The severity of dependence score correlates with medication overuse in persons with secondary chronic headaches. The Akershus study of chronic headache

The objective was to compare the Severity of Dependence Scale (SDS) score and pattern of medication use in persons with secondary chronic headache (?15 days/month for at least 3 months) in a cross-sectional epidemiological survey. A posted questionnaire screened for chronic headache. Neurological residents interviewed those with self-reported chronic headache. The International Classification of Headache Disorders was used. Split file methodology was employed for data analysis. People with secondary chronic headaches were identified in an age and gender stratified sample of 30,000 30–44 year olds from the general population. The interviews and examinations were conducted at the Akershus University Hospital, Oslo, Norway. The main outcome measure was the SDS score in those with and without medication overuse. Fifty-five (49%) of the 113 persons with secondary chronic headaches were found to have medication overuse. Fifty-eight percent overused simple analgesics and 31% overused combination analgesics. The SDS score was significantly higher among those with than without medication overuse (5.5 vs. 1.9). The sensitivity, specificity, positive and negative predictive values were 0.82, 0.82, 0.82 and 0.83, respectively. Thus the SDS score correlates with medication overuse, and a high SDS score suggests dependency-like behaviour in persons with secondary chronic headache. The use of SDS score in subjects with frequent pain episodes may contribute to the detection of medication overuse and better management of this group of patients.     

Management of medication overuse headache: 1-year randomized multicentre open-label trial

It is a general belief that patients with medication overuse headache (MOH) need withdrawal of acute headache medication before they respond to prophylactic medication. In this 1-year open-labelled, multicentre study intention-to-treat analyses were performed on 56 patients with MOH. These were randomly assigned to receive prophylactic treatment from the start without detoxification, undergo a standard out-patient detoxification programme without prophylactic treatment from the start, or no specific treatment (5-month follow-up). The primary outcome measure, change in headache days per month, did not differ significantly between groups. However, the prophylaxis group had the greatest decrease in headache days compared with baseline, and also a significantly more pronounced reduction in total headache index (headache days/month × headache intensity × headache hours) at months 3 ( P  = 0.003) and 12 ( P  = 0.017) compared with the withdrawal group. At month 12, 53% of patients in the prophylaxis group had ≥ 50% reduction in monthly headache days compared with 25% in the withdrawal group ( P  = 0.081). Early introduction of preventive treatment without a previous detoxification programme reduced total headache suffering more effectively compared with abrupt withdrawal. (ClinicalTrials.gov number, NCT00159588).     

Medication overuse headache: clinical features predicting treatment outcome at 1-year follow-up

We present a prospective study of 240 patients with medication overuse headache (MOH) treated with drug withdrawal and prophylactic medications. At 1-year follow-up, 137 (57.1%) patients were without chronic headache and without medication overuse, eight (3.3%) patients did not improve after withdrawal and 95 (39.6%) relapsed developing recurrent overuse. Age at time of MOH diagnosis, regular use of benzodiazepines, frequency and Migraine Disability Assessment (MIDAS) score of chronic headache, age at onset of primary headache, frequency and MIDAS score of primary headache, ergotamine compound overuse and daily drug intake were significantly different between successfully and unsuccessfully treated patients. Multivariate analysis determined the frequency of primary headache disorder, ergotamine overuse and disability of chronic headache estimated by MIDAS as independent predictors of treatment efficacy at 1-year follow-up.     

Gordian knot: medication overuse headache

Overuse of any kind of headache drugs may lead to the development of the medication overuse headache (MOH). Clinical features of MOH depend on the substance class that has been overused. Overuse of analgesics leads to a chronic tension-type like headache, the overuse of triptans to daily migraine-like headache or to the increase of migraine frequency. The delay between the drug overuse and onset of daily headache is shortest for triptans (1.7 years), longer for ergots (2.7 years) and longest for analgesics (4.8 years). Treatment includes withdrawal followed by structured acute therapy and initiation of specific prophylactic treatment for the underlying primary headache. The relapse rate after a successful withdrawal is about 30%. Predictors for relapse are tension-type headache and the overuse of analgesics in combination with codeine, caffeine or opioids.     

