Endogenous pain modulation after sleep restriction in migraine: a blinded crossover study

Abstract

Background: Patients with migraine are vulnerable to insufficient sleep, but the impact of sleep restriction is largely unknown. In addition, the importance of sleep may be different in patients with migraine who mostly have attack onsets during sleep, so called sleep-related migraine, compared to patients with non-sleep-related migraine. In this study we investigate the effect of sleep restriction on endogenous pain modulation in patients with migraine and healthy controls. We also compared the effect of sleep restriction in sleep-related and in non-sleep-related migraine.

Methods: Measurements were conducted in 39 patients with migraine between attacks and 31 controls, once after habitual sleep and once after two consecutive nights of partial sleep restriction. There were 29 and 10 patients with non-sleep-related and sleep-related migraine respectively. Test stimulus was 2-min tonic noxious heat to the left volar forearm. Temporal summation was calculated as the regression coefficient for rated pain in the late part of this 2-min stimulation. Conditioning stimulus was right hand-immersion in 7 °C water. Conditioned pain modulation was defined as the difference in rated pain with and without the conditioning stimulus and was calculated for temporal summation and mean rated pain for the test stimulus. The effect of sleep restriction on temporal summation and conditioned pain modulation was compared in migraine subjects and controls using two-level models with recordings nested in subjects.

Results: Conditioned pain modulation for temporal summation of heat pain tended to be reduced after sleep restriction in patients with migraine compared to controls (p = 0.060) and, in an exploratory analysis, was reduced more after sleep restriction in sleep-related than in non-sleep-related migraine (p = 0.017). No other differences between groups after sleep restriction were found for temporal summation or conditioned pain modulation.

Conclusion: Patients with migraine may have a subtly altered endogenous pain modulation system. Sleep restriction may have an increased pronociceptive effect on this system, suggesting a mechanism for vulnerability to insufficient sleep in migraine. This effect seems to be larger in sleep-related migraine than in non-sleep-related migraine.

Keywords: Adaptation; Conditioned pain modulation; Insufficient sleep; Interictal migraine; Sleep-related migraine; Temporal summation.

Fig. 1

Study overview. A Participants completed a sleep diary and wore an actigraph in the indicated time period. Patients also completed headache diaries. For the sleep restriction condition, participants slept four hours for two consecutive nights preceding one of the examination days. We balanced and randomised order of sleep conditions between examination days. To ensure flexibility, the interval between baseline and Day 1, and Day 1 and Day 2, was allowed to vary between 3–10 days and 1–4 weeks, respectively. B Overview of the inclusion process for patients with migraine

Fig. 2

Conditioned pain modulation (CPM) protocol. Firstly, participants underwent mechanical test stimulus (TS), i.e., determination of pressure pain threshold (PPT) and suprathreshold pain level (PP5, at VAS = 5/10 cm); at left (1) and right (2) trapezius muscles. Second, a two-minute tonic thermal TS at «pain6» (VAS = 6/10 cm) intensity was applied to the left volar forearm while participants continuously rated their pain. Third, mechanical TS was repeated. Fourth, thermal TS was repeated simultaneously with immersion of the right hand in circulating water (7 °C) (conditioning stimulus, CS); this constituted the CPM condition. Participants rated CS-induced pain by a verbal NRS. Finally, the mechanical TS was repeated for the third time

Fig. 3

Grand means and individual plots from the conditioned pain modulation (CPM) protocol. Visual analogue scale (0–10 cm). TS: test stimulus. CPM: Conditioned pain modulation. Y-axis unit is VAS-pain, x-axis unit is time in seconds. A Grand means for VAS responses to the thermal test stimulus (TS) from the thermal part of the conditioned pain modulation (CPM) protocol. Each line shows VAS per time for combinations of group (patients with migraine vs controls), sleep condition (sleep restriction vs habitual sleep), and stimulus condition (CPM vs thermal TS). The VAS responses follow a typical pattern for noxious tonic heat stimulations, including an initial peak, subsequent adaptation with a nadir around 25–65 s, and final temporal summation. The first and last five seconds were removed due to varying VAS measurements in these time periods. B Same as in A, showing VAS measurements from each test subject (numbered) for combinations of sleep and stimulus condition. Controls to the left and patients with migraine to the right

Fig. 4

Piecewise model and contrasts from the conditioned pain modulation (CPM) protocol. VAS: Visual analogue scale (0–10 cm). TS: test stimulus. CPM: Conditioned pain modulation. Time in seconds. A) Y-axis unit is VAS pain, x-axis unit is time in seconds. Linear regression lines from the piecewise regression model for the thermal part of the CPM protocol. Each regression line shows VAS by time for each combination of group (patients with migraine vs controls, sleep condition (sleep restriction vs habitual sleep), and stimulus condition (CPM vs thermal test stimulus (TS)). There was a significant three-way interaction between group, sleep, and stimulus condition. B) Bar plot showing CPM effect on temporal summation of pain for patients with migraine and controls after habitual sleep and sleep restriction; the bars show change in slope of the temporal summation regression line (ratio of vas/cm) from 30 s with only TS and TS in addition to CS (CPM condition). CPM effect on temporal summation of pain tended to be decreased after sleep restriction in patients with migraine compared to controls. In the column for patients with migraine in A, this can be seen as diverging regression lines for thermal TS and CPM after habitual sleep, while the regression lines converge after sleep restriction. There was also a tendency toward increased CPM effect on temporal summation of pain in patients with migraine compared to controls after habitual sleep. This can be seen in A as slightly converging regression lines for the thermal TS and CPM conditions after habitual sleep in controls, while the corresponding regression lines diverges in the migraine group

Fig. 5

Contrasts from exploratory analyses. CPM: Conditioned pain modulation. Bar plots showing CPM effect on temporal summation of pain for migraine subgroups after habitual sleep and sleep restriction; the bars show change in slope of the temporal summation regression line (ratio of vas/cm) from 30 s with only TS and TS in addition to CS (CPM condition). CPM effect on temporal summation was decreased more after sleep restriction in sleep-related patients with migraine compared to non-sleep-related patients with migraine