Prevention of migraines
||The neutrality of this article is disputed. (September 2012)|
Preventive (also called prophylactic) treatment of migraines can be an important component of migraine management. Such treatments can take many forms, including everything from surgery, taking certain drugs or nutritional supplements, to lifestyle alterations such as increased exercise and avoidance of migraine triggers.
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, which is a common problem among migraineurs. This is believed to occur in part due to overuse of pain medications, and can result in chronic daily headache.
- 1 Surgery
- 2 Acupuncture
- 3 Behavioral treatments
- 4 Gluten-free diet
- 5 Herbal and nutritional supplements
- 6 Manual therapy
- 7 Medical devices
- 8 Prescription drugs
- 9 Surgical treatments
- 10 Trigger avoidance
- 11 References
There have been major pharmacological advances for the treatment of migraine headaches, yet patients must still endure symptoms until the medications take effect. Furthermore, often they still experience a poor quality of life despite an aggressive regimen of pharmacotherapy. Migraine surgery techniques have proven most effective in selected patients, often resulting in permanent migraine prevention. The most effective appear to be those involving the surgical cauterization of the superficial blood vessels of the scalp (the terminal branches of the external carotid artery), and the removal of muscles in areas known as "trigger sites".
Cochrane reviews have found that acupuncture is effective in the treatment of migraines. The use of "true" acupuncture is not more efficient than sham acupuncture, however, both "true" and sham acupuncture appear to be more effective than routine care in the treatment of migraines, with fewer adverse effects than prophylactic drug treatment.
Sleep is often a good solution if a migraine is not so severe as to prevent it, as when a person awakes the symptoms will have most likely subsided.
In many cases where a migraine follows a particular cycle, attempting to interrupt the cycle may prolong the symptoms. Letting a headache "run its course" by not using painkillers can sometimes decrease the length of an episode. This is especially true of cases where vomiting is common, as often the headache will subside immediately after vomiting. Curbing the pain may delay vomiting, and prolong the headache.
Some individuals have a condition called celiac disease (or "gluten intolerance") that results in the body incorrectly processing gluten. Studies have suggested that 4%  of migraine sufferers have celiac disease, and for those who do, decreasing gluten intake may significantly reduce migraine frequency. Celiac disease and gluten sensitivity may be an underlying cause of migraines in some patients, and a gluten-free diet has been demonstrated to reduce, if not completely eliminate, migraines in these individuals. A study of 10 patients with a long history of chronic headaches that had recently worsened or were resistant to treatment found that all 10 patients were sensitive to gluten. MRI scans determined that each had inflammation in their central nervous systems caused by gluten-sensitivity. Seven out of nine of these patients that went on a gluten-free diet stopped having headaches completely. Another study showed that migraneurs were 10 times more likely than the general population to have celiac disease, and that for migraneurs with celiac disease, a gluten-free diet improved blood-flow to the brain and either eliminated migraines or reduced migraine frequency, duration, and intensity.
Herbal and nutritional supplements
Native butterbur contains some carcinogenic compounds, but a purified version, Petadolex, does not. A systematic review of two trials totalling 293 patients (60 and 233 patients) showed "moderate evidence of effectiveness ... for a higher than the recommended dose of the proprietary Petasites root extract Petadolex in the prophylaxis of migraine."
Cannabis was a standard treatment for migraines from 1874 to 1942. It has been reported to help people through an attack by relieving the nausea and dulling the head pain, as well as possibly preventing the headache completely when used as soon as possible after the onset of pre-migraine symptoms, such as aura.
The plant feverfew (Tanacetum parthenium) is a traditional herbal remedy believed to reduce the frequency of migraine attacks. A number of clinical trials have been carried out to test this claim, but a 2004 review article concluded that the results have been contradictory and inconclusive.
A systematic review stated that chiropractic manipulation, physiotherapy, massage and relaxation might be as effective as propranolol or topiramate in the prevention of migraine headaches; however, the research had some problems with methodology.
A transcutaneous electrical nerve stimulation device called Cefaly was approved by the Food and Drug Administration in the United States on March 11, 2014 for the prevention of migraines; this was the first medical device to get FDA approval for this purpose.
