The MIGREX study: Prevalence and risk factors of sexual dysfunction among migraine patients.

BACKGROUND: Migraine attacks have a high impact on daily activities. There is limited research on the burden of migraine on sexual functioning. OBJECTIVE: To determine the prevalence of sexual dysfunction in patients with migraine and its relationship with migraine features and comorbidities. METHOD: This is a cross-sectional study. We included migraine patients between 18 and 60 years-old from 8 Headache Clinics in Spain. We recorded demographic data and migraine features. Patients fulfilled a survey including comorbidities, Arizona Sexual Experiences Scale, Hospital Anxiety and Depression Scale and a questionnaire about migraine impact on sexual activity. A K-nearest neighbor supervised learning algorithm was used to identify differences between migraine patients with and without sexual dysfunction. RESULTS: We included 306 patients (85.6% women, mean age 42.3±11.1 years). A 41.8% of participants had sexual dysfunction. Sexual dysfunction was associated with being female (OR [95% CI]: 2.42 [1.17-5.00]; p<0.001), being older than 46.5 years (4.04 [2.48-6.59]; p<0.001), having chronic migraine (2.31 [1.41-3.77]; p=0.001), using preventive medication (2.45 [1.35-4.45]; p=0.004), analgesic overusing (3.51 [2.03-6.07]; p<0.001), menopause (4.18 [2.43-7.17]; p<0.001) and anxiety (2.90 [1.80-4.67]; p<0.001) and depression (6.14 [3.18-11.83]; p<0.001). However, only female gender, age, menopause and depression were the statistically significant variables selected in the model to classify migraine patients with or without sexual dysfunction (Accuracy [95% CI]: 0.75 (0.62-0.85), Kappa: 0.48, p=0.005). CONCLUSIONS: Sexual dysfunction is frequent in migraine patients visited in a headache clinic. However, migraine characteristics or use of preventive medication are not directly associated with sexual dysfunction. Instead, risk factors for sexual dysfunction were female gender, higher age, menopause and depression.

The MIGREX study: Prevalence and risk factors of sexual dysfunction among migraine patients / Estudio MIGREX: Prevalencia y factores de riesgo de disfunción sexual en pacientes con migraña

Background: Migraine attacks have a high impact on daily activities. There is limited research on the burden of migraine on sexual functioning. Objective: To determine the prevalence of sexual dysfunction in patients with migraine and its relationship with migraine features and comorbidities. Method: This is a cross-sectional study. We included migraine patients between 18 and 60 years-old from 8 Headache Clinics in Spain. We recorded demographic data and migraine features. Patients fulfilled a survey including comorbidities, Arizona Sexual Experiences Scale, Hospital Anxiety and Depression Scale and a questionnaire about migraine impact on sexual activity. A K-nearest neighbor supervised learning algorithm was used to identify differences between migraine patients with and without sexual dysfunction. Results: We included 306 patients (85.6% women, mean age 42.3 ±11.1 years). A 41.8% of participants had sexual dysfunction. Sexual dysfunction was associated with being female (OR [95% CI]: 2.42 [1.17–5.00]; p < 0.001), being older than 46.5 years (4.04 [2.48–6.59]; p < 0.001), having chronic migraine (2.31 [1.41–3.77]; p = 0.001), using preventive medication (2.45 [1.35–4.45]; p = 0.004), analgesic overusing (3.51 [2.03–6.07]; p < 0.001), menopause (4.18 [2.43–7.17]; p < 0.001) and anxiety (2.90 [1.80–4.67]; p < 0.001) and depression (6.14 [3.18–11.83]; p < 0.001). However, only female gender, age, menopause and depression were the statistically significant variables selected in the model to classify migraine patients with or without sexual dysfunction (Accuracy [95% CI]: 0.75 (0.62–0.85), Kappa: 0.48, p = 0.005). Conclusions: Sexual dysfunction is frequent in migraine patients visited in a headache clinic. However, migraine characteristics or use of preventive medication are not directly associated with sexual dysfunction. Instead, risk factors for sexual dysfunction were female gender, higher age, menopause and depression.(AU)

