12:49 a.m. - 2007-09-27
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Organic dissociative syndrome associated with antimigraine pharmacotherapy.
This report describes an acute organic brain syndrome with a fugue-like state in association with antimigraine pharmacotherapy. The differential diagnosis of: 1. possible psychotoxic effects of the combination of propranolol, imipramine, and Butalbital ( Fioricet ); 2. confusional migraine with amnesia; and 3. psychogenic dissociation is considered. Although organically induced dissociative states are of clinical, neuropsychological and medico-legal significance, the DSM-III and DSM-III-R have specific categories only for dissociative conditions that are strictly psychogenic in origin.
Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from Butalbital ( Fioricet ) compounds.
BACKGROUND: The overuse of short-acting barbiturate medications for the acute treatment of headache is a common problem in the United States. Most experts agree that withdrawal from these medications is necessary for subsequent headache treatment to be successful, yet there are few published articles outlining effective methods of drug withdrawal. OBJECTIVE: To evaluate the safety and effectiveness of phenobarbital loading for withdrawal from overuse of short-acting barbiturate compounds in inpatients with headache. DESIGN AND METHODS: We performed a retrospective chart review of 18 consecutive patients in an inpatient pain rehabilitation program who were withdrawn from overuse of Butalbital ( Fioricet )-combination medications using a phenobarbital-loading protocol. RESULTS: Eighteen patients with headache hospitalized in an inpatient pain unit for withdrawal from overuse of combination Butalbital ( Fioricet ) preparations underwent a phenobarbital-loading protocol. Short-acting barbiturate medications were discontinued, and patients received 120 mg of oral phenobarbital until their score on a predetermined scale reached target levels, and the drug was then discontinued. All patients were effectively treated with no serious adverse events. The median number of doses required varied significantly, and could not be predicted by the patient's prior intake. CONCLUSIONS: Management of Butalbital ( Fioricet ) withdrawal can be simplified by using a phenobarbital-loading protocol, taking advantage of the natural tapering afforded by the drug's long half-life. This method possesses most of the characteristics of an ideal drug withdrawal program for patients with headache who are overusing medications.
Attenuation by Butalbital ( Fioricet ) of capsaicin-induced c-fos-like immunoreactivity in trigeminal nucleus caudalis.
We examined the effects of Butalbital ( Fioricet ) (30, 100, and 1000 micrograms/kg) on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within lamina I, IIo of the trigeminal nucleus caudalis and the nucleus of the solitary tract 2 hours after the intracisternal injection of capsaicin (0.1 mL; 15.25 mg/mL) or vehicle in urethane-anesthetized guinea pigs (N = 45). Robust c-fos-LI was observed within nuclei of cells in the trigeminal nucleus caudalis after capsaicin (329 +/- 35). Butalbital ( Fioricet ) dose-dependently reduced the number of labeled cells to a maximum of 66% (1000 micrograms/kg intraperitoneally [i.p.], P < .01) in lamina I, IIo but not within area postrema, medial reticular nucleus, or the nucleus of the solitary tract. Pretreatment with bicuculline (30 micrograms/kg i.p.) blocked the effect of Butalbital ( Fioricet ), thereby suggesting the importance of the GABAA receptor to activation involved in the transmission of nociceptive information. Our studies suggest the possibility that GABAA receptors might provide an important therapeutic target in migraine and related headache disorders.
Distribution of Butalbital ( Fioricet ) in postmortem tissues and fluids from non-overdose cases.
During the investigation of fatal aviation accidents, postmortem samples from the pilots/co-pilots are submitted to the Federal Aviation Administration's (FAA) Civil Aerospace Medical Institute (CAMI) for toxicological analysis. Although therapeutic levels for most drugs are typically reported in the scientific literature for blood and plasma, blood specimens are received in only approximately 70% of our cases. Therefore, it is imperative for an accident investigator and forensic toxicologist to be able to estimate drug concentrations in an aviation accident victim's blood from available tissue drug concentrations. This is exemplified by a recent aviation fatality in which Butalbital ( Fioricet ) was identified in the muscle tissue of a pilot. In this case, no blood was available for analysis, but investigators needed to know the approximate Butalbital ( Fioricet ) concentration expected in the victim's blood. Certain side effects of Butalbital ( Fioricet ), such as drowsiness, sedation, dizziness, and a feeling of intoxication, could affect pilot performance and become a significant factor in an aviation accident. Thus, our laboratory determined the distribution of Butalbital ( Fioricet ) in various postmortem tissues and fluids. The distribution coefficients for Butalbital ( Fioricet ), expressed as specimen/blood ratios, were found to be as follows: 0.66 +/- 0.09 (muscle, n = 4), 0.98 +/- 0.09 (kidney, n = 4), 0.87 +/- 0.06 (lung, n = 4), 0.75 +/- 0.03 (spleen, n = 4), 0.96 +/- 0.07 (brain, n = 3), 2.22 +/- 0.04 (liver, n = 4), and 0.91 +/- 0.17 (heart, n = 2). The results obtained from our limited number of cases suggest that muscle, kidney, lung, spleen, brain, liver, and heart could be used, in a cautious and conservative fashion, to estimate Butalbital ( Fioricet ) blood concentrations.
