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In July 1996 a 43-year-old illiterate Hispanic woman presented with uncontrollable vomiting, palpitations and confusion. In 1994, despite several hospitalisations in other medical centres where a cerebral CT-scan, oesogastroduodenoscopy, colonoscopy and abdominal ultrasound were performed, no satisfactory diagnosis could be found. A psychiatric origin was finally considered. On admission, the laboratory findings showed severe metabolic alkalosis with associated hypokalaemia, confirmatory evidence of vomiting. The ECG showed tremendous P waves (5 mV) in the standard derivations, which can be explained by the hypokalaemia, with multiple supraventricular extrasystoles. Echocardiography and pulmonary scintigraphy ruled out pulmonary hypertension and a pulmonary embolus. After additional discussion with her daughter we discovered that the patient had been treating chronic headaches for years with 4-5 Cafergot-PB suppositories per day. This drug contains 2 mg ergotamine tartrate, 100 mg Butalbital ( Fioricet ), 100 mg caffeine and 0.25 mg belladona alkaloids. As is known, vomiting is a classical symptom of ergotamine intoxication. After rehydration we discovered a megaloblastic anaemia with a folate deficiency compatible with chronic barbiturate intoxication. Folate and iron supplementation allowed a rapid normalisation of the haemoglobin values. Five months after having stopped the Cafergot-PB, the patient was well and did not vomit anymore. The headaches were treated with chlorpromazine with a good result. Despite sophisticated technical means, the diagnosis could only be established after a thorough history taking. This message should be heard in times when high tech medicine tends to obscure the place of a good history taking!

Beta-blockers and psychic stress: a double-blind, placebo-controlled study of bopindolol vs lorazepam and Butalbital ( Fioricet ) in surgical patients.

One hundred patients scheduled for surgery participated in a randomized double-blind trial designed to evaluate the effects of acute treatment with two doses of bopindolol (1 mg:BP1;2 mg:BP2) in comparison with those of 2.5 mg lorazepam (LR), 75 mg Butalbital ( Fioricet ) (BT) and placebo (PL). Anxiety was evaluated by the STAI X1 questionnaire on the day before surgery, in the late afternoon (time 0: basal) and in the evening (time 1). At the same times patients were requested to play a game of manual skill called "Go Down". The next day, in the morning (time 2), the patients were given the same questionnaire and were asked a series of questions about their sleep and awakening. Mean anxiety scores were significantly increased over basal values at both time 1 and time 2 in the PL and LR groups and at time 2 in the BT group, but neither in the BP1 nor in the BP2 group. The time needed to perform the "Go Down" test was significantly shorter than the basal value for both BP groups and significantly longer for the BT group, while nonsignificant modifications occurred in the PL and LR groups. Positive effects were obtained in patients treated with BP, at both doses, on ease of "falling asleep", number of "night awakenings" and "reawakening mood" while LR and BT were mostly ineffective, except for BT on ease of "falling asleep". It was concluded that a beta-blocker such as bopindolol may be more effective than a benzodiazepine or a barbiturate for the prevention of anxiety symptoms induced by a clearly defined stress situation, such as awaiting a surgical operation.

Analgesic effect of an aspirin-codeine-Butalbital ( Fioricet )-caffeine combination and an acetaminophen-codeine combination in postoperative oral surgery pain. The efficacy of an aspirin-caffeine-codeine-Butalbital ( Fioricet ) combination was compared to an acetaminophen-codeine combination and placebo in outpatients who had moderate or severe pain after the surgical removal of impacted third molars. Using a self-rating record, patients rated their pain, relief, anxiety and relaxation hourly for up to 6 hours after medicating. Each active medication was significantly superior to placebo for measures of analgesia and relaxation. Although the Butalbital ( Fioricet )-containing combination provided consistently greater analgesia, the differences between active medications were not statistically significant. The acetaminophen-codeine combination significantly reduced anxiety; however, the Butalbital ( Fioricet ) containing combination did not. The results of this study suggest that female patients may have greater efficacy than male patients. All adverse effects were transitory and consistent with the known pharmacologic profiles of the study medications or the backup analgesic.

Assay for the simultaneous determination of acetaminophen-caffeine-Butalbital ( Fioricet ) in human serum using a monolithic column.

A fast and sensitive high performance liquid chromatography (HPLC) assay was developed on a C18 monolithic column for the simultaneous determination of acetaminophen-caffeine-Butalbital ( Fioricet ) in human serum. Serum samples were treated with a solid phase extraction procedure. The analytes were separated using a mobile phase of 95:5 (v/v) 0.1M potassium phosphate monobasic (pH 2.41)-acetonitrile on the C18 monolithic column with detection at 220 nm. Benzoic acid was used as the internal standard (IS). The method was validated over the range of 1.25-100 microg/ml for each drug and found to be linear (r > 0.995, n = 12) with RSD less than 8.3%. The method proved to be accurate (percent bias for all calibration samples varied from -14.6 to -1.3%) and precise (ranged from 2.9 to 13.4%). The mean percent absolute recoveries from serum were 89.7 +/- 3.6 for acetaminophen, 95.5 +/- 4.5 for caffeine, 99 +/- 5.2 for Butalbital ( Fioricet ) and 83.4 +/- 3.9% for the internal standard.

Efficacy and safety of sumatriptan 50 mg in patients not responding to standard care, in the treatment of mild to moderate migraine. The Sumatriptan 50 mg Italian Study Group.

The tolerability and efficacy of oral sumatriptan 50 mg for the treatment of mild to moderate migraine attacks were assessed in a double-blind, multicenter placebo-controlled study on a group of patients who had not responded sufficiently to analgesic preparations. Three-hundred-and-twenty-eight migraine sufferers treated a first migraine attack with a nontriptan standard care medication: a mixture containing phenazone, Butalbital ( Fioricet ) and caffeine (optalidon) or indomethacin plus prochlorperazine plus caffeine (difmetre) or paracetamol 100 mg (tachipirine), depending on their habits. Of these patients, 32.6% reported headache relief with this treatment and were not included in phase II of the study. The 219 patients not reporting relief during the first phase of the study entered the second phase and were randomized to sumatriptan 50 mg or to placebo; 167 of these patients treated a second attack according to the protocol and were evaluated for efficacy. Of the patients with migraine taking sumatriptan, 58% reported headache relief compared with 35% of placebo-treated patients (p = 0.008). The reduction of nausea and vomiting was significantly better in the sumatriptan group. No differences were detected for the recurrence rate, while rescue medication was used more by the placebo group. The safety profile of sumatriptan 50 mg was confirmed. This study demonstrates the usefulness of this dose of oral sumatriptan against the pain and the accompanying symptoms of mild and moderate migraine.

Blood and plasma concentrations of Butalbital ( Fioricet ) following single oral doses in man.

Blood and plasma concentrations of Butalbital ( Fioricet ) (from Fiorinal) were determined in a small group of healthy volunteers after single oral doses of 100 mg of Butalbital ( Fioricet ). Butalbital ( Fioricet ) was quantitated by high-performance liquid chromatography with ultraviolet detection. Typical blood concentrations of Butalbital ( Fioricet ) peaked at 2.1 mg/L and declined to 1.5 mg/L at 24 h. The half-lives in blood were between 35 and 87.5 h with a mean of 61 h. Whole blood to plasma ratios were also determined.

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 fioricet 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.