Antecedentes: La migraña tiene un alto impacto en las actividades diarias, pero los datos sobre el impacto de la migraña en el funcionamiento sexual son limitados. Objetivo: Determinar la prevalencia de disfunción sexual en pacientes con migraña y su relación con las características y comorbilidades de la migraña. Métodos: Este es un estudio transversal. Se incluyeron pacientes con migraña de entre 18 y 60 años de ocho consultas de cefalea en España. Registramos datos demográficos y características de migraña. Los pacientes completaron una encuesta que incluía comorbilidades, la Escala de Experiencias Sexuales de Arizona, la Escala de Ansiedad y Depresión Hospitalaria y un cuestionario sobre el impacto de la migraña en la actividad sexual. Se usó un algoritmo de aprendizaje supervisado (k-nearest neighbors) para identificar diferencias entre pacientes con migraña, con y sin disfunción sexual. Resultados: Se incluyeron 306 pacientes (85,6% mujeres, edad media 42,3 ± 11,1 años). El 41,8% de los participantes tenía disfunción sexual. La disfunción sexual se asoció con ser mujer (OR [95%]: 2,42 [1,17-5,00]; p < 0,001), tener más de 46,5 años (4,04 [2,48-6,59]; p < 0,001), tener migraña crónica (2,31 [1,41-3,77]; p = 0,001), uso de medicación preventiva (2,45 [1,35-4.45]; p = 0,004), uso excesivo de analgésicos (3,51 [2,03-6,07]; p < 0,001), menopausia (4,18 [2,43-7,17]; p < 0,001), ansiedad (2,90 [1,80-4,67]; p < 0,001) y depresión (6,14 [3,18-11,83]; p < 0,001). Sin embargo, solo el sexo femenino, la edad, la menopausia y la depresión fueron las variables estadísticamente significativas seleccionadas en el modelo para clasificar a los pacientes con migraña, con o sin disfunción sexual (precisión [IC 95%]: 0,75 (0,62-0,85), kappa: 0,48, p = 0,005). Conclusiones: La disfunción sexual es frecuente en pacientes con migraña que son visitados en una consulta de cefalea.(AU)

The MIGREX study: Prevalence and risk factors of sexual dysfunction among migraine patients.

BACKGROUND: Migraine attacks have a high impact on daily activities. There is limited research on the burden of migraine on sexual functioning. OBJECTIVE: To determine the prevalence of sexual dysfunction in patients with migraine and its relationship with migraine features and comorbidities. METHOD: This is a cross-sectional study. We included migraine patients between 18 and 60 years-old from 8 Headache Clinics in Spain. We recorded demographic data and migraine features. Patients fulfilled a survey including comorbidities, Arizona Sexual Experiences Scale, Hospital Anxiety and Depression Scale and a questionnaire about migraine impact on sexual activity. A K-nearest neighbor supervised learning algorithm was used to identify differences between migraine patients with and without sexual dysfunction. RESULTS: We included 306 patients (85.6% women, mean age 42.3±11.1 years). A 41.8% of participants had sexual dysfunction. Sexual dysfunction was associated with being female (OR [95% CI]: 2.42 [1.17-5.00]; p<0.001), being older than 46.5 years (4.04 [2.48-6.59]; p<0.001), having chronic migraine (2.31 [1.41-3.77]; p=0.001), using preventive medication (2.45 [1.35-4.45]; p=0.004), analgesic overusing (3.51 [2.03-6.07]; p<0.001), menopause (4.18 [2.43-7.17]; p<0.001) and anxiety (2.90 [1.80-4.67]; p<0.001) and depression (6.14 [3.18-11.83]; p<0.001). However, only female gender, age, menopause and depression were the statistically significant variables selected in the model to classify migraine patients with or without sexual dysfunction (Accuracy [95% CI]: 0.75 (0.62-0.85), Kappa: 0.48, p=0.005). CONCLUSIONS: Sexual dysfunction is frequent in migraine patients visited in a headache clinic. However, migraine characteristics or use of preventive medication are not directly associated with sexual dysfunction. Instead, risk factors for sexual dysfunction were female gender, higher age, menopause and depression.