Death by managed care-denial of hospitalization for headache.
A 47-year-old man with a severe headache disorder, taking meperidine injections 8 to 12 times a day and approximately 6 Butalbital ( Fioricet )-containing tablets per day, was denied hospitalization for the management of headache and died while awaiting evaluation for detoxification by a psychiatric facility. The criteria for hospitalization and the implications of the denial of care by insurance companies are explored. The biases against the publication of such cases are reviewed.
Drug interactions of the components of Optalidon after oral administration.
An investigation involving seven successive was undertaken on several groups of 10 to 14 volunteers, in order to evaluate any drug interaction between the three active components of Optalidon, namely amidopyrine (A), Butalbital ( Fioricet ) (B), and caffeine (C). Each component was investigated after oral administration, alone and in combination either with one of the others (i.e. A+B, B+C, C+A) or with both of the others in Optalidon (A+B+C). The plasma concentration and urinary excretion were recorded for each component as a function of time. For amidopyrine, two metabolites, amino-4-antipyrine and acetamino-4-antipyrine, were also measured in the urine. Based on a pharmacokinetic model, the following conclusions can be drawn: a) There is no change in bioavailability due to the combination of the three components in Optalidon in respect to their single administration. Within each study, there is no significant difference between the elimination rate constants, areas under the plasma concentration/time curve and percentage excreted in urine for the three components administered alone or in any combination with the other components of Optalidon. b) Concerning the absorption half-life, there is no change for amidopyrine. Only caffeine and Butalbital ( Fioricet ) show a statistically significant interaction in respect to this parameter and, as a consequence, differences in the time and value of the maximal plasma concentration in Optalidon. However, these differences are scarcely of anyl clinical relevance.
Application of micellar electrokinetic capillary chromatography to forensic analysis of barbiturates in biological fluids.
Micellar electrokinetic capillary chromatography (MECC) is a form of capillary zone electrophoresis. Addition of a surfactant produces micelles in an aqueous/organic buffer. Separation of drugs is obtained via differences in the electrophoretic mobilities of the analytes within the capillary, resulting from their electrophoretic velocity and the electroosmotic flow of the buffer in a given electric field. The migration order is determined by the differential partitioning of the drugs between the micelles and the aqueous/organic phase. Barbiturates were extracted from various biological fluids at pH 4.5 with TOXI-TUBES B. MECC analyses were performed using a Waters Quanta 4000 Capillary Electrophoretic System with a 745 Data Module with a 75 microns x 60 cm capillary and an aqueous/organic buffer of 85% 10 mM borate, 10 mM phosphate, 100 mM sodium dodecyl sulfate and 15% acetonitrile at a pH of 8.5 with a voltage of 20 kV using ultraviolet absorption detection at 214 nm. Migration times were: phenobarbital, 7.78 min.; Butalbital ( Fioricet ), 8.01 min.; butabarbital, 8.23 min.; mephobarbital (internal standard), 8.88 min.; amobarbital, 9.41 min.; pentobarbital, 10.03 min. and secobarbital, 10.79 min. Correlation coefficients (r) between peak areas and concentration ranges of 3 to 60 micrograms/mL were from 0.964 to 0.999. Coefficients of variation (CV) ranged from 2.6 to 8.6% between days and 2.3 to 9.8% within day. Application of this methodology to four forensic cases of Butalbital ( Fioricet ) intoxication detected concentrations of 0.7 to 12.7 micrograms/mL in blood; 0.8 to 1.9 micrograms/mL in vitreous humor and 1.5 to 7.6 micrograms/mL in urine. MECC is applicable to forensic analysis of barbiturates extracted from biological fluids.