Tension-type headache with medication overuse: Pathophysiology and clinical implications

Tension-type headache (TTH) is the most prevalent primary headache disorder. An important factor in the long-term prognosis of TTH is the overuse of acute medications used to treat headache. There are many reasons why patients with TTH overuse acute medications, including biobehavioral influences, dependency, and a lack of patient education. Chronic daily headache occurs in 4.1% of the general population, and chronic tension-type headache and medication overuse headache (MOH) occur in approximately 2.2% and 1.5%, respectively. A proper diagnosis is essential for the treatment of these patients. Treatment should include pathological considerations concerning TTH and MOH, which include peripheral and central mechanisms. Because TTH with MOH carries the worst prognosis, more clinical studies focusing on the complex interaction and treatments of TTH and MOH are needed.     

Medication overuse headache: a critical review of end points in recent follow-up studies

No guidelines for performing and presenting the results of studies on patients with medication overuse headache (MOH) exist. The aim of this study was to review long-term outcome measures in follow-up studies published in 2006 or later. We included MOH studies with >6 months duration presenting a minimum of one predefined end point. In total, nine studies were identified. The 1,589 MOH patients (22% men) had an overall mean frequency of 25.3 headache days/month at baseline. Headache days/month at the end of follow-up was reported in six studies (mean 13.8 days/month). The decrease was more pronounced for studies including patients with migraine only (−14.6 days/month) compared to studies with the original diagnoses of migraine and tension-type headache (−9.2 days/month). Six studies reported relapse rate (mean of 26%) and/or responder rate (mean of 28%). Medication days/month and change in headache index at the end of follow-up were reported in only one and two of nine studies, respectively. The present review demonstrated a lack of uniform end points used in recently published follow-up studies. Guidelines for presenting follow-up data on MOH are needed and we propose end points such as headache days/month, medication days/month, relapse rate and responder rate defined as ≥50% reduction of headache frequency and/or headache index from baseline.     

Preliminary results of a withdrawal and detoxification therapeutic regimen in patients with probable chronic migraine and probable medication overuse headache

Chronic migraine (CM) is an invalidating condition affecting a significant population of headache sufferers, frequently associated with medication overuse headache (MOH). Controlled trials and guidelines for the treatment of MOH are currently not available. We studied the efficacy of a therapeutic regimen for the withdrawal of the overused drug and detoxification in a sample of patients suffering from probable CM and probable MOH during admission in eight hospitals of Piemonte–Liguria–Valle d’Aosta. Fifty patients, 42 females (84%) and 8 males (16%), mean age at observation 50.66±13.08 years, affected by probable CM and daily medication overuse following IHS diagnostic criteria were treated as inpatients or in a day hospital. Headache index (HI) and daily drug intake (DDI) were used for evaluating the severity of headache and medication overuse. The patients were treated by 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. Analgesics or triptans were used under medical control only in cases of severe rebound headache. Diagnostic protocol included routine blood tests (at admission and at discharge), dosage of B12 and folic acid. Patients underwent follow-up controls one, three and six months after discharge. The initial diagnosis was probable CM in almost all patients included in the study (41 patients); in nine patients the diagnosis was not specified (coded only as CDH). The overused medications were simple analgesics in 17 cases (34%), combination analgesics in 19 cases (38%), triptans alone or with analgesics in 13 cases (26%) and ergotamine in 2 cases (4%). We collected data from 39 patients at first follow–up (1 month), 32 after 3 months and 14 after 6 months. Mean HI was 0.91 at admission, 0.22 at discharge, 0.38 after 30 days, 0.46 after 3 months and 0.48 after 6 months. Mean DDI was 2.80 at admission, 0.39 at discharge, 0.41 after 1 month, 0.52 after 3 months and 0.59 after 6 months. These results are on average positive and tend to remain stable with time. Although preliminary and obtained on a limited number of patients at 6–month follow–up, our results seem to be encouraging about the use of the proposed therapeutic protocol.     