Equivalent dynamic human brain NK1-receptor occupancy following single-dose i.v. fosaprepitant vs. oral aprepitant as assessed by PET imaging.

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist.

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Occipital activation by pattern recognition in the early blind using auditory substitution for vision.

This PET study aimed at investigating the neural structures involved in pattern recognition in early blind subjects using sensory substitution equipment (SSE). Six early blind and six blindfolded sighted subjects were studied during three auditory processing tasks: a detection task with noise stimuli, a detection task with familiar sounds, and a pattern recognition task using the SSE. The results showed a differential activation pattern with the SSE as a function of the visual experience: in addition to the regions involved in the recognition process in sighted control subjects, occipital areas of early blind subjects were also activated. The occipital activation was more important when the early blind subjects used SSE than during the other auditory tasks. These results suggest that activity of the extrastriate visual cortex of early blind subjects can be modulated and bring additional evidence that early visual deprivation leads to cross-modal cerebral reorganization.

Decreased benzodiazepine receptor density in the cerebellum of early blind human subjects.

As a first approach to study the effect of early visual deprivation in the GABA-ergic inhibitory system, the distribution of benzodiazepine receptors (BZR) was accurately estimated using [11C]flumazenil ([11C]FMZ). Measurements were carried out in five subjects who became blind early in life and in five sighted control subjects. The interactions between [11C]FMZ and BZR were described using a non-linear compartmental analysis which permitted to estimate the BZR synaptic density independently of other model parameters. The distribution of BZR in the visual areas and other cortical regions of blind subjects was qualitatively and quantitatively similar to that of controls. However, the BZR density in the cerebellum was significantly lower in blind than in control subjects (P<0.01). Our findings suggest that modifications of the cerebellar neural circuitry may be concomitant to the already observed compensatory reorganization in cerebral areas of blind subjects.

[11C]flumazenil metabolite measurement in plasma is not necessary for accurate brain benzodiazepine receptor quantification.

In this work, a mathematical correction for metabolites has been validated which estimates the relative amount of [11C]flumazenil ([11C]FMZ) in the total plasma curve from the tissue kinetic data without the need for direct metabolite measurement in blood plasma samples. Kinetic data were obtained using a 90-min three-injection protocol on five normal volunteers. First, the relative amount of [11C]FMZ in plasma was modelled by a two-parameter exponential function. The parameters were estimated either directly by fitting this model to the blood plasma metabolite measurements, or indirectly from the simultaneous fitting of tissue time activity curves from several brain regions with a non-linear FMZ kinetic model. Second, the direct and indirect metabolite corrections were fixed and the FMZ compartmental parameters were determined on a regional basis in the brain. The validation was performed by comparing the regional values of benzodiazepine receptor density Bmax and equilibrium dissociation constant Kd obtained with the direct metabolite correction with those values obtained with the indirect correction. For Bmax, the correlation coefficient r2 was above 0.97 for all subjects and the slope values of the linear regression were within the interval [0.97, 1.2]. For Kd, r2 was above 0.96, and the slope values of the linear regression were within the interval [0.99, 1.1]. Simulation studies were performed in order to evaluate whether this metabolite correction method could be used in a clinical protocol where only a single [11C]FMZ injection and a linear compartmental model are used. The resulting [11C]FMZ distribution volume estimates were found to be linearly correlated with the true values, with r2=1.0 and a slope value of 1.1. The mathematical metabolite correction proved to be a feasible and reliable method to estimate the relative amount of [11C]FMZ in plasma and the compartmental model parameters for three-injection protocols. Although validation with real data is necessary, simulation results suggest that our analysis method may also be applied to single-injection protocols.