through inhibition of cytokines IL-6 and TNF-induced IL-8 production. Adiponectin induces the production of cytokine IL-10, which is anti-inflammatory. Adiponectin decreases migraine but, paradoxically, a sudden increase may worsen a headache [35].

Recent studies have shown that glial cells, previously thought to serve only a supportive role, are now known to directly influence the microenvironment of trigeminal ganglion neurons through gap junctions and paracrine signaling [46]. Following trigeminal activation, CGRP secreted from neuronal cell bodies activates adjacent glial cells to release nitric oxide (NO) and inflammatory cytokines which, in turn, initiate inflammatory events in the trigeminal ganglia that lead to peripheral sensitization [6, 26]. The neuronal glial signaling is thought to be an important process, ultimately leading to the initiation of migraine. The glial modulation of neurons through immune mediators is an unexplored area for new migraine medications . An excellent report on glia research by Drs. Moskovitz and Cooper appeared in these pages in the November/December 2010 issue [31].

It is generally accepted that migraines are partially mediated by prolonged activation of meningeal nociceptors (pain receptors). One possible explanation of how this occurs seems to be found in the physiology of mast cells. Mast cells are granulated immune cells that play a critical role in inflammation. They have been found to reside in high density in the intercranial dura, a peripheral tissue covering the brain [8]. Mast cells are located in close proximity to the blood vessels and the primary afferent nociceptive neurons.

When the mast cells are stimulated, they degranulate their contents into the local milieu. This activates the surrounding trigeminal meningeal nociceptors and promotes a prolonged state of excitation. It is not clear if there is a specific molecule released from the mast cells that is responsible for the propagation of migraine. Several of the degranulated molecules have implications for migraine. The list includes histamine, leukotrienes, the cytokines TNF and IL-6, and endothelin-1 [43, 15].

Once the meningeal nociceptors are activated by the release of mast cell molecules, they propagate a cascade of neuronal activation by releasing neuropeptides (e.g., CGRP, substance P). These activate and further degranulate residual mast cells and thus prolong the migraine headache. According to Levy et al. [24], the key lies in the increased expression of the phosphorylated form of the extracellular signal-related kinase (pERK). This is an anatomical marker for nociceptor activation and downstream signaling of the spinal trigeminal nucleus.

The association between seasonal allergies and headaches has been well documented in several studies [9, 1, 30, 52, 32, 29]. A recent study found that headaches are 1.5 times more common in those with atopic conditions (asthma, seasonal allergic rhinosinusitis, chronic bronchitis) than those without these disorders [1]. This relationship suggests that inflammatory changes in the nasal and sinus mucosa of individuals with seasonal allergic rhinosinusitis could be a potential trigger for migraines. Allergies may also partly explain the seasonal variation experienced by many migraine sufferers. However, several primary headache disorders, including migraine, are at least partly characterized by the presence of cranial autonomic symptoms (e.g., conjunctival injection, lacrimation, eyelid edema, rhinorrhea, nasal congestion, postnasal drip, and reddening of the face and ears) which closely resemble the signs and symptoms of seasonal allergic rhinosinusitis [9]. This overlap in symptomatic presentation can make it quite difficult to clinically distinguish headache secondary to seasonal allergic rhinosinusitis from primary headache associated with cranial autonomic symptoms. Accurate characterization of these headaches through a detailed history and physical examination is crucial since appropriate treatment highly depends upon a proper diagnosis.

Many patients who believe they have sinus headaches are suffering from migraine. In fact, sinus headache is the most common misdiagnosis of patients with migraine [9, 28, 3, 35]. For its part, the International Headache Society (IHS) does not recognize sinus headache as a diagnostic entity—unless it is associated with a confirmed diagnosis of underlying acute rhinosinusitis.

The immune system plays a key role in migraine pathogenesis. The involvement of CGRP is important in neurogenic vasodilation, peripheral sensitization, and the initiation of the migraine cascade. Various cytokines, including TNF, IL-1, and adiponectin, have been implicated in the precipitation of migraine.

The role of allergies in migraine remains a confusing area. In headache-prone individuals, seasonal allergies may be a trigger and most people diagnosed with sinus headaches are actually suffering from migraine.

The earliest work on the immune system and headache focused on mast cells and their role in propagating the cascade of neuronal activation when degranulated. The supporting glia cells, long thought to be inert, have been found to modulate neuronal activity—partly through immune mediators. The manipulation of immune system elements is a promising area of development for new headache therapies, although these may be many years in development. Note this originally appeared in Practical Pain Management, Vol. 11, Jan 2011.