The Cholinomimetic Agent Carbachol Induces Headache in Healthy Subjects

Cephalalgia ◽  
2009 ◽  
Vol 29 (2) ◽  
pp. 258-268 ◽  
Author(s):  
HW Schytz ◽  
T Wieneckey ◽  
PS Oturai ◽  
J Olesen ◽  
M Ashina
Keyword(s):  
Healthy Subjects ◽  
Rating Scale ◽  
Parasympathetic Nervous System ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Double Blind ◽  
Migraine Pathogenesis ◽  
Blind Crossover Study ◽  
Double Blind Crossover Study

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 μg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0–10. Velocity in the middle cerebral artery (Vmca) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0–30 min) ( P = 0.042) and in the postinfusion period (30–90 min) ( P = 0.027). Carbachol infusion caused a drop in Vmca ( P = 0.003) and an increase in STA diameter ( P = 0.006), but no increase in the RA diameter ( P = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.

Carbachol induces headache, but not migraine-like attacks, in patients with migraine without aura

Cephalalgia ◽  
2009 ◽  
Vol 30 (3) ◽  
pp. 337-345 ◽  
Author(s):  
HW Schytz ◽  
T Wienecke ◽  
J Olesen ◽  
M Ashina
Keyword(s):  
Crossover Study ◽  
Middle Cerebral Artery ◽  
Healthy Subjects ◽  
Migraine Without Aura ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Temporal Artery ◽  
Double Blind ◽  
Blind Crossover Study ◽  
Double Blind Crossover Study

Carbachol induces headache in healthy subjects, but the migraine eliciting effect of carbachol has not previously been studied. We hypothesized that the cholinomimetic agonist carbachol would induce headache and migraine-like attacks in migraineurs. Carbachol (3 µg/kg) or placebo was randomly infused into 18 patients with migraine without aura in a double-blind crossover study. Headache was scored on a verbal rating scale from 0 to 10. Velocity in the middle cerebral artery (VMCA) and diameter of the superficial temporal artery (STA) were recorded. Fifteen patients experienced headache after carbachol compared with eight after placebo ( P = 0.039). There was no difference in incidence of migraine-like attacks after carbachol ( n = 8) compared with placebo ( n = 6) ( P = 0.687). Carbachol caused a decrease in VMCA ( P = 0.044), but no change in STA ( P = 0.089) compared with placebo. The study demonstrated that carbachol provocation is not a good model for experimental migraine.

Prostaglandin E2 (PGE2) Induces Headache in Healthy Subjects

Cephalalgia ◽  
2009 ◽  
Vol 29 (5) ◽  
pp. 509-519 ◽  
Author(s):  
T Wienecke ◽  
J Olesen ◽  
PS Oturai ◽  
M Ashina
Keyword(s):  
Healthy Subjects ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Prostaglandin E ◽  
Double Blind Study ◽  
Mean Flow ◽  
Sensory Afferents ◽  
Double Blind

The role of prostanoids in nociception is well established. The headache-eliciting effects of prostaglandin E2 (PGE2) and its possible mechanisms have previously not been systematically studied in man. We hypothesized that infusion of PGE2 might induce headache and vasodilation of cranial vessels. PGE2 (0.40 μg kg−1 min−1) or saline was infused for 25 min into 11 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (VMCA) by transcranial Doppler and diameter of the superficial temporal artery (STA) by high-resolution ultrasonography. All 11 subjects reported headache on the PGE2 day and no subjects reported headache on the placebo day ( P = 0.001). During the immediate phase (0–30 min) ( P = 0.005) and the postinfusion phase (30–90 min) ( P = 0.005), the area under the curve for headache score was significantly larger on the PGE2 day compared with the placebo day. PGE2 caused dilatation of the STA (23.5%; 95% CI 14.0, 37.8) and the MCA (8.3%; 95% CI 4.0, 12.6). We suggest that PGE2 induces headache by activation and sensitization of cranial perivascular sensory afferents.

Vasoactive Intestinal Peptide Causes Marked Cephalic Vasodilation, but does not Induce Migraine

Cephalalgia ◽  
2008 ◽  
Vol 28 (3) ◽  
pp. 226-236 ◽  
Author(s):  
A Rahmann ◽  
T Wienecke ◽  
JM Hansen ◽  
J Fahrenkrug ◽  
J Olesen ◽  
...  
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Temporal Artery ◽  
High Frequency Ultrasound ◽  
Double Blind ◽  
Vascular Origin ◽  
Cranial Arteries ◽  
To Receive ◽  
Double Blind Crossover Study

