Chronic migraine: current concepts and ongoing treatments

Transcription

1 European Review for Medical and Pharmacological Sciences Chronic migraine: current concepts and ongoing treatments 2011; 15: A. NEGRO, M. ROCCHIETTI-MARCH, M. FIORILLO, P. MARTELLETTI Department of Medical and Molecular Sciences, Internal Medicine and Regional Referral Headache Centre, School of Health Sciences, Sapienza University of Rome, Sant Andrea Hospital, Rome (Italy) Abstract. Migraine is an episodic painful disorder occasionally developing into a chronic form. Such disorder represents one of the most common neurological diseases in clinical practice. Chronicization is often accompanied by the appearance of acute drugs overuse. Chronic migraine (CM) constitutes migraine s natural evolution in its chronic form and involves headache frequency of 15 days/month, with features similar to those of migraine attacks. Medication Overuse Headache (MOH) has been defined as a headache present on 15 days/month, with regular overuse for > 3 months of one or more drugs used for acute and/or symptomatic headache management. Subtypes of MOH attributed to different medications were delineated. Misuse of ergots, triptans, opioids or combination analgesics on 10 days/month was required to make the diagnosis of MOH, while 15 days/month were needed for simple analgesic-overuse headache. CM s low prevalence produces an extremely high disability grade. Therefore, special attention should be paid to both control and reduction of risk factors which might favour the migraine chronicization process and/or the outbreak of MOH. In MOH sufferers, the only treatment of choice is represented by drug withdrawal. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications. Different procedures have been suggested for withdrawal namely at home, at the hospital, with or without the use of steroids, with re-prophylaxis performed immediately or at the end of the washout period. At the moment we have not a total agreement whether prophylactic treatment should be started before, during, or after discontinuation of the overuse drug. Both drugs have been approved for CM treatment in view of their well-defined resistance to previous prophylaxis drugs. Recently, the PREEMPT clinical program has confirmed onabotulinumtoxina as an effective, safe, and well-tolerated prophylactic treatment for adults with CM. Key Words: Chronic migraine, Medication overuse headache, Risk factors, Drug abuse withdrawal, Prophylaxis, Onabotulintoxin A, BOTOX, Topiramate. Introduction Migraine is an episodic painful disorder which can gradually chronify and it is among the most common neurological disease in clinical practice. Such process is often accompanied by the appearance of acute drugs overuse. Chronic migraine (CM) constitutes migraine s natural evolution in its chronic form and involves headache frequency of 15 days/month, with features similar to those of migraine attacks 1. Chronic migraine s prevalence rate in general population is 2-4% 2. Overall, population studies estimate that patients who have low-frequency episodic migraine or high-frequency episodic migraine will transition to CM at the rate of about 2.5% per year 3. At present, CM represents the most important challenge for tertiary headache centers, to which over 50% of patients refer for monitoring the chronicization process and its possible complication with medication overuse headache (MOH). MOH affects 1-1.4% of general population, with prevalence rates similar across different countries 4-9 and an higher preponderance in women than in men 4. In general, compared with patients with episodic migraine, patients with migraine and MOH are more likely to be of female sex, have lower levels of educational attainment, be married, be unemployed, have migraine remission during pregnancy, be menopausal, have constipation, not use oral contraceptives, have higher use of health-care resources, and be on polypharmacy 10. Corresponding Author: Paolo Martelletti, MD; paolo.martelletti@uniroma1.it 1401

2 A. Negro, M. Rocchietti-March, M. Fiorillo, P. Martelletti About 30-50% of CM patients show multiple phases of acute drugs abuse evolving in MOH 11. Among patients in headache clinics or centres of tertiary care, patients with MOH form the largest group, together with migraine and tension-type headache, including subtypes of chronic daily headache. Up to 30% of patients in such centres in Europe, and even more than 50% in the USA, present with MOH It has been noted that the overuse of analgesics and chronic headache is not only prevalent in Europe and North America but also in Asian countries 15. Moreover, clinical evidence shows that overuse associated to chronic forms of headache can occur in childhood and early adolescence 16. Drug misuse disables the activity of standard effective therapy and rapidly worsens migraine crises patterns 17. Migraine s chronicization progression to CM and the subsequent appearance of MOH is realized through a period of several months or years, during which an increase of attacks frequency occurs. Such escalation often produces a daily or almost daily pattern, with a more or less faded symptomathology according to cases. The trend results more clear and frequent in patients presenting comorbidities with migraine, such as psychiatric or cardio-cerebrovascular disorders Such trend is often associated with the increase of drug intake and subsequent abuse. In some cases, symptom history becomes less adherent to a classic migraine attack Headache features differ from the original headache form since pain can vary according to severity and location. Furthermore, the assumption of previously effective medication could develop or worsen headache. Asthenia, nausea, anxiety or gastrointestinal problems are associated with pain symptomatology 24. Although MOH and CM are associated, the causal path is controversial (MOH as a cause or consequence). There are several different theories regarding the aetiology of MOH, including: (I) central sensitisation from repetitive activation of nociceptive pathways; (II) a direct effect of the medication on the capacity of the brain to inhibit pain; (III) cellular adaptation in the brain; (IV) a decrease in blood serotonin due to repetitive medication administration with alteration of serotonin receptors; and (V) changes in the periaqueductal grey matter 25. Classification The first edition of the International Classification of Headache Disorders (ICHD-I) was published in by the International Headache Society (IHS) in an effort to standardize criteria for headache disorders worldwide. Since its inception, the ICHD-I has been generally accepted by headache specialists internationally as the gold standard for classification of headache disorders. In 2004, the ICHD-II was published 27. Although chronic daily headache (CDH) was not included as a formal diagnosis, several different forms were described. They included chronic CM, MOH, chronic tension-type headache (CT- TH) (the only CDH incorporated in the ICHD-I), new daily persistent headache (NDPH) and hemicrania continua (HC). CDH syndromes include a group of headache disorders that occur on 15 days/month, for 4 h/day for >3 months. Whereas CM, CTTH, HC and NDPH are primary headache disorders, MOH is classified in the ICHD-II as a secondary headache. ICHD-II precludes the diagnosis of any of these headache types other than MOH if the patient is overusing acute medication. In these situations, the proposed diagnosis is just MOH. Chronic Migraine ICHD-II 27 included criteria for CM, which was classified as a complication of migraine. The original criteria for CM required headaches to meet criteria for migraine without aura on 15 days/month, for 3 months, without medication overuse. Since the criteria were felt to be overly restrictive and not applicable to most patients with CDH in 2006, the Headache Classification Committee published more inclusive criteria for CM, in which the disorder is defined by headaches on 15 days/month, for 3 months, of which 8 of the days fulfill criteria for migraine without aura or were successfully treated with acute care medications such as ergots or triptans 1,28. Whereas some physicians consider the revised 2006 criteria official, given their endorsement by the Headache Classification Committee, others believe that those criteria are not official until they are incorporated into the body of the ICHD. This means that not all headache specialists are using the same criteria, making current headache classification and, therefore, diagnoses very un- 1402

