Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study.

BACKGROUND: Chronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication. However, the mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. We performed a longitudinal epigenome-wide association study to identify DNA methylation (DNAm) changes associated with treatment response in patients with chronic migraine and medication overuse as part of the Chronification and Reversibility of Migraine clinical trial. Blood was taken from patients with chronic migraine (n = 98) at baseline and after a 12-week medication withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify DNAm changes associated with treatment response. Similarly, patients with ≥ 50% versus < 50% reduction in monthly migraine days (MMD) were compared. RESULTS: At the epigenome-wide significant level (p < 9.42 × 10-8), a longitudinal reduction in DNAm at an intronic CpG site (cg14377273) within the HDAC4 gene was associated with MHD response following the withdrawal of acute medication. HDAC4 is highly expressed in the brain, plays a major role in synaptic plasticity, and modulates the expression and release of several neuroinflammation markers which have been implicated in migraine pathophysiology. Investigating whether baseline DNAm associated with treatment response, we identified lower baseline DNAm at a CpG site (cg15205829) within MARK3 that was significantly associated with MMD response at 12 weeks. CONCLUSIONS: Our findings of a longitudinal reduction in HDAC4 DNAm status associated with treatment response and baseline MARK3 DNAm status as an early biomarker for treatment response, provide support for a role of pathways related to chromatin structure and synaptic plasticity in headache chronification and introduce HDAC4 and MARK3 as novel therapeutic targets.

DNA-methylation and immunological response in medication overuse headache.

OBJECTIVE: To investigate whether medication-overuse headache patients have differential DNA-methylation pattern. METHODS: We collected blood samples from 120 medication-overuse headache-patients, 57 controls (29 episodic migraine patients and 28 healthy controls) in a hypothesis-generating cross-sectional case-control pilot study; 100 of the medication-overuse headache-patients were followed for six months and samples were collected at two and six months for the longitudinal methylation analyses. Blood cell proportions of leucocytes (neutrophils, NK-cells, monocytes, CD8+ and CD4+ T-cells, and B-cells) and the neutrophile-lymphocyte ratio were estimated using methylation data as a measure for immunological analysis and a cell type-specific epigenome wide association study was conducted between medication-overuse headache-patients and controls, and longitudinally for reduction in headache days/month among medication-overuse headache-patients. RESULTS: We found a higher neutrophile-lymphocyte ratio in medication-overuse headache-patients compared to controls, indicating a higher immunological response in medication-overuse headache-patients (false discovery rate (adjusted p-value)<0.001). Reduction in headache days/month (9.8; 95% CI 8.1-11.5) was associated with lower neutrophile-lymphocyte ratio (false discovery rate adjusted p-value = 0.041).Three genes (CORIN, CCKBR and CLDN9) were hypermethylated in specific cell types in medication-overuse headache-patients compared to controls. No methylation differences were associated with reduction in headache days in medication-overuse headache-patients after six months. CONCLUSION: This pilot study was consistent with higher immunological response in medication-overuse headache-patients which decreased with a reduction in headache days in longitudinal analysis. medication-overuse headache-patients exhibited differential methylation in innate immune cells but did not exhibit longitudinal differences with alterations in headache days. Our study creates hypotheses for further biomarker searches.ClinicalTrials.gov Identifier: NCT02993289.

Candidate Genes and Proteomic Biomarkers of Serum and Urine in Medication-Overuse Headache.

Chronic headache is a topical problem of neurology, psychiatry and general practice. The medication-overuse headache (MOH) is one of the leading pathologies in the structure of chronic headache. However, early diagnosis of the MOH is challenging. We analyzed potential proteomic biomarkers of serum and urine in patients with MOH. METHODS: We searched PubMed, Springer, Scopus, Web of Science, ClinicalKey, and Google Scholar databases for English publications over the past 10 years using keywords and their combinations. RESULTS: We found and analyzed seven studies that met the search criteria for the purpose of the review, including 24 serum proteomic biomarkers and 25 urine proteomic biomarkers of MOH. Moreover, the candidate genes and locus of the studied serum (vitamin D-binding protein, lipocalin-type prostaglandin D2 synthase, apolipoprotein E, etc.) and urine proteomic biomarkers (uromodulin, alpha-1-microglobulin, zinc-alpha-2-glycoprotein, etc.) of MOH are presented in this review. CONCLUSIONS: The serum and urine proteomic biomarkers of MOH can potentially help with the identification of patients with MOH development. Due to the relevance of the problem, the authors believe that further investigation of the MOH proteomic biomarkers in different ethnic and racial groups of patients with primary headache is necessary. In addition, it is important to investigate whether medications of different drug classes influence the levels of serum and urine proteomic biomarkers.