Migraine headache misconceptions: barriers to effective care.
Migraine headaches affect 12% of the adult population in the United States and cause a significant economic loss due to decreased workplace productivity. Although interactions between pharmacists and individuals with headache are common, few pharmacists receive adequate training regarding migraine therapy. We refute several misconceptions that hinder effective care, such as that migraine is a vascular disease, triptans cause rampant cardiac-related morbidity and even mortality, a best oral triptan exists, sinus and tension headaches are prevalent, and migraine is a minor economic problem. Our pathophysiologic understanding demonstrates that migraine is a neurologic process of the trigeminovascular system, of which vascular effects are secondary. This process can result in a myriad of clinical signs and symptoms, often leading to a misdiagnosis of sinus or tension headache. The last decade's experience with triptans in more than half a billion people worldwide reveals a benign adverse-effect profile, particularly when taken early in an attack. Published reports and real-world experiences illustrate that these drugs do not merit fears of triptan-induced cardiac consequences in appropriately selected individuals. Society's productivity loss due to migraine is measured in billions of dollars. Restoring a patient's ability to function normally is now recognized as the primary treatment goal, not merely relieving pain. Thus, the overreliance on "pain killer" drugs such as Butalbital ( Fioricet )-containing products and the continued underutilization of migraine-specific drugs need to be addressed. Opportunities exist for pharmacists and other health care providers to dispel continually propagated migraine misconceptions and familiarize themselves with advances in therapy. Such actions will benefit patients, the health care system, and society as a whole. Comment: This is a marvelous review for residents and primary care practitioners.-Stewart J. Tepper This is a thought provoking article which deserves to be widely discussed. It contains many home truths which should have considerable impact for health care practitioners and will provide useful ammunition for patient groups and headache physicians battling to access resources for headache patients. We reached similar conclusions following our U.K. population survey of headache treatment and health care utilization. Undoubtedly, pharmacists and other health care professionals can act as important conduits to facilitate the prompt effective treatment of headache.-David S. Millson Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N, IMPACT Investigators. a factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441-2451. Background: Untreated, one-third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown. Methods: We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly. Results: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26%. Propofol reduced the risk by 19%, and nitrogen by 12%; the risk reduction with both of these agents (ie, total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients' baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients' baseline risk. Conclusions: Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be used first. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients. Comment: We do not know the mechanism of postop nausea, but it is likely to be both medication-induced and central, with potential central generators being nucleus tractus solitariuus and medullary area postrema. Both dopamine and serotonin are clearly involved, and probably Substance P, and we also do not know the relation between migrainous nausea and iatrogenic nausea. Although ondansetron, a 5-HT3-receptor antagonist was included in the randomization, aprepitant, the Substance P/NK1 antagonist antinauseant, synthesized by Richard Hargreaves and team, was not in the study. I included this article as food for thought: which of these medications should we use for our migraine patients, and should we combine multiple medications? I believe a randomized controlled trial of antinauseants alone in treatment of migraine nausea is in order.-Stewart J. Tepper I agree with Dr. Tepper that a randomized comparator trial is urgently needed for treatment of nausea in migraine. I was a little puzzled to see fentanyl and remifentanil described as potential antinausea agents. I would have assumed they are less effective or may actually cause nausea as predicted by their pharmacology. The early studies with ondansetron suggested a potential role in the acute treatment of migraine. However, later work using an early headache classifications and trial designs failed to confirm efficacy (Ferrari MD. 5-HT3-receptor antagonists and migraine. J Neurol. 1991;238:S53-S56). Perhaps the newer antinauseants deserve revisiting given recent developments with the IHS classification and trial designs.-David S. Millson Dodick DW, Martin V. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms. Cephalalgia. 