Acute treatment of migraine.

Acute treatment of migraine has benefited first from major advances in pharmacological science followed in short order, sometimes preceded, by an improved understanding of pathogenesis, especially of headache. This chapter reviews the mechanisms of migraine that provide an understanding of the pharmacology and therapeutic targets for acute migraine medications. General clinical approaches to acute therapy are reviewed, and indices of acceptable acute therapeutic outcomes are discussed. Currently the serotonin (5-HT) 1B/1D agonist group of drugs, triptans, forms the mainstay of acute therapeutic regimens. Other approaches to acute treatment such as simple analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), ergots, and combination medications are reviewed. Finally, the newest acute treatments that are currently exploratory or under clinical investigation are discussed.

Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks.

The efficacy of a 6-day regimen of frovatriptan for menstrual migraine (MM; attacks starting on day -2 to +3 of menses) prevention in women with difficult-to-treat MM was assessed. Women with a documented inadequate response to triptans for acute MM treatment were included in this placebo-controlled, parallel-group trial. Women were randomized to double-blind treatment for three perimenstrual periods (PMPs) with either frovatriptan 2.5 mg (q.d. or b.i.d.) or placebo initiated 2 days before anticipated MM. The efficacy analysis included 410 women with 85% completing three double-blind PMPs. The mean number of headache-free PMPs was 0.92 with frovatriptan b.i.d., 0.69 with frovatriptan q.d. and 0.42 with placebo [P < 0.001 (b.i.d.) and P < 0.02 (q.d.) vs. placebo]. When migraine occurred, severity was reduced with frovatriptan q.d. (P < 0.001) and b.i.d. (P < 0.001) vs. placebo. Both frovatriptan regimens were well tolerated. In women with difficult-to-treat MM, a 6-day regimen of frovatriptan significantly reduced MM incidence and severity.

History of childhood maltreatment is associated with comorbid depression in women with migraine.

BACKGROUND: A bidirectional relationship between migraine and depression suggests a neurobiological link. Adverse experiences, particularly childhood maltreatment, may alter neurobiological systems, and predispose to a multiplicity of adult chronic disorders. Our objective is to determine, within a headache clinic population of women, if depression moderates the abuse-migraine relationship. METHODS: At six headache specialty clinics, women with migraine were diagnosed using ICHD-II criteria, and frequency was recorded. A questionnaire regarding maltreatment history, headache characteristics, current depression, and somatic symptoms was completed. RESULTS: A total of 949 women with migraine completed the survey: 40% had chronic headache (> or =15 headache days/month) and 72% had "very severe" headache-related disability. Major depression was recorded in 18%. Physical or sexual abuse was reported in 38%, and 12% reported both physical and sexual abuse in the past. Migraineurs with current major depression reported physical (p < 0.001) and sexual (p < 0.001) abuse in higher frequencies compared to those without depression. Women with major depression were more likely to report sexual abuse occurring before age 12 years (OR = 2.30, 95% CI: 1.14 to 4.77), and the relationship was stronger when abuse occurred both before and after age 12 years (OR = 5.08, 95% CI: 2.15 to 11.99). Women with major depression were also twice as likely to report multiple types of maltreatment (OR = 2.07, 95% CI: 1.27 to 3.35) compared to those without depression. CONCLUSIONS: Childhood maltreatment was more common in women with migraine and concomitant major depression than in those with migraine alone. The association of childhood sexual abuse with migraine and depression is amplified if abuse also occurs at a later age.

High prevalence of somatic symptoms and depression in women with disabling chronic headache.