Neurostimulation initially used implantable neurostimulators similar to pacemakers for the treatment of intractable chronic migraines with encouraging good results. But the needed surgery with implantable neurostimulators is limiting the indication to severe cases.
At the 49th Annual meeting of the American Headache Society in June 2006, scientists from Ohio State University Medical Center  presented medical research on 47 candidates that demonstrated that TMS — a medically non-invasive technology for treating depression, obsessive compulsive disorder and tinnitus, among other ailments — helped to prevent and even reduce the severity of migraines among its patients. This treatment essentially disrupts the aura phase of migraines before patients develop full-blown migraines.
In about 74% of the migraine headaches, TMS was found to eliminate or reduce nausea and sensitivity to noise and light. Their research suggests that there is a strong neurological component to migraines. A larger study will be conducted soon to better assess TMS's complete effectiveness.
In June 2008, a hand-held apparatus designed to apply TMS as a preemptive therapy to avert a migraine attack at the onset of the aura phase was introduced in California.
Biofeedback has been used successfully by some to control migraine symptoms through training and practice.Biofeedback helps patient to be conscious of some physiologic parameters to control them and try to relax. This method is considered to be efficient for migraine prevention. A recent clinical trial has demonstrated that simple use of biofeedback as a relaxation technique has similar efficacy for migraine treatment to sophisticated sessions in clinics.
Hyperbaric oxygen therapy has been used successfully in treating migraines. This suggests that sufferers might be treated during an attack with a hyperbaric chamber of some sort, such as a Gamow bag (as is done in the treatment of "The Bends" and altitude sickness).
A 2006 review article by S. Modi and D. Lowder offers some general guidelines on when a physician should consider prescribing drugs for migraine prevention:
Following appropriate management of acute migraine, patients should be evaluated for initiation of preventive therapy. Factors that should prompt consideration of preventive therapy include the occurrence of two or more migraines per month with disability lasting three or more days per month; failure of, contraindication for, or adverse events from acute treatments; use of abortive medication more than twice per week; and uncommon migraine conditions (e.g., hemiplegic migraine, migraine with prolonged aura, migrainous infarction). Patient preference and cost also should be considered.
...Therapy should be initiated with medications that have the highest levels of effectiveness and the lowest potential for adverse reactions; these should be started at low dosages and titrated slowly. A full therapeutic trial may take two to six months. After successful therapy (e.g., reduction of migraine frequency by approximately 50 percent or more) has been maintained for six to 12 months, discontinuation of preventive therapy can be considered.
Preventive medication has to be taken on a daily basis, usually for a few weeks, before the effectiveness can be determined. Supervision by a neurologist is advisable. A large number of medications with varying modes of action can be used. Selection of a suitable medication for any particular patient is a matter of trial and error, since the effectiveness of individual medications varies widely from one patient to the next. Often preventive medications do not have to be taken indefinitely. Sometimes as little as six months of preventive therapy is enough to "break the headache cycle" and then they can be discontinued.
The most effective prescription medications include several drug classes:
A meta-analysis by the Cochrane Collaboration of nine randomized controlled trials or crossover studies, which together included 668 patients, found that propranolol had an "overall relative risk of response to treatment (here called the 'responder ratio')" was 1.94.
Anticonvulsants such as valproic acid and topiramate. A meta-analysis by the Cochrane Collaboration of ten randomized controlled trials or crossover studies, which together included 1341 patients, found anticonvulsants had an "2.4 times more likely to experience a 50% or greater reduction in frequency with anticonvulsants than with placebo" and a number needed to treat of 3.8. However, concerns have been raised about the marketing of gabapentin.
Tricyclic antidepressants (TCAs) such as amitriptyline and the newer selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are sometimes prescribed. Tricyclic antidepressants have been found to be more effective than SSRIs. A meta-analysis by the Cochrane Collaboration found selective serotonin reuptake inhibitors are no more effective than placebo. Another meta-analysis found benefit from SSRIs among patients with migraine or tension headache; however, the effect of SSRIs on only migraines was not separately reported. A randomized controlled trial found that amitriptyline was better than placebo and similar to propranolol.
