CHRONIC DAILY HEADACHE AND MEDICATION-OVERUSE HEADACHE.

[No authors listed]

Bentsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology. 2004;62:1706-1711. Background: The tricyclic antidepressant amitriptyline is the only drug with prophylactic efficacy for chronic tension-type headache. However, amitriptyline is only moderately effective, with headache reduction of approximately 30%, and treatment is often hampered by side effects. Mirtazapine is a relatively new so-called noradrenergic and specific serotonergic antidepressant, which is more specific and therefore generally better tolerated. Objective: To evaluate the efficacy of mirtazapine. Methods: Twenty-four nondepressed patients with chronic tension-type headache were included in a randomized, double-blind, placebo-controlled, crossover trial. All patients had tried numerous other treatments. Mirtazapine 15 to 30 mg/day or placebo was each given for 8 weeks separated by a 2-week wash-out period. Results: Twenty-two patients completed the study. The primary efficacy variable, area-under-the-headache curve (AUC; duration x intensity), was lower during treatment with mirtazapine (843) than during treatment with placebo (1275) (P= .01). Mirtazapine also reduced the secondary efficacy variables headache frequency (P= .005), headache duration (P= .03), and headache intensity (P= .03) and was well tolerated. Conclusions: Mirtazapine reduced AUC by 34% more than placebo in difficult-to-treat patients. This finding is clinically relevant and may stimulate the development of prophylactic treatments with increased efficacy and fewer side effects for tension-type headache and other types of chronic pain. Comment: I am happy to see these results on mirtazepine for chronic tension-type headache (CTTH), and I look forward to prescribing it for daily headache, despite its occasional adverse events of weight gain and somnolence, similar to amitriptyline. It is probably not quite right to state, as the authors did, that "the tricyclic antidepressant amitriptyline is the only drug with prophylactic efficacy for CTTH." For example, here are two randomized controlled studies suggesting efficacy for two very different medications for CTTH: * Saper JR, Silberstein SD, Lake AE III, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache. 1994;34:497-502. * Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache. 2002;42:470-482.-Stewart J. Tepper Zwart J-A, Hagen K, Svebak S, Stovner LJ, Holmen J. Analgesic overuse among subjects with headache, neck, and low-back pain. Neurology. 2004;62:1540-1544. Objectives: To examine the prevalence of chronic headache (>/=15 days/month) associated with analgesic overuse in relation to age and gender and the association between analgesic overuse and chronic pain (ie, migraine, nonmigrainous headache, neck, and low-back pain). Methods: In the Nord-Trondelag Health Study 1995 to 1997 (HUNT-2), a total of 51 383 subjects responded to headache questions (Head-HUNT), of which 51 050 completed questions related to musculoskeletal symptoms and 49 064 questions regarding the use of analgesics. Results: The prevalence of chronic headache associated with analgesic use daily or almost daily for >/=1 month was 1% (1.3% for women and 0.7% for men) and for analgesic overuse duration of 3 months 0.9% (1.2% for women and 0.6% for men). Chronic headache was more than seven times more likely among those with analgesic overuse (>/=1 month) than those without (odds ratio [OR]= 7.5; 95%CI: 6.6 to 8.5). Upon analysis of the different chronic pain subgroups separately, the association with analgesic overuse was strongest for chronic migraine (OR = 10.3; 95%CI: 8.1 to 13.0), intermediate for chronic nonmigrainous headache (OR = 6.2; 95%CI: 5.3 to 7.2), and weakest for chronic neck (OR = 2.6, 95%CI: 2.3 to 2.9) and chronic low-back (OR = 3.0; 95%CI: 2.7 to 3.3) pain. The association became stronger with increasing duration of analgesic use for all groups and was most evident among those with headache, especially those with migraine. Conclusions: Chronic headache associated with analgesic overuse is prevalent and especially chronic migraine is more strongly associated with frequent intake of analgesics than other common pain conditions such as chronic neck and chronic low-back pain. Esposito SB, Gherpelli JL. Chronic daily headaches in children and adolescents: a study of clinical characteristics. Cephalalgia. 2004;24(6):476-482. The clinical characteristics of chronic daily headache were studied in 40 children and adolescents, as well as the associated factors responsible for maintenance of the continuous headache pattern. The study of the clinical headache characteristics, showed a female preponderance (75%), mean age of 11 years old at the first consultation, and onset of headache symptomatology at a mean age of 8.5 years old. The average time interval for the evolution of sporadic headache into chronic daily headache was 1.4 years, and psychosocial stressors were present, acutely or chronically, during the period of headache-frequency increase in 47% of the children. Headaches were classified as transformed migraine (65%), mixed pattern (17.5%), and chronic tension-type headache (17.5%). Sixty percent of patients had mothers with migraine. Data regarding common analgesic use showed an average intake of 11.2 days/month. Romero CE, Baron JD, Knox AP, Hinchey JA, Ropper AH. Barbiturate withdrawal following internet purchase of fioricet. Arch Neurol. 