3 Chronic migraine: current concepts and ongoing treatments even throughout the world. In light of the fact that there may not be an ICHD-III for many years, this lack of consensus could continue for a long time, creating ongoing confusion in diagnosis and clinical trials. Medication Overuse Headache The IHS s 1988 classification termed the disorder drug-induced headache and differentiated between only ergotamine-induced and analgesic abuse headaches. Prior to 2004, most doctors referred to MOH as rebound headache. The MOH diagnosis itself did not exist. Instead, the ICHD-I included the section Headache associated with substances or their withdrawal, under which Headache induced by chronic substance use or exposure and Headache from substance withdrawal (chronic use) were subtypes. In the ICHD-II 27, MOH was defined as a headache present on 15 days/month, with regular overuse for >3 months of one or more drugs used for acute and/or symptomatic headache treatment. Criteria also required MOH to develop or markedly worsen during the period of medication overuse, and resolve or revert to its previous pattern within 2 months after discontinuation of the offending agent. Therefore, detoxification was required to make an official diagnosis. This meant deferring a diagnosis on a new patient for 2 months. Subtypes of MOH attributed to different medications were delineated. Those criteria also specified the number of usage days per month that were required to classify a patient with a particular type of MOH. Usage of ergots, triptans, opioids or combination analgesics on 10 days/month was required to make the diagnosis of MOH, while 15 days/month were needed for simple analgesic-overuse headache 29. In 2005, a revision to the ICHD-II criteria for MOH were published (ICHD-IIR1) 28. The major changes were the elimination of the headache characteristics for each MOH subtype, and the inclusion of a new subform called MOH attributed to combination of acute medications. This new subform allowed for the diagnosis of MOH in patients who were overusing medications of different classes, but not any single class. A 2- month period of withdrawal was still required before a definitive diagnosis of MOH could be made, and patients continued to be given a diagnosis of probable migraine (PM) until that time. In 2006 were published the so-called appendix criteria 1. This second revision to the MOH criteria of the ICHD-II classification is mainly intend- ed for research purposes and scientific evaluation and can be used in clinical trials but not for routine clinical diagnosis 1. An advantage of the research criteria is that they include patients from a prospective point of view (ie, at the time of consultation) and not retrospectively (ie, after withdrawal).criteria for MOH were again revised by the Headache Classification Committee in , eliminating the requirement that the headache resolves within 2 months after the discontinuation of the overused medication. MOH can be distinguished as simple (MOH Type I) or complex (MOH Type II). Simple cases involve relatively short-term drug overuse, relatively modest amounts of overused medications, minimal psychiatric contribution, and no history of relapse after drug withdrawal. In contrast, complex cases often present with multiple psychiatric comorbidities and a history of relapse 30. Chronicization of Migraine: Risk Factors Migraine attacks sometimes increase in frequency over time. Headache experts conceptualize this process with a model that envisions transition into and out of four distinct states: no migraine, low-frequency episodic migraine (<10 headaches per month), high-frequency episodic migraine (10-14 headaches per month), and chronic migraine (CM, 15 headaches per month). Transitions may be in the direction of increasing or decreasing headache frequency and are influenced by specific risk factors. In presence of CM s low prevalence, an extremely high disability grade has been ascertained, which is caused by such chronic form. Therefore, special attention should be paid to both control and reduction of risk factors which might favour the migraine chronicization process and/or the outbreak of MOH (Table I). Among the risk factors for chronicization are non-changeable agents such as demography, age, and socio-economic status, as well as changeable factors, such as obesity, caffeine use/misuse (dietary and drug-containing caffeine), sleep disorders (such as snoring and sleep apnea), endocrinologic alterations and specific psychological patterns 18. The underlying mechanisms explaining the relationship between the high frequency of the attacks and obesity are yet poorly understood. Anyhow, obesity is associated to a proinflamma- 1403