HLA class I alleles are associated with clinic-based migraine and increased risks of chronic migraine and medication overuse.

OBJECTIVE: We aimed to evaluate associations of human leukocyte antigen variants with migraine or headache in hospital and population-based settings. METHODS: The case-control study population, aged 30-70, included 605 clinic-based migraine patients in a medical center and 8449 population-based participants in Taiwan Biobank (TWB). Clinic-based cases were ascertained by neurologists. Participants in Taiwan Biobank were interviewed by a structured questionnaire including headache and migraine history; among them, 2394 had headache or migraine history while 6055 were free of headache and served as controls. All subjects were genotyped by Axiom Genome-Wide Single Nucleotide Polymorphism Arrays and imputed for eight classical human leukocyte antigen genes. Human leukocyte antigen frequencies were compared between clinic-based and self-reported patients and controls. We utilized likelihood ratio tests to examine human leukocyte antigen-disease associations and logistic regressions to estimate the effect of human leukocyte antigen alleles on migraine. RESULTS: Human leukocyte antigen-B and C showed significant associations with clinic-based migraine (q-value < 0.05). Human leukocyte antigen-B*39:01, human leukocyte antigen-B*51:01, human leukocyte antigen-B*58:01 and human leukocyte antigen-C*03:02 were significantly associated with migraine, with age and sex-adjusted odds ratios (95% CIs) of 1.80 (1.28-2.53), 1.50 (1.15-1.97), 1.36 (1.14-1.62) and 1.36 (1.14-1.62), correspondingly. Clinic-based migraineurs carrying human leukocyte antigen-B*58:01 or human leukocyte antigen-C*03:02 had 1.63 (1.11-2.39) -fold likelihood to have chronic migraine with medication-overuse headache compared to episodic migraine. However, no human leukocyte antigen genes were associated with self-reported headache or migraine in the community. CONCLUSIONS: Human leukocyte antigen class I genetic variants are positively associated with risk of clinic-based migraine but not self-reported migraine or headache and may contribute to migraine chronification and medication overuse.

The journey from genetic predisposition to medication overuse headache to its acquisition as sequela of chronic migraine.

Migraine remains one of the biggest clinical case to be solved among the non-communicable diseases, second to low back pain for disability caused as reported by the Global Burden of Disease Study 2016. Despite this, its genetics roots are still unknown. Its evolution in chronic forms hits 2-4% of the population and causes a form so far defined Medication Overuse Headache (MOH), whose pathophysiological basis have not been explained by many dedicated studies. The Global Burden of Disease Study 2016 has not recognized MOH as independent entity, but as a sequela of Chronic Migraine. This concept, already reported in previous studies, has been confirmed by the efficacy of OnabotulinumtoxinA in Chronic Migraine independently from the presence of MOH. The consistency of the current definitions of both Medication Overuse Headache and Chronic Migraine itself might be re-read on the basis of new evidences.

A systematic review and critical appraisal of gene polymorphism association studies in medication-overuse headache.

Purpose of review Medication-overuse headache is a secondary chronic headache disorder, evolving from an episodic primary headache type, caused by the frequent and excessive use of headache symptomatic drugs. While gene polymorphisms have been deeply investigated as susceptibility factors for migraine, little attention has been paid to medication-overuse headache genetics. In the present study we conducted a systematic review to identify, appraise and summarize the current findings of gene polymorphism association studies in medication-overuse headache. Methods A comprehensive literature search was conducted on PubMed and Web of Knowledge databases of primary studies that met the diagnostic criteria for medication-overuse headache according to the temporally-relevant Classification of Headache Disorder of the International Headache Society. Results A total of 17 candidate gene association studies focusing on medication-overuse headache were finally included in the qualitative review. Among these, 12 studies investigated the role of common gene polymorphisms as risk factors for medication-overuse headache susceptibility, six studies focused on the relationship with clinical features of medication-overuse headache patients, and four studies evaluated their role as determinants of clinical outcomes in medication-overuse headache patients. Conclusion Results of single studies show a potential role of polymorphic variants of the dopaminergic gene system or of other genes related to drug-dependence pathways as susceptibility factors for disease or as determinants of monthly drug consumption, respectively. In this systematic review, we summarize the findings of gene polymorphism association studies in medication-overuse headache and discuss the methodological issues that need to be addressed in the design of future studies.