A wide range of other pharmacological drugs have been evaluated to determine their efficacy in reducing the frequency or severity of migraine attacks. These drugs include beta-blockers, calcium antagonists, neurostabalizers, nonsteroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), other antidepressants, and other specialized drug therapies. The US Headache Consortium lists five drugs as having medium to high efficacy: amitriptyline, divalproex, timolol, propranolol and topiramate. Lower efficacy drugs listed include aspirin, atenolol, fenoprofen, flurbiprofen, fluoxetine, gabapentin, ketoprofen, metoprolol, nadolol, naproxen, nimodipine, verapamil and Botulinum A. Additionally, most antidepressants (tricyclic, SSRIs and others such as Bupropion) are listed as "clinically efficacious based on consensus of experience" without scientific support. Many of these drugs may give rise to undesirable side-effects, or may be efficacious in treating comorbid conditions, such as depression.
- Other drugs
- Methysergide was withdrawn from the US market by Novartis, but is available in Canadian pharmacies. Although highly effective, it has rare but serious side effects, including retroperitoneal fibrosis.
- Methylergometrine remains available in the US and is an active metabolite of methysergide. It is thought to carry the same risks and benefits as methysergide but has not been widely studied in migraine.
- Memantine, which is used in the treatment of Alzheimer's Disease, is beginning to be used off label for the treatment of migraines. It has not yet been approved by the FDA for the treatment of migraines.
- Aspirin can be taken daily in low doses such as 80 mg. The blood thinners in ASA have been shown to help some migraineurs, especially those who have an aura.
- Placebo is as effective as adding propanolol to patients not adequately controlled on topiramate. In a randomized controlled trial, both groups reduced their days with migraine by half.
A major advantage of migraine surgery is that, with the correct diagnostic techniques, a definite diagnosis can be made before the surgery is undertaken. Once a positive diagnosis has been made, the results of surgery are outstanding and provide permanent pain relief, as well as relief from the associated symptoms, such as nausea, vomiting, light sensitivity, and sound sensitivity. There are a number of surgical solutions to migraines, some of which are being used on selected patients with great success. Positive reports have appeared in the medical literature with regard to the surgical cauterization of the superficial blood vessels of the scalp (the terminal branches of the external carotid artery), and decompression of certain nerves around the head and neck.
Surgical cauterization of the superficial blood vessels of the scalp (the terminal branches of the external carotid artery) is only carried out if it has been established with certainty that these vessels are indeed the source of pain. It is a safe and relatively atraumatic procedure which can be performed in a day facility.
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. It is only effective in those who respond well to Botox injections in specific areas.
Botulinum toxin injection
Botulinum neurotoxin (Botox) injections have been approved in the US and UK for prevention of chronic migraines, but do not appear to work for episodic migraines. Several invasive surgical procedures are currently under investigation. One involves the surgical removal of specific muscles or the transection of specific cranial nerve branches in the area of one or more of four identified trigger points.
Closure of patent foramen ovale
There also appears to be a causal link between the presence of a patent foramen ovale and migraines. There is evidence that the correction of the congenital heart defect, patent foramen ovale (PFO), reduces migraine frequency and severity. Recent studies have advised caution, though, in relation to PFO closure for migraines, as insufficient evidence exists to justify this dangerous procedure.
General dietary restriction has not been demonstrated to be an effective approach to treating migraine.
However, personal experiences of migraine sufferers unanimously agree on a set of specific food items that trigger episodes, and these are what you'll find if you search for 'migraine triggers' (bananas, chocolate, nitrates, aged cheeses, red wine...) Many of these food triggers are often the same as the dietary restrictions generally given for patients prescribed MAO inhibitors who must follow a low Tyramine diet. Tyramine is an amino acid that helps regulate blood pressure, and since migraine is in part an irregularity in cranial blood pressure, it is likely that migraine sufferers also have a tyramine imbalance or sensitivity.
- Modi S, Lowder D (2006). "Medications for migraine prophylaxis". American Family Physician 73 (1): 72–8. PMID 16417067.
- Diener H, Limmroth V (2004). "Medication-overuse headache: a worldwide problem". The Lancet Neurology 3 (8): 475–83. doi:10.1016/S1474-4422(04)00824-5. PMID 15261608.