4 A. Negro, M. Rocchietti-March, M. Fiorillo, P. Martelletti Table I. Comorbidities of migraine and risk factors for developing chronicization and its complications. Comorbidities Vascular Raynaud s disease a, ischemic stroke (clinical/subclinical) a, WMLsa, claudication a, IMA a Cardiac PFO b, mitral valve prolapse b, atrial septal aneurysm b Psychiatric Depression a, anxiety a, bipolar disorder a, panic disorder a, multiple substance dependence b Neurological Epilepsy a, Tourette s syndrome b, MS a Miscellanea Snoring b, sleep apnea b, allergy/asthma a, systemic lupus erythematosus b, fibromyalgia b, chronic nonheadache pain conditions b, TMD (if combined with TTH) a, head traumasb, GERD Risk factors c Frequent migraine attack pattern b Combination with TTH b Caffeine misuse b Medication overuse b (barbiturates > ergots > triptans > opiods > AINS > analgesics) Modified Framingham risk scores a (smoking, obesity (BMI), self-reported BP, cholesterol levels, diabetes and not lipid profile) Snoring/sleep apnea b Suicide risk a Low levels of education Genetic factors Stressful events BMI body mass index BP blood pressure GERD gastroesophageal reflux disease IMA acute myocardial infarction MS multiple sclerosis PFO patent foramen ovale WMLs white matter lesions TTH tension-type headache TMD temporomandibular disorders Modified from Ref. [115, pp 14]. a Population-based studies; b Clinical reports; c Modifiable items. tory and protrombotic state 34. Infact, in the obese subjects inflammation markers are usually elevated (i.e. leucocytes, C-reactive protein, IL-6, TNFα) 35. Obesity can be considered as a proinflammatory state, in which increased inflammatory mediators, vascular hyperreactivity, plasma calcitonin gene-related peptide (CGRP) concentrations and decreased adiponectin concentrations are observed. These alterations can cause an increase in the frequency of migraine attacks as a consequence of central sensitization. Obesity and migraine may share some neurobiological abnormalities, orexins infact modulate both pain and metabolism. Moreover, dysfunction in the orexin pathways seems to be a risk factor for both conditions 35,36. Several studies have suggested that sleep disorders are increasingly observed in specific headache patterns (e.g. migraine, tension-type, cluster) and other non specific (chronic daily headache, awakening or morning headache). Interestingly, the sleep disorders associated are of varied types, including obstructive sleep apnea (OSA), insomnia, hypersomnia. Patients with chronic migraine are more likely daily snorers. Findings are consistent with the hypothesis that headache, particularly morning headache and chronic headache, may be consequent to a sleep disorder, in relation to sleep-disordered breathing. Insomnia is the most referred sleep disorder by patients and acute sleep disturbance is recognized as a common acute headache trigger 37,38. Worldwide vitamin D insufficiency is common in various populations. A number of observations suggests a correlation between low serum vitamin D levels and a higher incidence of chronic pain. Some case reports have shown a beneficial effect 1404

5 Chronic migraine: current concepts and ongoing treatments of vitamin D supplementation in patients with headache. It s well known that serum vitamin D levels show a strong relationship with latitude. In a recent study a tendency for headache prevalence to increase with increasing latitude was found 39. Moreover, available data indicate a higher frequency of headache attacks in autumn-winter than in summer. The presence of vitamin D receptor, 1α-hydroxylase and vitamin D-binding protein in the hypothalamus suggest a role of vitamin D deficiency in the pathogenesis of head pain 39. Finally, prevalence of gastroesophageal reflux disease (GERD) has recently shown to be increased in patients affected by migraine. A proposed mechanism is related to the common etiology of both disorders. Autonomic nervous system dysfunction plays in fact, an important role in the pathogenesis of both reflux disorders and migraine attacks, which may explain the overlap of GERD and migraine 40. In chronic patients the risk of abuse of pain killer medications increases up to 30% in general population, and to 80% in patients under treatment in specialized centers 80% 33,41,42. Migraine s progression from an episodic to a chronic form is generally influenced by baseline headache frequency, inappropriate use of rescue self-medication, absence of referral to headache centers during the worsening period in terms of headache days frequency, as well as by lack of education in avoiding trigger factors or inadequate life-style rhythms (fasting, sleepiness). Cross-sectional data from the Frequent Headache Epidemiology study and the American Migraine Prevalence and Prevention study (AMPP) show that patients with chronic daily headaches have lower levels of education and household income 3. In a study conducted on 8219 patients with Episodic Migraine (EM), as a part of the AMPP, the progression to chronic or transformed migraine (TM) had a rate of 2.5% per year, with an increased risk associated with any use of barbiturates and opiates, after adjusting for covariates, while triptans were not. NSAIDs were protective or inducers depending on the headache frequency (protective against transition to TM at low to moderate monthly headache days, associated with increased risk of transition to TM at high levels of monthly headache days) 43. Regarding opioids s association with migraine progression, the critical dose of exposure is around 8 days per month, and the effect is more pronounced in men 12,41. Barbiturates also induce migraine progression, and the effect is dose dependent (critical dose around 5 days of exposure per month) and more pronounced in women 12,41. Triptans induce migraine progression only in those with high migraine frequency at baseline (<14 days per month), but not overall 12,41. NSAIDs protect against migraine progression unless individuals have 10 or more headache days per month (when they become inducers, rather than protective). Finally, caffeine containing over-the-counter products increase risk of progression 12,41. The Severity of Dependence Scale (SDS) score has appear to be a significant predictor of medication overuse among chronic headache patients with sensitivity, specificity, positive and negative predictive values of 0.79, 0.84, 0.84 and 0.79, respectively, in men and 0.76, 0.77, 0.73 and 0.79 in women. Since the value of SDS for detecting medication overuse and dependency like behaviour among people with chronic headache, it may be used to identify chronic headache patients who may benefit from detoxification 44. A potential problem for the development of this form of headache arises from the recommendations that drugs have to be taken as early as possible in migraine. This approach, although correct for specific medications like triptans, increases the risk that patients will take more of the drug than is necessary, thus increasing the risk of inducing medication overuse. It has been noted that psychiatric comorbidity is often an important factor in the transformation of episodic headache and a negative prognostic indicator for headache treatment Furthermore, the presence of personality disorders are considered a complication for headache management and headache represents a symptom present in about 60% of patients affected by personality disorders admitted to an Emergency Department 20,48. Moreover, stressful events may contribute to the progression of migraine to a chronic form, modifying the inhibitory descendant mechanisms. Stress may intervene in the regulation of the immune network system. Elevated levels of TNFα, IL-1β, IL-6 and nitric oxide have been found in subjects undergoing to stressful events 49. Pathological abuse of nicotine or caffeine has not been found in patients with MOH 8. The relationship between migraine and smoking is controversial, even if a recent study underlined the important role of smoking as a trigger factor for migraine attacks

