Ictal adipokines are associated with pain severity and treatment response in episodic migraine

Abstract

Objective: To evaluate ictal adipokine levels in episodic migraineurs and their association with pain severity and treatment response.Methods: This was a double-blind, placebo-controlled trial evaluating peripheral blood specimens from episodic migraineurs at acute pain onset and 30 to 120 minutes after treatment with sumatriptan/naproxen sodium vs placebo. Total adiponectin (T-ADP), ADP multimers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]), leptin, and resistin levels were evaluated by immunoassays.Results: Thirty-four participants (17 responders, 17 nonresponders) were included. In all partici- Conclusions: Both pretreatment migraine pain severity and treatment response are associated with changes in adipokine levels. Adipokines represent potential novel migraine biomarkers and drug targets. Neurology ® 2015;84:1409-1418 GLOSSARY ADP 5 adiponectin; CI 5 confidence interval; CV 5 coefficient of variation; HMW 5 high molecular weight; ICHD-2 5 International Classification of Headache Disorders, second edition; IL-6 5 interleukin 6; LEP 5 leptin; LMW 5 low molecular weight; MMW 5 middle molecular weight; NRS 5 numeric rating scale; suma/nap 5 sumatriptan/naproxen sodium; T-ADP 5 total adiponectin; TNF-a 5 tumor necrosis factor a.Adipokines are biologically active proteins, predominantly secreted from adipose tissue, that participate in multiple processes, including the drive to feed and pain processesing. [1][2][3][4] Adiponectin (ADP), leptin (LEP), and resistin are 3 such adipokines. These adipokines modulate inflammation and endothelial function-processes that overlap with the proposed mechanisms of migraine pathophysiology. In addition, receptors for these adipokines are expressed in key structures implicated in migraine, including the hypothalamus and the cerebral microvasculature. [1][2][3][4] Previous studies have reported that interictal ADP levels are increased in those with migraine, and that ictal ADP levels decline with successful abortive treatment in women episodic migraineurs. [5][6][7] Studies evaluating interictal LEP levels in migraineurs have been inconclusive. [8][9][10][11][12] No previous studies have evaluated ictal LEP or resistin levels in migraineurs.

Adipokines and Migraine: A Systematic Review

“…Chai et al evaluated ictal T‐ADP and ADP multimers in participants with EM (Table ) . Although relatively small (n = 34), this study was the largest of all similar longitudinal ictal studies evaluating blood markers in episodic migraineurs to date.…”

“…Peripheral serum levels of T‐ADP and ADP multimers were evaluated in a total of 34 episodic migraineurs (women and men of all obesity status levels) before and after treatment with oral sumatriptan/naproxen vs placebo. There were no significant differences in demographics including sex and BMI, headache characteristics, or baseline laboratories including glucose, insulin, and cholesterol in those treated with active drug vs placebo . Notably, treatment responders had a higher BMI and lower glucose level compared to non‐responders.…”

“…Notably in responders HMW‐ADP was decreased and LMW‐ADP increased (both in an anti‐inflammatory direction) at 120 minutes after treatment as compared to onset. In non‐responders only LMW‐ADP was decreased (in a pro‐inflammatory direction) at 120 minutes …”

“…Review of references in these manuscripts and related‐reviews identified 2 additional studies . Of these 21 manuscripts, 6 were reviews, 3 were non‐adipokine studies, and 1 utilized an animal model of aura and were thus excluded, leaving 12 studies which evaluated blood levels of leptin in those with migraine . Of these 11 manuscripts, 6 included crude interictal leptin evaluations in those with migraine as compared to controls and 5 evaluated leptin levels before and after abortive or preventive therapy in those with migraine.…”

“…Of these 3 manuscripts using overlapping cohorts, the smallest cohort was excluded; 2 were included because one of the remaining 2 overlapping manuscripts included new data from men, leaving a total of 5 interictal manuscripts. Full review of the 5 manuscripts which evaluated leptin levels before and after abortive or preventive therapy in those with migraine, determined that none utilized overlapping cohorts and all were included …”