OBJECTIVE: To better define, in women with headache, the relationship of depression and somatic symptoms to headache, characterized by diagnoses, frequency, and disability. METHODS: At six headache specialty clinics, women with headache were classified using ICHD-II criteria, and frequency was recorded. A questionnaire addressing demographics, age at onset of headache, headache-related disability, somatic symptom, and depression severity was completed. Logistic regression was performed to measure the associations of headache frequency and headache-related disability with somatic symptom and depression severity. RESULTS: A total of 1,032 women with headache completed the survey, 593 with episodic (96% with migraine) and 439 with chronic headache (87% with migraine). Low education and household income was more common in chronic headache sufferers and in persons with severe headache disability. Somatic symptom prevalence and severity was greater in persons with chronic headache and with severe headache-related disability. Significant correlation was observed between PHQ-9 and PHQ-15 scores (r = 0.62). Chronic headache, severe disability, and high somatic symptom severity were associated with major depressive disorder (OR = 25.1, 95% CI: 10.9 to 57.9), and this relationship was stronger in the subgroup with a diagnosis of migraine (OR = 31.8, 95% CI: 12.9 to 78.5). CONCLUSIONS: High somatic symptom severity is prevalent in women with chronic and severely disabling headaches. Synergistic relationship to major depression exists for high somatic symptom severity, chronic headache, and disabling headache, suggesting a psychobiological underpinning of these associations.

Mismatch in how oestrogen modulates molecular and neuronal function may explain menstrual migraine.

This paper is designed to provide concepts and stimulate directions for further investigation of menstrual migraine. On the basis of experimental studies and literature review, we propose that abnormalities in how estrogen modulates neuronal function in migraine are due to a mismatch between its gene-regulation and membrane effects. In the interictal phase when estrogen levels peak, increased neuronal excitability is balanced by homeostatic gene regulation in brain cortex, and nociceptive systems. When levels fall at menses, mismatch in homeostatic gene regulation by estrogen unmasks non-nuclear mitogen-activated hyperexcitability of cell membranes, sensitizing neurons to triggers that activate migraine attacks. At the trough of estrogen levels, the down-regulating effect on inflammatory genes is lost and peptide modulated central sensitization is increased as is pain and disability of the migraine attack.

Eletriptan in the early treatment of acute migraine: influence of pain intensity and time of dosing.

This double-blind, placebo-controlled study was designed to evaluate the efficacy and tolerability of early treatment of a single migraine attack, when headache pain was mild, with two doses (20 mg and 40 mg) of eletriptan. Patients (N = 613; female 79%; mean age 39 years) meeting International Headache Society criteria for migraine were encouraged, but not required, to utilize early treatment, thus providing an opportunity to assess the relative contribution to efficacy of pain severity and timing of dose. For the total patient sample (mild-to-severe headaches), 2-h pain-free rates were significantly higher than placebo (22%) on both eletriptan 20 mg (35%; P < 0.01) and eletriptan 40 mg (47%; P < 0.0001). For the cohort of patients who treated their headache when the pain intensity was mild, the 2-h pain-free rate on eletriptan 40 mg was 68% compared with 25% on placebo (P < 0.0001). Pain intensity at the time of taking eletriptan appeared to influence outcome more than the timing of the dose relative to headache onset. Eletriptan was well-tolerated, with adverse event rates similar to placebo when mild headaches were treated.

Preference comparison of rizatriptan ODT 10-mg and sumatriptan 50-mg tablet in migraine.