6 A. Negro, M. Rocchietti-March, M. Fiorillo, P. Martelletti The mechanisms are yet not completely understood. Some hypotheses have been suggested: an enhancing effect of smoking on the activity of brain monoamines, a descrease in nitric oxide production, nicotine dependence or the well known comorbidity of migraine with psychiatric disorders, such as depression, where smoking prevalence has been shown to be increased 36,50,51. Conflicting results have also been found in population-based studies evaluating the association between caffeine and chronic headache. Some studies, infact, have reported a positive relationship between high caffeine consumption and prevalence of migraine. Furthermore, high caffeine consumption has been found to be a modest risk factor for onset of chronic daily headache 52. However, there is a high prevalence of smokers and individuals with a body-mass index of more than 30 among patients with MOH 4. The presence of these features might be indicative of frontal lobe dysfunction in patients with MOH. Previous studies reported that family history data uncovered an elevated risk of mood disorders and substance use disorders (alcohol, drugs) in the families of MOH patients 30. The risk of MOH is increased threefold if there is a family history of MOH or other substance abuse such as drug or alcohol abuse 10,53. The risk of developing drug overuse or substance abuse is increased fourfold if another family member has had MOH 53. Genetic studies have found an association between the Val66Met polymorphism in brain-derived neurotrophic factor, which is related to behavioural disorders and substance abuse, and increased analgesic drug consumption in patients with MOH 54. Another study found that allele 10 of the dopamine transporter gene (SLC6A3; also known as DAT1) was significantly under-represented in patients with MOH compared with patients with episodic migraine 55. Withdrawal from Drug Abuse In MOH sufferers, the only treatment of choice is represented by drug withdrawal. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications. The goal of this treatment is not only to detoxify the patients and stop the chronic headache but also to improve responsiveness to acute or prophylactic drugs 56. Most headache specialists consider drug withdrawal to be more effective if done abruptly because this is thought to be associated with fast resolution of the drug-induced pain-coping behaviour 17, This is likely to apply particularly in overuse of triptans, ergots, paracetamol, aspirin and NSAIDs, for which outpatient withdrawal programmes can be appropriate. However, due to the possibility of severe withdrawal symptoms, gradual withdrawal might be recommended for opioids, barbiturates and, in particular, benzodiazepines to reduce withdrawal symptoms. A survey of 22 studies dealing with therapy of drug-induced headache shows that most centres use drug withdrawal as the primary therapy 61. The discontinuation of the acute medication can result in worsening of the headache, nausea, vomiting, arterial hypotension, tachycardia, sleep disturbances, restlessness, anxiety, nervousness and rebound headache. Seizures or hallucinations, although rare, are observed in patients who overuse barbiturates containing anti-migraine drugs. These symptoms generally last between 2 and 10 days (average 3.5 days), but can persist for up to 4 weeks 59,62. Withdrawal symptoms are usually relieved by further intake of the overused medication, but this could lead to perpetuation of the overuse. The withdrawal headache seems to be shorter in patients who have taken triptans (mean 4.1 days) than in patients who have overused ergotamine (mean 6.7 days) or NSAIDs (mean 9.5 days) 63. Withdrawal from triptans is generally achieved in a short period of time (approximately 80% of patients are headache-free 4 days after starting the therapy) and without serious withdrawal symptoms 63,64. The detoxification period is based on the use of various classes of drugs, among which corticosteroids certainly are the most frequently employed. Oral prednisone constitutes the most common treatment during detoxification; when compared with placebo, it reduces the duration of withdrawal headache 57,59,65,66. In the follow-up period, the initial goal is to outline an effective prophylaxis therapy. Relapse percentages during the first year after withdrawal range between 22 and 44% Different procedures have been suggested for withdrawal namely at home, at the hospital, with or without the use of steroids, with re-prophylaxis performed immediately or at the end of the wash-out period. However, no final agreement 1406

7 Chronic migraine: current concepts and ongoing treatments has been reached except for withdrawal from abuse in order to reinstate the natural course of CM or high frequency-migraine Early introduction of preventive treatment without a previous detoxification programme reduced total headache suffering more effectively compared with abrupt withdrawal 73. Between the different drug withdrawal strategies, in-patient withdrawal seems the most helpful. An inpatient therapy should be performed in patients who take barbiturates, in those who are not able to stop taking medications as outpatients or in those with high levels of depression 24. Conversely, an outpatient treatment can be helpful in patients who are highly motivated and who do not take barbiturates 24,60,74,75. Outpatient treatment is a viable alternative for self-disciplined patients who take a single drug or analgesic not containing barbiturates, and who do not have a high level of depression or anxiety 74,76. A direct comparison between inpatient withdrawal and outpatient withdrawal treatment showed that both methods led to a significant decrease in headache days per month after 12 months and a reduction in migraine disability scores without superiority of one method 77. Since the outpatient withdrawal approach is less expensive than the inpatient approach, and is as successful in a motivated group of patients, it is the preferred choice in many cases 57,59,78. Another helpful alternative can be performing drug withdrawal infusion therapy within a dayhospital setting, limiting patients permanence in hospital at a maximum of 6 h during the infusion therapy 77,79. This approach is most effective in patients who are highly motivated and self disciplined and have showed positive results after 4 months and 1-2 years of follow-up 79. Treatments for the acute phase of drug withdrawal vary considerably between studies. They generally include fluid replacement, analgesics when strictly necessary for severe rebound headache, tranquillisers, sometimes neuroleptics and steroids. Steroids effectively reduce withdrawal symptoms, including rebound headache 65,80. In a large open-label trial involving 400 patients with chronic daily headache and medication overuse, oral prednisone (60 mg as a starting dose, then tapering down by 20 mg every second day), as part of an outpatient regimen, effectively reduced rebound headache and withdrawal symptoms 65. Conversely, a recent Norwegian placebo-controlled, randomised, double-blind study, including patients with both TTH and migraine, showed that prednisolone (60 mg as a starting dose, then tapering down by 20 mg every second day), given as part of an inpatient regimen during the first 6 days after medication withdrawal, was ineffective in treating withdrawal headache 81. In a very recent study prednisone 100 mg, given once a day for the first 5 days after medication withdrawal as part of an inpatient strategy, was effective in reducing medication withdrawal headache in 20 MOH patients with migraine as a primary headache 66. Rossi et al 82 randomly assigned 120 MOH patients to one of three groups: group A received only strong advice to withdraw overused medication(s); group B underwent a standard outpatient detoxification programme based on advice to a abrupt withdrawal of overused medication(s), plus oral prednisone for the first 8 days and personalised preventive treatment starting on day 1; group C underwent a standard inpatient detoxification programme based on the abrupt withdrawal of overused medication(s) plus oral prednisone for the first 8 days, personalised preventive treatment starting on day 1, parenteral fluid replacement and administration of antiemetics, and strict observation and support for 8 days. Boe et al 81 evaluated 100 MOH inpatients receiving prednisolone or placebo and pre-withdrawal advice. Krymchantowski and Moreira 75 randomised 150 MOH outpatients with moderate overuse of acute drugs other than opioids to a tapering course of prednisolone, regular naratriptan or no regular medication for 6 days, in addition to advice and rescue medication. No differences in terms of percentage of patients achieving successful withdrawal 75,82, headache frequency 75,82, headache intensity 75, and calculated mean headache 81, were found by these three studies after a follow-up period going from 8 days to 2 months. A withdrawal and detoxification therapeutic regimen that obtained good results at 6 months of follow-up in a sample of patients suffering from probable CM and probable MOH during admission in eight italian hospitals consisted in abrupt discontinuation of the overused drug and by a therapeutic protocol including i.v. hydration, dexamethasone, metoclopramide and benzodiazepines for 7-10 days. Prophylactic medication was started immediately after admission 83. Data suggest that the patients affected by CDH and medication overuse benefit from withdrawal therapy performed during hospitalization (dex- 1407