The course of migraine—a diary study in unselected patients

The course of disease and the predictive value of depression and anxiety in patients with migraine were prospectively examined. We recruited 393 migraineurs through articles in newspapers and performed a follow-up examination 30 months later. At baseline and follow-up, patients underwent a semistructured interview, filled out the Headache Impact Test (HIT-6), Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS) and they kept a headache diary for 30 days. One hundred and fifty-one patients (38.6%) were seen at follow-up. The baseline data of patients with and without follow-up were comparable. At follow-up the number of headache days per month had decreased from 9.6 ± 5.8 to 8.1 ± 6.3 ( P  < 0.001) and the proportion of patients with chronic headache (15.4%) and medication overuse (13%) had remained stable. SDS and SAS scores were associated with a high migraine frequency and high initial SDS scores predicted high migraine frequency at follow-up. This longitudinal study in unselected patients with migraine not excluding subjects with chronic headache, medication overuse, depression or anxiety does not point towards migraine as a progressive disease in the vast majority of patients and confirms the importance of psychiatric comorbidity.     

Topo–kinesthetic memory in chronic headaches. A new test for chronic patients: preliminary report

The objective of this study was to establish if chronic headaches with medication overuse can modify a topo–kinesthetic memory test. Nineteen patients with medication overuse headache (MOH), 13 patients with chronic tension–type headache (CTTH) without medication use and a group of "normal" subjects underwent a topo–kinesthetic memory test at T0 and after one month (T1); a control group of healthy volunteers was also tested to establish the baseline in our experimental setting. After one month, in the MOH patients there was a reduction of medication overuse from 3.3±2.65 to 1.1±2.23 (p<0.01), but no significant reduction in headache frequency and severity index, quality of life, anxiety and depression scores. The navigation time at T0 was 14.3±4.97, 27.9±10.12, 34.3±15.38 and 7.5±2.33, 10.1±2.95, 11.4±3.21 for control, MOH and CTTH with closed and open eyes, respectively (p<0.02). At T1, the MOH patients reached performances with open eyes similar to the healthy controls, while with closed eyes the navigation test reached times similar to those of CTTH patients. The topokinesthetic memory test seems both able to discriminate MOH and CTTH from healthy volunteers and to be related to pain scores but is not influenced by the use of drugs.     

Transformed migraine and medication overuse in a tertiary headache centre--clinical characteristics and treatment outcomes

Studies suggest that a substantial proportion of headache sufferers presenting to headache clinics may overuse acute medications. In some cases, overuse may be responsible for the development or maintenance of a chronic daily headache (CDH) syndrome. The objectives of this study are to evaluate patterns of analgesic overuse in patients consulting a headache centre and to compare the outcomes in a group of patients who discontinued medication overuse to those of a group who continued the overuse, in patients with similar age, sex and psychological profile. We reviewed charts of 456 patients with transformed migraine (TM) and acute medication overuse defined by one of the following criteria: 1. Simple analgesic use (>1000 mg ASA/acetaminophen) > 5 days/week; 2. Combination analgesics use (caffeine and/or butalbital) > 3 tablets a day for > 3 days a week; 3. Opiate use > 1 tablet a day for > 2 days a week; 4. Ergotamine tartrate use: 1 mg PO or 0.5 mg PR for > 2 days a week. For triptans, we empirically considered overuse > 1 tablet per day for > 5 days per week. Patients who were able to undergo detoxification and did not overuse medication (based on the above definition) after one year of follow-up were considered to have successful detoxification (Group 1). Patients who were not able to discontinue offending agents, or returned to a pattern of medication overuse within one year were considered to have unsuccessful detoxification (Group 2). We compared the following outcomes after one year of follow-up: Number of days with headache per month; Intensity of headache; Duration of headache; Headache score (frequency x intensity). The majority of patients overused more than one type of medication. Numbers of tablets taken ranged from 1 to 30 each day (mean of 5.2). Forty-eight (10.5%) subjects took >10 tablets per day. Considering patients seen in the last 5 years, we found the following overused substances: Butalbital containing combination products, 48%; Acetaminophen, 46.2%; Opioids, 33.3%; ASA, 32.0%; Ergotamine tartrate, 11.8%; Sumatriptan, 10.7%; Nonsteroidal anti-inflammatory medications other than ASA, 9.8%; Zolmitriptan, 4.6%; Rizatriptan, 1.9%; Naratriptan, 0.6%. Total of all triptans, 17.8%. Of 456 patients, 318 (69.7%) were successfully detoxified (Group 1), and 138 (30.3%) were not (Group 2). The comparison between groups 1 and 2 after one year of follow-up showed a decrease in the frequency of headache of 73.7% in group 1 and only 17.2% in group 2 (P < 0.0001). Similarly, the duration of head pain was reduced by 61.2% in group 1 and 14.8% in group 2 (P < 0.0001). The headache score after one year was 18.8 in group 1 and 54 in group 2 (P < 0.0001). A total of 225 (70.7%) successfully detoxified subjects in Group 1 returned to an episodic pattern of migraine, compared to 21 (15.3%) in Group 2 (P < 0.001). More rigorous prescribing guidelines for patients with frequent headaches are urgently needed. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications.     

