The present consensus is that both neuronal and vascular components are relevant in migraine and most probably interrelated. The neuronal structures involved are the cerebral cortex, the brainstem (periaqueductal gray matter, aminergic nuclei) and the peripheral as well as the central components of the trigeminovascular system. The sequence of activation and the relative role of these structures are still controversial.
There is no absolute cure for migraine since its pathophysiology has yet to be fully understood. There are two ways to approach the treatment of migraine headache with drugs: prevent the attacks, or relieve the symptoms during the attacks. Prevention involves the use of medications and behavioral changes. Drugs originally developed for epilepsy, depression, or high blood pressure to prevent future attacks have been shown to be extremely effective in treating migraine. With proper combination of drugs for prevention and treatment of migraine attacks most individuals can overcome much of the discomfort from this debilitating disorder.
Behaviorally, stress management strategies, such as exercise, relaxation techniques, biofeedback mechanisms, and other therapies designed to limit daily discomfort, may reduce the number and severity of migraine attacks. Making a log of personal triggers of migraine can also provide useful information for trigger-avoiding lifestyle changes, including dietary considerations, eating regularly scheduled meals with adequate hydration, stopping certain medications, and establishing a consistent sleep schedule. Hormone therapy may help some women whose migraines seem to be linked to their menstrual cycle. A weight loss program is recommended for obese individuals with migraine.
Prevention of migraines
If a patient has frequent, severely debilitating migraine headaches, prophylactic treatment may help. The goals of preventive therapy are to reduce the frequency, painfulness, and/or duration of migraines, and to increase the effectiveness of abortive therapy. Another reason to pursue these goals is to avoid medication overuse headache (MOH), otherwise known as rebound headache. This is a common problem and can result in chronic daily headache
Beta-blockers (propanolol), tricyclic antidepressants (amitriptyline), calcium channel blockers (verapamil, diltiazem, flunarizine) and anticonvulsants (valproic acid, topiramate) Valproate for the prophylaxis of episodic migraine in adults, 2013)] ["Topiramate for the prophylaxis of episodic migraine in adults, 2013" Linde M, Mulleners WM, Chronicle EP, McCrory DC. Cochrane Database Syst Rev. 2013 Jun 24; (http://www.ncbi.nlm.nih.gov/pubmed/23797676)] have the best evidence of efficacy in migraine prophylaxis, but none of these drugs are adequately effective against acute migraine attacks. ["Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial, 2010". Kenneth A Holroyd, Constance K Cottrell, Francis J O’Donnell, Gary E Cordingley, Jana B Drew, Bruce W Carlson, Lina Himawan. BMJ. 2010; 341: c4871 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947621/?tool=pmcentrez)]
There are three main aspects of treatment: trigger avoidance, acute symptomatic control, and pharmacological prevention. Traditionally, migraine treatment is subdivided into acute strategies to interrupt attacks and preventive ones to prevent attack occurrence.
In many patients with infrequent attacks, treatment at the time of an attack may suffice. Once the patient’s preference and eventual contraindications have been taken into consideration, several key features for the successful use of acute anti-migraine drugs should be followed:
- the drug should be taken as soon as the patient recognizes the aura or the onset of the acute migraine attack.
- the dose of drug should be high enough to be fully effective in migraine, also keeping in consideration the possible variability of the patient to drug response. (this is particularly important for NSAIDs, which need high dosing, usually up to 600- 1200 mg for ibuprofen)
- anti-emetic or pro-kinetic drugs (eg, domperidone, metoclopramide) administered at the same time as the anti-migraine drug is likely to facilitate the absorption of the primary drug and thus improve speed of action and efficacy of the latter.
- overuse of any acute anti-migraine drug may induce chronification and medication overuse headache (MOH); their intake should thus be restricted; to prevent MOH and prevent the onset of acute migraines, it is preferrable to avoid frequent administration of the same drug/drugs during subsequent attacks.
