The pathophysiology of medication‐The pathophysiology of medicationoveruse headache: Implications 

from our researchMi SMin Su

Department of Neurology, Chinese PLA General Hospital, BeijingSchool of Medicine Nankai University TianjinSchool of Medicine, Nankai University, Tianjin

2016‐06‐09

DISCLOSURES• Research Support: 

Hubei OULY pharmaceutical co., LTD (Hubei, China)

Our team

Prof. Shengyuan Yu

Overview

• Definition of MOH• Clinical file of MOH in Chinese mainlandP th h i l f MOH• Pathophysiology of MOH—research presentation

• Summaryy

Definition of  MOH

In ICHD‐3 beta, MOH is described as follows:‘‘Headache occurring on 15 or more days per month

developing as a consequence of regular overuse of acute orp g q gsymptomatic headache medication (on 10 or more or 15 ormore days per month depending on the medication) formore days per month, depending on the medication) formore than three months. It usually, but not invariably,resolves after the overuse is stopped.’’

Cephalalgia 2013;33(9):733‐735.

Dong Z, et al. Cephalalgia 2015; 35:644‐651.

Clinical file of MOH in Chinese mainland

Prevalence of MOH:

Worldwide: 1%–1.5%;

Chinese mainland: the 1‐year prevalence of MOH based onChinese mainland: the 1‐year prevalence of MOH based onnationwide study was 0.6% (0.3% for male and 0.9% for female);while the incidence of MOH was 7 4% in our clinic‐basedwhile the incidence of MOH was 7.4% in our clinic basedresearch, which accounted for almost half (49.5%) of CDH.

W t d ML t l C h l l i 2014 34 409 425Westergaard ML, et al. Cephalalgia 2014; 34:409‐425.Yu S, et al. Headache 2012; 52: 582–591.Dong Z, et al. PLoS One 2012; 7: e50898

Clinical file of MOH in Chinese mainland

Population characteristics of MOH patients:less well educated, lower annual incomes, female.

Overused  drugs:Combination analgesics were the most commonly overused

medications, and, caffeine (89.9%), aminopyrine (70.0%),medications, and, caffeine (89.9%), aminopyrine (70.0%),phenacetin (53.9%) and phenobarbital (48.8%) were the mostcommonly used specific components of these.commonly used specific components of these.

Dong Z, et al. Cephalalgia 2015; 35:644‐651.

Genetic susceptibility

Pathophysiology of MOH

Medication‐overuse personality characteristics

Pre‐existing headache

Adaptive

Cortical hyperexcitabilityCSD↑

Adaptive response Brainstem dysfunction

T i i l h iti it

5‐HT↓5‐HT2AR ↑

CGRP, NOsubstance P↑

Peripheral/central sensitization

Trigeminal  hypersensitivity

MOHFigure 1. The proposed development of medication‐overuse headache.

Pathophysiology of MOH—research presentationp y gy

A novel animal model for MOH via co‐administration of overdose  i t i t (RIZ) d i fl t (IS)rizatriptan (RIZ) and inflammatory soup (IS).

IS+RIZIS+RIZ IS+NS Behavior recording and tactile sensory tests

Fos expression in headache‐related brain

NS+NS NS+RIZ

Fos expression in headache related brain regions

Change of 5‐HT and 5‐HT2A receptorIS i fl t Change of 5 HT and 5 HT2A receptorIS: inflammatory soup 

RIZ: rizatriptan 4mg/kg

NS: normal saline * Data to be published

RIZ‐IS induced nociception‐related behavior, while RIZ didn’t.

Figure 2. The average time rats spending onexploration (A) and resting behavior (B) duringe p o at o ( ) a d est g be a o ( ) du g15 minutes after meningeal nociception.The horizontal axis showed the time betweenmeasurement and baseline, and the vertical axisrepresented the duration of each kind ofbehavior. As a result of inflammatory soupinfusion and rizatriptan administration (IS RIZinfusion and rizatriptan administration (IS‐RIZgroup), there was a significant decrease ofexploration behavior (A) and increase of restingbehavior (B) as compared to both the RIZ group(*p < 0.05) and the Con group (#p < 0.05). Theinflammatory soup infusion (IS group) produced

* Data to be published

a significant reduction of exploration behavior(A) as compared to Con group (△p < 0.05) andthe RIZ group (^p < 0.05).