- Fritsche G; Diener HC (November 2002). "Medication overuse headaches — what is new?". Expert Opin Drug Saf 1 (4): 331–8. doi:10.1517/147403188.8.131.521. PMID 12904133.
- Silberstein S, Tfelt-Hansen P, Dodick DW, Limmroth V, Lipton RB, Pascual J et al. (2008). "Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults.". Cephalalgia 28 (5): 484–95. doi:10.1111/j.1468-2982.2008.01555.x. PMID 18294250.
- Jensen, R.; Stovner, L. J. (2008). "Epidemiology and comorbidity of headache". The Lancet Neurology 7 (4): 354–361. doi:10.1016/S1474-4422(08)70062-0.
- Shevel E (2007). "Vascular Surgery for Chronic Migraine". Therapy 4 (4): 451–456. doi:10.2217/14750708.4.4.451.
- Mosser, W.; Guyuron, B.; Janis, E.; Rohrich, J. (Feb 2004). "The Anatomy of the Greater Occipital Nerve: Implications for the Etiology of Migraine Headaches". Plastic and Reconstructive Surgery 113 (2): 693–697; discussion 697–700. doi:10.1097/01.PRS.0000101502.22727.5D. ISSN 0032-1052. PMID 14758238.
- Guyuron, B. K. (Jan 2005). "Comprehensive surgical treatment of migraine headaches". Plastic and reconstructive surgery 115 (1): 1–9. ISSN 0032-1052. PMID 15622223.
- Poggi, T.; Grizzell, E.; Helmer, D. (Jul 2008). "Confirmation of Surgical Decompression to Relieve Migraine Headaches". Plastic and Reconstructive Surgery 122 (1): 115–122; discussion 122–4. doi:10.1097/PRS.0b013e31817742da. ISSN 0032-1052. PMID 18594393.
- Lee, M. S.; Ernst, E. (2011). "Acupuncture for pain: An overview of Cochrane reviews". Chinese Journal of Integrative Medicine 17 (3): 187–189. doi:10.1007/s11655-011-0665-7. PMID 21359919.
- Linde, K; Allais, G; Brinkhaus, B; Manheimer, E; Vickers, A; White, AR (2009). "Acupuncture for migraine prophylaxis". In Linde, Klaus. Cochrane Database of Systematic Reviews (Online) (1): CD001218. doi:10.1002/14651858.CD001218.pub2. PMC 3099267. PMID 19160193.
- Houle TT, Dhingra LK, Remble TA, Rokicki LA, Penzien DB (June 2006). "Not tonight, I have a headache?". Headache 46 (6): 983–90. doi:10.1111/j.1526-4610.2006.00470.x. PMID 16732844.
- "Erratum in: Am J Gastroenterol. 2003 Jul;98(7) 1674"
- Migraine Linked to Celiac Disease
- Migraine Headaches: Gluten Triggers Severe Headaches in Sensitive Individuals
- Butterbur Extract: Topic Overview. WebMD, Last Updated: June 30, 2009
- Agosti R, Duke RK, Chrubasik JE, Chrubasik S (Nov 2006). "Effectiveness of Petasites hybridus preparations in the prophylaxis of migraine: a systematic review". Phytomedicine 13 (9-10): 743–6. doi:10.1016/j.phymed.2006.02.008. PMID 16987643.
- Russo E (May 1998). "Cannabis for migraine treatment: the once and future prescription? An historical and scientific review". Pain 76 (1–2): 3–8. doi:10.1016/S0304-3959(98)00033-5. PMID 9696453. Retrieved 2008-08-30.
- Pittler MH, Ernst E. (2004). "Feverfew for preventing migraine". In Pittler, Max H. Cochrane Database of Systematic Reviews (1): CD002286. doi:10.1002/14651858.CD002286.pub2. PMID 14973986.
- Chaibi, Aleksander; Tuchin, Peter J.; Russell, Michael Bjørn (2011). "Manual therapies for migraine: A systematic review". The Journal of Headache and Pain 12 (2): 127–33. doi:10.1007/s10194-011-0296-6. PMC 3072494. PMID 21298314.