[Headache News]. / Neues bei Kopfschmerzen.

A review of the latest and most relevant information on different disorders of head and facial pain is presented. News from epidemiologic studies regarding the relationship between migraine and patent foramen ovale, the cardiovascular risk in migraine, and migraine behavior during menopause, and the development of white matter lesions or migraine genetics are presented. Regarding pathophysiology there are very recent insights regarding the role of the hypothalamus during prodromal phase and the interplay of brain-stem and hypothalamus during the attack. In the last year studies and metaanalysis generated new knowledge for the use of triptans in general as in menstrual related migraine and hemiplegic variants. Furthermore, new hope rises for the CGRP (calcitonin-gene related peptide)-antagonists, as the data for ubrogepant do not suggest hepatotoxicity but efficacy. In prophylactic migraine treatment the news are manly on how the new therapeutic approach with monoclonal antibodies against CGRP or its receptor is moving on. Additional newly generated data for already known prophylactic agents as for new approaches are compactly discussed. Although main developments in headache focus on migraine new data on trigemino-autonomic headache trigeminal neuralgia and new daily persistant headache became available.

HDAC3 role in medication consumption in medication overuse headache patients: a pilot study.

BACKGROUND: Medication overuse headache (MOH) is a common and debilitating disorder characterized by generation, perpetuation, and persistence of intense chronic migraine, caused by overuse of analgesics, triptans, or other acute headache compounds. It has been suggested that MOH could share some pathogenetic mechanisms with other kinds of drug addiction. In this regard, histone deacetylases 3 (HDAC3) seems to have a role in the memory processes involved in extinction of drug-seeking behavior in animal models. HDAC3 is inhibited by sodium valproate, a drug with proven efficacy in MOH. Recent evidence suggests an involvement of genetic factors in predisposition to medication overuse. RESULTS: In this association study, we sequenced all exons, intron/exon junctions, and 3'-5'UTR regions of HDAC3 in 23 MOH patients to investigate its role in medication overuse. Associations between genotypes with continuous and dichotomous clinical characteristics were tested by multivariate analysis and Fisher's exact test, respectively. Sequencing of HDAC3 revealed six single-nucleotide polymorphisms. The G allele of rs2530223 was significantly associated with the number of acute medications/month used and with the number of days/month in which medications were used (p = 0.006 and p = 0.007, respectively), but neither with headache frequency or intensity. None of the single-nucleotide polymorphisms (SNPs) was associated with clinical characteristics or response to sodium valproate. CONCLUSIONS: HDAC3 could be implicated in excessive medication consumption in MOH patients. Our preliminary findings provide support for the need of further investigation on larger independent samples to confirm and extend the role of HDAC3 in medication overuse headache.

Association of RAMP1†rs7590387 with the risk of migraine transformation into medication overuse headache.

OBJECTIVES/BACKGROUND: We herein investigated the role of polymorphisms in calcitonin gene-related peptide (CGRP)-related genes looking at the association of rs3781719 (T > C) in the calcitonin gene-related polypeptide-alpha (CALCA) gene and of rs3754701 (T > A) and rs7590387 (C > G) at the receptor activity modifying 1 (RAMP1) locus with triptan response in patients with migraine without aura (MwoA). In addition, their role was evaluated as risk factors for transformation of episodic migraine into medication overuse headache (MOH). The CGRP has a central role in the pathogenesis of migraine; however, little information is currently available concerning the role of polymorphisms in CGRP-related genes as determinants of clinical response to anti-migraine drugs or as risk factors for migraine chronification. METHODS: Genotyping was conducted retrospectively by real-time polymerase chain reaction allelic discrimination assay in 219 patients with MwoA and 130 with MOH in whom migraine was the primary headache type. Gene variants association was evaluated by logistic regression analysis adjusted by confounding factors. The threshold of statistical significance was set according to the total number of polymorphisms analyzed in the current study and in previous publications arising from overlapping datasets. RESULTS: No evidence of association was found between the three polymorphisms tested and triptan response in MwoA patients. Conversely, carriers of RAMP1 rs7590387GG displayed a lower risk of episodic migraine transformation into MOH (vs C allele carriers, odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.13-0.57, P = 0.0002; threshold of significance set at P < 0.0029). When genotype distribution for RAMP1 rs7590387 was compared between healthy controls (n = 209) and MOH patients, carriers of rs7590387GG were found at lower risk of developing MOH (OR: 0.43, 95%CI: 0.22-0.85, P = 0.011). CONCLUSION: These results suggest that RAMP1 rs7590387 may have a role in the transformation of episodic migraine into MOH.