Topiramate in patients with episodic migraine: reducing the risk for chronic forms of headache

OBJECTIVE: The aim was to evaluate whether preventive treatment with topiramate in patients with episodic migraine reduces the risk of developing chronic forms of headache. BACKGROUND: Chronic forms of headache, including chronic migraine or medication overuse headache (MOH), are characterized by 15 or more headache days per month. Acute medication overuse has been shown to be a risk factor for developing chronic headache, but it is not known whether preventive treatment can reduce the risk of developing chronic forms of headache or the development of MOH. METHODS: Pooled data from 3 trials in patients with episodic migraine randomized either to treatment with 100 mg topiramate per day (n = 384) or with placebo (n = 372) were analyzed with regard to the number of headache days during a prospective 4-week baseline period and the individual final 4 weeks of each patient's treatment during the planned 26-week double-blind treatment period. RESULTS: The number of headache days per month in the topiramate versus the placebo-treated groups was 7.3 +/- 3.0 versus 7.3 +/- 3.1 during baseline and 4.1 +/- 4.2 versus 5.6 +/- 4.9 during the final 4 weeks, respectively (P < .001). At the end of the study, 8 versus 16 patients fulfilled International Headache Society criteria of chronic headache (odds ratio: 2.11, P= .082). Moreover, a significantly lower number of patients receiving topiramate treatment reported an increase in headache days per month by the end of the study when compared to placebo (66 vs 88 patients, respectively; odds ratio: 1.49, P < .05). Finally, the number of days with usage of acute medication was significantly lower in the topiramate arm compared with placebo (3.3 +/- 3.7 vs 4.3 +/- 3.6, respectively; P < .001). CONCLUSION: Preventive treatment with topiramate in patients with episodic migraine may reduce the risk of developing chronic forms of headache.     

Medication overuse headache and chronic migraine in a specialized headache centre: field-testing proposed new appendix criteria

The classification subcommittee of the International Headache Society (IHS) has recently suggested revised criteria for medication overuse headache (MOH) and chronic migraine (CM). We field tested these revised criteria by applying them to the headache population at the Danish Headache Centre and compared the results with those using the current criteria. For CM we also tested two alternative criteria, one requiring > or = 4 migraine days/month and > or = 15 headache days/month, the second requiring > or = 15 headache days/month and > or = 50% migraine days. We included 969 patients with migraine or tension-type headache (TTH) among 1326 patients treated and dismissed in a 2-year period. Two hundred and eighty-five patients (30%) had TTH, 265 (27%) had migraine and 419 (43%) had mixed migraine and TTH. The current criteria for MOH classified 86 patients (9%) as MOH, 98 (10%) as probable MOH and 785 (81%) as not having MOH after a 2-month drug-free period. Using the appendix criteria, 284 patients (29%) were now classified as MOH, no patients as probable MOH and 685 (71%) as not having MOH. For CM only 16 patients (3%) fulfilled the current diagnostic criteria. This increased to 42 patients (7%) when we applied the appendix criteria. Using the less restrictive criteria of > or = 4 migraine days and > or = 15 headache days, 88 patients (14%) had CM, whereas the more restrictive criteria of > or = 15 headache days and > or = 50% migraine days resulted in 24 patients (4%) with CM. Our data suggest that the IHS has succeeded in choosing new criteria for CM which are neither too strict, nor too loose. For MOH, a shift to the appendix criteria will increase the number of MOH patients, but take into account the possibility of permanent changes in pain perception due to medication overuse and the possibility of a renewed effect of prophylactic drugs due to medication withdrawal. We therefore recommend the implementation of the appendix criteria for both MOH and CM into the main body of the International Classification of Headache Disorders.     

