Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors

We conducted a two-stage population-based headache survey among subjects aged > or = 15 in Taipei, Taiwan. Subjects with chronic daily headache (CDH) in the past year were identified, interviewed and followed-up. CDH was defined as a headache frequency > 15 days/month, with a duration > 4 h/day. Of the 3377 participants, 108 (3.2%) fulfilled the criteria for CDH, with a higher prevalence in women (4.3%) than men (1.9%). TM was the most common subtype (55%), followed by CTTH (44%). Thirty-four per cent of the CDH subjects overused analgesics. At the 2-year follow-up, 35% of the CDH subjects still had CDH. The significant predictors for persistent CDH at follow-up included: older age ( > or = 40 years) (RR = 2.4), CDH onset after 32 years (RR = 1.8), CDH duration > or = 6 years (RR = 2.0), medication overuse (RR = 1.8), and "daily" headache (RR = 2.1). We found that CDH is not uncommon in the community and its prevalence is similar among different populations. Older subjects and those with medication overuse may have a more protracted course of illness.     

Chronic daily headache in children and adolescents presenting to tertiary headache clinics

BACKGROUND: Adults with chronic daily headache often describe a transformation from episodic migraine and partial retention of migrainous features. Although chronic daily headache has not been investigated as carefully in the pediatric population, one study showed a predominance of coexisting daily headache and episodic migraine, without a clear history of transformation. OBJECTIVE: To identify the clinical features of chronic daily headache in children and adolescents, to evaluate the efficacy of current headache classification criteria, and to compare the features of coexistent daily and episodic headaches so as to determine whether they represent separate syndromes or different stages in the "transformation" process. DESIGN: We surveyed 189 consecutive patients, 18 years of age or younger, who presented for initial evaluation of daily or near daily headache at one of 9 tertiary headache clinics. Data were collected in semistructured interviews employing a standard questionnaire and analyzed using Statistical Analysis Systems and Stata statistical software computer programs. RESULTS: Of the patients enrolled, 70% were female and 87% were white. Mean age was 13.0 +/- 3.1 years. Male gender was associated with a higher degree of reported disability. A family history of headache (typically migraine) was described in 79%. Use of nonsteroidal anti-inflammatory drugs 5 days per week or more was reported by 44% of patients. The International Headache Society (IHS) criteria failed to classify 64% of patients and criteria proposed by Silberstein et al failed to classify 31% of patients. Participating physicians misclassified patients according to criteria of the IHS and Silberstein et al in one third of cases. Nearly one quarter of patients reported two separate headache types with distinguishing characteristics. "Baseline" headache was present 27.3 +/- 4.1 days per month with a mean pain intensity of 5.9 +/- 2.1 on a 10-point scale. Superimposed episodic headache occurred 4.7 +/- 3.8 days per month with a mean pain intensity of 8.4 +/- 1.4, and was more often accompanied by other migrainous symptoms. After logistic regression to control for pain intensity, the only statistically significant difference between the two headache types was a lower prevalence of tension-type head pain with the superimposed headache. CONCLUSIONS: Our data suggest that rather than having two coexistent headache types, children and adolescents with chronic daily headache have a single syndrome that, in many cases, will paroxysmally worsen and gather migrainous features.     

Repetitive intravenous prochlorperazine treatment of patients with refractory chronic daily headache