OBJECTIVE: To compare the proportion of patients who prefer rizatriptan orally disintegrating tablet (ODT) 10-mg to sumatriptan 50-mg tablet. BACKGROUND: Migraineurs express treatment preference based on a variety of attributes including the speed of pain relief and medication formulation. Rizatriptan ODT is an orally disintegrating formulation of rizatriptan, a selective 5-HT1B/1D receptor agonist. This study was conducted to determine patient preference between rizatriptan ODT 10-mg and sumatriptan 50-mg tablet for the acute treatment of migraine. METHODS: This was a multicenter, randomized, open-label, two-period crossover study conducted in the United States with 524 enrolled patients. Patients treated a single moderate or severe headache in each treatment period. Patients treated one migraine with either rizatriptan ODT 10-mg or sumatriptan 50-mg tablet, then treated a second migraine with the alternate therapy. Patients completed diary assessments at baseline, and 30, 45, 60, 90, and 120 minutes postdose and rated headache severity on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). At the final study visit following treatment of their second migraine, patients expressed preference for one of the two study medications by completing an interviewer-administered Global Preference Question and then responded to a self-administered series of questions to capture their most important reason for preferring one study medication over the other. Safety measurements were recorded through standard adverse experience reporting. RESULTS: Three hundred eighty-six patients treated two migraine attacks. For those patients who expressed a preference for either rizatriptan ODT or sumatriptan (n = 374), the percentage of patients who preferred rizatriptan ODT 10-mg (57%, n = 213) was significantly greater than those who preferred sumatriptan 50-mg tablet (43%, n = 161) (P<.01). For those patients who treated two migraine attacks and had drug severity measures for both attacks (n = 384), a significantly greater percentage of patients reported pain relief after taking rizatriptan ODT than sumatriptan at the 45- and 60-minute time points (38% versus 29% and 58% versus 49%, respectively) (P<.01). In addition, a significantly greater percentage of patients taking rizatriptan ODT reported a pain-free status at the 60- and 120-minute time points (23% versus 17% [P<.05] and 60% versus 52% [P<.01], respectively). Both rizatriptan ODT and sumatriptan were well tolerated. CONCLUSIONS: A significantly greater proportion of patients preferred rizatriptan ODT 10-mg to sumatriptan 50-mg tablet for the acute treatment of migraine. Efficacy and safety data are consistent with the preference findings.

Potential of the Migraine Disability Assessment (MIDAS) Questionnaire as a public health initiative and in clinical practice.

Migraine is not always well managed in clinical practice, often being under-diagnosed and under-treated. As a result, many sufferers never consult a physician or lapse from care after physician contact. Although most migraine care is provided by general practitioners, others, including specialists, emergency room physicians, pharmacists, and alternative practitioners, may also be involved. A method of standardizing clinical information about migraine is essential for coordinated, logical, and systematic care. The impact of migraine on the patient is an important clinical parameter but one that is seldom inquired about, perhaps because it exhibits such marked variability among and within individuals. Headache-related disability can be an objective and measurable index of this impact. The Migraine Disability Assessment (MIDAS) Questionnaire is a simple and validated instrument with potential for use in clinical practice, research, and public health. It can improve communication between patients and health-care professionals regarding the impact of migraine which, in turn, allows tailoring of the intensity of treatment to the severity of the illness. Changes in the MIDAS score may serve as an end point in assessing treatment efficacy. In populations, MIDAS scores may indicate the burden of migraine in the community and spark public health initiatives to improve management.

Comparison of postoperative headache after retrosigmoid approach: vestibular nerve section versus vestibular schwannoma resection.

OBJECTIVE: To evaluate intradural drilling as a mechanism for the development of postoperative headache after retrosigmoid craniectomy. STUDY DESIGN: A retrospective review of charts was performed on 565 retrosigmoid approaches to the cerebellopontine angle performed between January 1980 and January 1998. Patients treated with retrosigmoid vestibular nerve section without intradural drilling were compared with patients who underwent retrosigmoid removal of vestibular schwannomas in which intradural drilling was performed for exposure of the internal auditory canal. SETTING: Private practice tertiary referral center. PATIENTS: Consecutive patients undergoing retrosigmoid approach between January 1980 and January 1998 were reviewed. MAIN OUTCOME MEASURES: The presence of headache, duration of headache, and severity of headache were noted. RESULTS: In this large series, 54% of patients experienced headaches after vestibular schwannoma removal, and 5% of patients experienced headaches after vestibular nerve section (p < 0.01, chi-square). CONCLUSIONS: Postoperative headache is not a characteristic of retrosigmoid craniectomy in the absence of intradural drilling. Intradural drilling is a probable cause of headache after the retrosigmoid approach. Cranioplasty is not necessary to prevent a high incidence of postoperative headache after retrosigmoid approach.

Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle.

Transketolase (TK) reactions play a crucial role in tumor cell nucleic acid ribose synthesis utilizing glucose carbons, yet, current cancer treatments do not target this central pathway. Experimentally, a dramatic decrease in tumor cell proliferation after the administration of the TK inhibitor oxythiamine (OT) was observed in several in vitro and in vivo tumor models. Here, we demonstrate that pentose cycle (PC) inhibitors, OT and dehydroepiandrosterone (DHEA), efficiently regulate the cell cycle and tumor proliferation processes. Increasing doses of OT or DHEA were administered by daily intraperitoneal injections to Ehrlich's ascites tumor hosting mice for 4 days. The tumor cell number and their cycle phase distribution profile were determined by DNA flow histograms. Tumors showed a dose dependent increase in their G0-G1 cell populations after both OT and DHEA treatment and a simultaneous decrease in cells advancing to the S and G2-M cell cycle phases. This effect of PC inhibitors was significant, OT was more effective than DHEA, both drugs acted synergistically in combination and no signs of direct cell or host toxicity were observed. Direct inhibition of PC reactions causes a G1 cell cycle arrest similar to that of 2-deoxyglucose treatment. However, no interference with cell energy production and cell toxicity is observed. PC inhibitors, specifically ones targeting TK, introduce a new target site for the development of future cancer therapies to inhibit glucose utilizing pathways selectively for nucleic acid production.

Medical treatment of headache after suboccipital acoustic tumor removal.

OBJECTIVES: Suboccipital craniotomy is a frequently used surgical approach for removal of cerebellopontine angle (CPA) tumors. A frequently cited consequence, however, is the high incidence of postoperative headaches. Much has been written regarding prevention of these headaches, but little has been written of their treatment. The authors review their extensive experience in suboccipital tumor removal and the medical management of postoperative headache, highlighting the recent use of a regimen of divalproex sodium and verapamil. STUDY DESIGN: Retrospective chart review. METHODS: The charts of a consecutive series of patients having suboccipital craniotomies for CPA tumors were reviewed. Presence, duration, and severity of headache were noted. Medical treatments and their effectiveness were also noted. RESULTS: Between 1980 and 1997, 228 patients underwent suboccipital craniotomy for removal of CPA tumors. Of these patients, 124 (54.4%) complained of headache. For 62 (27.2%) the headaches persisted for more than a year after surgery. Twenty-nine patients (12.7%) received no relief from any medication. Ten of these patients received a regimen of divalproex sodium and verapamil, with all patients obtaining significant relief. CONCLUSION: Headache is a significant problem with the suboccipital approach for acoustic tumor removal. The majority of patients that complain of headache can be adequately treated with nonsteroidal anti-inflammatory drugs (NSAIDs). If pain is unrelieved by NSAIDs, treatment becomes problematic. The authors' early experience with divalproex sodium/verapamil is encouraging and deserves further investigation as a treatment for these refractory cases.

Inhibition of the oxidative and nonoxidative pentose phosphate pathways by somatostatin: a possible mechanism of antitumor action.

Long-acting somatostatin analogs have recently become supplemental drugs in the treatment of neurofibroma because of their marked tumor growth inhibitory effect. Somatostatin is currently under extended evaluation in other cancers as a possible supplemental drug to the treatment protocols in use. The mode of action is not known. Somatostatin has been shown to cause glucose intolerance by inhibiting glucose-6-phosphate dehydrogenase (G6PD) in fish liver. Recent data generated in our laboratory indicate that it is this pathway and the transketolase reactions of the pentose cycle (PC) which are directly involved in the ribose synthesis process of pancreatic adenocarcinoma cells. In cell culture, somatostatin alone inhibited glucose carbon recycling through the PC by 5.7%, which was increased to 19.8% in combination with oxythiamine, a competitive inhibitor of transketolase. Oxythiamine produced strong apoptosis in in-vitro hosted tumor cells. We hypothesize that somatostatin- and oxythiamine-induced antiproliferative action is mediated by the inhibition of G6PD, transketolase, or both.