2004;61:1111-1112. Background: The Internet enables businesses to advertise their pharmaceutical products and services without medical supervision. The internet also allows for the unsupervised purchase of medications that may have neurologic consequences. Objective: To describe acute withdrawal delirium following the abrupt discontinuation of Fioricet. Patient: The patient was a 37-year-old woman with a history of depression and migraine headaches but not drug abuse. She developed a florid withdrawal delirium following the discontinuation of a drug she purchased online. The medication, which contained butalbital, was self-administered in escalating doses for the treatment of chronic headaches. Daily doses of up to 750 to 1000 mg were reported. Results: The patient was admitted to the hospital for the treatment of unexplained seizures that were followed by several days of an intense withdrawal syndrome. Little improvement was noted after the administration of benzodiazepines and phenothiazine. After parenteral phenobarbital administration, her symptoms resolved. Conclusions: The withdrawal state from barbiturates is similar to that from ethanol. Tolerance can develop with prolonged abuse, leading to escalating drug doses to achieve the desired effect. The suggested management of both types of withdrawal syndromes is similar, but the relative resistance of the behavioral and autonomic features in patients was remarkable. Physicians should be aware of the ease with which medications can be purchased without supervision from the Internet pharmacies. The magnitude of the number of drugs that are made available through this means creates a proclivity to withdrawal states. Comment: There are two take-home lessons here. The first lesson is that abrupt butalbital discontinuation can produce life-threatening barbiturate withdrawal. Drs. Elizabeth Loder and David Biondi wrote an indispensable guide to safe withdrawal of these patients in 2003 (Loder E, Biondi D. Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache. 2003;43:904-909). The second lesson is that habituating, potentially life-threatening medications are available with ease on the internet, and we must be vigilant about asking our patients if they supplement our prescriptions. Dr. Steve Peroutka has written eloquently on headache information available on the internet (Peroutka S. Analysis of internet sites for headache. Cephalalgia. 2001;21:20-24). Romero et al's article describes sites for obtaining drugs.-Stewart J. Tepper Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Transformed migraine and medication overuse in a tertiary headache centre-clinical characteristics and treatment outcomes. Cephalalgia. 2004;24:483-490. 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 1 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 1 year were considered to have unsuccessful detoxification (Group 2). We compared the following outcomes after 1 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 more than 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 1 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 < .0001). Similarly, the duration of head pain was reduced by 61.2% in group 1 and 14.8% in group 2 (P < .0001). The headache score after 1 year was 18.8 in group 1 and 54 in group 2 (P < .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 < .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. Comment: This study highlights the difficulties faced in trying to obtain outpatient provision for successful detoxification. Isn't it about time the FDA took a fresh look at the risk/benefits for butobarbital combinations, which are still surprisingly available in the United States? Surely this must signal the death knell for these products. The New England Center for Headache have a tremendous database of knowledge on which to base pragmatic prescribing guidelines. I would endorse their concern and commend the approach they have taken.-David S. Millson Torbey MT, Geocadin RG, Razumovsky AY, Rigamonti D, Williams MA. Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache. Cephalalgia. 2004;24:495-502. The aim of the present study was to report on the utility of continuous Pcsf monitoring in establishing the diagnosis of idiopathic intracranial hypertension without papilledema (IIHWOP) in chronic daily headache (CDH) patients. We report a series of patients (n = 10) with refractory headaches and suspected IIHWOP referred to us for continuous Pcsf monitoring between 1991 and 2000. Pcsf was measured via a lumbar catheter and analyzed for mean, peak, highest pulse amplitude, and abnormal waveforms. A 1 to 2 day trial of continuous controlled CSF drainage (10 cc/hour) followed Pcsf monitoring. Response to CSF drainage was defined as improvement in headache symptoms. Patients with abnormal waveforms underwent a ventriculoperitoneal (VPS) or lumboperitoneal (LPS) shunt insertion. All patients had normal resting Pcsf (8 +/- 1 mmHg) defined as ICP < 15 mmHg. During sleep, all patients had B-waves and 90% had plateau waves or near plateau waves. All patients underwent either a VPS or LPS procedure. All reported improvement of their headache after surgery. Demonstration of pathological Pcsf patterns by continuous Pcsf monitoring was essential in confirming the diagnosis of IIHWOP, and provided objective evidence to support the decision for shunt surgery. Increased Pcsf was seen mostly during sleep and was intermittent, suggesting that Pcsf elevation may be missed by a single spot-check LP measurement. The similarity between IIHWOP and CDH suggests that continuous Pcsf monitoring in CDH patients may have an important diagnostic role that should be further investigated. Comment: This study confirms that elevated CSF pressure, as measured by continuous CSF pressure monitoring, may be linked to CDH.-Stewart J. Tepper.