8 A. Negro, M. Rocchietti-March, M. Fiorillo, P. Martelletti amethasone 4 mg i.v./day for 1 week, diazepam 6 mg/day for 10 days) plus prophylaxis with amitriptyline (from 10 to 20 mg/day) plus topiramate (from 50 to 100 mg/day) for at least 6 months. This combination seems a good pharmacological solution to reduce the risk of relapse 84. In patients with migraine plus MOH and low medical needs, effective drug withdrawal may be obtained through the imparting of advice alone 82. Non-pharmacological approaches for treatment of MOH are important tools to help patients to learn to restructure their cognitive approach to pain and to learn to tolerate discomfort and emotional distress 85. Short-term psychodynamic psychotherapy in association with pharmacological therapy improves headache in MOH, and the combination of both has had better outcomes than has pharmacological therapy alone for reducing long-term relapses and improving quality of life in a non-randomised study 86 and in a randomised 3-year follow-up study 87. In the study of Rossi et al 82 on 120 patients with uncomplicated MOH treated with three different modalities (only strong advice to withdraw overused medication, standard outpatient detoxification or standard inpatient programme), the numbers of patients who achieved successful withdrawal and had reduced headache frequency were not different between groups during the follow-up period of 60 days after withdrawal. In the follow-up period, the primary goal is to outline an effective prophylaxis therapy. Therapeutic success is usually strictly defined as a total absence of headache or an improvement (in terms of headache days/month) of more than 50% in a period of time from 1 to 6 months 24,88. In a review of 17 studies (1,101 patients), the mean success rate of withdrawal therapy, within a time window of 1-6 months, was found to be 72.4% 89. The treatment can be considered successful when clinical improvement is confirmed after at least 1 year of follow-up after withdrawal 24. Findings observed from recent studies suggest that patients have greatest risk for relapse within the first 12 months but have a decreased risk of relapse when they have avoided medication overuse for 12 months after withdrawal therapy 90. Other three investigations considering a longer observation period (9-35 months) 74,91,92 recorded success rates of 60, 70 and 73%, respectively. Studies with a longer follow-up period (4-6 years) found relapse rates of between 40 and 60% 69, An Italian report on different methods of withdrawal therapy found an increased risk for relapse of MOH in association with a long duration of migraine before medication overuse, a high number of previous preventive treatments and a high frequency of migraine after withdrawal therapy 99. In another work male sex, intake of combination analgesics after withdrawal therapy, and using the causative medication again after withdrawal therapy were found to be predictors of relapse 74. In the subgroup of patients with MOH plus migraine studied by Katsarava et al 100, after binary logistic regression analysis, three variables emerged as significant predictors of relapse: years with more than eight migraine days per month, higher frequency of migraine attacks after drug withdrawal, and a greater number of previous preventive treatments. More recently, use of codeine-containing drugs, high self-reported bodily pain as measured by the SF-36 questionnaire, and low self-reported sleep quality, were found to be predictors of a poor outcome 101. Conversely, in a multivariate analysis, the frequency of primary headache disorder, ergotamine overuse, and disability score for chronic headache estimated by MIDAS were indicated to be independent predictors of treatment efficacy at 1-year follow-up 91. Some researches, reported a better prognosis for patients who had migraine as the underlying primary headache disorder than for patients who had tension-type headache and for ergotamine or triptan withdrawal than for analgesic withdrawal 69. The future in relapse prevention of CM complicated by MOH consists in considering how drugs currently used, such as triptans and emerging therapies present responsivity profiles related to well-defined genetic polymorphisms 54, The feasible diagnostic setting for a tailored treatment of CM based on the application of pharmacogenomics will allow us to predetermine the efficacy of single old and new drugs by avoiding abuse and chronicization due to non-responsivity of the abused drug 105. Chronic Migraine Prophylaxis After Detoxification At the moment we have not a total agreement whether prophylactic treatment should be started 1408