- the patient should be informed (and keep in mind) that severity and response to treatment vary between attacks; patients may therefore require a prescription for several drugs of increasing potency to manage their attacks, allowing for a combined “stratified” (choice of drug according to severity of attack) and “step-wise within attack” (drugs of increasing potency during the attack) strategy. ["Prophylactic treatment of migraine; the patient's view, a qualitative study". Frans Dekker, Arie Knuistingh Neven, Boukje Andriesse, David Kernick, Ria Reis, Michel D Ferrari, and Willem JJ Assendelft. Published online 2012 March 9. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359207/)] ["Migraine - established concepts and new developments, 2013" Speck V, Maihöfner C. Fortschr Neurol Psychiatr. 2013 Jun;81(6):308-23. doi: 10.1055/s-0033-1335247. Epub 2013 Jun 17. (http://www.ncbi.nlm.nih.gov/pubmed/23775164)]
A number of analgesics are effective for treating migraines including:
Non-steroidal anti-inflammatory drugs (NSAIDs): Ibuprofen provides effective pain relief in about half of people. Naproxen can abort about one third of migraine attacks, which was 5% less than the benefit of sumatriptan. A 1000 mg dose of aspirin could relieve moderate to severe migraine pain, with similar effectiveness to sumatriptan. NSAIDs have also shown minor tendency of provoking MOH compared to paracetamol and other analgesics.
Paracetamol/acetaminophen, either alone or in combination with metoclopramide, is effective for migraines. ["Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults, 2012" Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society S. Holland, PhD, S.D. Silberstein, MD, FACP, F. Freitag, DO, D.W. Dodick, MD, C. Argoff, MD, and E. Ashman, MD. Neurology. 2012 April 24; 78(17): 1346–1353 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335449/)]
Cox-2 inhibitors, (celecoxib) eventhough represent a much more expensive type of drug, may have a greater efficiency than ibuprofen in addition to the advantage of having better gastric tolerance.
Simple analgesics combined with caffeine may help. Even by itself, caffeine can be useful during an attack, despite the fact that migraine sufferers are generally advised to limit their caffeine intake.
["Headache: insight, understanding, treatment and patient management, 2013" Diener HC.Department of Neurology and Headache Center, University Hospital Essen, Essen, Germany. Int J Clin Pract Suppl. 2013 Jan;(178):33-6. (http://www.ncbi.nlm.nih.gov/pubmed/23163546)]
["Ibuprofen with or without an antiemetic for acute migraine headaches in adults, 2013" Rabbie R, Derry S, Moore RA. Cochrane Database Syst Rev. 2013 Apr 30; (http://www.ncbi.nlm.nih.gov/pubmed/23633348)]
The 5-HT1D/1B agonists (triptans) are used almost exclusively in migraine headache. Two primary hypotheses have been proposed to explain the actions of these drugs. First, the triptans (as the ergot alkaloids and some antidepressants) may activate 5-HT1D/1B receptors on presynaptic trigeminal nerve endings to inhibit the release of vasodilating peptides. Second, the vasoconstrictor actions of direct 5-HT agonists (the triptans and ergot) may prevent vasodilation and stretching of the pain endings. It is possible that both mechanisms contribute in the case of some drugs.
Sumatriptan and its congeners are currently first-line therapy for acute severe migraine attacks in most patients, since they are highly effective for both pain and nausea in up to 75% of patients. ["Sumatriptan : treatment across the full spectrum of migraine, 2013" Silberstein SD, Marcus DA. Thomas Jefferson University, Jefferson Headache Center; Jun 21, 2013. (http://www.ncbi.nlm.nih.gov/pubmed/23786565)]
The different forms available include oral, injection, nasal spray, and oral dissolving tablets. They are not addictive, but may cause medication overuse headaches (MOH) if used more than 10 days per month. ["Medication overuse headaches, 2013". Abrams BM. Med Clin North Am. 2013 Mar.(http://www.ncbi.nlm.nih.gov/pubmed/23419631)] Most adverse effects are mild and include altered sensations (tingling, warmth, etc), dizziness, muscle weakness, neck pain, and for parenteral sumatriptan, injection site reactions. Chest discomfort occurs in 1-5% of patients, and chest pain has been reported, probably because of the ability of these drugs to cause coronary vasospasm. They are therefore contraindicated in patients with coronary artery disease and in patients with angina. Another disadvantage is the fact that their duration of effect (especially that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan) is often shorter than the duration of the headache. As a result, several doses may be required during a prolonged migraine attack, but their adverse effects limit the maximum safe daily dosage. In addition, these drugs are extremely expensive.