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Synaptic enhancement induced through callosal pathways in cat association cortex.

Cisse Y, Crochet S, Timofeev I, Steriade M.

Laboratoire de Neurophysiologie, Faculte de Medecine, Universite Laval, Quebec G1K 7P4, Canada.

The corpus callosum plays a major role in synchronizing neocortical activities in the two hemispheres. We investigated the changes in callosally elicited excitatory postsynaptic potentials (EPSPs) of neurons from cortical association areas 5 and 7 of cats under barbiturate or ketamine-xylazine anesthesia. Single pulses to callosal pathway evoked control EPSPs; pulse-trains were subsequently applied at different frequencies to homotopic sites in the contralateral cortex, as conditioning stimulation; thereafter, the single pulses were applied again to test changes in synaptic responsiveness by comparing the amplitudes of control and conditioned EPSPs. In 41 of 42 neurons recorded under barbiturate anesthesia, all frequencies of conditioning callosal stimuli induced short-term (5-30 min) enhancement of test EPSPs elicited by single stimuli. Neurons tested with successive conditioning pulse-trains at different frequencies displayed stronger enhancement with high-frequency (40-100 Hz) than with low-frequency (10-20 Hz) rhythmic pulse-trains; >100 Hz, the potentiation saturated. In a neuronal sample, microdialysis of an N-methyl-D-aspartate (NMDA) receptor blocker in barbiturate-treated cats suppressed this potentiation, and potentiation of callosally evoked EPSPs was not detected in neurons recorded under ketamine-xylazine anesthesia, thus indicating that EPSPs' potentiation implicates, at least partially, NMDA receptors. These data suggest that callosal activities occurring within low-frequency and fast-frequency oscillations play a role in cortical synaptic plasticity.

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[Efficacy and safety of antiepileptic therapy in children (a comparative analysis of valproates and barbiturates)]

[Article in Russian]

Pylaeva OA, Petrukhin AS, Voronkova KV.