Combined effect of common gene variants on response to drug withdrawal therapy in medication overuse headache.

PURPOSE: No information is currently available on genetic determinants of short-term response to drug withdrawal in medication overuse headache (MOH). In the present study, we aimed to evaluate the role of 14 polymorphisms in 8 candidate genes potentially relevant for drug addiction (OPRM1, DRD2, DBH, COMT, BDNF, SLC6A4, 5HT2A, and SLC1A2) as predictors for detoxification outcome of MOH patients at 2 months of follow-up. METHODS: Genotyping was conducted by PCR, PCR-RFLP analysis, or real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. The association between gene variants and risk of unsuccessful detoxification was evaluated by univariate and multivariate logistic regression analyses. RESULTS: One hundred and eight MOH patients with effective drug withdrawal therapy and 65 MOH patients with unsuccessful detoxification were available for the analysis. In the multivariable logistic regression analysis, triptan overuse (odds ratio (OR) 0.271, 95% confidence interval (CI) 0.083-0.890, P = 0.031) and TT genotype carriage of DRD2 NcoI (OR 0.115, 95% CI 0.014-0.982, P = 0.048) emerged as independent predictors for unsuccessful detoxification. In addition, carriers of at least four of the six top-ranked gene variants (P < 0.10) were found at higher odds for unsuccessful detoxification than patients with ≤3 high-risk genotypes (OR 3.40, 95% CI 1.65-7.01, P = 0.001). CONCLUSION: This exploratory study suggests that DRD2 NcoI may be a genetic determinant of detoxification outcome in MOH patients. Our findings also show that an approach based on the combination of multiple genetic markers could be clinically useful for identification of MOH patients at higher risk for unsuccessful detoxification.

Functional polymorphisms in COMT and SLC6A4 genes influence the prognosis of patients with medication overuse headache after withdrawal therapy.

BACKGROUND AND PURPOSE: It is currently unknown if common genetic variants influence the prognosis of patients with medication overuse headache (MOH). Here the role of two common single nucleotide polymorphisms in the COMT gene (rs4680 and rs6269), as well as the STin2 variable number tandem repeat (VNTR) polymorphism in the SLC6A4 gene, were evaluated as predictors for long-term outcomes of MOH patients after withdrawal therapy. METHODS: Genotyping was conducted by polymerase chain reaction (PCR), PCR restriction fragment length polymorphism analysis or real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. Gene variants association was evaluated by logistic regression analysis adjusted for clinical confounding factors, and the threshold of statistical significance for multiple testing was set at P < 0.012. RESULTS: Sixty-five MOH patients with unsuccessful detoxification and 83 MOH patients with effective drug withdrawal therapy were available for the analysis. rs4680G allele carriers or the COMT rs6269G-rs4680G haplotype were found to be associated with a lower risk of relapse within the first year after successful detoxification therapy, in comparison with homozygous rs4680A allele carriers [odds ratio (OR) 0.17, 95% confidence interval (CI) 0.05-0.61, P = 0.007] or with the COMT rs6269A-rs4680A haplotype (OR 0.19, 95% CI 0.06-0.54, P = 0.003), respectively. In addition, carriers of the STin2 VNTR short allele were found at higher odds for the composite poor outcome including unsuccessful withdrawal therapy and relapse within 12 months of follow-up after successful detoxification (OR 2.81, 95%CI 1.26-6.25, P = 0.009). CONCLUSIONS: Our results indicate that genotyping for COMT rs4680 and SLC6A4 STin2 VNTR could be useful for the identification of MOH patients at higher risk of poor prognosis after drug withdrawal.

Predictive index for the onset of medication overuse headache in migraine patients.

Migraine patients are particularly prone to develop medication overuse headache (MOH). However, the risk factors for the transformation of migraine to MOH are still not clear. We investigated gene polymorphisms, personality traits, and characteristics of headache and lifestyle in 47 migraine patients (aged 36.4 ± 10.3) and 22 MOH patients (aged 39.6 ± 9.9) who progressed from migraine and made a scoring system for a predictive index (PI) of the onset of MOH in patients with migraine. By multivariate logistic stepwise regression analysis, type of migraine, regular and sufficient dietary intake, and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) and dopamine D2 receptor (DRD2) C939T (rs6275) polymorphisms were selected as significant factors that contribute independently to the development from migraine to MOH (P < 0.05). The regression coefficients (ß) of these four selected factors were approximated and scored. The PI score in MOH patients (7.32 ± 1.60) was significantly higher than that in migraine patients (4.62 ± 1.83, P < 0.001). The proposed scoring system should in the future be the object of larger studies to confirm its validity.