OBJECTIVES: To investigate the efficacy and long-term outcome of intravenous prochlorperazine for the treatment of refractory chronic daily headache. BACKGROUND: Unlike dihydroergotamine, the treatment results of intravenous neuroleptics as first-line agents for refractory chronic daily headache have rarely been reported. METHODS: We retrospectively analyzed the data of inpatients with refractory chronic daily headache who received intravenous repetitive prochlorperazine treatment from November 1996 to March 1999. A semistructured telephone follow-up interview was done in September 1999. RESULTS: A total of 135 patients (44 men, 91 women) were recruited, including 95 (70%) with analgesic overuse. After intravenous prochlorperazine treatment, 121 (90%) achieved a 50% or greater reduction of headache intensity, including 85 (63%) who became headache-free. The mean hospital stay was 6.2 +/- 2.7 days, and mean total prochlorperazine used was 98 +/- 48 mg. Acute extrapyramidal symptoms occurred in 21 patients (16%). One hundred twenty-four patients (92%) were successfully followed up, with a mean duration of 14.3 +/- 7.5 months. Compared with pretreatment status, 93 patients (75%) considered their headache intensity decreased, and 86 patients (69%) considered their headache frequency decreased, although 40 (32%) still had a daily headache. Of the 87 patients with analgesic overuse who could be followed, 61 (70%) no longer overused analgesics. Poor response to prochlorperazine treatment (relative risk, 1.8) and presence of major depression (relative risk, 1.8) were predictors of persistent chronic daily headache at follow-up. CONCLUSIONS: Prochlorperazine was effective and safe in the treatment of patients with refractory chronic daily headache with or without analgesic overuse. Compared with dihydroergotamine, prochlorperazine seemed less effective at achieving "freedom from headache" during hospitalization, but had a similar outcome at follow-up.     

Prophylactic pharmacological treatment of chronic daily headache

Objective.—To review all the prophylactic pharmacological treatments for chronic daily headache from the past decade.
Background.—Chronic daily headache is among the most common diagnoses seen in specialized headache centers. Prior to 1988, there were no criteria for the diagnosis of chronic tension-type headache and chronic daily headache. An expanded chronic daily headache classification has been proposed.
Methods.—A MEDLINE search was performed using the following key words: chronic daily headache, intractable headache, transformed migraine, chronic tension headache, and chronic tension-type headache. We limited our review to those studies published in English in the last decade, including published abstracts and letters to the editor. Double-blind studies carried out prior to 1988 were also included.
Results.—Pharmacological treatments for chronic daily headache include antidepressants (tricyclics, tetracyclics, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors), anticonvulsants, muscle relaxants, 5-HT₁ agonists, ergots, 5-HT₂ antagonists, antianxiety agents, and miscellaneous drugs. Many of these reports are anecdotal, and most are open rather than double-blind studies.
Conclusions.—There is a great variety of pharmacological treatments available for chronic daily headache. Only the antidepressants have been extensively studied. Other medications may be used if these fail. Recommendations based on our experience at the Headache Unit of the Montefiore Medical Center are outlined here.     

A retrospective, comparative study on the frequency of abuse in migraine and chronic daily headache

OBJECTIVE: To assess and contrast the relative frequency of a past history of physical and/or sexual abuse in patients with chronic daily headache (CDH) versus migraine. BACKGROUND: A number of risk factors have been identified as risk factors for chronification of headache disorders. Limited data exist regarding the influence of physical and/or sexual abuse on primary headache disorders. METHODS: This was a retrospective chart review of 183 consecutive new headache patients seen from December 2004 through August 2005 at an outpatient tertiary-care center. Patients were included in the study if they had chronic daily headache (with criteria for medication over-use headache or chronic migraine), or migraine with or without aura. A history of physical and/or sexual abuse was systematically asked of all headache patients at their first visit in the clinic. This information was then transferred to a semi-standardized form and the relative frequency of abuse in both groups contrasted. RESULTS: Of the 161 patients included in the study, 90.1% were female with a mean age of 36.4 +/- 12.0. A total of 59.0% of the patients were diagnosed with CDH and 41.0% were diagnosed with migraine. Overall, 34.8% of all patients, 40.0% of CDH patients, and 27.3% of migraine patients had a history of physical and/or sexual abuse. The relative frequency of a history of physical and/or sexual abuse was higher in the CDH group as compared to the migraine group (P = .048). CONCLUSION: The relative frequency of abuse is higher in CDH sufferers than migraineurs, suggesting that physical and sexual abuse may be risk factors for chronification.     