Rizatriptan‐overuse could not induce pain directly via activating the nociceptive pathway.

Figure 3. The number of Fos‐ir neurons in TNC (A),RVM(B), and PAG (C). All values given were the mean± SD, n = 5. *p < 0.05 and **p < 0.01 versus controlgroup. #p < 0.05 and ##p < 0.01 versus RIZ group. ^p <0.01 versus IS group. (Fos‐ir = Fos‐immunoreactive;TNC t i i l l d li RVM t l

* Data to be published

TNC = trigeminal nucleus caudalis; RVM = rostralventrolmedial medulla; PAG = periaqueductal gray)

Rizatriptan‐induced hyperalgesia accounts for exacerbation p yp gof central sensitization in MOH to some extent.

Figure 4. The periorbital withdrawal thresholds of rats during the 21‐day experiment. Average ± SD werereported. Compared with the control (Con) group, all the other three groups showed an obvious decrease inperiorbital mechanical withdrawal thresholds (*p < 0 05) since the sixth day of the experiment Rats of IS RIZ

* Data to be published

periorbital mechanical withdrawal thresholds (*p < 0.05) since the sixth day of the experiment. Rats of IS‐RIZgroup also show decrease of withdrawal thresholds than control (*p < 0.05) after the third treatment (d4). Therats of IS‐RIZ group had lower thresholds than rats of RIZ group during the last week of the experiment (^p <0.05), and a decrease was also found compared with rats of IS group (#p < 0.05, ##p < 0.01).

Pathophysiology of MOH—research presentation

Figure 5. The serotonin expression in rats’ platelets (C) and raphe nuclei (D). All values given were the mean ± SD; f f * d ** l #

* Data to be published

n = 10 in figure C; n = 5 in figure D. *p < 0.05 and **p < 0.01 versus control group. #p < 0.05 versus RIZ group. 

D E

Figure 6. The 5‐HT2AR expression in rats’ brain. The numberof 5‐HT2AR‐ir neurons in TNC (A), PAG (B) and frontal cortex(C) were listed. *p < 0.05 and **p < 0.01 versus controlgroup. The 5‐HT2AR protein expression in rats’brainstem (D) and frontal cortex (E) were alsoreported. *p < 0.05 versus control group. #p < 0.05

* Data to be published

p p g p pversus RIZ group. ^p < 0.01 versus IS group.

Both medication‐overuse and repeated inflammatory stimuli could promote the up‐regulation of 5‐HT2A receptor, which p p g 2A p

plays a role in the process of central sensitization.

Figure 7. The correlation between expression of Fos and 5‐HT2AR in TNC (D), PAG (E) and frontal cortex (F). There was apositive correlation between expression of 5‐HT2AR‐irneurons and Fos‐ir neurons in TNC (D), and frontal cortex(F). (Fos‐ir = Fos‐immunoreactive; 5‐HT2AR‐ir = 5‐HT2AR‐i i TNC i i l l d li PAG

* Data to be published

immunoreactive; TNC = trigeminal nucleus caudalis; PAG =periaqueductal gray)

Conclusion

• Overuse of rizatriptan cannot induce pain directly but wouldaggravate headache by influencing the pain modulatingsystem, in which decrease of 5‐HT and upregulation of 5‐HT2Areceptor might play important roles.

• Both medication‐overuse and frequent headache attacks canpromote the process of neural plasticity in MOH to someextent.

Summaryy

MOH patients account for almost half of those with headache on≥15 days/month in China, and irrational use of analgesics shallbe one of the major concerns.

The pathophysiology behind MOH is complex, however, theneural plasticity induced by both chronic analgesic exposure andrecurring headache attacks maybe a central part in thepathogenesis of MOH.

Thanks for your attention!y