We hypothesized that intravenous infusion of the parasympathetic transmitter, vasoactive intestinal peptide (VIP), might induce migraine attacks in migraineurs. Twelve patients with migraine without aura were allocated to receive 8 pmol kg-1 min-1 VIP or placebo in a randomized, double-blind crossover study. Headache was scored on a verbal rating scale (VRS), mean blood flow velocity in the middle cerebral artery ( Vmean mca) was measured by transcranial Doppler ultrasonography, and diameter of the superficial temporal artery (STA) by high-frequency ultrasound. None of the subjects reported a migraine attack after VIP infusion. VIP induced a mild immediate headache (maximum 2 on VRS) compared with placebo ( P = 0.005). Three patients reported delayed headache (3-11 h after infusion) after VIP and two after placebo ( P = 0.89). Vmean mca decreased (16.3 ± 5.9%) and diameter of STA increased significantly after VIP (45.9 ± 13.9%). VIP mediates a marked dilation of cranial arteries, but does not trigger migraine attacks in migraineurs. These data provide further evidence against a purely vascular origin of migraine.

Pro-inflammatory and vasoconstricting prostanoid PGF2α causes no headache in man

Cephalalgia ◽  
2011 ◽  
Vol 31 (15) ◽  
pp. 1532-1541 ◽  
Author(s):  
Maria Antonova ◽  
Troels Wienecke ◽  
Jes Olesen ◽  
Messoud Ashina
Keyword(s):  
Healthy Volunteers ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Human Model ◽  
Prostaglandin E ◽  
Signalling Molecules ◽  
Prostaglandin F

Background: During two decades of migraine provocation studies with naturally occurring signalling molecules, vasodilators such as prostaglandin E2, prostaglandin I2 (prostacyclin) and prostaglandin D2 were shown to be able to induce headache in man. To elucidate the role of inflammation and vasodilatation in the generation of headache, we investigated whether the pro-inflammatory and vasoconstricting prostanoid prostaglandin F2α (PGF2α) would cause headache in a human model of headache. Methods: Twelve healthy volunteers were randomly allocated to receive 3.5 µg/kg/min PGF2α or placebo over 20 min in a two-way crossover study. We recorded headache intensity on a verbal rating scale, middle cerebral artery blood flow velocity (VMCA) and the diameters of the superficial temporal artery (STA) and radial artery (RA). Results: We found no difference in the area under the curve (AUC) for immediate headache (0–90 min) between PGF2α and placebo ( p = 0.144). The McNemar's test showed no difference in the incidence of immediate and delayed headache between verum and placebo ( p = 0.500 and p = 1.000, respectively). There was no difference in VMCA ( p = 0.776) and in the diameter of the STA ( p = 0.460) or RA ( p = 0.780) between PGF2α and placebo. Conclusion: The present study shows that PGF2α, unlike vasodilating prostaglandins, does not provoke headache. We suggest that the vasodilating abilities of prostaglandins are important for the induction of experimental headache in healthy volunteers.

The Effect of Propranolol on Glyceryltrinitrate-Induced Headache and Arterial Response

Cephalalgia ◽  
2004 ◽  
Vol 24 (12) ◽  
pp. 1076-1087 ◽  
Author(s):  
JF Tvedskov ◽  
LL Thomsen ◽  
LL Thomsen ◽  
HK Iversen ◽  
P Williams ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Migraine Without Aura ◽  
Rating Scale ◽  
No Reduction ◽  
International Headache Society ◽  
Cerebral Arteries ◽  
Superficial Temporal Artery ◽  
New Drugs ◽  
Prophylactic Effect ◽  
Double Blind

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 mg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) ( P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) ( P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with ( P = 0.003) and without pretreatment with propranolol ( P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients ( P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.

The Effects of Morphine–Neostigmine and Secretin Provocation on Pancreaticobiliary Morphology in Healthy Subjects: A Randomized, Double-blind Crossover Study Using Serial MRCP

2011 ◽  
Vol 35 (9) ◽  
pp. 2102-2109 ◽  
Author(s):  
Abeed H. Chowdhury ◽  
David J. Humes ◽  
Susan E. Pritchard ◽  
Luca Marciani ◽  
Penny A. Gowland ◽  
...  
Keyword(s):  
Crossover Study ◽  
Healthy Subjects ◽  
Double Blind ◽  
Blind Crossover Study ◽  
Double Blind Crossover Study

Lack of correlation between vasodilatation and pharmacologically induced immediate headache in healthy subjects

Cephalalgia ◽  
2011 ◽  
Vol 31 (6) ◽  
pp. 683-690 ◽  
Author(s):  
Messoud Ashina ◽  
Peer Tfelt-Hansen ◽  
Peter Dalgaard ◽  
Jes Olesen
Keyword(s):  
Healthy Subjects ◽  
Rating Scale ◽  
Superficial Temporal Artery ◽  
Experimental Studies ◽  
Temporal Artery ◽  
Arterial Diameter ◽  
Mean Velocity ◽  
Headache Intensity ◽  
Scatter Plots ◽  
The Mean