9 Chronic migraine: current concepts and ongoing treatments before, during, or after discontinuation of the overuse drug. A recent prospective, multicentre trial investigated three treatment groups: personalised preventive medication from day 1 (n=17); abrupt withdrawal plus rescue medication (n=20); and no preventive medication plus no advice to stop overused drugs (n=19) 73. There was not a significant difference between all three groups for the primary endpoint, change in headache days. The more pronounced reduction in the headache index in the first group compared with the second group might indicate an advantage for a personalised preventive medication without abrupt withdrawal. Even though many Authors are in favour of starting first line preventive treatments as soon as possible 58,59, these treatments have no influence on the prognosis. It is generally agreed that behavioural and psychological factors could potentially influence the induction, maintenance and outcome of MOH 24,30,62,106,107. Numerous factors (e.g. adverse effects, tolerability, cost, frequency of dosage, hesitancy to take daily medication, failure to complete treatment) negatively influence compliance with the preventive pharmacology for migraine prophylaxis 108. The choice of prophylactic drug in MOH should be based on the primary headache (migraine vs. tension-type headache), the possible side-effects of the drugs, the comorbidities, and the patient s preference and previous therapeutic experiences. A study conducted in a large series to assess prospectively the impact of prophylaxis on health-related quality of life (HRQOL), using the Short Form 36 (SF-36), and daily activities, using the Migraine Disability Assessment Score (MIDAS), indicates that migraine prophylaxis has the potential to reduce the global burden of migraine on individuals and society 109. Several epidemiologic surveys indicate that preventive therapies are significantly underutilized; only a minority of patients who could benefit from preventive therapy are currently treated (6-13% in population-based surveys) A study of patient adherence to prophylactic migraine medication showed that 35% of enrolled patients were non-adherent 113. Another report revealed that approximately 75% of the study population (n = 729) had stopped or switched prophylactic treatment for migraine after 1 year 114. Possible therapeutic agents in CM reprophylaxis after detoxification are OnabotulinumtoxinA and Topiramate 67,115. Both drugs have been approved for CM treatment in view of their welldefined resistance to previous prophylaxis drugs. OnabotulinumtoxinA (BOTOX ) OnabotulinumtoxinA is a substance obtained from the Gram-positive anaerobic bacterium Clostridium botulinum. Its action occurs through the block of peripheral acetylcholine release at the level of peripheral cholinergic nerve endings 116. Travelling in the general vascular circulation, OnabotulinumtoxinA reaches the extra-cellular space. The mechanism through wich OnabotulinumtoxinA exits from vasculature is unknown. At the level of neuromuscular injection, OnabotulinumtoxinA arrests spontaneous quantal release of acetylcholine via cleavage of SNAP-25 protein (synaptosomal protein with a molecular weight of 25 kda), producing muscular relaxation. Such mechanism of action is the base for both the botulism disorder then the use of OnabotulinumtoxinA as a therapeutic agent in clinical practice. Paralysis at muscular local level and reduced muscular contraction cannot explain alone OnabotulinumtoxinA s pain-relief. This suggests indirect reduction on central sensitization by inhibition of peripheral sensitization of nociceptive fibers, by inhibiting the release of neuromediators such as glutamate, substance P calcitonin gene-related peptide (CGRP) or c-fos gene expression from the peripheral termini of nociceptive fibers Blocking release of these neurotransmitters inhibits neurogenic inflammation; that, in turn, inhibits peripheral sensitization of nociceptive (pain-conducting) nerve fibers. As a result, peripheral pain signals to the central nervous system are reduced and, indirectly, central sensitization is blocked 117,118,123,124. This was proven in a human model of trigeminal sensitization in which OnabotulinumtoxinA effectively prevented capsaicin-induced pain, flare, and secondary hyperalgesia 124. A contribution of calcitonin gene-related peptide (CGRP) to migraine pathophysiology is suggested by a study on cultures of trigeminal ganglia neurons incubated with toxin; this incubation has shown the reduction of secretory stimulation of CGRP neurotransmitter respect to control cultures 120. One recent investigation conducted in female rats demonstrated that injection of BoNT type A into craniofacial muscles can rapidly decrease mechanical sensitivity of temporalis muscle noci- 1409

10 A. Negro, M. Rocchietti-March, M. Fiorillo, P. Martelletti ceptors through inhibition of glutamate release, and attenuate the vasogenic vasodilation caused by release of CGRP from muscle nociceptors 125. Initially used to treat strabismus in the 1970s, botulinum toxin now has more than a hundred possible medical applications. Its utility in neurologic conditions has largely involved treating movement disorders (particularly dystonia and conditions with muscle hyperactivity), although practically any hyperkinetic movement disorder may be relieved by botulinum toxin, including hemifacial spasm, tremor, tics, myoclonus, and spasticity. Recently, botulinum toxin has been shown to impact autonomic disorders by acting at acceptors on glands and smooth muscle, and consequently it has been used in the management of a number of other conditions including hypersecretory disorders, detrusor sphinchter dyssenergia or overactivity and gastrointestinal smooth muscle/sphincter spasm. OnabotulinumtoxinA has been reported to relieve pain in a variety of conditions, including migraine OnabotulinumtoxinA has been extensively used in our University-based Hospital during the last decade as pioneering off-label drug to treat drug-resistant CM patients 139. In 2000, an open-label study employing BOTOX (OnabotulinumtoxinA; Allergan, Inc., Irvine, CA, USA) reported its success in migraine prophylaxis 140. However, subsequent studies investigating the efficacy of BoNT on episodic migraine with different dosages or injection paradigms showed inconsistent but generally disappointing results 141. Nonetheless, trials targeting patients with chronic daily headache suggested that onabotulinumtoxina might be effective in treatment of CM 142. Results of 2 additional exploratory, well-designed, randomized, double-blind, placebo-controlled trials have provided further insight into which patients, dosages, and injection protocol may yield the best results from prophylactic OnabotulinumtoxinA therapy 126,143. Together, these trials recruited >1000 patients with CDH (>15 headache days per month) who could have had any combination of migraine and/or episodic or chronic tension-type headache. Baseline data from these studies indicated that the majority of patients enrolled likely suffered from CM 126,142,143. Overall, these exploratory phase 2 studies provided guidance and shaped the study design and the injection paradigm of the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program. Another controlled study demonstrated the effectiveness of 100 U OnabotulinumtoxinA in the treatment of patients with CM who specifically did not overuse pain medication 127. Efficacy results from previous trials in patients with episodic migraine (generally understood as occurring <15 days per month) have been negative 128, Results from exploratory trials in episodic migraine, chronic tension-type headache, and CDH have been mixed, but have suggested that OnabotulinumtoxinA may be useful as preventive treatment for CDH, specifically patients suffering from CM ,143,147,148. In another work subjects treated with OnabotulinumtoxinA showed improvements from baseline in measures of headache frequency, and improvements from baseline and in comparison with placebo treatment in headache impact and treatment satisfaction but did not differ from placebo-treated subjects in measures of headache frequency and severity 108. A recent meta-analysis of eight randomized, double-blind, placebo-controlled trials considering 1601 patients with a history of episodic migraine did not find significant clinical and statistical differences from placebo in lowering the frequency of migraine headaches 149. More recently, the PREEMPT clinical program has confirmed OnabotulinumtoxinA as an effective, safe, and well-tolerated prophylactic treatment for adults with CM 150. The Preempt Clinical Program These two phase 3, multicenter studies (PREEMPT 1 & 2) included a 28-day baseline screening phase and a 24-week randomized, double-blind, parallel-group, placebo-controlled phase followed by a 32-week open-label phase. PREEMPT recruited 1384 adult patients with CM who have 50% or more headache days fulfilling migraine or probable migraine criteria and have four or more distinct headache episodes at baseline screening. Qualified patients were equally randomized (1:1) to OnabotulinumtoxinA or placebo injection. The PREEMPT clinical program evaluated a standardized treatment paradigm on the basis of two previous exploratory phase 2 CM studies 126,143. All patients received a minimum intramuscular (IM) dose of 155 U of OnabotulinumtoxinA 1410