Chronic daily headache prophylaxis with tizanidine: a double-blind,placebo-controlled,multicenter outcome study

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.     

Comorbidity of depressive and anxiety disorders in chronic daily headache and its subtypes

OBJECTIVE: To investigate the frequency of depressive and anxiety disorders in patients with chronic daily headache. BACKGROUND: There is a lack of data in the literature on the extent of psychiatric comorbidity in patients with different subtypes of chronic daily headache. METHODS: We recruited consecutive patients with chronic daily headache seen in a headache clinic from November 1998 to December 1999. The subtypes of chronic daily headache were classified according to the criteria proposed by Silberstein et al. A psychiatrist evaluated the patients according to the structured Mini-International Neuropsychiatric Interview to assess the comorbidity of depressive and anxiety disorders. RESULTS: Two hundred sixty-one patients with chronic daily headache were recruited. The mean age was 46 years, and 80% were women. Transformed migraine was diagnosed in 152 patients (58%) and chronic tension-type headache in 92 patients (35%). Seventy-eight percent of patients with transformed migraine had psychiatric comorbidity, including major depression (57%), dysthymia (11%), panic disorder (30%), and generalized anxiety disorder (8%). Sixty-four percent of patients with chronic tension-type headache had psychiatric diagnoses, including major depression (51%), dysthymia (8%), panic disorder (22%), and generalized anxiety disorder (1%). The frequency of anxiety disorders was significantly higher in patients with transformed migraine after controlling for age and sex (P =.02). Both depressive and anxiety disorders were significantly more frequent in women. CONCLUSION: Psychiatric comorbidity, especially major depression and panic disorders, was highly prevalent in patients with chronic daily headache seen in a headache clinic. These results demonstrate that women and patients with transformed migraine are at higher risk of psychiatric comorbidity.     

5HT in migraine patients with medication-induced headache

Whole blood 5HT levels were measured in seven female migraine sufferers with chronic daily headache due to medication abuse, before and after abrupt medication withdrawal. A statistically significant increase in 5HT levels, from mean 4.89 mmol/1 to mean 6.59 mmol/l ( p < 0.05, Wilcoxon signed rank test), as well as a significant improvement in the number of headache-free days ( p < 0.05, Wilcoxon signed rank test), occurred after 4 weeks of withdrawal. We conclude from this pilot study that 5HT may be important in the physiopathogenesis of chronic daily headache. Alternatively, reduced 5HT may be the result of chronic daily headache or else an epiphenomenon.     

Use and abuse of analgesics in tension-type headache

Eighty patients suffering from tension-type headache for an average of 21 years were asked to report on all drugs they had ever taken (type, dosage, duration of intake, efficacy) or were taking currently. The patients had consumed on average 6.3 different drugs. The cumulative doses of derivatives of para-aminophenol, pyrazolone, and salicylic acid in some cases reached a maximum of several kilograms. Most drugs were classified by the patients as "moderately effective". The rating "very effective" was assigned primarily to barbiturates; however, barbiturates are no longer used as components of compound analgesic drugs in Austria. At the time of investigation, patients consumed 2.5 (mean) different drugs, primarily as compound preparations. Seventeen patients (21%) showed signs of possible analgesics- or ergotamine-induced headache and were therefore advised to undergo withdrawal therapy. Our results show that patients with tension-type headache are at considerable risk of becoming drug-dependent and of acquiring analgesics-induced headache.     

Are there predictive factors for long-term outcome after withdrawal in drug-induced chronic daily headache?