Clinical Aspects of Medication Overuse Headaches

Medication overuse headache (MOH) is a subset of chronic daily headache, occurring from overuse of 1 or more classes of migraine abortive medication. Acetaminophen, combination analgesics (caffeine combinations), opioids, barbiturates (butalbital), non‐steroidal anti‐inflammatory drugs, and triptans are the main classes of drugs implicated in the genesis of MOH. Migraine seems to be the most common diagnosis leading to MOH. The development of MOH is associated with both frequency of use of medication and behavioral predispositions. MOH is not a unitary concept. The distinction between simple (type 1) vs complex (type 2) forms is based on both the class of overused medication and behavioral factors, including psychopathology and psychological drug dependence. MOH is a challenging disorder causing decline in the quality of life and causing physical symptoms, such as daily and incapacitating headaches, insomnia, and non‐restorative sleep, as well as psychological distress and reduced functioning. MOH is associated with biochemical, structural, and functional brain changes. Relapse after detoxification is a challenge, but can be addressed if the patient is followed over a prolonged period of time with a combination of prophylactic pharmacotherapy, use of abortive medication with minimal risk of MOH, withholding previously overused medication, and providing psychological (cognitive‐behavioral) 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.     

Past, present, and future prospects of medication-overuse headache classification

The 1988 classification by the International Headache Society (IHS) first defined drug-induced headache as a specific disorder, belonging to secondary headaches, subtype 8.2 (headache induced by chronic substance use or exposure). In 2004 ICHD-II, this definition was replaced by medication-overuse headache (MOH). It was established that a definite diagnosis of MOH required the improvement of the disorder after cessation of medication overuse. The specific characteristics of the various subforms were also indicated. Later revisions have first eliminated these headache characteristics and then the diagnosis of probable MOH. The diagnosis of MOH has therefore become more useful to clinical aims. However, the last revision has eliminated the need to prove that the disorder is caused by drugs, that is, the headache improves after cessation of medication overuse. The classification of MOH as a secondary headache has therefore been modified, too. Clinical trials can consequently include in the same group patients with primary headache and drug overuse and patients with MOH.
We therefore propose to continue to use the diagnosis of probable MOH to research aims. We also propose to modify the classification of MOH subforms according to the presence or absence of a dependence-producing property of overused drugs. This will allow to better analyze the role of the various medications in inducing chronic headache and the outcomes of treatments.     

New appendix criteria open for a broader concept of chronic migraine

After the introduction of chronic migraine and medication overuse headache as diagnostic entities in The International Classification of Headache Disorders, Second Edition, ICHD-2, it has been shown that very few patients fit into the diagnostic criteria for chronic migraine (CM). The system of being able to use CM and the medication overuse headache (MOH) diagnosis only after discontinuation of overuse has proven highly unpractical and new data have suggested a much more liberal use of these diagnoses. The International Headache Classification Committee has, therefore, worked out the more inclusive criteria for CM and MOH presented in this paper. These criteria are included in the appendix of ICHD-2 and are meant primarily for further scientific evaluation but may be used already now for inclusion into drug trials, etc. It is now recommended that the MOH diagnosis should no longer request improvement after discontinuation of medication overuse but should be given to patients if they have a primary headache plus ongoing medication overuse. The latter is defined as previously, i.e. 10 days or more of intake of triptans, ergot alkaloids mixed analgesics or opioids and 15 days or more of analgesics/NSAIDs or the combined use of more than one substance. If these new criteria for CM and MOH prove useful in future testing, the plan is to include them in a future revised version of ICHD-2.     