- Schoenen, J; Allena, M; Magis, D (2010). "Neurostimulation therapy in intractable headaches". Handbook of clinical neurology / edited by P.J. Vinken and G.W. Bruyn. Handbook of Clinical Neurology 97: 443–50. doi:10.1016/S0072-9752(10)97037-1. ISBN 9780444521392. PMID 20816443.
- Reed, KL; Black, SB; Banta Cj, 2nd; Will, KR (2010). "Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches: Initial experience". Cephalalgia 30 (3): 260–71. doi:10.1111/j.1468-2982.2009.01996.x. PMID 19732075.
- Leone, M; Cecchini, AP; Franzini, A; Bussone, G (2011). "Neuromodulation in drug-resistant primary headaches: What have we learned?". Neurological sciences. 32 Suppl 1: S23–6. doi:10.1007/s10072-011-0554-z. PMID 21533707.
- Lister, Sam (2006-06-22). "Zapper brings hope to migraine sufferers". The Times (London). Retrieved 2010-05-22.
- Mohammad, Yousef (2006-06-22). "Magnets Zap Migraines". 49th Annual Scientific Meeting of the American Headache Society. Los Angeles, California. Retrieved 2006-07-04.
- http://medicalcenter.osu.edu/mediaroom/press/article.cfm?ID=4059[dead link]
- Nestoriuc Y, Martin A (2007). "Efficacy of biofeedback for migraine: a meta-analysis". Pain 128 (1–2): 111–27. doi:10.1016/j.pain.2006.09.007. PMID 17084028.
- Nestoriuc, Yvonne; Martin, Alexandra (2007). "Efficacy of biofeedback for migraine: A meta-analysis". Pain 128 (1–2): 111–27. doi:10.1016/j.pain.2006.09.007. PMID 17084028.
- Nestoriuc, Y; Martin, A; Rief, W; Andrasik, F (2008). "Biofeedback treatment for headache disorders: A comprehensive efficacy review". Applied psychophysiology and biofeedback 33 (3): 125–40. doi:10.1007/s10484-008-9060-3. PMID 18726688.
- Mullally, William J.; Hall, Kathryn; Goldstein, Richard (2009). "Efficacy of biofeedback in the treatment of migraine and tension type headaches". Pain physician 12 (6): 1005–11. PMID 19935987.
- Bennett MH, French C, Schnabel A, Wasiak J, Kranke P (2008). "Normobaric and hyperbaric oxygen therapy for migraine and cluster headache". In Bennett, Michael H. Cochrane Database Syst Rev (3): CD005219. doi:10.1002/14651858.CD005219.pub2. PMID 18646121.
- Eftedal OS, Lydersen S, Helde G, White L, Brubakk AO, Stovner LJ (2004). "A randomized, double blind study of the prophylactic effect of hyperbaric oxygen therapy on migraine". Cephalalgia 24 (8): 639–44. doi:10.1111/j.1468-2982.2004.00724.x. PMID 15265052.
- Fife William P, Fife Caroline E (1989). "Treatment of Migraine with Hyperbaric Oxygen". J. Hyperbaric Med 4 (1): 7–15. Retrieved 2008-08-06.
- Linde K, Rossnagel K (2004). "Propranolol for migraine prophylaxis". In Linde, Klaus. Cochrane Database Syst Rev (2): CD003225. doi:10.1002/14651858.CD003225.pub2. PMID 15106196.
- Chronicle E, Mulleners W (2004). "Anticonvulsant drugs for migraine prophylaxis". In Mulleners, Wim M. Cochrane Database Syst Rev (3): CD003226. doi:10.1002/14651858.CD003226.pub2. PMID 15266476.
- Steinman M, Bero L, Chren M, Landefeld C (2006). "Narrative review: the promotion of gabapentin: an analysis of internal industry documents". Ann Intern Med 145 (4): 284–93. doi:10.7326/0003-4819-145-4-200608150-00008. PMID 16908919.
- Kaniecki R, Lucas S. (2004). "Treatment of primary headache: preventive treatment of migraine". Standards of care for headache diagnosis and treatment. Chicago: National Headache Foundation. pp. 40–52.