OBJECTIVES: To investigate prognostic factors for long-term outcome of patients after inpatient withdrawal because of drug-induced chronic daily headache. PROCEDURES: Fifty-five patients (36 females) were re-examined by means of a standardized interview after inpatient withdrawal. The mean observation period was 9.28 +/- 2.85 years (mean +/- SD; median 8.58; range 5.00-13.50). RESULTS: Five years after withdrawal, one-third of the patients (34.6%) had an overall favourable outcome, one-third (32.7%) had no recurrent drug overuse and reported a clear-cut improvement of headache, and one-third (32.7%) developed recurrent drug overuse. Most relapses occurred within 2 years, and a small percentage within 5 years. No predictors for long-term outcome after inpatient withdrawal were found. CONCLUSIONS: All patients with drug-induced chronic daily headache should be considered as good candidates for inpatient withdrawal, and no patient should be excluded from that therapy.     

Long-term follow-up of patients treated for chronic headache with analgesic overuse

The study aim is to describe the long-term clinical outcome of 102 chronic headache patients with analgesic daily use. They were assessed for daily drug intake (DDI), headache index (HI) and quality of life (QoL) and compared with a parallel group of patients with active chronic daily headache but no analgesic overuse. For the primary study group, baseline 1995 DDI was 1.80 +/- 1.87 and did not differ significantly in 1999. Patients who daily continued to use analgesics had a higher 1995 baseline DDI (t = 2.275, P = 0.025), a longer drug abuse history (t = 2.282, P = 0.025) and a higher DDI (t = 4.042, P < 0.001) 4 years later. At 4 years of follow-up, only one-third of patients initially treated for chronic daily headache and analgesic overuse are successful in refraining from chronic overuse. Those subjects appear to have a persistence for combination analgesic agents; however, their QoL is slightly better than that of patients who revert to episodic headache or continue with chronic daily headache but do not overuse analgesic agents. Persistent analgesic overuse seems to be linked to the length of abuse and to the number of drugs ingested.     

Primary chronic daily headache: clinical and pharmacological aspects. A clinic-based study in Oman

This study on primary chronic daily headache was based on the 1996 proposed revision of the diagnostic criteria of the International Headache Society (IHS). To investigate the relative frequency, clinical characteristics, and associated features of primary chronic daily headache in Omani patients, 171 patients visiting the Neurology Clinic at Sultan Qaboos University Hospital were evaluated. Forty-five percent was diagnosed as suffering from primary chronic daily headache (female to male ratio, 1.7:1). Sixty-two percent suffered from transformed migraine and 34% from chronic tension-type headache. The average age across sexes was 32.3 +/- 12.3 years. A dull heavy feeling in the head was reported by 58% of patients and was associated in less than one third with associated features characteristic of migraine. All headache types shared the same trigger factors. All patients were taking medication, predominantly analgesics, at the time of their first visit. We concluded that primary chronic daily headache is very common with the relative frequency of transformed migraine being similar to that found in Mediterranean studies. Also in Oman, chronic use/overuse of analgesics and nonsteroidal anti-inflammatory drugs is a problem that coexists with primary chronic daily headache. Finally, the proposed revised IHS criteria are highly recommended as a standard classification system for this type of headache.     

Prevalence and Clinical Features of Chronic Daily Headache in a Headache Clinic

Although chronic daily headache is regarded as a syndrome encountered in headache clinics, clinical characteristics have only rarely been studied and the condition has not been documented in Thailand. To investigate the prevalence as well as clinical features of chronic daily headache in Thai patients, 220 patients visiting Chulalongkorn Headache Clinic were examined. Sixty cases (27.3%) were diagnosed as suffering from chronic daily headache (male to female ratio, 1:5.7).
The average age of these patients was 32.7 ± 9.6 years. Based on the International Headache Society (IHS) criteria, 30% of patients with chronic daily headache could be diagnosed as suffering from migraine end 36.7% from chronic tension-type headache, whereas the remainder had combined features of both headache types and were not classifiable. Diffuse steady pain was the most common headache type reported (65%), however, associated features characteristic of migraine were often noted. These included photophobia (70%), phonophobia (56.7%) and nausea (43%). Thirty-four cases (56.7%) reported that their headache could be aggravated by stress. Daily use of analgesics was reported in 58.3% of cases. We concluded that chronic daily headache is a common problem. Although the mechanism has not been fully clarified, the prevalence of associated psychological factors and analgesic overuse imply their involvement in the pathogenesis of this condition. The criteria of the IHS are not entirely suitable for diagnosis and classification of this disorder, and modification of this classification system is needed.     