Der gordische Knoten: medikamenteninduzierte Kopfschmerzen

Overuse of any kind of headache drugs may lead to the development of the medication overuse headache (MOH). Clinical features of MOH depend on the substance class that has been overused. Overuse of analgesics leads to a chronic tension-type like headache, the overuse of triptans to daily migraine-like headache or to the increase of migraine frequency. The delay between the drug overuse and onset of daily headache is shortest for triptans (1.7 years), longer for ergots (2.7 years) and longest for analgesics (4.8 years). Treatment includes withdrawal followed by structured acute therapy and initiation of specific prophylactic treatment for the underlying primary headache. The relapse rate after a successful withdrawal is about 30%. Predictors for relapse are tension-type headache and the overuse of analgesics in combination with codeine, caffeine or opioids.     

Kaplan Award 1998. Epidemiology of chronic daily headache in the general population

Background and Objectives.—Although chronic daily headache, mainly transformed migraine, is an important reason for consultation in headache clinics, its actual prevalence is unknown. This study analyzes the prevalence of the different types of chronic daily headache in an unselected population.
Methods.—A questionnaire exploring headache frequency was distributed to 2252 unselected subjects. Those having headache 10 or more days per month were given a headache diary and were seen by a neurologist who classified their headaches. The varieties of chronic daily headache were classified according to the second revision of IHS criteria proposed by Silberstein et al published in Neurology 1996;47:871.
Results.—The questionnaire was returned by 1883 subjects (83.5%). One hundred thirty-five admitted to headache 10 or more days per month. Chronic daily headache criteria were fulfilled by 89 individuals (4.7%). Eighty were women. Forty-two (47.2% of subjects with chronic daily headache and 2.2% of all subjects) had chronic tension-type headache. Analgesic overuse was found in 8 (17%). Transformed migraine was diagnosed in 45 (50.6% of subjects with chronic daily headache and 2.4% of all subjects). Fourteen (31.1%) individuals with this form of chronic daily headache overused ergots or analgesics. The remaining 2 cases in this series met the criteria of new daily persistent headache. No one was diagnosed as having hemicrania continua.
Conclusions.—Almost 5% of the general population (9% of women) suffers from chronic daily headache, the proportion of chronic tension-type headache and transformed migraine being quite similar. Less than one third overuse analgesics. The prevalence of chronic daily headache subtypes shown here differs from data obtained from headache clinics, emphasizing that caution is needed in extrapolating data from specialized units to the general population.     

Medication overuse headache: predictors and rates of relapse in migraine patients with low medical needs. A 1-year prospective study

The aim of this study was to evaluate the rates and predictors of relapse, after successful drug withdrawal, in migraine patients with medication overuse headache (MOH) and low medical needs. The study population, study design, inclusion criteria and short-term effectiveness of the medication withdrawal strategies have been described elsewhere (Rossi et al., Cephalalgia 2006; 26:1097). Relapsers were defined as those patients fulfilling, at follow-up, the new International Classification of Headache Disorders, 2nd edn, appendix criteria for MOH. Complete datasets were available for 83 patients. At 1 year's follow up, the relapse rate was 20.5%. Univariate analysis showed that patients who relapsed had a longer duration of migraine with more than eight headache days/month, a longer duration of drug overuse, had tried a greater number of preventive treatments in the past, had a lower reduction of headache frequency after withdrawal, and had previously consulted a greater number of specialists. Binary logistic regression analysis was performed, and three variables emerged as significant predictors of relapse: duration of migraine with more than eight headache days/month [odds ratio (OR) 1.57, P = 0.01], a higher frequency of migraine after drug withdrawal (OR 1.48, P = 0.04) and a greater number of previous preventive treatments (OR 1.54, P = 0.01). In patients with migraine plus MOH and low medical needs, relapse seems to depend on a greater severity of baseline migraine.