The efficacy of triptan 5-HT1 agonists in migraine is equal to or greater than that of other acute drug treatments such as parenteral, oral, or rectal ergot alkaloids.
["Emerging Drugs for Migraine Prophylaxis and Treatment, 2006" Marcelo E. Bigal, Abouch V.Krymchantowski. MedGenMed. 2006; 8(2): 31. Published online 2006 May 4. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785190/?tool=pmcentrez)]
Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects grain¾especially rye¾under damp growing or storage conditions. This fungus synthesizes histamine, acetylcholine, tyramine, and other biologically active products in addition to a score or more of unique ergot alkaloids. These alkaloids affect a-adrenoceptors, dopamine receptors, 5-HT receptors, and perhaps other receptor types. Similar alkaloids are produced by fungi parasitic to a number of other grass-like plants.
The accidental ingestion of ergot alkaloids in contaminated grain can be traced back more than 2000 years from descriptions of epidemics of ergot poisoning (ergotism). The most dramatic effects of poisoning are dementia with florid hallucinations; prolonged vasospasm, which may result in gangrene; and stimulation of uterine smooth muscle, which in pregnancy may result in abortion. In medieval times, ergot poisoning was called St. Anthony's fire after the saint whose help was sought in relieving the burning pain.
The ergot alkaloids act on several types of receptors. Their effects include agonist, partial agonist and antagonist actions at a-adrenoceptors and serotonin receptors (especially 5-HT1A and 5-HT1D; less for 5-HT1C, 5-HT2, and 5-HT3); and agonist or partial agonist actions at central nervous system dopamine receptors. Furthermore, some members of the ergot family have a high affinity for presynaptic receptors, whereas others are more selective for postsynaptic receptors. Structural variations increase the selectivity of certain members of the family for specific receptor types.
The action of ergot alkaloids on vascular smooth muscle is drug-, species-, and vessel-dependent, so few generalizations are possible. Ergotamine and related compounds potently constrict most human blood vessels in a predictable, and prolonged manner.This response is partially blocked by conventional a-blocking agents. However, ergotamine's effect is also associated with "epinephrine reversal" and with blockade of the response to other a agonists. This dual effect represents partial agonist action. Because ergotamine dissociates very slowly from the a receptor, it produces very long-lasting agonist and antagonist effects at this receptor. There is little or no effect at b adrenoceptors.
While much of the vasoconstriction elicited by ergot alkaloids can be ascribed to partial agonist effects at a adrenoceptors, some may be the result of effects at 5-HT receptors. The remarkably specific antimigraine action of the ergot derivatives was originally thought to be related to their actions on vascular serotonin receptors. Current hypotheses, however, emphasize their action on prejunctional neuronal 5-HT receptors.
Ergot derivatives are highly specific for migraine pain; they are not analgesic for any other condition. Therapy with ergotamine can be quite effective when given during the prodrome of an attack; it becomes progressively less effective if delayed, even though recent studies have shown that ergots can be useful for relieving the symptoms even if used hours after the attack. ["Orally Inhaled Dihydroergotamine for Acute Treatment of Migraine: Efficacy of Early and Late Treatments, 2011" Stewart J. Tepper, Shashidhar H. Kori, Peter J. Goadsby, Paul K. Winner, Min H. Wang, Stephen D. Silberstein, F. Michael Cutrer. Mayo Clin Proc. 2011 October;Correction in: Mayo Clin Proc. 2011 December; (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184024/?tool=pmcentrez)]
Ergotamine tartrate is available for oral, sublingual, rectal suppository, and inhaler use. It is often combined with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate) to facilitate absorption of the ergot alkaloid.
The vasoconstriction induced by ergotamine is long-lasting and cumulative when the drug is taken repeatedly, as in a severe migraine attack. Therefore, patients must be carefully informed that no more than 6 mg of the oral preparation may be taken for each attack and no more than 10 mg per week.