Chronic daily headache: a time perspective

OBJECTIVE: To determine the development and outcome of chronic daily headache in 258 headache practice patients, consisting of 50 men and 208 women. Chronic daily headache was defined as headaches occurring on at least 5 days per week for at least 1 year. METHODS: Two hundred fifty-eight patients with headache were interviewed and evaluated. Ninety-one patients were contacted by telephone for follow-up. RESULTS: Twenty-two percent of the patients had daily headaches from the onset, and 78% initially experienced intermittent headaches. Of the patients with initially intermittent headaches, 19% experienced an abrupt transition into daily headaches and 81%, a gradual one. In the patients with gradual transition, the transition of the initial, intermittent headaches into daily headaches took an average of 10.7 years. The initial headaches were mild in 33% of the patients and severe in 67%. The severe headaches were associated with nausea and vomiting significantly more often than the mild ones. However, the daily headaches that these patients ultimately developed were the same, regardless of whether the initial headaches were mild or severe. The patients who gradually developed daily headaches from initially intermittent headaches were contacted to determine the outcome of their headaches. Of these patients, 33% continued to have daily headaches and 67% again experienced intermittent headaches. Of the latter group, 88% of the patients who now had migraine also had migraine initially.     

Dextroamphetamine pilot crossover trials and n of 1 trials in patients with chronic tension-type and migraine headache

OBJECTIVE: To examine the preventive effects of dextroamphetamine in select small groups of patients with chronic tension-type and migraine headache. BACKGROUND: Neither amphetamine nor methylphenidate is used as a headache preventive. This study was undertaken after a chance observation led one of us to prescribe dextroamphetamine with apparent successes in specific patients with chronic tension-type or migraine headaches. METHODS: Two pilot trials were done. Trial 1 tested patients who were taking dextroamphetamine, while Trial 2 tested patients who had never taken this drug. Each trial obtained full data on eight subjects with chronic tension-type headache and eight subjects with migraine headache. A randomized, double-blinded, controlled, multiple-crossover design was used. Subjects took capsules containing dextroamphetamine or equi-stimulatory caffeine (the control) during four alternating 20-day periods. Trial 1 subjects took their pretrial dextroamphetamine dose at breakfast and lunch. Trial 2 subjects took 10 mg at these times. Subjects recorded the integer from 0 to 3 that represented their headache intensity during the previous 24 hours. The subject's data were the average daily headache grade for the two dextroamphetamine periods and for the two caffeine periods. The differential effect of amphetamine and caffeine on each group of eight subjects and on each individual was analyzed by t-tests. RESULTS: In both trials, the tension-type and migraine groups had lower mean daily headache grades in the amphetamine than in the caffeine periods. P values for these differences indicated that there were real drug effects, on the average, in the migraine groups (P<.05) and suggestive but inconclusive effects in the tension-type groups (P<.10). The individual n of 1 analyses showed that five tension-type and three migraine subjects in Trial 1 and three tension-type and three migraine subjects in Trial 2 had considerably lower mean daily headache grades on amphetamine with P values indicating, at various levels of significance (from P<.05 to P<.001), real amphetamine effects. Twelve of the remaining 18 patients had lower, albeit not significant, mean daily grades with amphetamine. No subject in either trial had a significantly lower mean daily headache grade on caffeine. CONCLUSIONS: Dextroamphetamine had real preventive effects on chronic tension-type and migraine headaches in some subjects. These results should encourage other investigators to study its effects on these headaches.     

