This study assessed the clinical features of NDPH, the effectiveness of drug-based treatment and the risk factors for treatment effects in the largest sample in China mainland to date. We found that there were significant differences in demographic and clinical characteristics between NDPH and MOH patients. The presence of trigger factors is an independent factor for the treatment effect of NDPH patients. The patients with stress-related trigger factors had a better outcome than those with infection-related trigger factors.
Clinical features of NDPH
Our study revealed a male predominance (female/male=0.9:1), which is nearly similar to data from India (0.8:1)  but contrary to data from the USA (2:1) . The mean age at onset for NDPH is 26.7 years, which is similar to that reported by Uniyal et al. (28.24 years)  (Table 5). The clinical characteristics of the NDPH in our study were bilateral localization, non-throbbing nature, and a typical lack of association with nausea and vomiting; these characteristics were similar to those of chronic tension type headache in many cases. However, other summarized literature demonstrated the presence of migraine-like features in NDPH patients, with a proportion of 35-64.1%(8, 9, 11-13). NDPH typically occur in individuals without a prior headache history (1). In our study, there was one patient (1.4%) had headache history. However, other summarized literature demonstrated the presence of prior headache history in NDPH patients, with a proportion of 7-54%(4, 12). In terms of comorbid mental disorders in NDPH, the majority of our patients had anxiety (38/73, 52.1%) and depressive (27/73, 36.9%) symptoms. Uniyal et al. even reported a more common prevalence of anxiety (92.7%) and depression (89.1%) in their patients . The causal relationship between anxiety, depression and chronic headaches or vice versa is still unclear  (Table 5). None of the patients had medication overuse in our study. However, Prakash et al. and Kung et al. reported medication overuse in 13% and 8.7% of their patients, respectively [12, 14]. Moreover, an observational study by Peng et al. also reported that NDPH patients had a higher proportion (34.8%) of medication overuse . We consider the following possible reasons for these findings. First, most of the patients in our cohort showed headache characteristics similar to those of tension-type headaches, which means that the headache is mild to moderate, so analgesics may not be necessary. Reidy et al. also found that youth with NDPH were less likely to have medication overuse compared to youth with CM . Another reason may be that even when analgesics were used, most of them were not effective for NDPH patients.
Infection and stress events are the two main trigger factors of NDPH , while the proportion varies among different studies. Most of our patients (22/73, 30.1%) complained that their self-reported triggering events were related to stressful events, which is higher than the corresponding data reported by Uniyal et al. (5/55, 9.1%)  and Rosen (9/97, 9%) . Another factor in our study was infection (15.1%). Some authors have found that some NDPH patients who had been infected with viruses before headache, such as Epstein-Barr virus (EBV) , herpes simplex virus (HSV) , cytomegalovirus (CMV) , and dengue virus (DENV) , speculated that chronic central nervous system inflammation may be involved in the pathophysiological mechanism of NDPH . However, only a few patients suffered NDPH after infections, which suggests that some unknown mechanism needs to be further explored. Other trigger factors reported by other studies, such as surgery procedures with intubation, withdrawal from SSRIs, human papilloma virus vaccination [2, 10], and Valsalva event , were absent in our study.
Comparison between NDPH and MOH
We found several significant differences in sex predominance, age at onset of CDH, duration of CDH, educational level and pain intensity between NDPH and MOH. First, NDPH occurred more often in males than in females. The most likely reason is that primary headache diseases in general, especially migraine, are more common in women , and these are the main risk factors for MOH because pre-existing headache is a necessary prerequisite. Second, our study showed that NDPH patients, compared to MOH patients, had an earlier age at onset of CDH but a longer duration of CDH, which would lead to more severe disability and therefore significantly affect the individual’s quality of life. Finally, compared with MOH, NDPH patients are more likely to have a higher educational level, which has not been revealed in a previous study. The main reason may be that MOH patients attained a lower education level , which is a risk factor for medication overuse in headache patients . This difference needs to be confirmed in further clinical studies.
Treatment and prognosis of NDPH
NDPH has two subtypes: a self-limiting subtype that typically resolves within several months without therapy and a refractory subtype that is resistant to aggressive treatment regimens . Vanast first found that 78% of patients became headache-free by 24 months  and considered NDPH a benign headache. In contrast, most subsequent studies considered it to be the most refractory to treatment and can persist for many years . The likely reason for NDPH becoming more refractory was that most studies enrolled NDPH patients who had headache durations of more than 6 months . In our study, the duration of headache was also more than 6 months in all patients, and the mean headache duration was 10.6 years. Our current study did not reveal that any NDPH patients self-resolved during an average follow-up of 31 months. The effective treatment rate of NDPH was 50% in our study, which was close to the effective treatment rate (67%) found by Prakash et al . Although there was no significant difference in headache duration, it seems that the shorter duration has a better outcome (68.8% vs. 43.5%). Our results also supported that treatment in the early stage might improve the effectiveness of NDPH, which is similar to the result from Peng et al . In our study, we found that the patients with trigger factors had a better prognosis than those without trigger factors (71.4% vs 32.4%, p=0.002), which is similar to the data from India . In addition, stress is the main trigger factor of NDPH patients, and patients with stress-related trigger factors had a better outcome than those with infection-related trigger factors. We speculate that the likely reason is that these patients may handle life stress appropriately after consulting a doctor, which is helpful in reducing the frequency and severity of headaches.