After overdosage with ergotamine and similar agents, vasospasm is severe and prolonged. This vasospasm is not easily reversed by a antagonists, serotonin antagonists, or combinations of both.
Ergotamine is typical of the ergot alkaloids that have a strong vasoconstrictor spectrum of action.
The advantages of ergotamines are their low cost, long duration of action and long clinical experience. The major disadvantages, however, are the lack of evidence regarding their effective doses, their potent and sustained generalized vasoconstrictor effect, and the fact that they can induce drug overuse headache (MOH) very fast and in quite low doses, especially when combined to caffeine.
Caffeine usually increases absorbtion of all ergot derivatives, but patients should be advised of the fact that excessive intake of caffeine or other metilxantines can cause alone mild headaches and MOH, quite quickly in time and at relatively low doses.
Parenteral dihydroergotamine (DHE) is today considered the most effective ergot derivative in migraine treatment.
["Emerging Drugs for Migraine Prophylaxis and Treatment, 2006" Marcelo E. Bigal, Abouch V.Krymchantowski. MedGenMed. 2006; 8(2): 31. Published online 2006 May 4.
A single dose of intravenous dexamethasone, when added to standard treatment of a migraine attack, is associated with a 26% decrease in headache recurrence in the following 72 hours.
Antiemetics by mouth may help relieve symptoms of nausea and help prevent vomiting, which can diminish the effectiveness of orally taken analgesics. In addition, some antiemetics, such as metoclopramide, are prokinetics and help gastric emptying, which is often impaired during episodes of migraine. The earlier these drugs are taken in the attack, the better their effect.
Acupuncture can be effective in the treatment of migraines. There is consistent evidence that acupuncture provides additional benefit to treatment of acute migraine attacks only or to routine care. There is no evidence for an effect of ’true’ acupuncture over sham interventions, though this is difficult to interpret, as exact point location could be of limited importance. Available studies suggest that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment, and has fewer adverse effects. Acupuncture should be considered a treatment option for patients willing to undergo this treatment.
In some patients chiropractic manipulation, physiotherapy, massage and relaxation might be as effective as propranolol or topiramate in the prevention of migraine headaches. There is some tentative evidence of benefit for: magnesium, coenzyme Q(10), riboflavin, vitamin B(12),fever-few, and butterbur. There have been reported cases of herbal medicine being useful in migraine treatment. ["A Case of Migraine Without Aura That Was Successfully Treated With an Herbal Medicine, 2013" Takaku S, Osono E, Kuribayashi H, Takaku C, Hirama N, Takahashi H.; J Altern Complement Med. 2013 Jun 12 (http://www.ncbi.nlm.nih.gov/pubmed/23758551)]
Devices and surgery
Medical devices, such as biofeedback and neurostimulators, have some advantages in the migraine treatment, mainly when common antimigraine medication is contraindicated or in case of medication over use. Biofeedback helps people to be conscious of some physiologic parameters to control them and try to relax and may be efficient for migraine treatment. Neurostimulation uses implantable neurostimulators similar to pacemakers for the treatment of intractable chronic migraines with encouraging results for severe cases. Migraine surgery which involves decompression of certain nerves around the head and neck may be an option in certain people who do not improve with medications.
Long term prognosis in people with migraines is variable. Most people with migraines have periods of lost productivity due to their disease however typically the condition is fairly benign and is not associated with an increased risk of death.
There are four main patterns to the disease:
- symptoms can resolve completely
- symptoms can continue but become gradually less with time
- symptoms may continue at the same frequency and severity
- attacks may become worse and more frequent
Migraines with aura appears to be a risk factor for ischemic stroke while migraines without aura do not appear to be a factor. Young adult, being female, using hormonal contraception, and smoking further increases this risk. There also appears to be an association with cervical artery dissection.
Researchers now believe that migraine is the result of fundamental neurological abnormalities caused by genetic mutations at work in the brain. New models are aiding scientists in studying the basic science involved in the biological cascade, genetic components and mechanisms of migraine. Understanding the causes of migraine as well as the events that effect them will give researchers the opportunity to develop and test drugs that could be more targeted to preventing or interrupting attacks entirely. Therapies currently being tested for their effectiveness in treating migraine include magnesium, coenzyme Q10, vitamin B12, riboflavin, fever-few, and butterbur.