11 Chronic migraine: current concepts and ongoing treatments administered to 31 injection sites across 7 head and neck muscles using a fixed-site, fixed-dose (FSFD) injection paradigm (each injection was 5 U in 0.1 ml). Up to 40 U of additional OnabotulinumtoxinA could have been administered IM at the physician s discretion using a FTP strategy into 8 additional injection sites across 3 head and neck muscles (temporalis, occipitalis, and/or trapezius muscles). Thus, the minimum dose was 155 U and the maximum dose was 195 U administered to 39 sites 150. The injections were administered every 12 weeks for two injection cycles. Afterwards, all patients received another three cycles of OnabotulinumtoxinA injections during the open-label phase. The primary end point of PREEMPT 1 was the mean change in number of headache episodes per 4 weeks at week 24, while in PREEMPT 2 and the pooled studies, the primary end point was amended to mean change in frequency of headache days. At baseline, the OnabotulinumtoxinA group had significantly fewer headache episodes, migraine episodes, and more total cumulative hours of headache occurring on headache days compared with the placebo group in the PREMPT 1 and the pooled PREMPT. In PREEMPT 1, no significant between-group difference for OnabotulinumtoxinA versus placebo was observed for the primary end point, headache episodes ( 5.2 vs 5.3; p = 0.344). However statistically significant reductions from baseline for frequency of headache days after OnabotulinumtoxinA treatment compared with placebo treatment in both PREEMPT 1 (p =.006) and PREEMPT 2 (p <.001) were observed at week 24 and at all other time points 151,152. Statistically significant improvement from baseline after OnabotulinumtoxinA compared with placebo treatment was seen for headache episodes in PREEMPT 2 (p =.003) 152, but not in PREEMPT Pooled analysis demonstrated that OnabotulinumtoxinA treatment significantly reduced mean frequency of headache days ( 8.4 OnabotulinumtoxinA, 6.6 placebo; p <.001) and headache episodes ( 5.2 onabotulinumtoxina, 4.9 placebo; p =.009) 150. Secondary end points included mean change in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe Headache Impact Test-6 (HIT-6) score (60 or higher) at week 24. Disability and HRQoL (Migraine-specific Quality of Life questionnaire [MSQ version 2.1]) also were assessed. All efficacy analyses used the intent-to-treat population. All these efficacy variables, except for the frequency of acute medication intakes, showed significant between-group differences favoring OnabotulinumtoxinA at all time points. Adverse events (AEs) occurred in 62.4% of the OnabotulinumtoxinA group and 51.7% of the placebo group. Most AEs were mild to moderate in severity, and few patients discontinued the trial (OnabotulinumtoxinA, 3.8%; placebo, 1.2%) due to AE. The only AEs reported with an incidence over 5% in the OnabotulinumtoxinA group were neck pain (8.7%) and muscular weakness (5.5%). Comments One major achievement of PREEMPT is that it proves that patients with CM is an appropriate target group and offers a guide of injection paradigm. PREEMPT results support previous studies 126,142,143 which identified CM patients as the ones most likely to benefit from OnabotulinumtoxinA treatment. Results from the OnabotulinumtoxinA pivotal studies confirm that patients with CM, including those who were overusing acute headache medication during the 28-day baseline period, benefit from this treatment In addition, the primary end point of the pooled study was the frequency of headache days, which is considered more sensitive than headache episodes and fulfills recently proposed clinical trial guidelines for evaluating headache prophylaxis in CM 153. Despite these data, the design of the PRE- EMPT study was object of critics, particularly regarding the diagnosis of CM (65% of patients had medication overuse, which precludes the diagnosis of CM according to the HIS), the high percentage (35%) of patients that never before received any pharmacological prophylaxis), and the effectiveness of blinding (sine OnabotulinumtoxinA weakens muscles and changes the facial expression while placebo does not) 154. Another important achievement of PREEMPT is having provide an injection paradigm wich uses a combination of fixed and FTP injection sites ensuring optimal distribution of OnabotulinumtoxinA on the base of symptoms of the individual patients 126,143. The fixed-site approach, with sites 1411