The study aimed at a comparative analysis of safety and efficacy of valproic acid (valproate) and barbiturates in the treatment of epilepsy in children. Two hundred and forty children were treated with valproate, 94% being assigned to depakine and depakine chrono, and 210 children received barbiturates. Therapeutic effect (a decrease of seizures frequency by 2 and more times or remission) was detected in 82 of 127 (65 +/- 8.53%) patients for valproate monotherapy and only in 26 of 89 (30 +/- 9.45%) for barbiturates monotherapy. An efficacy of antiepileptic therapy in children was significantly higher (p<0.05) for valproates as compared to barbiturates. A drug withdrawal due to poor tolerability was recorded in 6 of 127 (5 +/- 3.7%) patients treated with valproate in monotherapy and in 14 of 210 (7 +/- 3.45%)--in polytherapy; in 53 of 89 (59 +/- 10.2%) patients treated with barbiturates in monotherapy and in 78 of 121 (65 +/- 8.53%) patients treated with barbiturates in polytherapy. Therefore, adverse effects occurred more often in barbiturates than in valproate treatment both for mono- and polytherapy (p<0.05). The results of the study confirmed the high efficacy and safety of valproates, specifically depakine chrono, in the treatment of epilepsy in children. depakine chrono in-take is associated with lower frequency of adverse effects; side-effects are mostly of dose-dependent character and do not result in the drug withdrawal. The authors do not recommend using barbiturates in the first-line treatment in children, because of the lower efficacy, high frequency of medical complications that might result in the drug withdrawal and reducing of the efficacy of other antiepileptic medications.

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The studies on the structure-activity relationship of allyl substituted oxopyrimidines searching for the novel antagonist or agonist of barbiturates to the sleep mechanism based on the uridine receptor theory -barbituric Acid to uridine (part i)(1))-.

Yamamoto I.

Faculty of Pharmaceutical Sciences, Hokuriku University.

Thirty-six allyl substituted oxopyrimidine analogues such as barbituric acid (BA), barbiturates, uracil, thymine, and related derivatives including 13 new compounds were synthesized and their pharmacologic effects ([hypnotic activity, anticonvulsant activity against pentylentetrazol (PTZ)-induced seizures, and LD(50)]) and interactions with the barbiturates were evaluated in mice and rats. The results are briefly and parially summarized as follows. BA prolonged pentobarbital (PB)-induced sleep and had some central depressant effects. N,5,5-Triallyl-BA exhibited some hypnotic and anticonvulsant activities, although the other 5,N-allyl-compounds did not show any activity except for allobarbital (AlloB). N-Allyl-BA, 5-allyl-BA, N(1),N(3),5-triallyl-BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA also prolonged PB-induced sleep. Interestingly, N,5,5-triallyl-BA was the most potent in the interaction with AlloB, phenobarbital (PheB), amobarbital (AB), PB, and thiopental (TP) but not barbital (B). N(1),N(3),5,5-Tetraallyl-BA prolonged AlloB-, PB-, and AB-induced sleep but not B-, PheB-, and TP-induced sleep. N(1),N(3),5-Triallyl-B prolonged only PB- and TP-induced sleep. 5,5-Diallyl-BA prolonged PheB- and TP-induced sleep. N,5-Diallyl-BA prolonged only TP-induced sleep. In contrast, BA and N(1),N(3),5-triallyl-AB tended to antagonize AlloB, AB, and B. N(1),N(3),5,5-Tetraallyl-BA also slightly antagonized B, PheB, and TP. 5,5-Diallyl-BA antagonized only AB. The prolonging effects of BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA on PB-induced sleep were dose dependent. These results indicate that the position and number of allyl groups substituted on the structure of BA play an important role in their depressant activities. This review deals with the structure-activity relationship of allyl-substituted oxopyrimidines as part of our search for antagonists and agonists of barbiturates as well as their mechanisms of action.

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