Background: The causal relationship between experimental headache and vasodilatation has not been fully clarified. In the present study, we combined headache and vascular data from eight experimental studies and conducted detailed statistical analyses. Given that substances used in all these experiments were vasodilators we examined a possible correlation between headache scores and increases in arterial diameter. Methods: We identified nine studies and retrieved raw data in 89 healthy subjects (46 females, 43 males), mean age 27 years (range 18–59 years). The following variables were collected: maximal median headache intensity scores on a verbal rating scale (VRS) during immediate headache (0–120 minutes); the mean velocity of blood flow in the middle cerebral artery (VmeanMCA); and the diameter of the frontal branch of the superficial temporal artery (STA) during the maximal median headache intensity. Results: The scatter plots show no relationship between maximal headache score and the relative changes in VmeanMCA and diameter of the STA. The main analyses of covariance showed a significant effect only of heart rate on headache ( p = .014). The interaction tests were insignificant for all variables. Conclusions: The major outcome is a finding of no linear relationship between experimental immediate headache and dilatation of the MCA or STA.

Headache Characteristics During the Development of Tolerance to Nitrates: Pathophysiological Implications

Cephalalgia ◽  
2000 ◽  
Vol 20 (5) ◽  
pp. 437-444 ◽  
Author(s):  
I Christiansen ◽  
HK Iversen ◽  
J Olesen
Keyword(s):  
Healthy Subjects ◽  
Superficial Temporal Artery ◽  
Temporal Artery ◽  
Continuous Treatment ◽  
Isosorbide Mononitrate ◽  
Temporal Association ◽  
Organic Nitrates ◽  
Double Blind ◽  
Insight Into ◽  
Development Of Tolerance

Recent studies suggest that nitric oxide (NO) plays an important role in nitrate‐induced headache and in spontaneous migraine attacks. Organic nitrates act as prodrugs for NO and headache is a predominant adverse effect of nitrates but often disappears during continuous treatment. Insight into tolerance to headache could lead to insight into vascular headache mechanisms in general. The specific aim of the present study was therefore to characterize the headache and accompanying symptoms during continuous nitrate administration until a state of tolerance to headache had developed. 5‐isosorbide‐mononitrate (5‐ISMN) 30 mg three times daily was administered orally for 7 days in 11 healthy subjects in a double‐blind, randomized placebo controlled cross‐over design. Wash‐out between periods was 14 days or more. Haemodynamic data from the present study were compared to the observed changes of headache over time. Headache during 5‐ISMN was longer lasting and more severe compared to placebo ( P < 0.004). In 10 subjects the headache fulfilled the pain sub‐criteria for migraine and in five subjects all diagnostic criteria for migraine without aura were fulfilled. Conversely, 20 min of intravenous infusion of glyceryl trinitrate caused a milder headache and no migraine. The present results therefore suggest that NO may elicit a migraine attack in many healthy subjects if a high enough dose is given for several hours. A close temporal association between the disappearance of headache and the attenuation of the 5‐ISMN induced dilatation of the superficial temporal artery was observed. In contrast, tolerance in the middle cerebral artery already appeared after 24 h, which was earlier than the development of tolerance to headache. If vasodilatation is the cause of headache the results point to extracerebral arteries. However, cytotoxic and pain modulating central nervous system effects of NO, the time courses of which are unknown, may also play a role, involving both intra‐ and extracranial arteries.

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial

Cephalalgia ◽  
2021 ◽  
pp. 033310242097539
Author(s):  
Nita Katarina Frifelt Wienholtz ◽  
Casper Emil Christensen ◽  
Ditte Georgina Zhang ◽  
Hande Coskun ◽  
Hashmat Ghanizada ◽  
...  
Keyword(s):  
Early Treatment ◽  
Intravenous Infusion ◽  
Migraine Without Aura ◽  
Superficial Temporal Artery ◽  
Area Under The Curve ◽  
Temporal Artery ◽  
Randomised Clinical Trial ◽  
Trigeminovascular System ◽  
Double Blind ◽  
Nociceptive Transmission

Objective To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. Methods A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. Results Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo ( p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) ( p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo ( p < 0.001). Conclusions and relevance: Early treatment with intravenously administered sumatriptan prevented PACAP38-induced migraine. Prevention of migraine attacks was associated with vasoconstriction by sumatriptan in the earliest phases of PACAP provocation. These results suggest that sumatriptan prevents PACAP38-induced migraine by modulation of nociceptive transmission within the trigeminovascular system. Trial Registration: ClinicalTrials.gov (NCT03881644).

Sign in / Sign up

Export Citation Format

Share Document