Thiamine supplementation to cancer patients: a double edged sword.

The objectives of this review are to (a) explain the mechanism by which thiamine (vitamin B1) promotes nucleic acid ribose synthesis and tumor cell proliferation via the nonoxidative transketolase (TK) pathway; (b) estimate the thiamine intake of cancer patients and (c) provide background information and to develop guidelines for alternative treatments with antithiamine transketolase inhibitors in the clinical setting. Clinical and experimental data demonstrate increased thiamine utilization of human tumors and its interference with experimental chemotherapy. Analysis of RNA ribose indicates that glucose carbons contribute to over 90% of ribose synthesis in cultured cervix und pancreatic carcinoma cells and that ribose is synthesized primarily through the thiamine dependent TK pathway (> 70%). Antithiamine compounds significantly inhibit nucleic acid synthesis and tumor cell proliferation in vitro and in vivo in several tumor models. The medical literature reveals little information regarding the role of the thiamine dependent TK reaction in tumor cell ribose production which is a central process in de novo nucleic acid synthesis and the salvage pathways for purines. Consequently, current thiamine administration protocols oversupply thiamine by 200% to 20,000% of the recommended dietary allowance, because it is considered harmless and needed by cancer patients. The thiamine dependent TK pathway is the central avenue which supplies ribose phosphate for nucleic acids in tumors and excessive thiamine supplementation maybe responsible for failed therapeutic attempts to terminate cancer cell proliferation. Limited administration of thiamine and concomitant treatment with transketolase inhibitors is a more rational approach to treat cancer.

Nonoxidative pentose phosphate pathways and their direct role in ribose synthesis in tumors: is cancer a disease of cellular glucose metabolism?

Pentose phosphate pathways (PPP) are considered important in tumor proliferation processes because of their role in supplying tumor cells with reduced NADP and carbons for intracellular anabolic processes. Direct involvement of PPP in tumor DNA/RNA synthesis is not considered as significant as in lipid and protein syntheses. Currently, PPP activity in tumor cells is measured by lactate production, which shows a moderate activity: about 4% to 7% compared with glycolysis. Recent data generated in our laboratory indicate that PPP are directly involved in ribose synthesis in pancreatic adenocarcinoma cells, through oxidative steps (< 31%) and transketolase reactions (69%). These findings raise serious questions about the adequacy of lactate in measuring PPP activity in tumors. We hypothesize that ribose, not lactate, is the major product of PPP in tumor cells. Control of both oxidative and nonoxidative PPP may be critical in the treatment of cancer. PPP are substantially involved in the proliferation of human tumors, which raises the prospect of new treatment strategies targeting specific biochemical reactions of PPP by hormones related to glucose metabolism, controlling thiamine intake, the cofactor of the nonoxidative transketolase PPP reaction, or treating cancer patients with antithiamine analogues.

Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation.

This study investigates the significance of the glucose-6-phosphate dehydrogenase (G6PD) catalyzed oxidative and the transketolase (TK) catalyzed nonoxidative pentose cycle (PC) reactions in the tumor proliferation process by characterizing tumor growth patterns and synthesis of the RNA ribose moiety in the presence of respective inhibitors of G6PD and TK. Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85% of de novo ribose synthesis in RNA from [1,2-(13)C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85%). Five days of treatment with the TK inhibitor oxythiamine (OT) and the G6PD inhibitor dehydroepiandrosterone-sulfate (0.5 microM each) exerted a 39 and a 23% maximum inhibitory effect on cell proliferation in culture, which was increased to 60% when the two drugs were administered in combination. In vivo testing of 400 mg/kg OT or dehydroepiandrosterone-sulfate in C57BL/6 mice hosting Ehrlich's ascitic tumor cells revealed a 90.4 and a 46% decrease in the final tumor mass after 3 days of treatment. RNA ribose fractional synthesis through the TK reaction using metabolites directly from glycolysis declined by 9.1 and 23.9% after OT or the combined treatment, respectively. Nonoxidative PC reactions play a central regulating role in the carbon-recruiting process toward de novo nucleic acid ribose synthesis and cell proliferation in vitro and in vivo. Therefore, enzymes or substrates regulating the nonoxidative synthesis of ribose could also be the sites to preferentially target tumor cell proliferation by new anticancer drugs.