12 A. Negro, M. Rocchietti-March, M. Fiorillo, P. Martelletti remain unchanged regardless of where the patient s pain is located, distributes OnabotulinumtoxinA to muscles that align with the peripheral nerve distribution of the cervical and trigeminal sensory system, which is believed to be the target-end organ for OnabotulinumtoxinA in treating CM. the first prophylactic (preventative) treatment to receive a specific licence for patients with chronic migraine. In October 2010, the U.S. Food and Drug Administration (FDA) approved injection of OnabotulinumtoxinA (BOTOX ) for the treatment of chronic migraine headaches in adult patients. The PREEMPT Injection Paradigm The injection paradigm adopted in PREEMPT studies can be used as a guideline for a correct administration of OnabotulinumtoxinA 155. The first injections have to be done into the corrugator, procerus, frontalis, and temporalis, following that order, with patient placed supine while is sitting for injections into the occipitalis, cervical paraspinal, and trapezius muscles. Before the injection the physician palpates each muscle to verify muscle delineation, and determined whether there was any muscle tenderness and areas of pain that required additional treatment, and cleans the skin in accord to standard practice for IM injections (e.g., with alcohol). To ensure the stability of the protein, the package insert for OnabotulinumtoxinA (BOTOX ) recommends reconstitution with preservative-free normal saline (0.9% Sodium Chloride, USP) 156. Once a 100 U vial of OnabotulinumtoxinA has been reconstituted, it must be injected or immediately stored in a refrigerator at 2-8 C in the original vial (not in a syringe) and bused within 24 hours 156 or as indicated in the local package insert. It is suggested the use of a sterile 30-gauge, 0.5-inch needle while a 1-inch needle is allowed in the neck region for patients with thick neck muscles. The insertion of the with the bevel up is at approximately a 45-degree angle. After the insertion into the muscle the plunger is pulled back with the other hand to ensure no blood return, and the plunger is then pushed to administer 0.1 ml (5 U) to each injection site. After the procedure is recommended to take patients under observation for minutes. An important is no to rub or massage the affected areas for 24 hours. In July 2010 botulinum toxin type A has been licenced by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK for the prophylaxis of headaches in adults who have CM. This is the first licence worldwide of botulinum toxin type A for this indication, and is also Topiramate The use of topiramate in preventing migraine s chronicization process or in reverting consolidated CM is well known 157,158. Topiramate is a sulfamate-substituted monosaccaride, presenting several mechanisms of molecular action such as effects inhibition of voltage dependent channels of calcium and sodium, signal enhancement of GABA A receptors, modulation of glutamate-mediated neurotransmission and carbonic anhydrase inhibition 159. In migraine, such spectrum of actions could reduce nociceptive transmission at the central system level through trigeminovascular modulation and inhibition of the cortical spreading depression A 26 week randomized double-blind placebocontrolled trial have shown that migraine s preventative treatment with Topiramate at a dosage of 100 or 200 mg/day, but not 50 mg/day, is able to reduce the risk of transformation to a chronic form 159. The most common adverse events (AEs) during topiramate treatment were paresthesias (8.0%), cognitive symptoms (7.3%), fatigue (4.7%), insomnia (3.4%), nausea (2.3%), loss of appetite, anxiety, and dizziness (2.1%) 2. Paresthesia, due to the inhibition of carbonic anhydrase, is the most common side-effect although it does not constitute the main reason for therapy discontinuation. Cognitive symptoms are represented by concentration/attention as well as memory difficulties 158. In a randomized double-blind placebo-controlled trial in patients with chronic migraine and MOH, both topiramate s efficacy and tolerance have been investigated in the prevention of CM, with a dose target of 100 mg per day. Topiramate considerably reduced the mean number of monthly headache days (primary endpoint) compared with placebo. In the subgroup of patients with drugs abuse, mostly triptans, topiramate reduced significantly the mean number of monthly migraine days from baseline. However, side-eff 1412

13 Chronic migraine: current concepts and ongoing treatments ects were reported by 75% of the patients in the topiramate group compared with 37% in the placebo group 163. In another randomized, double-blind placebocontrolled parallel group multicenter trial, topiramate has been tested in the prevention of CM. Titration period was of 4 weeks with a maintenance period of 12 weeks and the final mean topiramate maintenance was 86 mg/day. Topiramate proved to be effective in reducing migraine headache days and migraine headache days relative to baseline 164. Although from these investigations Topiramate results well-tolerated, eventual adverse events are possible. Láinez et al. analysed three large multicentre studies and found that therapy discontinuation occurred in 25% of patients administered with Topiramate and in 1% of patients treated with placebo. The majority of AEs appeared during the titration period, generally within 6 weeks. These data suggest that in case patients do no present AEs in such period, they will be safe from such events 165. In conclusion, migraine s preventative treatment with Topiramate is able to reduce the risk of transformation into a chronic form. Such progression risk is extremely high in a subset of patients with elevated migraine frequency and frequent acute medication intake 158. Furthermore, a recent study pooled HRQoL data from 3 large randomized, placebo-controlled trials of topiramate for prevention of migraine 166. They found improvement in 3 domains of functionality: restriction of daily activities, prevention of daily activities, and emotional function. OnabotulinumtoxinA vs. Topiramate In 2009 were published the results of the first randomized, controlled comparison of OnabotulinumtoxinA with another preventive agent for CM 167. This trial compared the efficacy and safety of OnabotulinumtoxinA and topiramate prophylactic treatment in patients with CM. Significant within, but no between-group, improvements were observed for all primary (treatment responder rate) and secondary endpoints (mean change from baseline in number of HA/migraine days per month, HA/migraine-free days per month, days on HA medication, and average severity of HA/migraine episodes per month). The only between-group difference was a marked improvement at month 9 in the topiramate respect the OnabotulinumtoxinA group, likely because a different timing of somministration between the two groups. Although OnabotulinumtoxinA and topiramate resulted in similar efficacy in this study, the 2 treatments resulted in different AE profiles. The overall discontinuation rate was higher in the topiramate than in the OnabotulinumtoxinA group (43.3% vs. 36.7%), with AEs being the primary reason for withdrawal in the topiramate group and lost to follow-up in the OnabotulinumtoxinA group. Of relevance is the difference between groups in discontinuation rates because of treatment-related AEs. Fewer than 10% of patients taking OnabotulinumtoxinA withdrew from the study because of unacceptable treatment-related AEs, while more than 20% of patients taking topiramate withdrew for such reasons. The results of this study are in accord with controlled trials in the CM population that have reported discontinuation rates of 25% to 44.2% in the topiramate group compared with 10% to 25% in the OnabotulinumtoxinA group 126,143,163,164. Migraine patients often suffer greatly as a result of the adverse effects of the drugs used, showing fatigue, dizziness, reduced concentration, loss of appetite, weight gain, hair loss and changes in libido. These side effects are not known in association with OnabotulinumtoxinA 168. Given the substantial AEs and adherence issues associated with available pharmacotherapies for CM, the relatively mild AEs associated with OnabotulinumtoxinA treatment may present an attractive treatment alternative. The safety profile indicates that OnabotulinumtoxinA is safe and well-tolerated in the CM population, with few patients discontinuing treatment due to AEs ( %) 126,143, ,169. In contrast, other prophylactic headache treatments report discontinuation rates due to AEs as high as 12.7% 169. Conclusions Chronic migraine represents today the most important challenge in the area of clinical headache medicine. Refractoriness of patients to therapies, high risk of coexistence with MOH and forthcoming multiple comorbidities that these patients present should focus our attention 1413

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