Tryptophan hydroxylase 2 gene polymorphisms in Japanese patients with medication overuse headaches.

PURPOSE: We investigated whether tryptophan hydroxylase 2 (TPH2) gene polymorphisms were involved in the aggravation of migraines due to the overuse of medication. METHODS: Forty-seven migraine patients (6 males and 41 females; 36.4 10.3 years) and 22 MOH patients (1 male and 21 females; 39.6 9.9 years) who had migraines participated in this study. The genotypes for the TPH2 gene polymorphisms (rs4565946, rs4570625, and rs4341581) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The rs4565946, rs4570625, and rs4341581 genotypes were similarly distributed between migraine patients and MOH patients. CONCLUSION: The results of this study showed no association between tryptophan TPH2 gene polymorphisms and the complication of MOH in patients with migraines.

Cortical response to somatosensory stimulation in medication overuse headache patients is influenced by angiotensin converting enzyme (ACE) I/D genetic polymorphism.

BACKGROUND: Medication overuse headache (MOH) is a disabling health problem. Convincing evidence attributes a pathophysiologic role to central sensitization. By recording somatosensory evoked potentials (SSEPs) in patients with MOH, we observed increased sensitization and deficient habituation to repetitive sensory stimuli consistent with drug overuse. The renin-angiotensin system in the brain seems to play a relevant role in neural plasticity and dependence behavior. We therefore sought differences in SSEP sensitization and habituation in patients with MOH who underwent angiotensin converting enzyme (ACE) I/D polymorphism analysis. METHODS: We recorded median-nerve SSEPs (two blocks of 100 sweeps) in 43 patients with MOH. We measured N20-P25 amplitudes, and assessed sensitization using the first block amplitudes, and habituation using amplitude changes between the two sequential blocks. According to their genotype, subjects were divided into three groups: "D/D", "D/I" and "I/I" carriers. RESULTS: The habituation slope of the two SSEP block amplitudes was significantly increased in the D/D subgroup (n = 16) with respect to that of the I/I subgroup (n = 6), with the D/I subgroup (n = 21) falling in between. In D/D carriers, the habituation slope correlated positively with the duration of the overuse headache, and the first SSEP block amplitudes, a measure of sensitization, increased in strict relationship with the type of overused medication in the MOH patients overall and in the D/D subgroup; this was not so in the D/I and I/I subgroups. CONCLUSION: In patients with MOH, the homozygote D/D ACE polymorphism influences habituation and sensitization to repeated sensory stimuli in strict relationship with medication overuse. We suggest that angiotensin peptides influence neuronal mechanisms of plasticity by interacting with central monoaminergic synaptic transmission.

[Addictive behaviour in medication overuse headache: A review of recent data]. / Comportement addictif chez les patients souffrant de céphalée par abus médicamenteux : une revue des données de la littérature.

INTRODUCTION: Some data in the current medical literature suggests a link between medication overuse headache (MOH) and addictive behaviors. We present here a review of the clinical and biological data highlighting the role of addictive behaviors in MOH. RESULTS: One third to one half of MOH patients will relapse in their overuse within five years following withdrawal of the offending medication. Some studies have shown that two thirds of MOH patients fulfil DSM-IV criteria for dependence concerning their use of acute headache medication. Moreover, there is a co-morbidity between substance related disorders and MOH and some data suggest a familial co-transmission between MOH and substancerelated disorders. In a prospective study, the use of acute headache medication containing psychoactive substances like opiate derivates increase the risk of transformation from an episodic headache to MOH suggesting the role of conditioning factors among other psychological variables as catastrophizing and a low self-efficacy. Finally, data from the neuroimagery, biology and genetic fields suggest the presence of common pathophysiological features between MOH and addiction. In particular, a study found a hypometabolism in the prefrontal cortex of MOH patients, not recovering after withdrawal, such abnormality being described in addicted patients and suggesting an inability of the prefrontal cortex to inhibit craving. PERSPECTIVES: All these data suggest that with MOH we face two sets of patients. The first one, in which medication overuse is mainly due to the worsening of the headache course, with minimal psychiatric contribution ; the second one, in which addictive behavior can play a major role. In the first case, education can simply lead to a significant reduction of medication intake, whereas in the second case a pluridisciplinary follow-up must be proposed before, during and after acute headache detoxification. CONCLUSION: A pluridisciplinary approach is the only way to reduce the relapse rate which remains too high in MOH.