Dehydroepiandrosterone-sulfate inhibits pancreatic carcinoma cell proliferation in vitro and in vivo.

BACKGROUND: Dehydroepiandrosterone-sulfate (DHEA-S) is a potent inhibitor of glucose-6 phosphate dehydrogenase, the rate limiting enzyme of the hexose monophosphate shunt, a biochemical pathway that provides substrate for DNA synthesis in neoplastic tissue. DHEA-S has been shown to inhibit the growth of neoplasms arriving from human skin, lung, colon, and mammary tissue. This study evaluates the effect of DHEA-S on human pancreatic cancer cell lines in vitro and in vivo. METHODS: In vitro, the human pancreatic adenocarcinoma cell lines MiaPaCa-2, Capan-1, Capan-2, CAV and Panc-1 were treated with concentrations of 1.9 mumol/L to 1000 mumol/L DHEA-S in 1% dimethylsulfoxide (DMSO) for 5 consecutive days. Cell proliferation was determined by a nonradioactive cell proliferation assay and compared with DMSO treated controls. In vivo testing was performed by inoculating two cell lines, MiaPaCa-2 and Panc-I, into the flank of 40 male nude athymic mice in four study groups. After 1 week of growth, 667 mg/kg DHEA-S in 1% DMSO or 0.2 ml 1% DMSO alone in the control group was administered by daily intraperitoneal injection. Body weight and tumor size was recorded weekly, and tumor weight was measured after 3 weeks of treatment. RESULTS: In vitro cell proliferation was decreased in the five cell lines by 36% to 62% of controls (p < 0.001) at 500 mumol/L DHEA-S. In vivo, after 2 weeks, tumor size was only 76% (p < 0.008) and 67% (p < 0.005) of the controls. After 3 weeks of treatment, tumor size was 73% (p < 0.001) and 53% (p < 0.001) of controls, and tumor weight was decreased by 73% in MiaPaCa-2 (p < 0.001) and 66% in Panc-1 (p < 0.001). Radioimmunoassay measurements of DHEA-S and testosterone from DHEA-S treated mouse plasma showed a significant increase in circulating levels of these hormones. CONCLUSIONS: DHEA-S achieves high serum levels after intraperitoneal injection without elevation of serum testosterone levels and produces no significant toxicity. Treatment with DHEA-S results in a significant reduction of proliferation of human pancreatic cancer cells in culture and when grown as subcutaneous tumors in athymic nude mice.

Local resection of tumors of the ampulla of Vater.

Local resection of an ampullary tumor with reimplantation of the pancreatic and bile ducts was first described by William S. Halsted in 1899. Technical hazard and unsuitability in malignant ampullary tumors have unfortunately led to a disregard for this operation that is unwarranted. Radical pancreaticoduodenectomy is now the most common method of resecting benign and malignant ampullary tumors. Experience was gained with two high-risk patients with benign adenomatous polyps obstructing the ampulla of Vater. Their medical unsuitability for radical pancreaticoduodenectomy led us to revive the procedure of wide local excision of these tumors with reimplantation of the pancreatic and bile ducts. Operative time and blood loss were substantially less than radical resection and postoperative recoveries were relatively uncomplicated. Radical resection of benign ampullary tumors may be appropriate for good-risk patients in whom the risk of local recurrence outweighs the operative risk. We suggest that local resection of benign ampullary tumors is the procedure of choice in high-risk patients and that it be considered in palliation of limited local malignancies of the ampulla in high-risk patients.