In 2010, a team of researchers found a common mutation in the gene for a certain potassium ion channel. Potassium channels are important for keeping a nerve cell at rest and mutations in them can lead to overactive cells that respond to much lower levels of pain.
Aquaporins, a potential therapeutic target for migraine with aura
The major symptom of migraine, the headache pain, is mediated by neuronal activity along the trigeminovascular pathway. Activation and sensitization of primary afferent neurons (PANs) in the trigeminal ganglion (TG) is the first step in driving this nociceptive pathway. It has been observed that AQ-1 is heavily expressed in a population of small diameter primary sensory neurons of TG, and co-localized with a marker of peptidergic nociceptors, substance P . In addition to the dorsal root ganglion, the expression of TRPV1 in rat TG was detected recently. Furthermore, the co-localization of 5-HT1B receptors with substance P was also identified in the human TG.
Based on these observations, it is tempting to speculate that AQP-1 might be co-expressed with TRPV1 receptors, substance P, or 5-HT1B receptors in the neuronal cells and small diameter afferent nerve fibers of trigeminal ganglion and their connecting structures, thus involved in the pathophysiology of migraine. This hypothesis is highly supported by recent results that show how AQP-1 is co-expressed with calcitonin gene related peptide (CGRP), a nociceptive marker, in TG neurons. Recent data support the idea that AQP-1 upregulation in TG might be disease specific; in fact AQP-1 deficiency can significantly decrease the firing frequency of upper cervical dorsal horn neurons.
["Aquaporin 1, a potential therapeutic target for migraine with aura, 2010" Guang-Yin Xu, Fen Wang, Xinghong Jiang, Jin Tao. Mol Pain. 2010; 6: 68. Published online 2010 October 25. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974658/)]
OnabotulinumtoxinA and chronic migraine prophylaxis
OnabotulinumtoxinA has recently been approved by regulatory agencies in the UK and United States for treatment of chronic migraine. As such, onabotulinumtoxinA is the only prophylactic therapy specifically approved for chronic migraine. Most headache clinicians would agree that acute episodic migraine and chronic migraine differ in their pathophysiology, etiology, diagnosis, and response to pharmacological as well as nonpharmacological therapies.
Neurotoxins obtained from Clostridium botulinum are potent inhibitors of neurotransmission between neurons and muscle, and signaling between neurons. Of the 7 botulinum neurotoxin serotypes, botulinum neurotoxin type A (onabotulinumtoxinA) has been the most thoroughly investigated in preclinical and clinical studies.
Based on preclinical studies, onabotulinumtoxinA is known to inhibit the release of excitatory neurotransmitters from both motor and sensory neurons by preventing vesicle fusion to the cell membrane. In addition to the well-documented myorelaxant effects of this neurotoxin, onabotulinumtoxinA can exert a direct analgesic effect that likely involves inhibition of primary and secondary nociceptive neurons. The inhibitory effects of onabotulinumtoxinA are also likely to involve suppressing the activity of myogenic trigger points and decreasing the persistent nociceptive barrage that promotes and maintains central sensitization.
Traditionally, onabotulinumtoxinA has been used clinically for the treatment of neuromuscular disorders including focal dystonias and relief of pain associated with cervical and oromandibular dystonias. At the cellular level, it is well established that onabotulinumtoxinA blocks the presynaptic release of the neurotransmitter acetylcholine from motor neurons at neuromuscular junctions, and thus can suppress overactivity of specific muscles. Interestingly, the sites of onabotulinumtoxinA injections are topographically similar to the myogenic trigger points associated with referred pain locations in the head, neck, and shoulders. Of clinical significance, muscle pain and tenderness, especially in the shoulders and neck, are physiological symptoms associated with migraine and are more commonly observed as migraine chronifies. Sustained signaling from tonic contraction of craniofacial muscles is sufficient to induce prolonged sensitization of nociceptive neurons. Thus, onabotulinumtoxinA may suppress the activity of myogenic trigger points and decrease the persistent nociceptive barrage that promotes and helps maintain central sensitization.