Genomic expression patterns in medication overuse headaches.

BACKGROUND: Chronic daily headache (CDH) and chronic migraine (CM) are one of the most frequent problems encountered in neurology, are often difficult to treat, and frequently complicated by medication-overuse headache (MOH). Proper recognition of MOH may alter treatment outcome and prevent long term disability. OBJECTIVE: This study identifies the unique genomic expression pattern MOH that respond to cessation of the overused medication. METHODS: Baseline occurrence of MOH and typical pattern of response to medication cessation were measured from a large database. Whole blood samples from patients with CM with or without MOH were obtained and their genomic profile was assessed. Affymetrix human U133 plus2 arrays were used to examine the genomic expression patterns prior to treatment and 6-12 weeks later. Headache characterisation and response to treatment based on headache frequency and disability were compared. RESULTS: Of 1311 patients reporting daily or continuous headaches, 513 (39.1%) reported overusing analgesic medication. At follow-up, 44.5% had a 50% or greater reduction in headache frequency, while 41.6% had no change. Blood genomic expression patterns were obtained on 33 patients with 19 (57.6%) overusing analgesic medication with a unique genomic expression pattern in MOH that responded to cessation of analgesics. Gene ontology of these samples indicated a significant number were involved with brain and immunological tissues, including multiple signalling pathways and apoptosis. CONCLUSIONS: Blood genomic patterns can accurately identify MOH patients that respond to medication cessation. These results suggest that MOH involves a unique molecular biology pathway that can be identified with a specific biomarker.

Role of 2 common variants of 5HT2A gene in medication overuse headache.

OBJECTIVE: The aim of the present study was to evaluate a possible involvement of 2 polymorphisms of the serotonin 5HT2A receptor gene (A-1438G and C516T) as risk factors for medication overuse headache (MOH) and whether the presence of these polymorphic variants might determine differences within MOH patients in monthly drug consumption. BACKGROUND: Despite a growing scientific interest in the mechanisms underlying the pathophysiology of MOH, few studies have focused on the role of genetics in the development of the disease, as well as on the genetic determinants of the inter-individual variability in the number of drug doses taken per month. METHODS: Our study was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Genotype-specific risks were estimated as odds ratios with associated 95% confidence intervals by unconditional logistic regression and adjusted for age and gender. A stepwise multiple linear regression analysis was employed to identify significant predictors of the number of drug doses taken per month. RESULTS: No significant association was found between 5HT2A A and 1438G and C516T gene polymorphisms and MOH risk. In contrast, a higher consumption of monthly drug doses was observed among 516T 5HT2A carriers (median 50, range 13-120) compared to 516CC patients (median 30, range 12-128) (Mann-Whitney U-test, P = .018). In the stepwise multiple regression analysis, C516T 5HT2A polymorphism (P = .018) and class of overused drug (P = .047) emerged as significant, independent predictors of the monthly drug consumption in MOH patients. CONCLUSIONS: Although our results do not support a major role of the A-1438G and C516T polymorphic variants of the 5HT2A gene in the susceptibility of MOH, our findings support an influence of the C516T polymorphism on the number of symptomatic drug doses taken and, possibly, on the drug-seeking behavior in these patients.

What is the role of dependence-related behavior in medication-overuse headache?

Medication-overuse headache (MOH) can be viewed as an interaction between the worsening of the primary headache course and individual predispositions for dependence. We present here a review of the clinical and biological data raising the role of dependence-related behavior in MOH. Indeed, several clinical studies show that acute headache medications containing psychoactive components (barbiturates, opiates) are associated with an increased risk of MOH. Diagnostic and Statistical Manual of Mental Disorders, 4th edition substance dependence criteria were identified in a sub-group of MOH patients. Comorbidity between MOH and substance-related disorders has also been showed. Recent neuroimaging, biological, and pharmacogenetic studies suggest the existence of an overlap between the pathophysiological mechanisms of MOH and those of substance-related disorders. These data support the proposition of separating 2 sets of MOH patients: the first one in which the illness is mainly due to the worsening of the headache course, and the second one in which behavioral issues are a major determinant of the illness. Detection of a psychological dependence component in a sub-group of MOH patients should have direct relevance to disease management.