Experimentally induced spinal nociceptive sensitization increases with migraine frequency: a single-blind controlled study

Roberto De Icco, Armando Perrotta, Valentina Grillo, Giuseppe Cosentino, Grazia Sances, Giorgio Sandrini, Cristina Tassorelli, Roberto De Icco, Armando Perrotta, Valentina Grillo, Giuseppe Cosentino, Grazia Sances, Giorgio Sandrini, Cristina Tassorelli

Abstract

The nitric-oxide donor nitroglycerin (NTG) administration induces a facilitation of nociceptive pathways in episodic migraine. This study aims to test the hypothesis that induced spinal sensitization could be more pronounced in patients affected by high-frequency migraine (HF-MIG) with respect to low-frequency migraine (LF-MIG). We enrolled 28 patients with LF-MIG (1-5 migraine days/month), 19 patients with HF-MIG (6-14 migraine days/month), and 21 healthy controls (HCs). Spinal sensitization was evaluated with the neurophysiological recording of the temporal summation threshold (TST) of the nociceptive withdrawal reflex at the lower limb. Temporal summation threshold was recorded at baseline and 30, 60, and 120 minutes after NTG administration (0.9 mg sublingual). Spinal sensitization was detected in LF-MIG at 60 (P = 0.010) and 120 minutes (P = 0.001) and in HF-MIG at 30 (P = 0.008), 60 (P = 0.001), and 120 minutes (P = 0.001) after NTG administration. Temporal summation threshold did not change in HC (P = 0.899). Moreover, TST reduction was more pronounced in HF-MIG with respect to LF-MIG (P = 0.002). The percentage of patients who developed a migraine-like headache after NTG was comparable in the 2 migraine groups (LF-MIG: 53.6%, HF-MIG: 52.6%, P = 0.284), whereas no subjects in the HC group developed a delayed-specific headache. Notably, the latency of headache onset was significantly shorter in the HF-MIG group when compared with the LF-MIG group (P = 0.015). Our data demonstrate a direct relationship between migraine frequency and both neurophysiological and clinical parameters, to suggest an increasing derangement of the nociceptive system control as the disease progresses, probably as a result of the interaction of genetic and environmental factors.

Conflict of interest statement

C. Tassorelli received honoraria for the participation in advisory boards or for oral presentations from: Allergan, ElectroCore, Eli-Lilly, Novartis, and Teva. C. Tassorelli has no ownership interest and does not own stocks of any pharmaceutical company. C. Tassorelli serves as Chief Section Editor of Frontiers in Neurology—Section Headache Medicine and Facial Pain and on the editorial board of The Journal of Headache and Pain. The remaining authors have no conflicts of interest to declare.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Percent change of the temporal summation threshold after NTG administration in the experimental groups. HC, healthy controls; LF-MIG, low-frequency migraine group; HF-MIG, moderate- to high-frequency migraine group. ▲ intragroup analysis: time point vs baseline P < 0.05. In table: ANOVA intergroup post hoc comparisons. ANOVA, analysis of variance.
Figure 2.
Figure 2.
Percent change of the temporal summation threshold after NTG administration: comparison between MIG+ and MIG− patients. MIG+: patients who developed migraine-like attacks after NTG administration. MIG−: patients who did not develop migraine-like attacks after NTG administration. Panel A: MIG+ vs MIG− comparison in the LF-MIG group (low-frequency migraine). Panel B: MIG+ vs MIG− comparison in the HF-MIG group (moderate- to high-frequency migraine). ● MIG + vs MIG— P < 0.05.
Figure 3.
Figure 3.
Percent change of VAS of temporal summation after NTG administration in the experimental groups. Panel A: VAS-I: visual analogue scale score recorded for the first stimulus of the temporal summation. Panel B: VAS-V: visual analogue scale score recorded for the fifth stimulus of the temporal summation. ▲ intragroup analysis: time point vs baseline P < 0.05. In table: ANOVA intergroup post hoc comparisons. ANOVA, analysis of variance; HC, healthy controls; HF-MIG, moderate- to high-frequency migraine group; LF-MIG, low-frequency migraine group.
Figure 4.
Figure 4.
Correlation between percentage modification of TST after NTG administration and days of headache per month. TST, temporal summation threshold of the NWR. Dotted line represents linear regression. Panel A: correlation between percentage reduction of TST at 60 minutes after NTG administration and days of headache per month: Pearson −0.491; P = 0.001. Panel B: correlation between percentage reduction of TST at 120 minutes after NTG administration and days of headache per month: Pearson −0.332; P = 0.023. NWR, nociceptive withdrawal reflex.

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