While the exact mechanism by which onabotulinumtoxinA functions to reduce the number and severity of headaches in chronic migraineurs is not yet known, the neurotoxin is likely to function by multiple mechanisms involving inhibition of neurotransmitter release from motor neurons and from sensory nociceptive neurons associated with muscle fibers. The blocking of acetylcholine release from motor neurons would cause relaxation of overactive muscle fibers and consequently result in a decrease in secretion of inflammatory mediators responsible for sensitization of primary nociceptive neurons. OnabotulinumtoxinA could also function by directly inhibiting the release of proinflammatory mediators from the free endings of peripheral primary nociceptors. Another potential target of onabotulinumtoxinA is directly blocking activity of the trigeminal nerves that provide sensory innervation to the head and face. Results from animal studies have provided evidence that onabotulinumtoxinA can block the stimulated release of CGRP, glutamate, and substance P from trigeminal neurons and inhibit activation of second-order neurons within the spinal cord responsible for transmission of pain signals.In particular, data from inflammatory pain models clearly demonstrate an antinociceptive effect of onabotulinumtoxinA.
Based on these findings, one might assume that the primary therapeutic benefit of using onabotulinumtoxinA for chronic migraine is to repress secretion of inflammatory mediators from trigeminal neurons that mediate the development of peripheral and central sensitization.
["Insights Into the Mechanism of OnabotulinumtoxinA in Chronic Migraine, 2012" Paul L. Durham, PhD and Roger Cady, MD. BMC Fam Pract. 2012; 13: 13. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306767/?tool=pmcentrez)]
Nicotinic acid and Respiratory chain
One novel, but not really new treatment option, is the administration of niacin (nicotinic acid) through intravenous and/or oral routes. Nicotinic acid, nicotinamid, and tryptophan (via quinoline acid) are co-factors for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD converts to NADP by phosphorylation in the presence of the enzyme NAD+ kinase. NADP and NAD are coenzyme for many dehydrogenases, participating in many hydrogen transfer processes. NAD is important in catabolism of fat, carbohydrate, protein and alcohol as well as cell signaling and DNA repair and NADP mostly in anabolism reaction such as fatty acid and cholesterol synthesis. High energy requirements (brain) or high turnover rate (gut, skin) organs are usually the most susceptible to their deficiency.
NAD and NADP are necessary for the electron transport chain (also known as respiratory chain), responsible of sintetizing ATP and water from oxygen. Eukaryotic cells have mitochondria, which produce ATP from products of the citric acid cycle, fatty acid oxidation, and amino acid oxidation. At the mitochondrial inner membrane, electrons from NADH and succinate pass through the electron transport chain to oxygen, which is reduced to water. The electron transport chain comprises an enzymatic series of electron donors and acceptors. Each electron donor passes electrons to a more electronegative acceptor, which in turn donates these electrons to another acceptor, a process that continues down the series until electrons are passed to oxygen, the most electronegative and terminal electron acceptor in the chain. Passage of electrons between donor and acceptor releases energy, which is used to generate a proton gradient across the mitochondrial membrane by actively “pumping” protons into the intermembrane space, producing a thermodynamic state that has the potential to do work. Complex I (NADH coenzyme Q reductase) accepts electrons from the Krebs cycle electron carrier nicotinamide adenine dinucleotide (NADH), and passes them to coenzyme Q (ubiquinone), which also receives electrons from complex II (succinate dehydrogenase). UQ passes electrons to complex III (cytochrome bc1 complex), which passes them to cytochrome c (cyt c). Cyt c passes electrons to Complex IV (cytochrome c oxidase), which uses the electrons and hydrogen ions to reduce molecular oxygen to water.