- Jackson JL, Shimeall W, Sessums L et al. (2010). "Tricyclic antidepressants and headaches: systematic review and meta-analysis". BMJ 341: c5222. doi:10.1136/bmj.c5222. PMC 2958257. PMID 20961988.
- Moja P, Cusi C, Sterzi R, Canepari C (2005). "Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches". In Moja, Lorenzo. Cochrane Database Syst Rev (3): CD002919. doi:10.1002/14651858.CD002919.pub2. PMID 16034880.
- Tomkins G, Jackson J, O'Malley P, Balden E, Santoro J (2001). "Treatment of chronic headache with antidepressants: a meta-analysis". Am J Med 111 (1): 54–63. doi:10.1016/S0002-9343(01)00762-8. PMID 11448661.
- Ziegler D, Hurwitz A, Hassanein R, Kodanaz H, Preskorn S, Mason J (1987). "Migraine prophylaxis. A comparison of propranolol and amitriptyline". Arch Neurol 44 (5): 486–9. doi:10.1001/archneur.1987.00520170016015. PMID 3579659.
- Koehler, PJ; Tfelt-Hansen PC (Nov 2008). "History of methysergide in migraine.". Cephalalgia 28 (11): 1126–35. doi:10.1111/j.1468-2982.2008.01648.x. PMID 18644039. Retrieved 11 December 2011.
- Silberstein SD, Dodick DW, Lindblad AS, Holroyd K, Harrington M, Mathew NT et al. (2012). "Randomized, placebo-controlled trial of propranolol added to topiramate in chronic migraine.". Neurology 78 (13): 976–84. doi:10.1212/WNL.0b013e31824d5846. PMC 3310312. PMID 22377815.
- Shevel, Elliot (2007). "Vascular surgery for chronic migraine". Therapy 4 (4): 451–6. doi:10.2217/14750708.4.4.451.
- Kung, TA; Guyuron, B; Cederna, PS (January 2011). "Migraine surgery: a plastic surgery solution for refractory migraine headache". Plastic and reconstructive surgery 127 (1): 181–9. doi:10.1097/PRS.0b013e3181f95a01. PMID 20871488.
- BOTOX(R) Receives First Authorisation in UK as Preventative Treatment in Chronic Migraine
- Naumann, M.; So, Y.; Argoff, E.; Childers, K.; Dykstra, D.; Gronseth, S.; Jabbari, B.; Kaufmann, C.; Schurch, B.; Silberstein, S. D.; Simpson, D. M.; Therapeutics Technology Assessment Subcommittee of the American Academy of Neurology (May 2008). "Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology". Neurology 70 (19): 1707–1714. doi:10.1212/01.wnl.0000311390.87642.d8. ISSN 0028-3878. PMID 18458231.
- Post, M. C.; Luermans, J.; Plokker, H.; Budts, W. (Jan 2007). "Patent foramen ovale and migraine". Catheterization and Cardiovascular Interventions 69 (1): 9–9. doi:10.1002/ccd.20931. ISSN 1522-1946. PMID 17143907.
- "Patent foramen ovale and migraine". Current pain and headache reports 11 (3): 236–240. Jun 2007. doi:10.1007/s11916-007-0196-2. ISSN 1531-3433. PMID 17504652.
- Harder, B. (2005). "Against the Migraine". Science News 167 (8): 119–120. doi:10.2307/4016110. JSTOR 4016110.
- Schürks, M; Diener, HC (2009). "Closure of patent foramen ovale in the prevention of migraine: Not enough evidence in favor". Nature Clinical Practice Neurology 5 (1): 22–3. doi:10.1038/ncpneuro0971. PMID 19048002.
- Sarens, T; Herroelen, L; Van Deyk, K; Budts, W (2009). "Patent foramen ovale closure and migraine: Are we following the wrong pathway?". Journal of neurology 256 (1): 143–4. doi:10.1007/s00415-009-0126-9. PMID 19172218.
- Holzhammer J, Wöber C (2006). "Alimentary trigger factors that provoke migraine and tension-type headache". Schmerz (in German) 20 (2): 151–9. doi:10.1007/s00482-005-0390-2. PMID 15806385.