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- Title
MIGRAINE TREATMENT.
- Authors
Millson, David S.; Tepper, Stewart J.
- Abstract
Wenzel R, Dortch M, Cady R, Loland JH, Diamond S. Migraine headache misconceptions: barriers to effective care.Pharmacotherapy. 2004;24:638-648.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-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. TepperThis 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. TepperI 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, anα-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. The primary efficacy variable was the headache response rate, ie, headache score improvement from moderate/severe at baseline to mild/none at 2 hour. Of 45 enrolled patients, 44 patients (20:24[M:F]; mean age± SD= 40± 9 years) completed the study. Response rates were 69% for LY293558 (P= .017 vs. placebo), 86% for sumatriptan (P<.01 vs. placebo), and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P<.01 for all comparisons) on all other measures of improvement in pain and migraine-associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n= 2; 1 mild, 1 severe). Fifty-three percent of patients who took sumatriptan (n= 8; 7 mild, 1 moderate) and 31% of those who received placebo reported AEs (n= 5; 4 mild, 1 severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.Comment: This is a seminal proof of concept study for the first AMPA/KA antagonist demonstrating potential efficacy approaching that of subcutaneous (SC) sumatriptan in acute migraine. I would be intrigued to know if the adverse events (AEs) relating to SC sumatriptan were perceived by patients with prior triptan experience (difficult to avoid in the United States!) and may have allowed them to identify treatment. The important next step must be to dose range the new agent and to identify either a rapidly acting oral formulation or parenteral route (eg, intranasal, transdermal). This small scale efficacy trial, if confirmed for a nonvasoactive AMPA/KA antagonist, may pave the way for an alternative to the triptans.—David S. Millson
- Subjects
HEADACHE; CLUSTER headache; PAIN management; SYMPTOMS; THERAPEUTICS; TENSION headache; WORK environment
- Publication
Headache: The Journal of Head & Face Pain, 2004, Vol 44, Issue 10, p1059
- ISSN
0017-8748
- Publication type
Abstract
- DOI
10.1111/j.1526-4610.2004.4207_1.x