A significant diurnal variation in headache intensity was shown in TTH through utilization of computerized EMA, with headache being weakest in the morning, worsening toward the evening, and peaking afterward.
When the effect of time was modeled as a random effect, the models fit better than when the effect was modeled as a fixed effect. In addition, the estimated variances of those random effects were significantly different from zero. These results suggested that there was significant between-individual variation in the effect of time. In other words, the pattern of diurnal variation of TTH was different among patients, while a certain diurnal pattern was still observed when averaged for all patients.
The heterogeneity of diurnal patterns of headache intensity may stem from different subtypes of tension-type headache and sex. However, the analysis failed to show a significant difference in diurnal patterns between chronic and episodic tension-type headache or between women and men. Another possibility is that medication use influenced the time course of headache. While prophylactic medication use did not show any significant difference in the diurnal pattern of headache intensity, on-demand medication use was related to a significant difference in diurnal pattern of headache intensity. The headache intensity decreased earlier in the evening in patients who used on-demand medication during the study period, which might reflect the effect of the medication.
The circadian variation in the probability of acute headache exacerbations also showed a specific diurnal pattern. The estimated average number of headache exacerbations was small in the morning, reached a peak just after noon, and then gradually decreased towards night. These results were consistent with a previous study in which almost half of TTH patients reported that their usual headache attack onset was during the day . In this prospective study using computerized EMA, it was possible to determine more accurate and detailed information on the temporal distribution of headache exacerbations. Neither subtype of headache nor medication use was related to a significant difference of circadian variation on the probability of acute headache exacerbation.
Circadian pain intensity variation generally has been discussed in relation to endogenous opioid peptides and melatonin [5, 6]. However, their involvement in TTH has not yet been established [10, 11]. Furthermore, a previous study reported that the diurnal pattern itself was different for plasma melatonin between patients with chronic TTH and healthy controls . Further investigation is necessary in order to clarify the biological origin of the circadian variation of pain intensity in TTH. In addition, psychosocial factors such as daily social activities and related psychological symptoms also provide a possible basis for the circadian variation in TTH. The temporal relationship between headache intensity and psychosocial factors also needs to be investigated. It is of note that the distribution of headache exacerbations in TTH seems to be different than migraine. In most previous studies, migraine attacks were reported to occur more often in the morning [1, 13, 14] and sometimes during sleep , although a few studies showed peak attack frequency in the afternoon .
There are some limitations to the present study. Firstly, external clock time was used for the time axis in this study. This approach might cause between-individual variations in the effect of time, which might disappear with consideration of individual sleep-wake cycles. However, whether to use external clock time or individual sleep-wake cycles as the time axis is dependent on the hypothesis. Second, computerized EMA is not perfect, although it has an advantage over recalled self-reporting because it is able to capture the time course of headache intensity in a more detailed and accurate manner. Signal-contingent recordings were not continuous, but were sparse so that brief changes in headache intensity might have been missed, which was partly solved by dividing time into specific time blocks, sacrificing high time resolution. In addition, although correspondence between momentary headache intensity and recording time was accurate, there might have been a lag between the time of headache exacerbation and the time of making an event-contingent recording, despite instruction to make event-contingent recordings as soon as possible when headache was acutely exacerbated. Third, although we tried to explore the effect of medication on the diurnal pattern of headache by analyzing the interaction with medication use, it would be better if we could investigate only patients who were free of medication, especially for the investigation of pathophysiology. Fourth, the number of patients was rather small, thus the generalizability of this study might be limited.