Niacin is a well-known over-the-counter (OTC) supplement primarily used for its ability to favorably influence cholesterol levels. Recently, there have been anecdotal reports demonstrating the effectiveness of niacin for aborting acute migraine attacks, and for preventing migraine headaches. Reasons for niacin's effectiveness can only be considered hypothetical, and require clarification from future randomized controlled trials. In acute migraine headaches some of the symptoms arise from activation of the trigeminovascular complex. Activation of this complex leads to intracranial vasoconstriction causing the migraine aura, followed by headache due to vasodilation of the extracranial vessels and activation of the perivascular nociceptive nerves. When taken intravenously or orally, niacin causes cutaneous flushing that might abort the acute symptoms of migraine by vasodilating the intracranial vessels, thus preventing the subsequent vasoconstriction of the extracranial vessels. There is evidence that niacin is an effective peripheral vasodilator, but its ability to influence central mechanisms (i.e., cerebral blood flow and cranial hemodynamics) involved in migraine headaches have not been well studied. Niacin causes peripheral vasodilation and cutaneous flushing by inducing the production of prostaglandin D2 (PGD2) in the skin, leading to a marked increase of its metabolite, 9α, 11β-PGF2, in the plasma.
Some reports demonstrated prophylactic benefits of niacin when administered orally every day. It is now recognized that a deficit of mitochondrial energy metabolism (i.e., impaired mitochondrial phosphorylation potential) plays a role in the pathogenesis of chronic migraine headaches. Niacin maintains adequate mitochondrial energy metabolism by increasing substrate availability to complex I, and this is how it might function as an effective prophylactic agent for migraine prevention. Two other nutritional agents (riboflavin and coenzyme Q10) augment complex I of the mitochondrial respiratory chain, and have been subjected to clinical trials demonstrating their effectiveness for the prevention of migraine headaches. A deficit of mitochondrial energy metabolism may play a role in the pathogenesis of migraine. Since niacin improves mitochondrial energy metabolism by increasing substrate availability to complex I, it might also be an effective agent for migraine prevention.
["The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature, 2005" Jonathan Prousky and Dugald Seely; Nutrition Journal, 2005, 4,3;(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC548511/#!po=82.1429)]
Mitochondrial metabolism deficits
Patients with deficits of mitochondrial metabolism are not only more often subject to headaches and general CNS disorders, but present also a greater susceptibility to drugs and toxins that inhibit the electron transport chain. Statins, for example, very common drugs used to improve serum cholesterol levels, include among their adverse effects (AEs) both muscle and non-muscle collateral effects.
The demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 (CYP)3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many non-muscle statin AEs.
Statins inhibit the enzyme HMG-CoA reductase, at a stage early in the mevalonate pathway. This pathway generates a range of other products in addition to cholesterol, such as coenzyme Q10, heme-A, and isoprenylated proteins, which have pivotal roles in cell biology and human physiology and potential relevance to benefits as well as risks of statins. Additionally, cholesterol itself is not merely a final product (with its own range of vital roles) but also an intermediate to a suite of additional products of fundamental relevance to health and well-being, such as sex steroids, corticosteroids, bile acids and vitamin D, several of which have been shown to be affected with statin administration. The biochemical influences of statins extend well beyond the lipid profile and its constituents (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), and even beyond the direct products of the mevalonate pathway, to include a wide swath of products and functions modified through these as well as nonmevalonate effects of statins, ranging from nitric oxide and inflammatory markers to polyunsaturated fatty acids,among many others.
Although the HMG-CoA reductase inhibitors are reported to be associated with increased occurrence of headache, the mechanism is poorly understood. Migraine headaches may be triggered in previously asymptomatic individuals by unique combinations of trigger factors. There has been one report of migraine headaches triggered by the combined exposure to pravastatin and reduced barometric pressure in an airline captain, but the association mechanism has not yet been fully comprehended.
["Altitude-induced migraine headache secondary to pravastatin: case report, 2008" Ramsey CS, Snyder QC. USAF School of Aerospace Medicine, Brooks AFB, TX, USA. Aviat Space Environ Med. 1998 Jun;69(6):603-6. (http://www.ncbi.nlm.nih.gov/pubmed/9641408)]
["Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism, 2008" Beatrice A. Golomb, M.D., Ph.D. and Marcella A. Evans, B.S. Am j cardiovasc drugs, 2008 (8)6; 373-418 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849981/)]