2004;24:417-424. Triptans are the treatment of choice for acute migraine. While seemingly a homogenous group of drugs, results from a meta-analysis reveal significant differences in efficacy and tolerability among oral triptans. The incidence of drug-related central nervous system (CNS) side-effects with some triptans is as high as 15% and may be associated with functional impairment and reduced productivity. The occurrence of adverse events associated with triptans in general, and CNS side-effects in particular, may lead to a delay in initiating or even avoidance of an otherwise effective treatment. Potential explanations for differences among triptans in the incidence of CNS side-effects may relate to pharmacological and pharmacokinetic differences, including receptor binding, lipophilicity, and the presence of active metabolites. Of the triptans reviewed, at clinically relevant doses, almotriptan 12.5 mg, naratriptan 2.5 mg, and sumatriptan 50 mg had the lowest incidence of CNS side-effects, while eletriptan 40 and 80 mg, rizatriptan 10 mg, and zolmitriptan 2.5 and 5 mg had the highest incidence. The most likely explanations for the differences in CNS side-effects among triptans are the presence of active metabolites and high lipophilicity of the parent compound and active metabolites. Eletriptan, rizatriptan, and zolmitriptan have active metabolites, while lipophilicity is lowest for almotriptan and sumatriptan. If CNS side-effects are a clinically relevant concern in the individual patient, use of a triptan with a low incidence of CNS side-effects may offer the potential for the earlier initiation of treatment and more effective outcomes. Comment: This article raises more questions than it answers. CNS penetration and liphophilicity do indeed go hand in hand as described by Professor Peter Goadsby in his review (Goadsby P. A triptan too far? J Neurol Neurosurg Psychiatry. 1999;66:121). However, this relationship is questionable in relation to naratriptan which is at least as liphophilic as zolmitriptan and rizatriptan. For naratriptan the FDA mandated a maximum daily dose of 5 mg due to concerns relating to CNS toxicity with higher doses. This also explains why the subcutaneous formulation was abandoned. I do not believe that active metabolites contribute significantly to CNS activity unless they accumulate (which is not the case). Triptan metabolites are usually less liphophilic generated by first pass through the liver (in many cases N-demethylation) which renders them more water soluble and enhances renal elimination. CNS side-effects are also related to onset of action with a trade-off for increased efficacy within 30 minutes with oral formulations of eletriptan, rizatriptan, and zolmitriptan versus the slower onset of naratriptan and frovatriptan. Other factors predicting CNS penetration relate to uptake and competition for the P-gp phospho glycoprotein pump which facilitates the exclusion of lipophilic drugs from the CNS and for which eletriptan is a substrate.-David S. Millson Sender J, Bradford S, Watson D, Lipscombe S, Rees T, Manley R, Dowson AJ. Setting up a Specialist headache Clinic in primary care: general practitioners with a special interest in headache. headache Care. 2004;1:165-171. Part of the National Health Service modernization process is to develop General Practitioners with Special Interest (GPwSI) services for intermediate care. Management of headache is currently poor in the United Kingdom due to a lack of trained health care professionals, patients not accessing care, and a reliance on ineffective medications. This warrants the development of GPwSI in headache services. The Royal College of General Practitioners has produced a framework document for the development of an intermediate care service for headache. While this describes what needs to be present in such a service, it does not address the practicalities of implementing it. This article provides organizational and practical guidance for setting up such a service. The majority of headache patients can be managed by multidisciplinary GP- or GPwSI-based care teams located in Primary Care Trusts. Relatively few patients need to referred to secondary care services. The processes of headache management are the same for the whole case mix, involving initial screening, diagnosis, assessment of severity, prescription of therapies tailored to the individual patient's needs, and proactive follow-up. However, the successful implementation of such services poses significant economic and professional challenges to both health care providers and physicians that must be overcome for this program to be successful. Comment: As an American who travels to the United Kingdom a bit, and counts many British as friends, let me try to summarize how this works. The UK National Health Service (NHS) is hierarchical, and specialists are limited in number and often difficult to access for general practitioners (GPs), especially in the hinterlands. Since GPs provide the majority of care in the United Kingdom, control has been placed regionally in Primary Care Trusts run by primary care doctors. A provision has been instituted to allow GPs with special interest in particular specialties to train to provide care in place of specialists, to reduce the burden of referrals to the overtaxed specialists. These GPs with Special Interest (GPwSIs, pronounced "gypsies") have the potential to give outstanding and badly needed care, and headache is an obvious need. The training would be similar to what Dr. Andy Dowson has championed with his Migraine in Primary Care Advisors (MIPCA) in the United Kingdom, and Roger Cady and the Primary Care Network (PCN) provides to primary care practitioners in the United States, but longer and with more bureaucratic documentation. In the United States, certified headache fellowships exist, and we do not distinguish between the training of the doctors at onset-any interested licensed physician can do a headache fellowship. US qualifying headache Boards, in the works, may also be allowed for licensed physicians who have completed certified fellowships.-Stewart J. Tepper Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia. 2004;24:596-602. Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicenter trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine.
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