Withdrawal therapy improves chronic daily headache associated with long-term misuse of headache medication: a retrospective study

Chronic daily headache (CDH) associated with long-term misuse of headache medication is a common clinical problem which is refractory to most treatments. The present study is a retrospective analysis of the effect of drug withdrawal therapy in patients with CDH and frequent long-term use of headache symptomatic medication. One hundred and one adult patients (74 women and 27 men, aged between 16 and 72 years, mean age 43 years) were evaluated 1-3 months after drug withdrawal therapy had been initiated. The mean headache frequency at baseline was 26.9+/-4.0 days per month. Fifty-seven (56%) patients were significantly improved (defined as at least 50% reduction in number of headache days) after a period of drug withdrawal therapy. Based on the outcome of the drug withdrawal therapy, the patients were divided into three categories: group I, those who had between 0 and 10 headache days per month (n = 41), group II, those who had 11-20 days (n = 37), and group III, those who had 21-30 days (n = 23). The mean headache frequencies in groups I, II and III were 5.6+/-2.8 days, 15.7+/-2.5 days and 28.7+/-2.4 days, respectively. Treatment with amitriptyline was offered to patients in whom no improvement had been achieved. Ten of those 22 patients (36%) experienced a significant (> or = 50%) reduction of headache days. It is concluded that out-patient drug withdrawal therapy is the treatment of choice in patients with CDH and frequent long-term use of headache symptomatic medication, and that about one quarter of these CDH patients do not respond to drug withdrawal therapy only.     

Major life changes before and after the onset of chronic daily headache: a population-based study

Chronic daily headache (CDH), when defined as ≥ 15 headache days per month, affects 3–5% of the adult population. Major life changes are putative precipitating events for onset of chronic pain, including chronic headache. This study compared the occurrence of specific life events between CDH cases and episodic headache controls in a community sample. CDH cases (180+ headache days per year: n  = 206) and episodic headache controls (2–104 headache days per year: n  = 507) were identified from a randomly selected adult US population. Subjects were interviewed about the occurrence of certain major life changes or events (change of residence, employment status, marital status, related to their children, deaths of relatives or close friends, and 'extremely stressful' ongoing situations) occurring in a defined time period. Events that occurred during the same year or year before frequent headache onset in cases or in an equivalent time period in controls were considered to be antecedent events. Those that occurred after this time were considered subsequent events. Compared with episodic headache controls, CDH cases had more major life changes in the year before or same year as CDH onset. After adjusting for age, gender, headache type and year of event, the odds of CDH increased additionally with each antecedent event [odds ratio (OR) 1.20 (1.1, 1.3), P  < 0.001], but not with subsequent events [OR 0.94 (0.8, 1.1), P  < 0.4]. In secondary analyses, the association between antecedent events and CDH was significant only for the approximately half of CDH cases who were aged ≥ 40 years [OR 1.33 (1.2, 1.50) vs. OR 1.04 (0.9, 1.2), P  < 0.05 for interaction by age]. These results suggest that major life changes are associated with the onset of chronic daily headache, particularly in middle age.     

From migraine to chronic daily headache: the biological basis of headache transformation

Migraine headache carries the potential of transforming into chronic daily headache (CDH) over a period of time. Although several risk factors for migraine progression to CDH have been identified, the biological basis of this transformation is unknown. In this review, the consequences of stressful life events and medication overuse, 2 risk factors associated with the development of CDH, on brain processes involved in headache are examined. The extensive overlap in both neural circuitry and cellular events that occur with stress, medication overuse, and migraine provide insight into potential mechanisms that may lead to CDH. Particular attention is devoted to the effect of stress and medication overuse on peripheral and central neuroimmune interactions that can facilitate pain signaling. These interactions include the degranulation of mast cells in the dura, causing the sensitization of primary afferent neurons, as well as the activation of glial cells in the brain that can lead to central sensitization. It is hypothesized that the biological processes involved in migraine headache are directly impacted by stress, medication overuse, and other risk factors, resulting in a reduced threshold for induction of headache and transformation of episodic migraine to CDH.